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Lung function, obesity and physical fitness in young children: The EXAMIN YOUTH study
Journal Pre-proof Lung function, obesity and physical fitness in young children: The EXAMIN YOUTH study Sabrina Köchli, Katharina Endes, Tim Bartenstein, Jakob Usemann, Arno SchmidtTrucksäss, Urs Frey, Lukas Zahner, Henner Hanssen PII:
S0954-6111(19)30327-0
DOI:
https://doi.org/10.1016/j.rmed.2019.105813
Reference:
YRMED 105813
To appear in:
Respiratory Medicine
Received Date: 17 May 2019 Accepted Date: 4 November 2019
Please cite this article as: Köchli S, Endes K, Bartenstein T, Usemann J, Schmidt-Trucksäss A, Frey U, Zahner L, Hanssen H, Lung function, obesity and physical fitness in young children: The EXAMIN YOUTH study, Respiratory Medicine (2019), doi: https://doi.org/10.1016/j.rmed.2019.105813. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.
Lung function, obesity and physical fitness in young children: The EXAMIN YOUTH Study
Sabrina Köchli PhDa, Katharina Endes PhDa, Tim Bartenstein MSca, Jakob Usemann MDb,c, Arno Schmidt-Trucksäss MDa, Urs Frey MDb, Lukas Zahner PhDa, Henner Hanssen MDa
a
Department of Sport, Exercise and Health, Medical Faculty, University of Basel, Basel, Switzerland
b
Pediatric Pulmonology, University Children`s Hospital (UKBB), University of Basel, Basel, Switzerland
c
Pediatric Respiratory Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Address correspondence to: Prof Dr Henner Hanssen, University of Basel, Department of Sport, Exercise and Health, Birsstrasse 320B, CH-4052 Basel, [email protected], Tel.: +41 612074746 Running title: Childhood obesity and lung function Keywords: Body mass index, blood pressure, cardiorespiratory fitness, pulmonary function Word count: 3056 Number of tables/figures: 3/2 Conflict of Interest: none. Source of founding: The study was self-funded. Financial Disclosure: none Clinical Trial Registration: ClinicalTrials.gov: NCT02853747; URL: https://clinicaltrials.gov/ct2/show/NCT02853747
1
Abbrevations: BMI
body mass index
BP
blood pressure
CRF
cardiorespiratory fitness
FEF 25-75
forced expiratory flow at 25 to 75%
FEV1
forced expiratory volume in one second
FVC
forced vital capacity
PEF
peak expiratory flow
2
Abstract Objective: The prevalence of obesity and physical inactivity in children are increasing globally. The study aimed to investigate the association of obesity and cardiorespiratory fitness (CRF) with patterns of lung function in young children. Methods: In this cross-sectional study, lung function, body mass index (BMI), blood pressure (BP) and CRF (shuttle run stages) were measured in an unselected cohort of 1246 children aged 7.2±0.4 years. All parameters and lung function, such as the ratio of forced expiratory volume in one second (FEV1) to forced vital capacity (FVC), were assessed by standardized procedures for children. Statistical models were applied for systematic adjustment of potential confounders. Results: Obese children had significantly higher FEV1 (Coef. (95 % CI) (1.57 (1.50;1.64) L) and FVC (1.75 (1.67;1.83) L) compared to normal weight children (1.38 (1.37;1.40) L; (1.53 (1.51;1.54) L, respectively). However, with each unit increase of BMI, FEV1/FVC decreased (-0.003 (-0.005;-0.001)) due to a disproportional increase in FVC compared to FEV1. Per stage increase of CRF, FEV1 (0.017 (0.008;0.025) L) and FVC increased (0.022 (0.012;0.031) L)). In obese children, higher CRF was independently associated with higher FEV1/FVC (0.03 (0.5E-4; 0.06)) due to a higher increase of FEV1 over FVC with increasing fitness. Conclusions: The decrease of FEV1/FVC with increasing BMI suggests that childhood obesity is associated with an imbalance of ventilation and airway flow. In children with obesity, higher CRF is associated with an improved FEV1/FVC ratio. Physical exercise programs may have the potential to improve patterns of lung function in children with obesity.
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Introduction In adults, higher body mass index (BMI) is considered a general risk factor for the development of obstructive pulmonary disease and obesity has been associated with reduced forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)1–3. In children, the prevalence of childhood overweight and obesity has risen by nearly 30% in the last 30 years4. However, several cohort studies have investigated the effects of obesity on lung function in children, with inconsistent data on the association of BMI with FEV1 and FVC. A recent meta-analysis in obese children showed that higher BMI was associated with a decreased FEV1/FVC ratio but with no significant changes in FEV1 and FVC5. In young children, FVC may increase more rapidly than airway diameters and FEV16. Childhood development is known to affect lung function and it has been suggested that the FEV1/FVC ratio decreases with increasing age and height until adolescents7,8. Epidemiological surveys of the past 20 years demonstrate an association between an increased prevalence of obesity and elevated blood pressure (BP) in children and adolescents9,10. Whether BP may be associated with lung function independent of BMI has been a matter of debate and potential physiological mechanisms remain unclear11,12. Besides obesity and high BP, there is a global trend for decreasing levels of physical activity and fitness in adults and children. About 80% of children aged 13-15 years do not achieve the recommendations of 60 minutes daily physical activity13. Regular physical activity and high fitness are related to several health benefits, such as reduction of obesity and hypertension during lifespan14,15. Physical inactivity has been shown to reduce FEV1, whereas participation in vigorous physical activity predicted a slower reduction of FEV1 at older age in men and women16. Only few studies investigated the association of physical activity and fitness with lung function in children. Physical activity has been shown to be positively associated with FVC in young girls17. There is limited evidence that physical fitness during
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childhood may be associated with higher FEV1 and FVC but not with changes in the FEV1/FVC ratio18. Our study aimed to investigate the association of body composition, BP and cardiorespiratory fitness (CRF) on lung function in a large cohort of young children with a focus on overweight and obese subjects using elaborate adjustment models. We hypothesized that lung function specifically in children with overweight and obesity was affected by individual physical fitness levels.
Methods Study design and participants This cross-sectional study was embedded in the large-scale EXAMIN YOUTH study. Children were included if they were between the ages of 6 and 8 years and had written consent from their parents. All measurements took place on-site during regular school hours in the morning and children had to remain fastened before the medical screening. Ethical approval was given by the Ethics Committee of the University of Basel (EKBB, Basel, No.258/12). The study complied to the Guidelines for Good Clinical Practice of the Declaration of Helsinki19. The manuscript was prepared according to the STROBE guidelines.
Measurements Spirometry To assess lung function, objective parameters of respiratory function such as the ratio of FEV1/FVC, FEV1, FVC, peak expiratory flow (PEF) and forced expiratory flow at 25 to 75%
(FEF25-75)
were
measured
in
accordance
with
the
American
Thoracic
Society/European Respiratory Society guidelines20. Measurements of lung function were assessed using a validated spirometer (EasyOne Diagnostic, Andover, MA, USA) by one
5
single experienced investigator. The test was repeated at least five times, whereby the best test was used for statistical analysis. The results were rated as valid if the degree of quality was between grade A (minimum three acceptable attempts and difference of the two best FEV1- and FVC-values ≤ 100 ml) and C (minimum two acceptable attempts and difference of the two best FEV1- and FVC ≤ 200 ml) as defined by the manufacturer`s manual and in accordance with recent recommendations21.
Anthropometrics Body weight and body fat were measured using an electrical impedance device (InBody 170 Biospace device; InBody Co., Seoul, Korea). Body height was assessed with a wall-mounted stadiometer (Seca 206; Seca, Basel, Switzerland)BMI was calculated as weight divided by height squared (kg/m2). Children were categorised in clinical relevant BMI groups defined as normal weight (< 85th percentile), overweight (> 85th percentile) and obese (> 95th percentile) in their sex and age group22. To reduce inter-observer variability, an automated oszillograph (Oscillomate, CAS Medical Systems, Branford, CT, USA) was used to assess BP. According to the American Heart Association guidelines, BP was measured five times after a rest of 5 minutes. The mean of the three measurements with the smallest variation was taken for further analysis. Systolic BP and diastolic BP were classified according of the population-based German KiGGS study23. Children with a BP over the 90th percentile were categorised as normal-high BP and over the 95th percentile as hypertensive.
Cardiorespiratory fitness To assess CRF the validated and well-established 20-m shuttle run test was performed24,25. The 20-m shuttle run test is a good indicator of maximal endurance exercise capacity in children. A standardized five minutes warm-up preceded the progressive CRF test. All
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participants had to run between two lines (separated by a distance of 20 meters) back and forth as long as possible. The running speed was defined by two acoustic bleep signals. Every minute, the speed was increased by 0.5km/h with an initial speed of 8km/h. The test was stopped if a child failed to cross the line twice in a row. The test result was defined by the number of stages reached (1 stage = 1min), counted with a precision of 0.5 stages.
Statistical analysis Tukey-Anscombe Plots were used to assess variance homogeneity and normal QQ plots of the residuals were used to assess normality. To compare differences of lung function parameters between groups, univariate analysis of covariance (ANCOVA) was performed. Pearson’s correlation analysis was used to assess collinearity between BMI and BP. Multiple linear regression analysis was applied to analyze the association of lung function (FEV1/FVC, FEV1, FVC, PEF, FEF25-75) with BMI, BP and physical fitness. Different models were fitted to adjust for age and sex as well as body weight, height, BP and CRF. Collinearity between BMI and BP was assessed. 95% confidence intervals were presented for measures of effect to indicate the amount of uncertainty and a 2-sided level of significance of 0.05 denotes statistical significance. Z-score for lung function parameters was calculated according to the Global Lung Function Initiative (GLI)26. We refrained from using z-scores in the ANCOVA and regression analysis since these z-scores already account for height and other confounders. We preferred to use multiple adjustment models to adjust for different combinations of confounders. For analyses and graphics, an up-to-date version of Stata 15 (StataCorp LP, College Station, TX, USA) was used. The sample size of the cross-sectional study was given by the number of children and parents giving their consent.
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Results In total, 3068 children were invited to participate in this cross-sectional study. 1690 children received written consent from their parents to take part in the medical screening. 444 children were excluded from the study, either because of absence due to illness, missing or invalid spirometry data, leaving 1246 (74%) children with complete measurements in the study (Figure 1). Age, sex, BMI and shuttle run data of the 444 excluded children are presented in supplement Table S1. The population of children excluded were slightly smaller with higher body fat and lower fitness levels. Based on a modified questionnaire survey27, 89% of children were Caucasian and only 2.3% of children were reported to have asthma. Parents were asked if their children had any chronic disease such as asthma. Table 1 shows the population characteristics of our cohort. It can be seen from the z-scores for lung function as calculated according to the GLI (Table 1), our cohort did not significantly differ from the reference population26. According to the relevant BMI categories, 1081 (87%) were normal weight, 10% were overweight and 3% obese. Based on systolic BP, 76% were categorised as normotensive children (n=950), 10% as high-normal BP (n=120) and 14% as hypertensive (n=176). Boys showed higher FEV1, FVC and PEF, but lower FEV1/FVC ratio compared to girls (Table 1). Children reported to have asthma in the questionnaire had a lower FEV1/FVC (0.88 (0.82;0.94) ratio compared to children without asthma (0.91 (0.90;0.91); p=0.03).
Group differences across clinical categories Table 2 shows the results across clinical categories of BMI und BP in relation to lung function. Children with overweight and obesity had independently higher FEV1, FVC and PEF compared to normal weight children (p<0.001). Associations of overweight and obesity with a lower FEV/FVC ratio were not independent of BP. Association of clinical categories
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of systolic BP with lung function were BMI dependent. Normal weight children had better CRF compared to overweight and obese children (shuttle run stages: 3.95, 2.79 and 1.94, respectively; p<0.001). Children with obesity were significantly taller (p<0.001) and older (p=0.03) compared to normal weight peers.
Regression analysis and adjustment models Data on regression analysis are represented in Table 3. Per unit increase in BMI, we observed increases in FEV1 (0.029 (0.023;0.036) L), FVC (0.038 (0.031;0.045) L), PEF (0.051 (0.033;0.069) L/s) and FEF25-75 (0.022 (0.009;0.035) L/s), independent of BP and physical fitness. However, with each unit increase of BMI the FEV1/FVC ratio decreased (-0.003 (0.005;-0.001)) due to a disproportional increase in FVC compared to FEV1. The correlation of FEV1 and FVC with BMI is graphically depicted in Figure 2A. Body weight was also associated with lower FEV1/FVC (-0.002 (-0.003;-0.3E-3)) and higher FEV1 (0.010 (0.006;0.014) L)), FVC (0.014 (0.010;0.018) L) and PEF (0.017 (0.010;0.028) L/s), independent of body height, BP and shuttle run. Per unit increase of body height, we found independent increases in FEV1 (0.017 (0.014;0.020) L), FVC (0.018 (0.015;0.022) L), PEF (0.030 (0.021;0.038) L/s) and FEF25-75 (0.019 (0.013;0.026) L/s). However, body height was not independently associated with FEV1/FVC. In addition, systolic BP and diastolic BP were not independently associated with lung function in our cohort of children. Pearson’s correlation analysis showed that systolic BP (r=0.31, p<0.001) and diastolic BP (r=0.15, p<0.001) were correlated with BMI. One unit increase in shuttle run was associated with increased FEV1 (0.017 (0.008:0.025) L), FVC (0.022 (0.012;0.031) L), PEF (0.046 (0.022;0.071) L/sand FEF25-75 (0.019 (0.001;0.038) L/s) after adjusting for confounders. The FEV1/FVC ratio was not associated with CRF in the overall cohort. In children with obesity but not in normal weight children, higher CRF was
9
associated with higher FEV1/FVC (0.03 (0.5E-4; 0.06)), independent of age, gender, BP, body height and weight. The correlations of FEV1 and FVC with CRF (shuttle run stages) in children with obesity are shown in Figure 2B. There was a disproportional increase of FEV1 compared to FVC with increasing CRF.
Discussion This is the first study to investigate the association of body composition, BP and physical fitness with lung function in young children. Childhood overweight and obesity were associated with higher FEV1, FVC and PEF. BMI and body weight were related to a lower FEV1/FVC due to a disproportional increase of FVC relative to FEV1 with increasing BMI. CRF was associated with increased FEV1, FVC, PEF and FEF25-75. In children with obesity, CRF was significantly associated with a higher FEV1/FVC ratio, due to a favourable increase of FEV1 over FVC with increasing fitness. A recent meta-analysis summarized the associations of obesity and overweight with lung function in adults and children. Obese adults showed lower FEV1 and FVC compared to normal weight adults. In contrast, children with overweight and obesity tended to have higher FEV1 and FVC compared to normal weight children5. Most of the studies included in this meta-analysis reported small sample sizes. Several studies reported that BMI was associated with increased FEV1 and FVC and a lower FEV1/FVC ratio in non-asthmatic children28–30. Similar to these results, we found an inverse correlation between BMI and FEV1/FVC ratio in our large cohort of children. Childhood obesity and overweight were significantly and positively associated with FEV1, FVC, PEF and FEF25-75. In our study, children with obesity were taller and older compared to normal weight children. This can be explained by advanced development and growth in older children, even if the age-range covered only several months in our study population. Moreover, high caloric intake is directly associated
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with growth in young children. Children with obesity are taller and, therefore, tend to have higher lung volumes. For this reason, systematic adjustments for confounders are important to discuss our findings. Body weight was associated with a lower FEV1/FVC ratio independent of height and age. This was due to a disproportional increase of FVC compared to FEV1 with increasing body weight. Our data are in line with previous reports of differences in timing and growth of lung volumes and airflow during childhood until adolescence, demonstrating distinct patterns of disproportional increases of FVC compared to FEV131. Our results provide further evidence that an increasing BMI and weight gain can be considered as independent risk factors for a mismatch of ventilation and airway flow during childhood lung development. With respect to gender differences, our results are in line with previous reports. Boys showed higher FEV1, FVC and PEF but lower FEV1/FVC compared to girls. In accordance with these results, Quanjer et al. (2012) found that boys had larger lungs, but girls were able to empty their lungs faster in proportion to their lung volume26. A previous cross-sectional study found a positive association of systolic BP with FEV1 in 5year-old children12. Similar results were found in the Determinants of Adolescent Social Well-Being and Health (DASH) study in children aged 11-13 years11. Longitudinal data showed that changes in FEV1 from 11 to 23 years were associated with changes in systolic BP11. The authors argued that an association between mechanical properties of BP and the respiratory system may be part of the normal physiological development in childhood. In our cohort of young children, higher FEV1 and FVC and a reduced FEV1/FVC ratio were associated with systolic BP, but not independent of body height and weight. In our clinical categorization, the association between systolic BP and lung function did not remain significant after adjustment for BMI. Based on the results of our large cohort and in contrast to the above findings, the association of BP with lung function seems to arise predominantly through the confounding with BMI.
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Physical activity is essential for a number of wide-ranging health benefits. In adults, participation in daily vigorous physical activity has been shown to slow down the decline in FEV1 during lifespan16,32. The association of CRF with lung function in children remained unclear. We objectively measured CRF by assessing shuttle run stages in children. CRF was independently associated with higher FEV1, FVC, PEF and FEF25-75, but not FEV1/FVC. These results are in line with a recent study, which demonstrated that CRF was positively associated with 2-3% higher FEV1 and FVC, but not with FEV1/FVC.18 In a longitudinal analysis, higher physical fitness during childhood was associated with higher lung volumes in adulthood18. Most importantly, subgroup analysis of children with obesity in our study revealed that fitter children had better FEV1/FVC, which was not evident in normal weight children. Obesity is related to a higher airway resistance and restricted tidal volume changes, which directly affect smooth muscle cell plasticity of the bronchia33. Exercise has the potential to improve smooth muscle function of bronchia and thereby improve lung function in children with obesity34. Moreover, exercise may beneficially affect the elastic properties of lungs and airways, which improve airway flow and FEV1. Future studies are warranted to investigate whether lung function in children at risk of developing obstructive pulmonary disease may be improved by regular exercise. Some limitations in our study need to be discussed. For example, children with larger lung functions may have had better exercise performance. Our study is associative in nature and thus no differentiation in terms of causality can be made. Children who were excluded from the medical screening to due absence on the day of assessment or insufficient data quality (n=444; Figure 1), were slightly smaller with higher body fat and lower fitness levels (Table S1). Although the differences were small, a notable selection bias has occurred. Our cohort represents an unselective population with an expected prevalence of asthma about 9%35. In our cohort, families were asked to mention any chronic diseases of their children. Few
12
children were described as being asthmatic, which is considered to be related to underreporting. The z-scores for FEV1/FVC, FEV1, FVC and FEF25-75 were comparable to the reference values of the Quanjer GLI reference equations26, indicating that our population represents an unselected, healthy population. In order to understand the effect of obesity in high-risk populations, future studies in a selected population of asthmatic children may investigate the association of lung function with childhood obesity and physical fitness in pulmonary disease as compared to healthy children. Our findings are related to a Caucasian population with a small percentage of other ethnical groups. Differences in ethnicity have been shown to affect the pattern of lung development during childhood31 and therefore our findings cannot be generalized to other ethnic groups. A strength of our study is the large sample size and the limited age range of young children. During childhood, the lungs continuously develop, and especially during puberty, age adaptations occur rapidly. Investigating a large sample of children at the same age therefore reduces a developmental impact on our findings. Future studies may still investigate the interrelation of lung function, BMI and CRF in a wider age range from infancy to adolescence to account for the dynamic pattern of lung function development during childhood.
Conclusion In conclusion, childhood obesity is associated with lower FEV1/FVC due to a disproportional increase of FVC compared to FEV1 with increasing BMI. Childhood obesity was associated with an imbalance of ventilation and airway flow independent of body height and other confounders. In children with obesity, a favourable increase of FEV1 over FVC with increasing CRF was observed. In these children, higher CRF was associated with improved and balanced FEV1/FVC ratio, which may be related to better smooth muscle cell plasticity of the bronchia. Exercise intervention trials are warranted to investigate whether ventilation
13
inhomogeneity and airflow impairments in children with obesity can be compensated by regular exercise and achieving higher CRF. Implementation of lung function screening and subsequent physical activity interventions within primary prevention programs in young children may help reduce the burden of pulmonary disease later in life.
Acknowledgements The authors of this manuscript thank the children, as well as their parents and teachers, and the heads of schools, who participated in this study. We also would like to acknowledge the support and cooperation of the Cantonal Office of Sport of Basel-Stadt and the Department of Education of Basel-Stadt.
Formating of funding sources This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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30. Cibella F, Bruno A, Cuttitta G, Bucchieri S, Melis MR, De Cantis S, La Grutta S, Viegi G. An elevated body mass index increases lung volume but reduces airflow in Italian schoolchildren. PloS One. 2015;10(5):e0127154. doi:10.1371/journal.pone.0127154 31. Quanjer PH, Stanojevic S, Stocks J, Hall GL, Prasad KVV, Cole TJ, Rosenthal M, PerezPadilla R, Hankinson JL, Falaschetti E, et al. Changes in the FEV1/FVC ratio during childhood and adolescence: an intercontinental study. European Respiratory Journal. 2010;36(6):1391–1399. doi:10.1183/09031936.00164109 32. Pelkonen M, Notkola I-L, Lakka T, Tukiainen HO, Kivinen P, Nissinen A. Delaying Decline in Pulmonary Function with Physical Activity. American Journal of Respiratory and Critical Care Medicine. 2003;168(4):494–499. doi:10.1164/rccm.200208-954OC 33. Frey U, Latzin P, Usemann J, Maccora J, Zumsteg U, Kriemler S. Asthma and obesity in children: current evidence and potential systems biology approaches. Allergy. 2015;70(1):26–40. doi:10.1111/all.12525 34. Fredberg JJ, Inouye D, Miller B, Nathan M, Jafari S, Helioui Raboudi S, Butler JP, Shore SA. Airway Smooth Muscle, Tidal Stretches, and Dynamically Determined Contractile States. American Journal of Respiratory and Critical Care Medicine. 1997;156(6):1752–1759. doi:10.1164/ajrccm.156.6.9611016 35. Mallol J, Crane J, von Mutius E, Odhiambo J, Keil U, Stewart A. The International Study of Asthma and Allergies in Childhood (ISAAC) Phase Three: A global synthesis. Allergologia et Immunopathologia. 2013;41(2):73–85. doi:10.1016/j.aller.2012.03.001
Figure legends
Figure 1.
Flow diagram
Figure 2A
Association of body mass index with FEV1 and FVC (n=1246) FEV1, forced expiratory volume in one second; FVC, forced vital capacity
Figure 2B
Association of shuttle run stages with FEV1 and FVC in the subgroup of children with obesity (n=43) FEV1, forced expiratory volume in one second; FVC, forced vital capacity
17
Table 1. Population characteristics of the study.
Parameter
Total
n
Mean±SD
Boys
n
Mean±SD
Girls
n
p
Mean±SD
Age
7.2±0.4
1246
7.2±0.4
626
7.2±0.4
620
0.313
Height (cm)
124.6±5.5
1246
124.8±5.2
626
124.4±5.8
620
0.261
Weight (kg)
24.8±4.8
1246
24.9±4.7
626
24.6±4.8
620
0.220
BMI (kg/m2)
15.9±2.2
1246
15.9±2.2
626
15.8±2.2
620
0.257
Percentage body fat (%)
15.4±7.7
1246
14.0±7.3
626
16.8±7.7
620
<0.001
Heart rate (bpm)
85.8±10.3
1246
85.4±10.3
626
86.1±10.8
620
0.220
Systolic BP (mmHg)
103.8±7.7
1246
103.9±7.5
626
103.8±8.0
620
0.825
Diastolic BP (mmHg)
64.1±6.9
1246
64.1±6.9
626
64.1±7.0
620
0.944
FEV1/FVC
0.91±0.07
1246
0.90±0.07
626
0.91±0.07
620
0.002
FEV1/FVC (z-score)
0.32±1.14
1246
0.31±1.08
626
0.32±1.19
620
0.965
FEV1 (L)
1.40±0.25
1246
1.44±0.25
626
1.35±0.24
620
<0.001
FEV1 (z-score)
-0.31±1.15
1246
-0.25±1.19
626
-0.37±1.10
620
0.060
FVC (L)
1.55±0.28
1246
1.60±0.29
626
1.49±0.26
620
<0.001
FVC (z-score)
-0.45±1.12
1246
-0.40±1.16
626
-0.49±1.08
620
0.196
PEF (L/s)
3.15±0.65
1246
3.25±0.70
626
3.05±0.63
620
<0.001
FEF 25-75 (L/s)
1.81±0.47
1246
1.83±0.46
626
1.79±0.46
620
0.167
FEF 25-75 (z-score)
-0.12±1.04
1246
-0.03±1.02
626
-0.21±1.05
620
0.003
20-m Shuttle Run (stages)
3.8±1.5
1246
4.0±1.6
626
3.5±1.3
620
<0.001
BMI, body mass index; BP, blood pressure; FEV1/FVC, ratio of forced expiratory volume in 1 second to forced vital capacity; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; PEF, peak expiratory flow; FEF 25-75, forced expiratory flow at 25-75%; SD, standard deviation
Table 2. Lung function in relation to clinical categories of body mass index and blood pressure
Parameter
n
FEV1/FVC
p
Mean (95% CI) BMI
FEV1 (L)
p
Mean (95% CI) 0.050
FVC (L)
p
Mean (95% CI) <0.001
PEF (L/s)
p
Mean (95% CI) <0.001
FEF 25-75 (L/s) Mean (95% CI)
0.006
0.012
Normal weight
1081
0.91 (0.90;0.91)
1.38 (1.37;1.40)
1.53 (1.51;1.54)
3.13 (3.09;3.17)
1.80 (1.77;1.83)
Overweight
122
0.89 (0.88;0.90)
1.48 (1.43;1.52)
1.66 (1.61;1.70)
3.28 (3.17;3.39)
1.84 (1.76;1.93)
Obese
43
0.90 (0.88;0.92)
1.57 (1.50;1.64)
1.75 (1.67;1.83)
3.34 (3.15;3.54)
1.96 (1.82;2.10)
BMIa
0.192
<0.001
<0.001
0.001
0.125
Normal weight
1081
0.91 (0.90;0.91)
1.39 (1.37;1.40)
1.53 (1.51;1.55)
3.13 (3.09;3.17)
1.80 (1.77;1.83)
Overweight
122
0.90 (0.89;0.91)
1.46 (1.42;1.50)
1.64 (1.59;1.68)
3.26 (3.14;3.38)
1.84 (1.75;1.92)
Obese
43
0.91 (0.89;0.93)
1.54 (1.47;1.62)
1.72 (1.64;1.80)
3.36 (3.16;3.56)
1.95 (1.81;2.09)
Systolic BP
0.036
0.014
<0.001
0.665
0.443
Normotensive
950
0.91 (0.91;0.92)
1.39 (1.38;1.41)
1.53 (1.52;1.55)
3.14 (3.10;3.18)
1.81 (1.78;1.84)
High-normal
120
0.90 (0.89;0.91)
1.40 (1.36;1.45)
1.56 (1.51;1.61)
3.17 (3.06;3.29)
1.79 (1.71;1.88)
Hypertensive
176
0.90 (0.89;0.91)
1.45 (1.41;1.48)
1.62 (1.58;1.66)
3.19 (3.09;3.28)
1.85 (1.78;1.92)
Systolic BP
b
0.162
0.620
0.273
p
0.944
0.747
Normotensive
950
0.91 (0.90;0.91)
1.40 (1.38;1.41)
1.54 (1.52;1.56)
3.15 (3.11;3.19)
1.81 (1.78;1.84)
High-normal
120
0.90 (0.89;0.91)
1.40 (1.36;1.44)
1.56 (1.51;1.60)
3.16 (3.05;3.28)
1.79 (1.70;1.87)
Hypertensive
176
0.90 (0.89;0.91)
1.42 (1.38;1.45)
1.58 (1.54;1.61)
3.14 (3.04;3.23)
1.83 (1.76;1.90)
Diastolic BP
0.847
0.300
0.294
0.511
0.589
Normotensive
965
0.91 (0.90;0.91)
1.39 (1.38;1.41)
1.54 (1.52;1.56)
3.14 (3.09;3.18)
1.80 (1.77;1.83)
High-normal
107
0.91 (0.90;0.92)
1.43 (1.38;1.47)
1.58 (1.53;1.63)
3.20 (3.08;3.32)
1.83 (1.74;1.92)
Hypertensive
174
0.91 (0.90;0.92)
1.41 (1.38;1.45)
1.56 (1.52;1.60)
3.18 (3.08;3.28)
1.84 (1.77;1.91)
Diastolic BP
b
0.857
0.611
0.690
0.728
0.744
Normotensive
965
0.91 (0.90;0.91)
1.40 (1.38;1.41)
1.54 (1.53;1.56)
3.14 (3.10;3.18)
1.81 (1.78;1.84)
High-normal
107
0.91 (0.90;0.92)
1.42 (1.38;1.47)
1.57 (1.52;1.62)
3.19 (3.07;3.31)
1.82 (1.74;1.91)
Hypertensive
174
0.91 (0.90;0.92)
1.40 (1.37;1.44)
1.55 (1.51;1.59)
3.16 (3.07;3.26)
1.83 (1.76;1.90)
Adjusted for age and gender, p value across lowest and highest category (univariate analysis of covariance) a
b
additionally adjusted for systolic and diastolic blood pressure additionally adjusted for BMI
BMI, body mass index; BP, blood pressure; FEV1/FVC, ratio of forced expiratory volume in 1 second to forced vital capacity; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; PEF, peak expiratory flow; FEF 25-75, forced expiratory flow at 25-75%
Table 3. Regression analysis for the association of body composition, blood pressure, physical activity and fitness with lung function
Parameter
Model
FEV1/FVC
FEV1
FVC
PEF
FEF 25-75
(change per unit)
(L change per unit)
(L change per unit)
(L/s change per unit)
(L/s change per unit)
B (95% CI)
B (95% CI)
B (95% CI)
B (95% CI)
B (95% CI) Body weight (kg)
1
-0.002
p <0.001
(-0.002;-0.001) 2
-0.002
1
-0.9E-3
0.018
0.1E-3
0.012
1
-0.003
0.805
-0.003
0.001
1
-0.001 (-0.001;-0.6E-3)
<0.001
0.017
0.028
0.004
0.029
<0.001
0.004 (0.002;0.006)
<0.001
0.026
0.018
<0.001
0.036
<0.001
0.038
<0.001
0.005 (0.003;0.008)
0.003
0.037
0.030
<0.001
0.040
<0.001
0.051
<0.001
0.005 (-0.7E4;0.010)
0.238
0.021
0.002
0.019
0.001
(0.013;0.026) <0.001
0.019
0.002
(0.007;0.031) <0.001
(0.033;0.069) <0.001
0.005
(0.017;0.026)
(0.024;0.056) <0.001
<0.001
(-0.003;0.013)
(0.021;0.038)
(0.031;0.045) <0.001
0.017
0.018
p
(0.012;0.023)
(0.031;0.043)
(0.030;0.043) <0.001
<0.001
(0.010;0.028)
(0.015;0.022)
(0.023;0.036) 0.033
0.014
0.033
p
(0.026;0.041)
(0.023;0.029)
(0.022;0.034)
(-0.005;-0.001) Percentage body fat (%)
0.022
<0.001
(0.010;0.018)
(0.014;0.020)
(-0.005;-0.001) 4
<0.001
(0.020;0.024)
(-0.001;0.001) BMI (kg/m2)
0.010
0.026
p
(0.023;0.029)
(0.006;0.014)
(-0.002;-0.2E-3) 3
<0.001
(0.019;0.024)
(-0.003;-0.3E-3) Body height (cm)
0.021
p
0.022
0.001
(0.009;0.035) 0.054
0.002 (-0.002;0.005)
0.422
5
0.2E-3
0.725
(-0.001;0.001) Systolic BP (mmHg)
1
-0.001
-0.5E-3
0.002
1
-0.4E-3
0.053
-0.2E-3
0.195
1
0.6E-4
0.471
-0.002 (-0.005;0.001)
0.951
0.003
0.2E-3
0.962
0.3E-3
0.004
0.017
<0.001
0.001
0.004
0.789
0.5E-3
0.382
0.4E-3
0.001
(0.008;0.025)
0.022 (0.012;0.031)
Model 1 = adjusted for age and sex Model 2 = model 1 plus adjusted for body height, systolic, diastolic blood pressure and shuttle run (stages) Model 3 = model 1 plus adjusted for body weight, systolic, diastolic blood pressure and shuttle run (stages) Model 4 = model 1 plus adjusted for systolic, diastolic blood pressure and shuttle run (stages) Model 5 = model 1 plus adjusted for body weight, body height, systolic, diastolic blood pressure and shuttle run (stages)
0.062
-0.003
0.004
0.578
0.4E-3
0.183
0.010
0.092
0.046 (0.022;0.071)
0.098
-0.001
0.531
0.002
0.339
(-0.002;0.006) 0.865
-0.3E-3
0.843
(-0.004;0.003) 0.118
(-0.005;0.044) <0.001
0.003
(-0.005;0.002)
(-0.005;0.005) 0.940
0.001
(-0.001;0.006)
(-0.001;0.010)
(-0.010;0.011) <0.001
0.004
-0.012 (-0.020;-0.005)
(-0.008;0.002)
(-0.001;0.002) 0.953
0.016
(-0.2E-3;0.009)
(0.002;0.006)
(-0.009;0.010) 0.210
0.006
-0.018 (-0.028;-0.008)
(-0.001;0.003)
(-0.002;0.002)
(-0.002;0.003) 7
0.5E-4
<0.001
(0.004;0.008)
(0.001;0.005)
(-0.001; 0.3E-3) 20-m Shuttle Run (stages)
<0.001
(-0.002;0.002)
(-0.001;0.2E-3) 6
0.005
-0.012 (-0.016;-0.009)
(0.003;0.006)
(-0.001;0.7E-5) Diastolic BP (mmHg)
<0.001
(-0.014;-0.007)
(-0.001;-0.3E-3) 6
-0.011
0.007
0.420
(-0.011;0.025) <0.001
0.019 (0.001;0.038)
0.042
Model 6 = model 1 plus adjusted for body height, body weight and shuttle run (stages) Model 7 = model 1 plus adjusted for body height, body weight, systolic and diastolic blood pressure BMI, body mass index; BP, blood pressure; FEV1/FVC, ratio of forced expiratory volume in 1 second to forced vital capacity; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; PEF, peak expiratory flow; FEF 25-75, forced expiratory flow at 25-75%
Enrollment
Figure 1.
3068 primary school children invited to participate 1378 without consent
Analysis
Recruitment
1690 with written consent for participation 221 ill at the day of examination or relocated 1469 children with anthropometric data 223 without valid lung function data 1246 children with complete data
2
Figure 2A.
1.4
1.6
FEV1
Mean 95% CI
1.2
Volume (L)
1.8
FVC
10
15
20
Body mass index (kg/m2)
25
30
FVC
1.4
1.6
1.8
FEV1
Mean 95% CI
1.2
Volume (L)
2
2.2
Figure 2B.
0
1
2
Shuttle run (stages)
3
4
Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
S0954-6111(19)30327-0
DOI:
https://doi.org/10.1016/j.rmed.2019.105813
Reference:
YRMED 105813
To appear in:
Respiratory Medicine
Received Date: 17 May 2019 Accepted Date: 4 November 2019
Please cite this article as: Köchli S, Endes K, Bartenstein T, Usemann J, Schmidt-Trucksäss A, Frey U, Zahner L, Hanssen H, Lung function, obesity and physical fitness in young children: The EXAMIN YOUTH study, Respiratory Medicine (2019), doi: https://doi.org/10.1016/j.rmed.2019.105813. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.
Lung function, obesity and physical fitness in young children: The EXAMIN YOUTH Study
Sabrina Köchli PhDa, Katharina Endes PhDa, Tim Bartenstein MSca, Jakob Usemann MDb,c, Arno Schmidt-Trucksäss MDa, Urs Frey MDb, Lukas Zahner PhDa, Henner Hanssen MDa
a
Department of Sport, Exercise and Health, Medical Faculty, University of Basel, Basel, Switzerland
b
Pediatric Pulmonology, University Children`s Hospital (UKBB), University of Basel, Basel, Switzerland
c
Pediatric Respiratory Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Address correspondence to: Prof Dr Henner Hanssen, University of Basel, Department of Sport, Exercise and Health, Birsstrasse 320B, CH-4052 Basel, [email protected], Tel.: +41 612074746 Running title: Childhood obesity and lung function Keywords: Body mass index, blood pressure, cardiorespiratory fitness, pulmonary function Word count: 3056 Number of tables/figures: 3/2 Conflict of Interest: none. Source of founding: The study was self-funded. Financial Disclosure: none Clinical Trial Registration: ClinicalTrials.gov: NCT02853747; URL: https://clinicaltrials.gov/ct2/show/NCT02853747
1
Abbrevations: BMI
body mass index
BP
blood pressure
CRF
cardiorespiratory fitness
FEF 25-75
forced expiratory flow at 25 to 75%
FEV1
forced expiratory volume in one second
FVC
forced vital capacity
PEF
peak expiratory flow
2
Abstract Objective: The prevalence of obesity and physical inactivity in children are increasing globally. The study aimed to investigate the association of obesity and cardiorespiratory fitness (CRF) with patterns of lung function in young children. Methods: In this cross-sectional study, lung function, body mass index (BMI), blood pressure (BP) and CRF (shuttle run stages) were measured in an unselected cohort of 1246 children aged 7.2±0.4 years. All parameters and lung function, such as the ratio of forced expiratory volume in one second (FEV1) to forced vital capacity (FVC), were assessed by standardized procedures for children. Statistical models were applied for systematic adjustment of potential confounders. Results: Obese children had significantly higher FEV1 (Coef. (95 % CI) (1.57 (1.50;1.64) L) and FVC (1.75 (1.67;1.83) L) compared to normal weight children (1.38 (1.37;1.40) L; (1.53 (1.51;1.54) L, respectively). However, with each unit increase of BMI, FEV1/FVC decreased (-0.003 (-0.005;-0.001)) due to a disproportional increase in FVC compared to FEV1. Per stage increase of CRF, FEV1 (0.017 (0.008;0.025) L) and FVC increased (0.022 (0.012;0.031) L)). In obese children, higher CRF was independently associated with higher FEV1/FVC (0.03 (0.5E-4; 0.06)) due to a higher increase of FEV1 over FVC with increasing fitness. Conclusions: The decrease of FEV1/FVC with increasing BMI suggests that childhood obesity is associated with an imbalance of ventilation and airway flow. In children with obesity, higher CRF is associated with an improved FEV1/FVC ratio. Physical exercise programs may have the potential to improve patterns of lung function in children with obesity.
3
Introduction In adults, higher body mass index (BMI) is considered a general risk factor for the development of obstructive pulmonary disease and obesity has been associated with reduced forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)1–3. In children, the prevalence of childhood overweight and obesity has risen by nearly 30% in the last 30 years4. However, several cohort studies have investigated the effects of obesity on lung function in children, with inconsistent data on the association of BMI with FEV1 and FVC. A recent meta-analysis in obese children showed that higher BMI was associated with a decreased FEV1/FVC ratio but with no significant changes in FEV1 and FVC5. In young children, FVC may increase more rapidly than airway diameters and FEV16. Childhood development is known to affect lung function and it has been suggested that the FEV1/FVC ratio decreases with increasing age and height until adolescents7,8. Epidemiological surveys of the past 20 years demonstrate an association between an increased prevalence of obesity and elevated blood pressure (BP) in children and adolescents9,10. Whether BP may be associated with lung function independent of BMI has been a matter of debate and potential physiological mechanisms remain unclear11,12. Besides obesity and high BP, there is a global trend for decreasing levels of physical activity and fitness in adults and children. About 80% of children aged 13-15 years do not achieve the recommendations of 60 minutes daily physical activity13. Regular physical activity and high fitness are related to several health benefits, such as reduction of obesity and hypertension during lifespan14,15. Physical inactivity has been shown to reduce FEV1, whereas participation in vigorous physical activity predicted a slower reduction of FEV1 at older age in men and women16. Only few studies investigated the association of physical activity and fitness with lung function in children. Physical activity has been shown to be positively associated with FVC in young girls17. There is limited evidence that physical fitness during
4
childhood may be associated with higher FEV1 and FVC but not with changes in the FEV1/FVC ratio18. Our study aimed to investigate the association of body composition, BP and cardiorespiratory fitness (CRF) on lung function in a large cohort of young children with a focus on overweight and obese subjects using elaborate adjustment models. We hypothesized that lung function specifically in children with overweight and obesity was affected by individual physical fitness levels.
Methods Study design and participants This cross-sectional study was embedded in the large-scale EXAMIN YOUTH study. Children were included if they were between the ages of 6 and 8 years and had written consent from their parents. All measurements took place on-site during regular school hours in the morning and children had to remain fastened before the medical screening. Ethical approval was given by the Ethics Committee of the University of Basel (EKBB, Basel, No.258/12). The study complied to the Guidelines for Good Clinical Practice of the Declaration of Helsinki19. The manuscript was prepared according to the STROBE guidelines.
Measurements Spirometry To assess lung function, objective parameters of respiratory function such as the ratio of FEV1/FVC, FEV1, FVC, peak expiratory flow (PEF) and forced expiratory flow at 25 to 75%
(FEF25-75)
were
measured
in
accordance
with
the
American
Thoracic
Society/European Respiratory Society guidelines20. Measurements of lung function were assessed using a validated spirometer (EasyOne Diagnostic, Andover, MA, USA) by one
5
single experienced investigator. The test was repeated at least five times, whereby the best test was used for statistical analysis. The results were rated as valid if the degree of quality was between grade A (minimum three acceptable attempts and difference of the two best FEV1- and FVC-values ≤ 100 ml) and C (minimum two acceptable attempts and difference of the two best FEV1- and FVC ≤ 200 ml) as defined by the manufacturer`s manual and in accordance with recent recommendations21.
Anthropometrics Body weight and body fat were measured using an electrical impedance device (InBody 170 Biospace device; InBody Co., Seoul, Korea). Body height was assessed with a wall-mounted stadiometer (Seca 206; Seca, Basel, Switzerland)BMI was calculated as weight divided by height squared (kg/m2). Children were categorised in clinical relevant BMI groups defined as normal weight (< 85th percentile), overweight (> 85th percentile) and obese (> 95th percentile) in their sex and age group22. To reduce inter-observer variability, an automated oszillograph (Oscillomate, CAS Medical Systems, Branford, CT, USA) was used to assess BP. According to the American Heart Association guidelines, BP was measured five times after a rest of 5 minutes. The mean of the three measurements with the smallest variation was taken for further analysis. Systolic BP and diastolic BP were classified according of the population-based German KiGGS study23. Children with a BP over the 90th percentile were categorised as normal-high BP and over the 95th percentile as hypertensive.
Cardiorespiratory fitness To assess CRF the validated and well-established 20-m shuttle run test was performed24,25. The 20-m shuttle run test is a good indicator of maximal endurance exercise capacity in children. A standardized five minutes warm-up preceded the progressive CRF test. All
6
participants had to run between two lines (separated by a distance of 20 meters) back and forth as long as possible. The running speed was defined by two acoustic bleep signals. Every minute, the speed was increased by 0.5km/h with an initial speed of 8km/h. The test was stopped if a child failed to cross the line twice in a row. The test result was defined by the number of stages reached (1 stage = 1min), counted with a precision of 0.5 stages.
Statistical analysis Tukey-Anscombe Plots were used to assess variance homogeneity and normal QQ plots of the residuals were used to assess normality. To compare differences of lung function parameters between groups, univariate analysis of covariance (ANCOVA) was performed. Pearson’s correlation analysis was used to assess collinearity between BMI and BP. Multiple linear regression analysis was applied to analyze the association of lung function (FEV1/FVC, FEV1, FVC, PEF, FEF25-75) with BMI, BP and physical fitness. Different models were fitted to adjust for age and sex as well as body weight, height, BP and CRF. Collinearity between BMI and BP was assessed. 95% confidence intervals were presented for measures of effect to indicate the amount of uncertainty and a 2-sided level of significance of 0.05 denotes statistical significance. Z-score for lung function parameters was calculated according to the Global Lung Function Initiative (GLI)26. We refrained from using z-scores in the ANCOVA and regression analysis since these z-scores already account for height and other confounders. We preferred to use multiple adjustment models to adjust for different combinations of confounders. For analyses and graphics, an up-to-date version of Stata 15 (StataCorp LP, College Station, TX, USA) was used. The sample size of the cross-sectional study was given by the number of children and parents giving their consent.
7
Results In total, 3068 children were invited to participate in this cross-sectional study. 1690 children received written consent from their parents to take part in the medical screening. 444 children were excluded from the study, either because of absence due to illness, missing or invalid spirometry data, leaving 1246 (74%) children with complete measurements in the study (Figure 1). Age, sex, BMI and shuttle run data of the 444 excluded children are presented in supplement Table S1. The population of children excluded were slightly smaller with higher body fat and lower fitness levels. Based on a modified questionnaire survey27, 89% of children were Caucasian and only 2.3% of children were reported to have asthma. Parents were asked if their children had any chronic disease such as asthma. Table 1 shows the population characteristics of our cohort. It can be seen from the z-scores for lung function as calculated according to the GLI (Table 1), our cohort did not significantly differ from the reference population26. According to the relevant BMI categories, 1081 (87%) were normal weight, 10% were overweight and 3% obese. Based on systolic BP, 76% were categorised as normotensive children (n=950), 10% as high-normal BP (n=120) and 14% as hypertensive (n=176). Boys showed higher FEV1, FVC and PEF, but lower FEV1/FVC ratio compared to girls (Table 1). Children reported to have asthma in the questionnaire had a lower FEV1/FVC (0.88 (0.82;0.94) ratio compared to children without asthma (0.91 (0.90;0.91); p=0.03).
Group differences across clinical categories Table 2 shows the results across clinical categories of BMI und BP in relation to lung function. Children with overweight and obesity had independently higher FEV1, FVC and PEF compared to normal weight children (p<0.001). Associations of overweight and obesity with a lower FEV/FVC ratio were not independent of BP. Association of clinical categories
8
of systolic BP with lung function were BMI dependent. Normal weight children had better CRF compared to overweight and obese children (shuttle run stages: 3.95, 2.79 and 1.94, respectively; p<0.001). Children with obesity were significantly taller (p<0.001) and older (p=0.03) compared to normal weight peers.
Regression analysis and adjustment models Data on regression analysis are represented in Table 3. Per unit increase in BMI, we observed increases in FEV1 (0.029 (0.023;0.036) L), FVC (0.038 (0.031;0.045) L), PEF (0.051 (0.033;0.069) L/s) and FEF25-75 (0.022 (0.009;0.035) L/s), independent of BP and physical fitness. However, with each unit increase of BMI the FEV1/FVC ratio decreased (-0.003 (0.005;-0.001)) due to a disproportional increase in FVC compared to FEV1. The correlation of FEV1 and FVC with BMI is graphically depicted in Figure 2A. Body weight was also associated with lower FEV1/FVC (-0.002 (-0.003;-0.3E-3)) and higher FEV1 (0.010 (0.006;0.014) L)), FVC (0.014 (0.010;0.018) L) and PEF (0.017 (0.010;0.028) L/s), independent of body height, BP and shuttle run. Per unit increase of body height, we found independent increases in FEV1 (0.017 (0.014;0.020) L), FVC (0.018 (0.015;0.022) L), PEF (0.030 (0.021;0.038) L/s) and FEF25-75 (0.019 (0.013;0.026) L/s). However, body height was not independently associated with FEV1/FVC. In addition, systolic BP and diastolic BP were not independently associated with lung function in our cohort of children. Pearson’s correlation analysis showed that systolic BP (r=0.31, p<0.001) and diastolic BP (r=0.15, p<0.001) were correlated with BMI. One unit increase in shuttle run was associated with increased FEV1 (0.017 (0.008:0.025) L), FVC (0.022 (0.012;0.031) L), PEF (0.046 (0.022;0.071) L/sand FEF25-75 (0.019 (0.001;0.038) L/s) after adjusting for confounders. The FEV1/FVC ratio was not associated with CRF in the overall cohort. In children with obesity but not in normal weight children, higher CRF was
9
associated with higher FEV1/FVC (0.03 (0.5E-4; 0.06)), independent of age, gender, BP, body height and weight. The correlations of FEV1 and FVC with CRF (shuttle run stages) in children with obesity are shown in Figure 2B. There was a disproportional increase of FEV1 compared to FVC with increasing CRF.
Discussion This is the first study to investigate the association of body composition, BP and physical fitness with lung function in young children. Childhood overweight and obesity were associated with higher FEV1, FVC and PEF. BMI and body weight were related to a lower FEV1/FVC due to a disproportional increase of FVC relative to FEV1 with increasing BMI. CRF was associated with increased FEV1, FVC, PEF and FEF25-75. In children with obesity, CRF was significantly associated with a higher FEV1/FVC ratio, due to a favourable increase of FEV1 over FVC with increasing fitness. A recent meta-analysis summarized the associations of obesity and overweight with lung function in adults and children. Obese adults showed lower FEV1 and FVC compared to normal weight adults. In contrast, children with overweight and obesity tended to have higher FEV1 and FVC compared to normal weight children5. Most of the studies included in this meta-analysis reported small sample sizes. Several studies reported that BMI was associated with increased FEV1 and FVC and a lower FEV1/FVC ratio in non-asthmatic children28–30. Similar to these results, we found an inverse correlation between BMI and FEV1/FVC ratio in our large cohort of children. Childhood obesity and overweight were significantly and positively associated with FEV1, FVC, PEF and FEF25-75. In our study, children with obesity were taller and older compared to normal weight children. This can be explained by advanced development and growth in older children, even if the age-range covered only several months in our study population. Moreover, high caloric intake is directly associated
10
with growth in young children. Children with obesity are taller and, therefore, tend to have higher lung volumes. For this reason, systematic adjustments for confounders are important to discuss our findings. Body weight was associated with a lower FEV1/FVC ratio independent of height and age. This was due to a disproportional increase of FVC compared to FEV1 with increasing body weight. Our data are in line with previous reports of differences in timing and growth of lung volumes and airflow during childhood until adolescence, demonstrating distinct patterns of disproportional increases of FVC compared to FEV131. Our results provide further evidence that an increasing BMI and weight gain can be considered as independent risk factors for a mismatch of ventilation and airway flow during childhood lung development. With respect to gender differences, our results are in line with previous reports. Boys showed higher FEV1, FVC and PEF but lower FEV1/FVC compared to girls. In accordance with these results, Quanjer et al. (2012) found that boys had larger lungs, but girls were able to empty their lungs faster in proportion to their lung volume26. A previous cross-sectional study found a positive association of systolic BP with FEV1 in 5year-old children12. Similar results were found in the Determinants of Adolescent Social Well-Being and Health (DASH) study in children aged 11-13 years11. Longitudinal data showed that changes in FEV1 from 11 to 23 years were associated with changes in systolic BP11. The authors argued that an association between mechanical properties of BP and the respiratory system may be part of the normal physiological development in childhood. In our cohort of young children, higher FEV1 and FVC and a reduced FEV1/FVC ratio were associated with systolic BP, but not independent of body height and weight. In our clinical categorization, the association between systolic BP and lung function did not remain significant after adjustment for BMI. Based on the results of our large cohort and in contrast to the above findings, the association of BP with lung function seems to arise predominantly through the confounding with BMI.
11
Physical activity is essential for a number of wide-ranging health benefits. In adults, participation in daily vigorous physical activity has been shown to slow down the decline in FEV1 during lifespan16,32. The association of CRF with lung function in children remained unclear. We objectively measured CRF by assessing shuttle run stages in children. CRF was independently associated with higher FEV1, FVC, PEF and FEF25-75, but not FEV1/FVC. These results are in line with a recent study, which demonstrated that CRF was positively associated with 2-3% higher FEV1 and FVC, but not with FEV1/FVC.18 In a longitudinal analysis, higher physical fitness during childhood was associated with higher lung volumes in adulthood18. Most importantly, subgroup analysis of children with obesity in our study revealed that fitter children had better FEV1/FVC, which was not evident in normal weight children. Obesity is related to a higher airway resistance and restricted tidal volume changes, which directly affect smooth muscle cell plasticity of the bronchia33. Exercise has the potential to improve smooth muscle function of bronchia and thereby improve lung function in children with obesity34. Moreover, exercise may beneficially affect the elastic properties of lungs and airways, which improve airway flow and FEV1. Future studies are warranted to investigate whether lung function in children at risk of developing obstructive pulmonary disease may be improved by regular exercise. Some limitations in our study need to be discussed. For example, children with larger lung functions may have had better exercise performance. Our study is associative in nature and thus no differentiation in terms of causality can be made. Children who were excluded from the medical screening to due absence on the day of assessment or insufficient data quality (n=444; Figure 1), were slightly smaller with higher body fat and lower fitness levels (Table S1). Although the differences were small, a notable selection bias has occurred. Our cohort represents an unselective population with an expected prevalence of asthma about 9%35. In our cohort, families were asked to mention any chronic diseases of their children. Few
12
children were described as being asthmatic, which is considered to be related to underreporting. The z-scores for FEV1/FVC, FEV1, FVC and FEF25-75 were comparable to the reference values of the Quanjer GLI reference equations26, indicating that our population represents an unselected, healthy population. In order to understand the effect of obesity in high-risk populations, future studies in a selected population of asthmatic children may investigate the association of lung function with childhood obesity and physical fitness in pulmonary disease as compared to healthy children. Our findings are related to a Caucasian population with a small percentage of other ethnical groups. Differences in ethnicity have been shown to affect the pattern of lung development during childhood31 and therefore our findings cannot be generalized to other ethnic groups. A strength of our study is the large sample size and the limited age range of young children. During childhood, the lungs continuously develop, and especially during puberty, age adaptations occur rapidly. Investigating a large sample of children at the same age therefore reduces a developmental impact on our findings. Future studies may still investigate the interrelation of lung function, BMI and CRF in a wider age range from infancy to adolescence to account for the dynamic pattern of lung function development during childhood.
Conclusion In conclusion, childhood obesity is associated with lower FEV1/FVC due to a disproportional increase of FVC compared to FEV1 with increasing BMI. Childhood obesity was associated with an imbalance of ventilation and airway flow independent of body height and other confounders. In children with obesity, a favourable increase of FEV1 over FVC with increasing CRF was observed. In these children, higher CRF was associated with improved and balanced FEV1/FVC ratio, which may be related to better smooth muscle cell plasticity of the bronchia. Exercise intervention trials are warranted to investigate whether ventilation
13
inhomogeneity and airflow impairments in children with obesity can be compensated by regular exercise and achieving higher CRF. Implementation of lung function screening and subsequent physical activity interventions within primary prevention programs in young children may help reduce the burden of pulmonary disease later in life.
Acknowledgements The authors of this manuscript thank the children, as well as their parents and teachers, and the heads of schools, who participated in this study. We also would like to acknowledge the support and cooperation of the Cantonal Office of Sport of Basel-Stadt and the Department of Education of Basel-Stadt.
Formating of funding sources This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Figure legends
Figure 1.
Flow diagram
Figure 2A
Association of body mass index with FEV1 and FVC (n=1246) FEV1, forced expiratory volume in one second; FVC, forced vital capacity
Figure 2B
Association of shuttle run stages with FEV1 and FVC in the subgroup of children with obesity (n=43) FEV1, forced expiratory volume in one second; FVC, forced vital capacity
17
Table 1. Population characteristics of the study.
Parameter
Total
n
Mean±SD
Boys
n
Mean±SD
Girls
n
p
Mean±SD
Age
7.2±0.4
1246
7.2±0.4
626
7.2±0.4
620
0.313
Height (cm)
124.6±5.5
1246
124.8±5.2
626
124.4±5.8
620
0.261
Weight (kg)
24.8±4.8
1246
24.9±4.7
626
24.6±4.8
620
0.220
BMI (kg/m2)
15.9±2.2
1246
15.9±2.2
626
15.8±2.2
620
0.257
Percentage body fat (%)
15.4±7.7
1246
14.0±7.3
626
16.8±7.7
620
<0.001
Heart rate (bpm)
85.8±10.3
1246
85.4±10.3
626
86.1±10.8
620
0.220
Systolic BP (mmHg)
103.8±7.7
1246
103.9±7.5
626
103.8±8.0
620
0.825
Diastolic BP (mmHg)
64.1±6.9
1246
64.1±6.9
626
64.1±7.0
620
0.944
FEV1/FVC
0.91±0.07
1246
0.90±0.07
626
0.91±0.07
620
0.002
FEV1/FVC (z-score)
0.32±1.14
1246
0.31±1.08
626
0.32±1.19
620
0.965
FEV1 (L)
1.40±0.25
1246
1.44±0.25
626
1.35±0.24
620
<0.001
FEV1 (z-score)
-0.31±1.15
1246
-0.25±1.19
626
-0.37±1.10
620
0.060
FVC (L)
1.55±0.28
1246
1.60±0.29
626
1.49±0.26
620
<0.001
FVC (z-score)
-0.45±1.12
1246
-0.40±1.16
626
-0.49±1.08
620
0.196
PEF (L/s)
3.15±0.65
1246
3.25±0.70
626
3.05±0.63
620
<0.001
FEF 25-75 (L/s)
1.81±0.47
1246
1.83±0.46
626
1.79±0.46
620
0.167
FEF 25-75 (z-score)
-0.12±1.04
1246
-0.03±1.02
626
-0.21±1.05
620
0.003
20-m Shuttle Run (stages)
3.8±1.5
1246
4.0±1.6
626
3.5±1.3
620
<0.001
BMI, body mass index; BP, blood pressure; FEV1/FVC, ratio of forced expiratory volume in 1 second to forced vital capacity; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; PEF, peak expiratory flow; FEF 25-75, forced expiratory flow at 25-75%; SD, standard deviation
Table 2. Lung function in relation to clinical categories of body mass index and blood pressure
Parameter
n
FEV1/FVC
p
Mean (95% CI) BMI
FEV1 (L)
p
Mean (95% CI) 0.050
FVC (L)
p
Mean (95% CI) <0.001
PEF (L/s)
p
Mean (95% CI) <0.001
FEF 25-75 (L/s) Mean (95% CI)
0.006
0.012
Normal weight
1081
0.91 (0.90;0.91)
1.38 (1.37;1.40)
1.53 (1.51;1.54)
3.13 (3.09;3.17)
1.80 (1.77;1.83)
Overweight
122
0.89 (0.88;0.90)
1.48 (1.43;1.52)
1.66 (1.61;1.70)
3.28 (3.17;3.39)
1.84 (1.76;1.93)
Obese
43
0.90 (0.88;0.92)
1.57 (1.50;1.64)
1.75 (1.67;1.83)
3.34 (3.15;3.54)
1.96 (1.82;2.10)
BMIa
0.192
<0.001
<0.001
0.001
0.125
Normal weight
1081
0.91 (0.90;0.91)
1.39 (1.37;1.40)
1.53 (1.51;1.55)
3.13 (3.09;3.17)
1.80 (1.77;1.83)
Overweight
122
0.90 (0.89;0.91)
1.46 (1.42;1.50)
1.64 (1.59;1.68)
3.26 (3.14;3.38)
1.84 (1.75;1.92)
Obese
43
0.91 (0.89;0.93)
1.54 (1.47;1.62)
1.72 (1.64;1.80)
3.36 (3.16;3.56)
1.95 (1.81;2.09)
Systolic BP
0.036
0.014
<0.001
0.665
0.443
Normotensive
950
0.91 (0.91;0.92)
1.39 (1.38;1.41)
1.53 (1.52;1.55)
3.14 (3.10;3.18)
1.81 (1.78;1.84)
High-normal
120
0.90 (0.89;0.91)
1.40 (1.36;1.45)
1.56 (1.51;1.61)
3.17 (3.06;3.29)
1.79 (1.71;1.88)
Hypertensive
176
0.90 (0.89;0.91)
1.45 (1.41;1.48)
1.62 (1.58;1.66)
3.19 (3.09;3.28)
1.85 (1.78;1.92)
Systolic BP
b
0.162
0.620
0.273
p
0.944
0.747
Normotensive
950
0.91 (0.90;0.91)
1.40 (1.38;1.41)
1.54 (1.52;1.56)
3.15 (3.11;3.19)
1.81 (1.78;1.84)
High-normal
120
0.90 (0.89;0.91)
1.40 (1.36;1.44)
1.56 (1.51;1.60)
3.16 (3.05;3.28)
1.79 (1.70;1.87)
Hypertensive
176
0.90 (0.89;0.91)
1.42 (1.38;1.45)
1.58 (1.54;1.61)
3.14 (3.04;3.23)
1.83 (1.76;1.90)
Diastolic BP
0.847
0.300
0.294
0.511
0.589
Normotensive
965
0.91 (0.90;0.91)
1.39 (1.38;1.41)
1.54 (1.52;1.56)
3.14 (3.09;3.18)
1.80 (1.77;1.83)
High-normal
107
0.91 (0.90;0.92)
1.43 (1.38;1.47)
1.58 (1.53;1.63)
3.20 (3.08;3.32)
1.83 (1.74;1.92)
Hypertensive
174
0.91 (0.90;0.92)
1.41 (1.38;1.45)
1.56 (1.52;1.60)
3.18 (3.08;3.28)
1.84 (1.77;1.91)
Diastolic BP
b
0.857
0.611
0.690
0.728
0.744
Normotensive
965
0.91 (0.90;0.91)
1.40 (1.38;1.41)
1.54 (1.53;1.56)
3.14 (3.10;3.18)
1.81 (1.78;1.84)
High-normal
107
0.91 (0.90;0.92)
1.42 (1.38;1.47)
1.57 (1.52;1.62)
3.19 (3.07;3.31)
1.82 (1.74;1.91)
Hypertensive
174
0.91 (0.90;0.92)
1.40 (1.37;1.44)
1.55 (1.51;1.59)
3.16 (3.07;3.26)
1.83 (1.76;1.90)
Adjusted for age and gender, p value across lowest and highest category (univariate analysis of covariance) a
b
additionally adjusted for systolic and diastolic blood pressure additionally adjusted for BMI
BMI, body mass index; BP, blood pressure; FEV1/FVC, ratio of forced expiratory volume in 1 second to forced vital capacity; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; PEF, peak expiratory flow; FEF 25-75, forced expiratory flow at 25-75%
Table 3. Regression analysis for the association of body composition, blood pressure, physical activity and fitness with lung function
Parameter
Model
FEV1/FVC
FEV1
FVC
PEF
FEF 25-75
(change per unit)
(L change per unit)
(L change per unit)
(L/s change per unit)
(L/s change per unit)
B (95% CI)
B (95% CI)
B (95% CI)
B (95% CI)
B (95% CI) Body weight (kg)
1
-0.002
p <0.001
(-0.002;-0.001) 2
-0.002
1
-0.9E-3
0.018
0.1E-3
0.012
1
-0.003
0.805
-0.003
0.001
1
-0.001 (-0.001;-0.6E-3)
<0.001
0.017
0.028
0.004
0.029
<0.001
0.004 (0.002;0.006)
<0.001
0.026
0.018
<0.001
0.036
<0.001
0.038
<0.001
0.005 (0.003;0.008)
0.003
0.037
0.030
<0.001
0.040
<0.001
0.051
<0.001
0.005 (-0.7E4;0.010)
0.238
0.021
0.002
0.019
0.001
(0.013;0.026) <0.001
0.019
0.002
(0.007;0.031) <0.001
(0.033;0.069) <0.001
0.005
(0.017;0.026)
(0.024;0.056) <0.001
<0.001
(-0.003;0.013)
(0.021;0.038)
(0.031;0.045) <0.001
0.017
0.018
p
(0.012;0.023)
(0.031;0.043)
(0.030;0.043) <0.001
<0.001
(0.010;0.028)
(0.015;0.022)
(0.023;0.036) 0.033
0.014
0.033
p
(0.026;0.041)
(0.023;0.029)
(0.022;0.034)
(-0.005;-0.001) Percentage body fat (%)
0.022
<0.001
(0.010;0.018)
(0.014;0.020)
(-0.005;-0.001) 4
<0.001
(0.020;0.024)
(-0.001;0.001) BMI (kg/m2)
0.010
0.026
p
(0.023;0.029)
(0.006;0.014)
(-0.002;-0.2E-3) 3
<0.001
(0.019;0.024)
(-0.003;-0.3E-3) Body height (cm)
0.021
p
0.022
0.001
(0.009;0.035) 0.054
0.002 (-0.002;0.005)
0.422
5
0.2E-3
0.725
(-0.001;0.001) Systolic BP (mmHg)
1
-0.001
-0.5E-3
0.002
1
-0.4E-3
0.053
-0.2E-3
0.195
1
0.6E-4
0.471
-0.002 (-0.005;0.001)
0.951
0.003
0.2E-3
0.962
0.3E-3
0.004
0.017
<0.001
0.001
0.004
0.789
0.5E-3
0.382
0.4E-3
0.001
(0.008;0.025)
0.022 (0.012;0.031)
Model 1 = adjusted for age and sex Model 2 = model 1 plus adjusted for body height, systolic, diastolic blood pressure and shuttle run (stages) Model 3 = model 1 plus adjusted for body weight, systolic, diastolic blood pressure and shuttle run (stages) Model 4 = model 1 plus adjusted for systolic, diastolic blood pressure and shuttle run (stages) Model 5 = model 1 plus adjusted for body weight, body height, systolic, diastolic blood pressure and shuttle run (stages)
0.062
-0.003
0.004
0.578
0.4E-3
0.183
0.010
0.092
0.046 (0.022;0.071)
0.098
-0.001
0.531
0.002
0.339
(-0.002;0.006) 0.865
-0.3E-3
0.843
(-0.004;0.003) 0.118
(-0.005;0.044) <0.001
0.003
(-0.005;0.002)
(-0.005;0.005) 0.940
0.001
(-0.001;0.006)
(-0.001;0.010)
(-0.010;0.011) <0.001
0.004
-0.012 (-0.020;-0.005)
(-0.008;0.002)
(-0.001;0.002) 0.953
0.016
(-0.2E-3;0.009)
(0.002;0.006)
(-0.009;0.010) 0.210
0.006
-0.018 (-0.028;-0.008)
(-0.001;0.003)
(-0.002;0.002)
(-0.002;0.003) 7
0.5E-4
<0.001
(0.004;0.008)
(0.001;0.005)
(-0.001; 0.3E-3) 20-m Shuttle Run (stages)
<0.001
(-0.002;0.002)
(-0.001;0.2E-3) 6
0.005
-0.012 (-0.016;-0.009)
(0.003;0.006)
(-0.001;0.7E-5) Diastolic BP (mmHg)
<0.001
(-0.014;-0.007)
(-0.001;-0.3E-3) 6
-0.011
0.007
0.420
(-0.011;0.025) <0.001
0.019 (0.001;0.038)
0.042
Model 6 = model 1 plus adjusted for body height, body weight and shuttle run (stages) Model 7 = model 1 plus adjusted for body height, body weight, systolic and diastolic blood pressure BMI, body mass index; BP, blood pressure; FEV1/FVC, ratio of forced expiratory volume in 1 second to forced vital capacity; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; PEF, peak expiratory flow; FEF 25-75, forced expiratory flow at 25-75%
Enrollment
Figure 1.
3068 primary school children invited to participate 1378 without consent
Analysis
Recruitment
1690 with written consent for participation 221 ill at the day of examination or relocated 1469 children with anthropometric data 223 without valid lung function data 1246 children with complete data
2
Figure 2A.
1.4
1.6
FEV1
Mean 95% CI
1.2
Volume (L)
1.8
FVC
10
15
20
Body mass index (kg/m2)
25
30
FVC
1.4
1.6
1.8
FEV1
Mean 95% CI
1.2
Volume (L)
2
2.2
Figure 2B.
0
1
2
Shuttle run (stages)
3
4
Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: