Effect of supervised training on FEV1 in cystic fibrosis: A randomised controlled trial

Journal of Cystic Fibrosis 12 (2013) 714 – 720 www.elsevier.com/locate/jcf

Original Article

Effect of supervised training on FEV1 in cystic fibrosis: A randomised controlled trial ☆, ☆☆ Susi Kriemler a, e,⁎, Stephanie Kieser b , Sibylle Junge c , Manfred Ballmann c , Alexandra Hebestreit b , Christian Schindler a , Christoph Stüssi d , Helge Hebestreit

b

a

Swiss Tropical and Public Health Institute, University of Basel, Switzerland Pediatric Department, Julius-Maximilians-Universität Würzburg, Germany Pediatric Pulmonology and Neonatology, Medizinische Hochschule Hannover, Germany d Department of Pediatrics, Cantonal Hospital of Münsterlingen, Switzerland e Institute for Social and Preventive Medicine, University of Zürich, Switzerland b

c

Received 16 November 2012; received in revised form 7 March 2013; accepted 7 March 2013 Available online 13 April 2013

Abstract Background: Long-term exercise interventions have been shown to improve vital capacity in cystic fibrosis (CF). Yet, no data are available indicating positive effects of long-term exercise training on FEV1. Methods: 39 Swiss patients with CF were randomly divided into strength training (ST, n = 12), endurance training (AT, n = 17) and controls (CONCH, n = 10), and also compared with age-matched Swiss (n = 35) and German (n = 701) CF registry data. A partially supervised training of 3 × 30 min/week for 6 months took place with measurements at baseline and after 3, 6, 12 and 24 months. Primary outcome was FEV1 at 6 months. Results: FEV1 increased significantly in both training groups compared with CONCH (AT:+5.8 ± 0.95, ST:+7.4 ± 2.5, CONCH:− 11.5 ± 2.7% predicted, p b 0.001) and both registry groups at 6 months. At 24 months, changes in favour of the training groups persisted marginally compared with CONCH, but not compared with registry data. Conclusions: A partially supervised training over 6 months improved FEV1 but effects were basically gone 18 months off training. Regular longterm training should be promoted as essential part of treatment in CF. © 2013 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Exercise capacity; Lung function; Physical activity; Pulmonary rehabilitation

1. Introduction While modern advances in medicine have extensively increased survival in cystic fibrosis (CF), the health of young

people with the multi-organ disease is compromised in many respects [1]. Strategies using exercise training to slow deterioration in lung function and improvement in psychological wellbeing and exercise capacity have therefore gained importance.

Abbreviations: AT, Aerobic training; CF, Cystic fibrosis; CONCH, Control group Switzerland; COND, Control group Germany; FEV1, Forced expiratory volume in one second; FVC, Forced vital capacity; RV/TLC, Residual volume over total lung capacity; ST, Strength training; VO2peak, Maximal oxygen consumption at peak endurance; VPA, Vigorous physical activity; Wmax, Maximal watt performance ☆ This study was developed and initiated at the Triemli Hospital (former work place of SK) of Zürich, Switzerland and at the Pediatric Department, Julius-Maximilians-Universität Würzburg, Germany and was supported by a grant from the Swiss CF foundation and the German Mukoviszidose e.V. ☆☆ This study is registered as clinical trial at http://www.clinicaltrials.gov (NCT00231686). ⁎ Corresponding author at: Swiss Tropical and Public Health Institute, University of Basel, Socinstrasse 59, 4002 Basel, Switzerland. Tel.: + 41 61 284 83 92. E-mail addresses: [email protected] (S. Kriemler), [email protected] (S. Kieser), [email protected] (S. Junge), [email protected] (M. Ballmann), [email protected] (A. Hebestreit), [email protected] (C. Schindler), [email protected] (C. Stüssi), [email protected] (H. Hebestreit). 1569-1993/$ -see front matter © 2013 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jcf.2013.03.003

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Several studies have demonstrated favourable effects of exercise programmes in children and adults with cystic fibrosis (CF) [2–7]. In these studies, an increase in physical activity was associated with a gain in exercise capacity [2–4,6] a stabilisation or even an improvement in lung function [2,3,5] and a higher quality of life [2,3,6]. Well-designed long-term physical conditioning studies found an increase in forced vital capacity (FVC), but not in FEV1 [2,3,5]. The primary objective of this randomised controlled trial was to determine the effects of a 6-month partially supervised aerobic training or a supervised strength training programme in comparison to no intervention on FEV1 in patients with CF. Secondary outcome measures included additional lung function measures, markers of exercise capacity, physical activity, body composition, and quality of life (QoL). We also tested longterm effects 6 and 18 months after the end of the intervention. 2. Methods 2.1. Design and study population Suitable patients were recruited from Swiss CF centres. Inclusion criteria for this study were a diagnosis of CF, an age of at least 12 years, a FEV1 of at least 35% of predicted [8], and the ability to perform physical activity without harm. Exclusion criteria were non-CF related chronic diseases and conditions posing an increased risk to the patient when exercising. Fortytwo from 60 eligible patients agreed to participate. At the end of the baseline assessments, patients were randomly assigned to the strength training (ST), aerobic training (AT) or the control group (CONCH) by a lot that was drawn by the subjects with closed eyes from an opaque bag. Due to an unusual deterioration of physical health in the CONCH, we added a separate control group from a parallel study in Germany (COND) who was tested with the same methodology and at the same time points while the intervention arm was different from the Swiss study [3]. We also retrieved lung function data from the Swiss and German CF patients' registry with the same age than our study population [9,10]. Written informed consent was obtained from the patients and their guardians, if the patients were under 18 years of age. The ethics committees of the medical faculties of all participating centres approved the study protocol and procedures. 2.2. Intervention Patients in the intervention groups consented to perform three training sessions per week of 30 to 45 minute duration for the first six months of the study. Strength training was performed in fitness centres which agreed to provide free access to the participants for one year. Detailed information can be found in the appendix. Briefly, the ST was monitored by diary cards that had to be filled out at the fitness centres. The cards contained the upper and lower body strength training exercises including load and number of repetitions for the one predefined set of 6–9 repetitions. A fitness instructor checked the cards and provided assistance at least once each week over the study

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period. This included the supervision of adequately conducting the exercises and advice for adaptation of the load which was increased by 5% if repetitions could be performed more than 9 times in one set. AT was based on individual preferences performed either in a fitness centre or at home on a stationary bike. Patients could have free access to a fitness centre or a bike at home for one year that was provided free of charge. AT was done initially at 65% of VO2peak which was controlled by heart rate monitors that provided a target heart rate at the selected oxygen uptake level. After each month the resistance of the bike was increased by 10% if patients were able to continue to pedal with ease after 30 min at the given resistance. Patients of the intervention groups were called once a month during the first 6 months of the study to check on their training adherence and, if necessary, training visits were performed in case of open questions or adherence problems. After the first six months, patients in the intervention groups were encouraged to maintain their training, but no further steps were taken to increase adherence. Patients in the control group were told to keep their physical activity level constant for the first 12 months of the study. Free access to a fitness centre for one year after the first year was offered to them. However, this option was not chosen by any of the control subjects. No counselling or provision of any suggestion regarding physical activity or exercise was given to any of the participants during the second year of the study. 2.3. Outcome measures Patients were seen in their respective centre at study entry (December 2000 to March 2001) and after 3, 6, 12 and 24 months. The intervention period lasted 6 months. All assessors were trained in a pilot study two months before the main study. On each visit, the primary outcome variable FEV1 was determined as well as secondary outcome variables (additional pulmonary function measures, anthropometry including body composition, shortterm muscle power, maximal aerobic power, physical activity). Outcome assessors were blinded for pulmonary function, but not for secondary outcomes with respect to the participant's group allocation. However, they were not involved in the supervision and delivery of the intervention. The order of the testing was always the same: 1. anthropometry, 2. pulmonary function, 3. Wingate test, 4. incremental cycle test after a rest period of 30 min after the Wingate test. An additional predefined secondary outcome (quality of life) will be reported separately. Detailed information about testing procedures is provided in the supplementary appendix. Skinfold thickness was determined at four sites and percent body fat and lean body mass calculated [11,12]. FVC, FEV1 and residual volume relative to total lung capacity (RV/TLC) were determined by standard spirometry and for FVC and FEV1 expressed as %predicted [8]. Muscle power was assessed on a calibrated mechanically braked cycle ergometer using the Wingate test protocol [13]. Subjects then completed a continuous incremental cycling task to volitional fatigue [14]. VO2peak was determined as highest VO2 over 30 s, and maximal Watt performance (Wmax) was taken as the power maintained over the final completed 1-minute stage during the test. Physical activity was determined by accelerometry

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for 7 days [15,16]. Training compliance was measured in the ST group by cards that were meant to be regularly filled out during each training session. AT mounted a heart rate monitor while they were performing each exercise bout. Cards were checked and heart rate monitors downloaded once a month. 2.4. Data analysis and statistics Statistical analyses were based on an intention to treat principle. The intervention and control groups were compared for baseline characteristics using regression analyses adjusted for age and gender. Additional adjustments for skinfold thickness and muscle mass were done for aerobic performance. We used mixed linear models with follow up values (at 3, 6, 12 and 24 months) as dependent variables, group (ST, AT, CONCH, COND REGCH, REGD), gender and age as fixed factors and the respective baseline values as covariates. The German control group (COND) and the two groups from the Swiss and German CF patient registries were added due to the overall small sample size of the study and due to an unusual deterioration of the Swiss control group. For each outcome measure, the size of the intervention effect is reported as difference between baseline and the follow up value between the respective control or registry group (CH or D) and each intervention group after adjusting for age, sex, and baseline value. Secondary analyses were performed by testing interactions of the intervention with gender and age. Aerobic and anaerobic performance outcomes were additionally adjusted for skinfold thickness and fat-free mass. All analyses were performed using Stata statistical software release 10 (Statistical Solutions Ltd., Cork, Ireland). Data are reported as means ± standard deviation in tables and means ± 95% confidence intervals in figures if not stated otherwise. Statistical significance was defined at p b 0.05. Our study was designed to have 3 arms of equal size (i.e., ST, AT and control). The power calculation was targeted to a one way ANOVA comparing average effects across arms at the usual significance level of 5%. With 20 subjects per arm, we had more than 80% power to detect a true overall difference in the mean effects of the 3 treatments provided that the standard deviation of these effects equalled at least 0.43 times the standard deviation (SD) of the outcome within groups. For instance, this condition would be satisfied if, compared with the control group, the true average effects of the two treatments were both higher by 0.8 SD or if the two treatment effects were higher by 0.9 SD and 0.45 SD, respectively. 3. Results Forty two patients entered the study. Despite extensive efforts, it was not possible to recruit the intended 60 patients. Fig. 1 gives sample size information throughout the study. Three patients were excluded from the study at the baseline visit due to an initial FEV1 below 35% predicted. No patient had to be excluded for the other specified exclusion criteria. Three participants (2 AT, 1 ST) dropped out of the study during the first 2 months due to exacerbation (n = 1) or non-compliance (n = 2). Two patients of the AT group died during the second year of the study (one in a

car accident, one because of a deterioration of disease). An additional three patients (1 AT, 2 CON) dropped out after the 6 month period for unclear reasons. Individual missing data during the scheduled visits were due to malfunctioning of the metabolic card (n = 3), a broken arm that prevented Wingate testing (n = 1), or non-compliance with physical activity monitors (n = 9). Table 1 describes baseline characteristics of the study population by group. There were no major differences among both intervention and the respective control groups regarding clinical characteristics and treatment regimens except for Wmax that was significantly higher in the ST and time in VPA that was significantly lower in the AT compared to COND. Overall, participants in the training groups fulfilled at least 65% of all training sessions (i.e. 2 of 3 per week) and 80% of all performed the requested 3 sessions per week. One-third of patients did not report training in written form, but only orally during testings. No adverse effects such as injuries, pneumothorax, asthma attacks or hypoglycaemia occurred. 3.1. Primary and secondary outcome(s) Results of all outcomes are documented in Figs. 2 and 3 (for exact raw and adjusted values see Supplementary Tables 1–3). As shown in Figs. 2 and 3, compared with CONCH FEV1 and FVC were significantly improved in both training groups at 3, 6 and 12 months and remained improved at 24 months for ST. When compared with COND and both registry groups (REGCH and REGD), effects in favour of the intervention groups were statistically highly significant at 6 months (all p b 0.001). Differences in changes ranged from 8 to 10% compared with pooled baseline values, but all effects were lost 18 months off training. Intervention effects compared to COND and the registry groups were very comparable for FVC and FEV1 at each time point. Compared with CONCH, hyperinflation expressed as RV/TLC was significantly improved in both training groups at 6 months and for ST even at 3 and 12 months. Compared with COND the training effect on the reduction of hyperinflation was found for the ST group at 6 months. Compared with CONCH, effects on aerobic performance were statistically significant at 6 months for both groups and at 3 and 12 months for the ST group. Compared with COND, changes of VO2peak were statistically significant for the AT group. All other secondary outcomes including body composition, average or moderate-and-vigorous physical activity and muscle power (Wingate test) were not significantly different among groups at any assessment (Supplementary Table 1). 4. Discussion This study documents that positive health effects of a 6-month partially supervised exercise programme to improve pulmonary function including FEV1, FVC and hyperinflation as well as aerobic performance can be attained. These results are of major importance as lung function and aerobic performance are relevant determinants and predictors of health in CF [17–19]. Moreover, no side effects of the training occurred which proves that exercise

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Assessed for eligibility and invited to participate (n=42)

FEV1 <35%pred (n=3)

Consented and present baseline measures (n=39) for comparison due to an unexpected deterioration of lung function in the Controls CH

Randomization

Aerobic Training (n=17)

Strength Training (n=12)

Controls CH (n=10)

Controls D (n=15)

month of assessment 0 3 6 12 24

month of assessment 0 3 6 12 24

month of assessment 0 3 6 12 24

month of assessment 0 3 6 12 24

17

14

15

15

12

12

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10

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8

15

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FVC

17

14

15

15

12

12

11

11

11

11

10

10

10

8

8

15

13

13

12

11

RV/TLC

17

14

13

15

12

12

11

10

11

11

10

10

10

8

8

14

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14

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10

VO2peak

17

15

15

14

11

9

11

8

8

8

10

10

10

8

7

15

13

13

12

9

Wmax

17

15

15

15

11

12

11

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10

10

10

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7

15

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physical activity

16

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10

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10

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13

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8

5

6

Mean power legs

15

12

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9

12

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8

14

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14

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Mean power arms

15

12

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10

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10

10

10

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7

lean body mass

17

15

15

15

12

12

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10

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8

15

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% bodyfat

17

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Primary outcome FEV 1 Secondary outcomes

Fig. 1. Flow of participants. Flow of individual participants through study, with outcome measures.

can safely be performed without harm [20]. However, all significant positive effects of the training were attained at the end of the partially supervised training period at 6 months, but at most subtle effects remained 6- and 18 months after the programme was ended. The finding of improved pulmonary function in both training groups is without doubt clinically relevant. While short-term improvement of FEV1 during a training period of 2 weeks in hospital has been shown [6], this is the first long-term training study in CF that documents significant training effects in favour of FEV1. Other exercise trials documented improvements of FVC with durations of training ranging from 6 months to 3 years [2,3,5], but none of them reached significant improvements in FEV1. The type of supervision with at least one weekly contact to keep compliance and motivation up was sufficient. This finding is supported by the loss of beneficial training effects, once the

supervision was stopped, and also by the fact that none of the controls chose to take up the offered option of free access to a fitness centre after the first year. Why regular exercise might be effective in decreasing the loss of pulmonary function is not well understood. Postulated mechanisms are mechanical vibrations of the body, increased ventilation facilitating mechanical cleaning of the airways [21], and inhibition of the amiloride-sensitive sodium channel in respiratory epithelium [22] leading to an increased water content of the mucus in the CF lung during exercise and facilitating mucus expectoration. Alternatively or additionally, exercise has also been shown to stimulate anabolic mediators such as growth hormone and insulin-like growth factor I in CF [23], and may also act through improvements in insulin resistance, immune function [24], induction of tissue growth factors or through altered neuroendocrine control of metabolism as suggested [25]. In the

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Table 1 Baseline characteristics of participants.

Sample size, n Females, n (%) Age, yrs Mutation ΔF508 homo-/heterocygot Mutation 3995ins Insulin treatment IV antibiotics at least once a year Exocrine pancreas insufficiency Pseudomonas positive Oral corticosteroids BMI, kg/m2 Body fat, % FFM, kg FVC, % predicted FEV1, % predicted RV/TLC, % Physical activity, cpm Time in VPA, h/week VO2,peak mL/kg/min Wmax, W/kg MP leg, W/kg MP arm, W/kg

Aerobic training

Strength training

Controls CH

Controls D

17 4 (25) 23.8 [21.5–26.5] 8/4 0 3 11 16 16 1 19.1 [17.8–20.3] 14.4 [12.5–16.4] 46.0 [42.5–49.5] 79 [71–87] 65 [55–74] 37 [33–42] 376 [217–535] 3.6 [2.3–4.9]b 35.0 [32.0–38.0] 3.2 [2.9–3.4] 5.9 [5.4–6.5] 2.9 [2.5–3.2]

12 5 (42) 19.0 [16.0–22.0] 8/3 1 2 6 12 10 1 19.4 [18.0–20.8] 14.0 [11.7–16.2] 47.5 [43.5–51.5] 80 [71–90] 67 [57–78] 37 [32–42] 438 [254–622] 5.1 [3.7–6.6] 37.7 [33.6–41.7] 3.6 [3.4–3.9]bb 7.0 [6.4–7.5] 3.2 [2.9–3.6]

10 5 (50) 20.3 [17.0–23.6] 3/4 3 0 5 9 10 0 19.6 [18.1–21.1] 13.9 [11.5–16.4] 47.9 [43.6–52.3] 87 [77–97] 75 [63–87] 33 [28–38] 397 [208–585] 3.8 [2.3–5.3] 39.1 [35.4–42.9] 3.4 [3.1–3.7] 6.3 [5.7–6.9] 3.0 [2.6–3.4]

15 9 (60) 19.5 [16.8–22.2] 7/4 0 0 11 14 9 1 20.9 [19.6–22.1] 16.7 [14.7–18.7] 49.2 [45.7–52.8] 84 [75–92] 69 [59–79] 40 [35–45] 465 [286–644] 6.2 [4.8–7.7] 38.0 [36.7–43.3] 2.9 [2.7–3.2] 6.6 [6.0–7.1]

Values are adjusted means [95% CI] unless stated otherwise. Adjustments were done for sex, skinfolds and fat free mass (FFM). CH: Swiss; D: German; BMI: body mass index; FFM: fat free mass; FVC: forced vital capacity; FEV1: forced expiratory volume in 1 s; RV: residual volume; TLC: total lung capacity; cpm: counts per minute; VPA: vigorous physical activity in hours per week; VO2peak: peak oxygen uptake; Wmax: maximal power over the final completed 1-min stage; MP: mean power, W: Watts. Sig differences to CONCH (a) and to COND (b); one symbol denotes p b 0.05, two symbols p b 0.001.

ST group, the improvement in FVC was most probably due to a reduction of hyperinflation as RV/TLC improved in parallel. Although there is no literature of mechanisms that could help to explain the positive effects of ST on lung function, it may be related to the training of respiratory muscles and to an erecting of the thorax that may have led to an opening of functional air space. The difference in change of aerobic fitness (i.e.VO2peak and Wmax) between the training and control groups at 6 months was

Fig. 2. Changes in FEV1 in both training groups vs. controls. Change in forced expiratory volume in 1 s (FEV1[%predicted], from baseline to 24 months in the aerobic training group (AT), strength training group (ST), the Swiss (CONCH) and German (COND) control groups. The primary outcome, i.e. the change in FEV1 after 6 months, is highlighted. Data are presented as means ± 95%CI. Adjustments were done for age, sex and FEV1 baseline value. CONCH versus ST (a) and AT (b), COND versus ST(c) and AT (d); one symbol denotes p b 0.05, two symbols p b 0.01, three symbols p b 0.001.

10–17% of baseline values. This positive effect was reached right after the 6-month supervised intervention period, but faded with time and was lost 18 months later. This is an important finding, suggesting that training in order to be effective has to be continuously supervised to reach long-term maintenance of improved endurance performance. As only one [3] out of 6 randomised controlled exercise training studies [2–6] assessed long-term effects after the training had stopped, the question remains open whether type, intensity or duration of the training regimen plays a role in determining long-term beneficial effects. So far, a freely chosen and individualised physical activity programme, even without supervision, seems to have the potential for attaining persisting long-term effects up to at least 1.5 years after the end of training [3]. There were no differences in changes in percent body fat or muscle mass among groups. This suggests that a significant increase in muscle mass was not reached, not even in the ST group where it may be expected after a 6 month training period. It is possible that the intervention was too mild, the compliance of the training intensity lower than reported, or that nutritional requirements to increase muscle mass were not met. Alternatively, peripheral muscles of patients may be unable to hypertrophy due to progressive chronic disease or due to an inherited defect of the muscle cell causing ineffective mitochondrial oxidative phosphorylation as suggested [26]. There are some limitations of the study to be addressed. We acknowledge that the Swiss control group was not representative of the general CF community although randomly selected. The decline in lung function especially during the first year was

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Fig. 3. Changes in lung function in both training groups vs. controls. Change in lung function (FVC [%predicted] and RV/TLC[%]) and aerobic performance (VO2peak [ml ∗ kg−1∗min−1], Watts [W∗ kg−1] from baseline to 24 months in the aerobic training group (AT) and strength training group (ST) compared with the Swiss (CONCH) and German (COND) control groups. Data are presented as means ± 95%CI. All outcomes were adjusted for age, sex, the respective baseline value, VO2peak and Watts additionally for skinfolds and fat free mass. CONCH versus ST (a) and AT (b), COND versus ST(c) and AT (d); one symbol denotes p b 0.05, two symbols p b 0.01, three symbols p b 0.001.

clearly higher than what is expected as natural decline from CF registries [9,10]. We therefore included a second control group (COND) that was selected from a comparable study in Germany which was highly representative when compared with the German and Swiss CF registry (Fig. 4) and did not differ in clinical characteristics and treatment regimens [9,10]. By comparing the training groups with the COND and also with both age-matched registry groups, the effects of the intervention became weaker, but were still statistically significant at 6 months with a clinically meaningful improvement of FEV1 of about 10%.

Fig. 4. Long-term changes of FEV1 in controls vs. CF registry data. Decline of forced expiratory volume in 1 s (FEV1) in both CF control groups compared with Swiss (REGCH, n = 35) and German (REGD, n = 701) cystic fibrosis registry data (only patients with CF older than 12 years and with an FEV1 N 35% were included, participants of the CONCH and COND were excluded). Data are presented as means ± SE. Adjustments were done for age and sex.

In contrast to the comparison with the Swiss CONCH no significant long-term effects were observed on lung function which was very consistent irrespective of comparison group. One reason that might explain in part the more severe drop of physical health in the CONCH is the occurrence of a frame shift mutation 3905insT of the CF gene that is associated with a severe phenotype apparent in 3 of our 10 Swiss control subjects [27]. Despite major efforts to recruit 60 patients into the study, we could only enrol 42. Nevertheless, power was sufficient to reveal multiple significant and clinically meaningful results. Furthermore, we did not measure nutritional intakes which may have helped to differentiate findings of the training on body composition. Although both control groups were comparable for most outcomes including aerobic performance, vigorous physical activity in the COND group was significantly higher, which could have biassed our results. Due to a lack of compliance to report each training session in about 35% of the study population, a dose–response relation between training volume and change in FEV1 could not be tested. In conclusion, a 6-month supervised AT or ST programme led to transient improvements in lung function including FEV1, and an improvement in aerobic performance in patients with CF underlining the importance of physical activity for all patients regardless of their mutations. Further studies may reveal whether a combination of aerobic and strength training may lead to more beneficial changes in physical health. The absence of long-term

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effects suggests that persisting changes of activity behaviour can be attained only with continuation of an intervention that is at least partially supervised which can easily be implemented in every CF care.

[10]

Acknowledgements [11]

We fondly thank all the CF patients for participating in the study and all the master students for their support in recruiting patients and conducting the assessments. The authors have reported to CHEST that there is no potential conflict of interest with any company or organisation whose products or services were used for the study or discussed in the article. This study was supported by a grant from the Swiss CF Foundation and the German Mukoviszidose e.V. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.jcf.2013.03.003.

[12]

[13] [14] [15] [16] [17]

[18]

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