Abstract
The effects of a 3-month physical training programme on airway inflammation and clinical outcomes were studied in school-aged children with asthma.
Subjects with persistent allergic asthma (aged 12.7±3.4 yrs; n = 34) were randomly allocated into training and control groups. Exercise consisted of twice-weekly 50-min sessions for 12 weeks. Inflammation was assessed by levels of exhaled nitric oxide, blood eosinophils, eosinophil cationic protein, C-reactive protein, and total and mite-specific immunoglobulin (Ig)E. Lung volumes and bronchial responsiveness to methacholine were determined. The Paediatric Asthma Quality of Life Questionnaire and Paediatric Asthma Caregiver's Quality of Life Questionnaire were used to evaluate activity restrictions, symptoms and emotional stress. The efficacy of the training was assessed by accelerometry.
Following the programme, the exercise group spent twice as much time as the controls undertaking moderate-to-vigorous activities. No differences in changes were seen between groups for asthma outcomes. However, total IgE decreased more in the exercise group, as did mite-specific IgE.
Training did not increase inflammation in children with persistent asthma, and may have decreased both total and allergen-specific immunoglobulin E levels. It is concluded that there is no reason to discourage asthmatic children with controlled disease to exercise.
The increase in the prevalence of asthma observed in most developed countries has been accompanied by important changes in lifestyle 1. Reduced physical activity has been associated with increased asthma prevalence 2–4, and high levels of physical activity have been suggested to prevent disease progress 5. Physical training may reduce breathlessness and asthma symptoms by strengthening respiratory muscles and decreasing ventilatory rate during exercise. Training programmes in asthma have not, however, shown any improvement in lung function in controlled trials 5–12. The effects on airway inflammation are largely unknown.
Heavy physical activity has also been related to asthma occurrence and exacerbation. In elite athletes, asthma is diagnosed more frequently than in the general population 13. This has been attributed to airway inflammation and increased bronchial responsiveness induced by high-intensity long-term exercise, such as competitive swimming or long-distance running. Asthma symptoms may attenuate after discontinuing training and competition 14, 15. Atopy and type of sport appear to be the two major risk factors, with atopic long-distance runners having the highest risk of asthma compared to nonatopic non-athletes 16.
The effects of a 3-month physical training programme on airway inflammation and clinical outcomes were studied in school-aged children with persistent asthma. The aim of the present study was to determine a rationale for exercise and sporting guidance for children and their parents.
METHODS
Patient selection
Atopic school-aged children with controlled asthma, treated with a small-to-moderate dose of inhaled corticosteroids (ICSs) for a period of ≥1 yr and followed in the outpatient clinic of University Hospital of Sâo Joâo (Porto, Portugal), were invited to participate. The study was explained to parents and patients, and informed consent was obtained from those willing to participate. After 131 telephone invitations, 34 children were included (fig. 1⇓). Atopy was defined by a positive skin-prick test result (weal of ≥3 mm in diameter when the control solutions gave the expected results) to at least one aeroallergen (house dust mites, pollens, animal dander and moulds). All subjects were sensitised to Dermatophagoides pteronyssinus.
Flow chart showing participants in the study.
All 34 children used ICSs, 22 long-acting β2-agonists, 32 short-acting β2-agonists and nine leukotriene antagonists, and 19 had been receiving specific immunotherapy against house mites for ≥1 yr. The median (range) time since diagnosis was 4 (2–10) yrs. Controlled disease was defined as: 1) no exacerbation necessitating oral steroids or an increase in inhaled steroids during the preceding 4 weeks, 2) no more than three times weekly use of rescue short-acting β2-agonists, and 3) no indication to change maintenance treatment.
Study design
Patients were randomly allocated to a 12-week exercise training programme or standard care by a blinded computer-generated randomisation schedule with a blocking factor of four. Allocation numbers were encoded on labels placed in each case report form by an outside researcher, and patients were assigned the next available allocation number in sequence. The baseline and final assessments each included two hospital visits, 1 week apart. The patient and research team became aware of the allocations following the second baseline visit.
Training programme
The exercise group undertook submaximal aerobic exercise designed as a moderately intensive training programme including both lower and upper extremity activities. During the 12-week training programme, between February and May 2005, the sessions were held twice a week, for 50 min per session. All sessions were carried out in an indoor gymnasium. Subjects were instructed to use β2-agonists before the training or, if necessary, during the session. A typical session started with a warm-up period (10 min) with arm and leg exercise. This was followed by submaximal training (30–35 min), including aerobic exercises, strength training, and some balance and coordination exercises, and a cool-down period (7–10 min). In order to offer an enjoyable training session, various recreational games were played. The control group subjects continued their usual daily routine.
Measurements
Exhaled nitric oxide (eNO) levels were determined using chemiluminescence in accordance with the recommendations of the American Thoracic Society (ATS), with an exhalatory flow rate of 50 mL·s−1 (NIOX; Aerocrine, Stockholm, Sweden) 17. Blood eosinophil numbers were counted.
Serum C-reactive protein (CRP) levels were measured using a highly sensitive assay (Dade Behring CardioPhase hsCRP using the Behring Nephelometer BNII; Dade Behring, Marburg, Germany). The assay could detect a minimum CRP concentration of 0.175 mg·L−1. Serum total and mite-specific immunoglobulin (Ig)E and eosinophil cationic protein (ECP) levels were measured by fluorometric enzyme immunoassay (Phadia, Uppsala, Sweden).
Accelerometry
Compliance with the programme was assessed using an accelerometer. Physical activity was measured using an Actigraph monitor (model 7164; Computer Science and Applications, Shalimar, FL, USA) between weeks 8 and 12. The Actigraph uses a uniaxial accelerometer that measures vertical acceleration and deceleration in 1-min epochs. This accelerometer can be used to discriminate between light, moderate and vigorous levels of physical activity 18. The monitor was affixed above the iliac crest of the right hip with an elastic belt and adjustable buckle. The subjects were instructed to wear the monitor for 1 week and to remove it for sleep. Data from days 1–7 were downloaded into a computer. Movement counts were converted into the mean time per day spent in resting or light (<3 metabolic equivalents of the task (METs)), moderate (3–6 METs), vigorous (6–9 METs) and very vigorous (>9 METs) physical activity. The time per day spent doing moderate, vigorous and very vigorous levels of activity were combined into one variable, the moderate-to-vigorous physical activity category.
Lung function tests and bronchial responsiveness
Spirometry was performed using a calibrated computerised pneumotachograph spirometer (SensorMedics Vmax 22; SensorMedics, Yorba Linda, CA, USA) according to ATS recommendations. Bronchial responsivenss was assessed by methacholine challenge test performed according to recommendations 19.
Recording of peak expiratory flow variability
Peak expiratory flows (PEFs) were measured using a PIKO-1 (Ferraris Respiratory, Hertford, UK). The minimum morning PEF and maximum evening PEF were determined, respectively, as the lowest and highest PEF during the 1-week monitoring period 20. The daily amplitude of PEF variation was determined according to the following formula and expressed as a percentage: amplitude = (highest PEF – lowest PEF)/highest PEF.
Paediatric Asthma Quality of Life Questionnaire and Paediatric Asthma Caregiver’s Quality of Life Questionnaire
The Paediatric Asthma Quality of Life Questionnaire (PAQLQ) is a disease-specific questionnaire for the evaluation of health-related quality of life in asthmatic children. The self-administered form of the questionnaire was used 21. It includes 23 items in three domains, activity limitation (n = 5), symptoms (n = 10) and emotional function (n = 8). Both the scores of the three domains and the overall score range from 1 (maximum impairment) to 7 (no impairment). Clinical changes in PAQLQ score were considered minimal or moderate if they were >0.5 and >1.0, respectively 22. The impact of the child’s asthma on the caregiver’s normal daily activities and emotional functioning were assessed using the self-administered Paediatric Asthma Caregiver’s Quality of Life Questionnaire (PACQLQ) 23. This is a 13-item questionnaire that assesses caregiver burden during a 1-week recall period. It contains four items in an activities domain and nine items in an emotional function domain. Individual items are weighted equally. Total and domain scores range 1–7, with higher scores indicating a more positive response.
Statistical analysis
All analyses were conducted using the intention-to-treat approach, including all randomised patients who had at least one post-baseline efficacy variable measurement. Baseline characteristics were compared using Fisher’s exact test for categorical variables or an unpaired t-test for numerical variables; changes within groups were compared using a paired t-test and differences between the exercise and control groups were compared by ANCOVA, with the baseline value as covariate. In order to detect a 25% effect of the intervention using eNO as the main outcome, the estimated sample size would be 30 subjects 24. A p-value of <0.05 was regarded as significant.
RESULTS
At baseline, with the exception of long-acting β2-agonist use, no significant differences were observed between the two groups (table 1⇓). A few subjects used either short-acting β2-agonists twice daily or long-acting β2-agonists, according to the asthma management plan established by their doctor. However, no differences existed between the groups considering the overall use of β2-agonists. The training programme was completed by all except for two children. In the control group, one subject was lost to follow-up because of nonadherence, and a child in the exercise group withdrew due to excessive extracurricular activities. Therefore, 32 children, 16 in each group, underwent the final examination at the end of the 12-week period. All of the children were able to maintain the intensity of the training sessions without suffering asthma exacerbations. No changes in medication occurred during the programme. In the end, the exercise group spent almost twice as much time as the controls in moderate-to-vigorous activities as assessed by accelerometry (30±13 versus 16±11 min; p = 0.027), but showed no differences in the time spent resting (469±88 versus 528±44 min; p = 0.073) or in light physical activity (119±60 versus 113±31 min; p = 0.799).
Baseline characteristics of randomised patients by intervention group
Inflammation and other asthma outcomes
No differences in change in level of eNO, blood eosinophil number, serum ECP or serum CRP were observed between groups (table 2⇓). However, in the exercise group, there was a significant decrease in serum total and mite-specific IgE compared to the controls. Changes in lung function, peak expiratory variability, airway responsiveness and quality-of-life scores were nonsignificant between groups. The percentage of subjects achieving a clinically important improvement in the PAQLQ score from baseline did not differ between groups. Individual variations for each outcome are illustrated (fig. 2 of online supplementary material).
Changes in biomarkers, lung function, bronchial responsiveness, body mass index(BMI), and quality of life related to asthma at baseline and after 12 weeks
DISCUSSION
A physical training programme of moderate intensity did not affect inflammatory or other clinical outcomes in children with good asthma control. The present results are valid for subjects permitted to use effective medication against exercise-induced asthma symptoms.
A recent Cochrane review 25 pooled data from 13 studies and 455 subjects, and could not show physical training to improve lung function or decrease wheezy episodes. However, physical training improved cardiopulmonary fitness and maximum expiratory ventilation. In the present programme, children started their physical activity at an almost recreational level, and a more intense and vigorous programme could have produced greater improvements. However, it has been shown that the best way of increasing activity level is spending more time on moderate-intensity exercise and less on high-intensity activity 26. Short periods of vigorous physical activity do not influence overall activity, probably due to decreased compensatory activity outside the training sessions 27.
The intervention period was 12 weeks in the present study, which is the longest among published studies of controlled randomised design 25. It is possible that a longer intervention, or more frequent sessions, might have created differences between the groups. It could also be argued that children in the training programme were supervised by health professionals, which could limit the possible negative effects of exercise. It is unlikely that increased awareness of the disease affected the outcomes, since no additional medical visits were paid by the intervention group. If any unlikely benefit existed with the use of long-acting β2-agonists, this would have been in favour of the control group. Other strengths of the present study include the use of validated tools for the measurement of physical activity and quality of life, and the assessment of inflammation.
Regular exercise has induced various degrees of airway inflammation, depending on type of sport and the medical history of the athlete 16. In contrast with asthmatics, the increased numbers of inflammatory cells in healthy athletes’ airways do not correlate with exercise-induced symptoms or bronchial responsiveness 28. Recently, it has been observed that healthy children undertaking outdoor recreational activities exhibit a significant increase in eNO, dependent on ambient ozone levels, but with no changes in lung function test results 29. Neither of these effects was observed in the present study with asthmatic subjects. Although the decrease in eNO was larger in the non-exercising group following the programme, no significant differences between groups were observed. All of the present children were treated with ICSs, which may have suppressed the exercise effect.
In the present study, performed between late winter and early spring, significant differences between groups were observed in change in total and mite-specific IgE. Seasonal variations in mite allergen exposure may account for changes in total and specific IgE in mite-sensitive asthmatics 30, but exercise seemed to boost this effect. This has been observed in a mouse model of allergic asthma, in which moderately intense aerobic exercise attenuated lung inflammatory responses 31, 32. In ovalbumin-sensitised mice, exercise reduced mucus production, lung epithelial cell hypertrophy, secretion of type-2 T-helper cell-type cytokines, expression of adhesion molecules and production of ovalbumin-specific IgE 31. In another recent animal study, moderate training decreased numbers of bronchoalveolar eosinophil and peribronchial cells expressing interleukin-4 and -5 but had no effect on total IgE levels 32. In the present study, the lack of effect on other outcomes besides IgE may suggest that the balance between the pro- and anti-inflammatory effects of exercise in asthma would be null in respect to markers of airway inflammation, such as eNO. However, since physiological changes during the training were not addressed, this may represent a random effect. This can only be clarified in further studies. Seasonal variations in mite allergen load may also account for the eNO changes in both groups. In children who are sensitised to indoor allergens, higher dust mite allergen exposure has been associated with increased eNO levels 33.
The exercise group showed significant improvements in all domains of asthma-related quality of life, even with a moderate increase in activity, whereas changes in the control children were only significant for the activities domain. Failure to achieve a significant difference between groups could be due to the inclusion of subjects that are already well-controlled, leaving little room for improvement, and to a type II error due to small sample size. This is in contrast with the trial of Basaran et al. 34, in which a significant improvement occurred in the exercise group compared to control group. However, in that study, a significant baseline difference in symptom scores was observed between groups.
In a physical intervention programme for school-aged children, an extra burden is placed upon the family. Additional to medication administration, ongoing care and disease monitoring, the caregiver is required to drive the child to a sports training centre and stay there until the session ends several times weekly for 12 weeks. Nevertheless, the additional burden introduced to the family did not have a negative impact on caretakers’ quality of life.
Currently, Global Initiative for Asthma guidelines do not include recommendations for exercise as part of the treatment of patients with asthma 35. Exercise is a powerful trigger for asthma symptoms. For this reason, caretakers may be reluctant to permit their asthmatic children to engage in sports practice, fearing an exacerbation of the disease. Every child with asthma should be questioned about exercise performance, tolerance and symptoms. It is concluded that there is no reason for discouraging asthmatic children with controlled disease from exercise.
Support statement
A. Moreira holds a grant from the Finnish Centre for International Mobility (Helsinki, Finland) and a fellowship from the European Academy of Allergy and Clinical Immunology.
Statement of interest
None declared.
Acknowledgments
The authors would like to thank the patients and their families for cooperation with the study programme. They would also like to thank students from the Faculty of Sports (University of Porto, Porto, Portugal) for monitoring the training sessions, M. do Carmo Palmares and G. Figueiredo (Dept of Immunology, Faculty of Medicine, University of Porto) for assistance with measurements, T. Jacinto and J. Pipa (Immuno-allergology, Hospital of Sâo Joâo, Porto, Portugal) for carrying out lung function and provocation tests, S. Gomes (Dept of Immunology) for the assistance with patient enrolment and recruitment, and L. Almeida (Dept of Immunology) for help with blood sampling and processing.
Footnotes
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This article has supplementary material accessible from www.erj.ersjournals.com
- Received December 19, 2007.
- Accepted July 5, 2008.
- © ERS Journals Ltd
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