An open-label study examining the effect of pharmacological treatment on mannitol- and exercise-induced airway hyperresponsiveness in asthmatic children and adolescents with exercise-induced bronchoconstriction.

BACKGROUND: Mannitol- and exercise bronchial provocation tests are both used to diagnose exercise-induced bronchoconstriction. The study aim was to compare the short-term treatment response to budesonide and montelukast on airway hyperresponsiveness to mannitol challenge test and to exercise challenge test in children and adolescents with exercise-induced bronchoconstriction. METHODS: Patients were recruited from a paediatric asthma rehabilitation clinic located in the Swiss Alps. Individuals with exercise-induced bronchoconstriction and a positive result in the exercise challenge test underwent mannitol challenge test on day 0. All subjects then received a treatment with 400 µg budesonide and bronchodilators as needed for 7 days, after which exercise- and mannitol-challenge tests were repeated (day 7). Montelukast was then added to the previous treatment and both tests were repeated again after 7 days (day 14). RESULTS: Of 26 children and adolescents with exercise-induced bronchoconstriction, 14 had a positive exercise challenge test at baseline and were included in the intervention study. Seven of 14 (50%) also had a positive mannitol challenge test. There was a strong correlation between airway responsiveness to exercise and to mannitol at baseline (r = 0.560, p = 0.037). Treatment with budesonide and montelukast decreased airway hyperresponsiveness to exercise challenge test and to a lesser degree to mannitol challenge test. The fall in forced expiratory volume in one second during exercise challenge test was 21.7% on day 0 compared to 6.7% on day 14 (p = 0.001) and the mannitol challenge test dose response ratio was 0.036%/mg on day 0 compared to 0.013%/mg on day 14 (p = 0.067). CONCLUSION: Short-term treatment with an inhaled corticosteroid and an additional leukotriene receptor antagonist in children and adolescents with exercise-induced bronchoconstriction decreases airway hyperresponsiveness to exercise and to mannitol.

Baseline leptin and leptin reduction predict improvements in metabolic variables and long-term fat loss in obese children and adolescents: a prospective study of an inpatient weight-loss program.

BACKGROUND: It is unclear whether high plasma leptin in obese individuals represents leptin resistance or whether individuals with marked reductions in leptin concentrations in response to weight loss may be at greater risk of regaining weight. Moreover, whether changes in leptin predict metabolic improvements during weight loss is uncertain. OBJECTIVE: The objective was to prospectively examine associations between plasma leptin, body fat, and weight and metabolic risk factors in obese children during weight loss. DESIGN: In obese children and adolescents [n = 203; mean age: 14.1 y, >98th body mass index (BMI) percentile for age and sex] participating in a 2-mo inpatient weight-loss program, we measured changes in body composition (by dual-energy X-ray absorptiometry), plasma leptin, insulin, and lipids. After discharge, anthropometric measures and plasma leptin were remeasured at 6 (n = 139) and 12 (n = 100) mo. RESULTS: During the 2-mo program, mean (±SD) weight and fat loss were 13.9 ± 4.0 kg and 9.2 ± 2.5 kg, respectively; and mean plasma leptin decreased by 76%. Weight and fat loss were sustained, and no significant differences in BMI-SD score (SDS) or body composition were found between 12 and 2 mo. Baseline leptin was a negative predictor for percentage fat loss at 2, 6, and 12 mo (P < 0.05). The percentage change in leptin during the 2-mo intervention positively correlated with the relative change in fasting insulin, the relative change in LDL cholesterol at 2 mo, percentage fat loss, and change in BMI-SDS at 2 and 6 mo (P < 0.02). CONCLUSIONS: Even in obese children with strongly elevated baseline leptin, large leptin reductions that predict short- and long-term loss of body fat and improvements in lipids and insulin sensitivity can be achieved. Thus, increased plasma leptin in obese children may not necessarily reflect leptin resistance; many children appear to remain leptin sensitive at this age.

During rapid weight loss in obese children, reductions in TSH predict improvements in insulin sensitivity independent of changes in body weight or fat.

BACKGROUND: Although serum TSH is often elevated in obesity and may be linked to disorders of lipid and glucose metabolism, the clinical relevance of these relationships remains unclear. SUBJECTS: Subjects were obese children and adolescents (n=206; mean age 14 yr) undergoing rapid weight and fat loss in a standardized, multidisciplinary, 2-month, in-patient weight loss program. DESIGN: This was a prospective study that determined thyroid function, glucose and lipid parameters, leptin, anthropometric measures, and body composition measured by dual-energy x-ray absorption at baseline and at the end of the intervention. RESULTS: At baseline, 52% of children had TSH concentrations in the high normal range (>2.5 mU/liter), but TSH was not correlated with body weight, body mass index sd scores, lean body mass, or body fat percentage. At baseline, independent of adiposity, TSH significantly correlated with total cholesterol (P=0.008), low-density lipoprotein cholesterol (P=0.013), fasting insulin (P=0.010), homeostatic model assessment (HOMA) (P=0.004), and leptin (P=0.006). During the intervention, mean body fat, TSH, HOMA, and fasting insulin decreased by 21, 11, 53, and 54%, respectively. Change (Δ) in TSH did not correlate with Δbody weight or Δbody composition, but ΔTSH significantly correlated with, Δfasting insulin and ΔHOMA, independent of Δbody weight or Δbody composition (P<0.05). CONCLUSION: TSH concentrations are elevated in obese children but are not correlated with the amount of excess body weight or fat. During weight loss, independent of changes in body weight or composition, decreases in elevated serum TSH predict decreases in fasting insulin and HOMA. These findings suggest interventions that target high TSH concentrations during weight loss in obese subjects may improve insulin sensitivity.

Improvements in PM10 exposure and reduced rates of respiratory symptoms in a cohort of Swiss adults (SAPALDIA).

RATIONALE: Reductions in mortality following improvements in air quality were documented by several studies, and our group found, in an earlier analysis, that decreasing particulate levels attenuate lung function decline in adults. OBJECTIVES: We investigated whether decreases in particulates with an aerodynamic diameter of less than 10 microm (PM10) were associated with lower rates of reporting respiratory symptoms (i.e., decreased morbidity) on follow-up. METHODS: The present analysis includes 7,019 subjects who underwent detailed baseline examinations in 1991 and a follow-up interview in 2002. Each subject was assigned model-based estimates of average PM10 during the 12 months preceding each health assessment and the difference was used as the exposure variable of interest (DeltaPM10). Analyses were stratified by symptom status at baseline and associations between DeltaPM10 and change in symptom status during follow-up were adjusted for important baseline characteristics, smoking status at follow-up, and season. We then estimated adjusted odds ratios for symptoms at follow-up and numbers of symptomatic cases prevented due to the observed reductions in PM10. MEASUREMENTS AND MAIN RESULTS: Residential exposure to PM10 was lower in 2002 than in 1991 (mean decline 6.2 microg/m3; SD = 3.9 microg/m3). Estimated benefits (per 10,000 persons) attributable to the observed changes in PM10-levels were: 259 (95% confidence interval [CI]: 102-416) fewer subjects with regular cough, 179 (95% CI, 30-328) fewer subjects with chronic cough or phlegm and 137 (95% CI, 9-266) fewer subjects with wheezing and breathlessness. CONCLUSIONS: Reductions in particle levels in Switzerland over the 11-year follow-up period had a beneficial effect on respiratory symptoms among adults.

Effect of physical activity on heart rate variability in normal weight, overweight and obese subjects: results from the SAPALDIA study.

Many studies have demonstrated an association of both a sedentary lifestyle and a high body mass index (BMI) with greater risk for cardiovascular disease. Within the prospective SAPALDIA cohort (Swiss cohort Study on Air Pollution and Lung Diseases in Adults), we investigated whether regular exercise was protective against reduced heart rate variability (HRV), a clinically relevant predictor of cardiovascular morbidity and mortality, and whether adverse effects of obesity and weight gain on HRV were modified by regular exercise. Twenty-four-hour electrocardiograms were recorded in 1,712 randomly selected SAPALDIA participants aged >or=50, for whom BMI was assessed in the years 1991 and 2001-2003. Other examinations included an interview investigating health status (especially respiratory and cardiovascular health and health relevant behaviours including physical activity) and measurements of blood pressure, body height and weight. The association between regular physical activity and HRV and interactions with BMI and BMI change was assessed in multivariable linear regression analyses. Compared to sedentary obese subjects, SDNN (standard deviation of all RR intervals) was 14% (95% CI: 8-20%) higher in sedentary normal weight subjects; 19% (CI: 12-27%) higher in normal weight subjects exercising regularly >or=2 h/week; and 19% (CI: 11-28%) higher in obese subjects exercising regularly >or=2 h/week. Compared with sedentary subjects who gained weight, those who gained weight but did exercise regularly had a 13% higher SDNN (CI: 7-20%). Regular physical exercise has strong beneficial effects on cardiac autonomic nervous function and thus appears to offset the negative effect of obesity on HRV.

Effects of a multidisciplinary inpatient intervention on body composition, aerobic fitness, and quality of life in severely obese girls and boys.

PURPOSE: The last few decades have seen a major increase in the prevalence of juvenile obesity. Inpatient treatment programs are used mainly in children with severe obesity and related comorbidities. The aim of this study was to evaluate the gender differences of an 8-week multidisciplinary inpatient program on body weight, body composition, aerobic fitness, and quality of life of severely obese children and adolescents. METHODS: Body weight was measured daily, and body composition, aerobic fitness, and quality of life were measured at the beginning and the end of an 8-week multidisciplinary inpatient program in 130 severely obese patients (52 girls, 78 boys), median (25th, 75th percentile) age of 13.8 (12.1, 15.0) years, median body weight of 89.4 kg (77.1, 100.1), and a body mass index of 33.4 (30.1, 36.6) kg/m(2), which is well above the 98th percentile. The inpatient program was based on a multidisciplinary treatment and education program that focused on daily physical activity, a 1200-1600 kcal/day balanced nutrition regimen, and a behavior modification therapy. RESULTS: All results are expressed as medians (25th, 75th percentiles). At the end of the program all patients had lost a significant amount of body weight: 12.7 kg (10.8, 16.6), p < .001, girls 11.6 kg (9.7, 13.2), boys 13.7 kg (11.7, 17.3), p < .001, absolute body fat 8.0 kg (6.8, 10.0) p < 001, girls 7.0 kg (5.7, 8.1), boys 9.4 kg (7.6, 11.0) p < .001, % body fat per kg body weight: 4.9% (3.2, 6.6) p < .001, girls 3.7% (2.7, 4.9), boys 5.7% (4.0, 7.5) p < .001, and absolute fat free (or lean body) mass: 1.8 kg (0.64, 3.0) p < .001, girls 1.8 kg (0.87, 3.2), boys 1.7 kg (0.50, 2.9) p = .43. In addition, all measurements of aerobic fitness: VO(2)peak (mL/min.kg) and peak mechanical power (watts and watt/kg) and of quality of life increased significantly (p < .001, p < .001, p < .004 to p < .001). CONCLUSION: A multidisciplinary inpatient treatment program including moderate calorie restriction, daily physical activity, and behavior modification induced a major weight loss, a decrease in body fat, and an increse in aerobic fitness as well as the quality fo life of severely obese children and adolescents. Weight loss and the decrease in body fat (absolute and percent) were significantly more pronounced in boys than girls.

High incidence of exercise-induced bronchoconstriction in triathletes of the Swiss national team.

AIM: To assess the progression of bronchial reactivity (BR) and incidence of bronchial hyperreactivity (BH), exercise-induced bronchoconstriction (EIB) and asthma in triathletes over 2 years. METHODS: Subjects were seven athletes from the Swiss national triathlon team (mean (SD) age 24.3 (4.8) years), who initially were not asthmatic, not treated with antiasthmatic medication, and who had performed at international level for more than 3 consecutive years (2001-2003). To assess BR, BH and EIB, subjects ran on a 400 m track for 8 min at intensities equal to the anaerobic threshold. Tests were conducted in ambient temperatures of 4.4 (2.8) degrees C, -8.8 (2.4) degrees C and 3.6 (1.5) degrees C, and humidity of 52 (16)%, 83 (13)% and 93 (2)%. Forced expiratory volume in 1 s (FEV(1)) was measured before and at 2, 5, 10 and 15 min after EIB, and 5 min after inhalation of a beta2 agonist. Two methods were used to calculate the incidence: (1) the standard assessment; (2) extrapolation of the decrease in FEV(1) to the BH limit. RESULTS: BR increased significantly in the seven athletes (FEV(1): year, p = 0.04; year x EIB, p = 0.002; EIB p<0.001). Within 2 years, BR had increased significantly and even reached BH in some athletes. Three athletes exhibited BH. After extrapolation of the decrease in FEV(1) in all seven athletes, the limit of 10% by definition for BH was determined to occur within 1.77-4.81 years, resulting in 21-57% of athletes with newly developed BH per year. CONCLUSION: Athletes develop EIB quickly, a rate of increase 195-286 times that of the normal rate for development of asthma.

Follow-up of the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA 2) 1991-2003: methods and characterization of participants.

OBJECTIVES: The Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) was designed to investigate the health effects from long-term exposure to air pollution. METHODS: The health assessment at recruitment (1991) and at the first reassessment (2001-3) consisted of an interview about respiratory health, occupational and other exposures, spirometry, a methacholine bronchial challenge test, end-expiratory carbon monoxide (CO) measurement and measurement for atopy. A bio bank for DNA and blood markers was established. Heart rate variability was measured using a 24-hour ECG (Holter) in a random sample of participants aged 50 years and older. Concentrations of nitrogen dioxide (NO2), sulphur dioxide (SO2), ozone (O3) and particulates in ambient air have been monitored in all study areas since 1991. Residential histories collected over the 11 year follow-up period coupled with GIS modelling will provide individual long-term air pollutant exposure estimates. RESULTS: Of 9651 participants examined in 1991, 8715 could be traced for the cohort study and 283 died. Basic information about health status was obtained for 8047 individuals (86% of alive persons), 6 528 individuals (70%) agreed to the health examination and 5 973 subjects (62%) completed the entire protocol. Non-participants in the reassessment were on average younger than participants and more likely to have been smokers and to have reported respiratory symptoms in the first assessment. Average weight had increased by 5.5 kg in 11 years and 28% of smokers in 1991 had quit by the time of the reassessment.

Effect of ipratropium bromide on EIB in children depends on vagal activity.

PURPOSE: Ipratropium bromide (IB) has been used to prevent exercise-induced bronchoconstriction (EIB), but its effect varies among individuals. We hypothesized that such variability may reflect individual differences in vagal activity (VA), and therefore determined whether a correlation exists between VA and the effect of IB on EIB in 13.0 (+/-0.8)-yr-old children with asthma and documented EIB. METHODS: Subjects served as their own control and were tested on three occasions in an ambient temperature of 5 degrees C. Visit I included no treatment. In visits II and III (counterbalanced sequence) subjects inhaled either 500 microg IB or 0.9% NaCl as a placebo, 45 min before exercise provocation. Investigators and the subjects were blinded to the inhaled substance. VA was assessed by a 4-s exercise test (3). The ratio of resting ECG R-R-interval at full inspiration to the lowest R-R interval during 4-s cycling was taken as an index of VA. Eight-minute cycling at constant work rate (HR=173+/-4 bpm) at 5 degrees C was used to provoke EIB. A two-factor (treatment x time) repeated-measures ANOVA was used. RESULTS: The exercise-induced drop in FEV1 was similar in the three sessions. However, because the IB caused a 15.7+/-4.1 increase in FEV1 preexercise, the postexercise values after a placebo or no treatment were consistently lower than after IB. The beneficial response to IB, compared with no treatment and with placebo, was positively correlated to VA (for FEV1: r=0.91, P=0.002; and r=0.90, P=0.002, respectively). CONCLUSION: We suggest that the therapeutic effect of IB on exercise-induced asthma may be related to vagal activity.

Facial cooling enhances exercise-induced bronchoconstriction in asthmatic children.

PURPOSE: Exercising in cold air enhances bronchial responsiveness (BR) as compared with exercising in warm air. This may be due to intrathoracic cooling or to increased vagal activity caused by facial cooling. The purpose of this study was to compare the effects on BR of cold air inhalation and of facial exposure to cold air, as well as the combined effect of both. METHODS: Fourteen children with asthma (eight girls) performed four exercise challenge tests in a climatic chamber, under one of the following conditions: 1) inhaling warm air while the face was exposed to warm air (WW, 21 degrees C, 25% relative humidity (RH)); 2) inhaling warm air while the face was exposed to cold air (WC, 0 degrees C, 80% RH); 3) inhaling cold air while the face was exposed to cold air (CC); and 4) inhaling cold air while the face was exposed to warm air (CW). The study was analyzed, using a one- and two-way ANOVA. RESULTS: Postexercise forced expiratory volume in the first second (FEV1) and maximal mid-expiratory flow (MMEF) values as percent predicted (% pred) showed significant reductions over time (P < 0.001), significant differences among the four experimental conditions (P < 0.001) and a significant condition x time interaction (FEV1:P < 0.001, MMEF:P < 0.01). FEV1 was significantly lower for CC and WC, as compared with WW and CW at 5 and 10 min postexercise. The lowest postexercise values for FEV1 occurred in the CC and WC sessions (76% predicted in both). A similar pattern was obtained for MMEF. CONCLUSION: Facial cooling combined with either cold or warm air inhalation causes the greatest EIB, as compared with the isolated challenge with cold air inhalation. We suggest that vagal mechanisms play a major role in exercise and cold-induced bronchoconstriction.