Asthma and Childhood Obesity: Understanding Potential Mechanisms and Identifying Strategies to Improve Respiratory Symptoms
Phase: PHASE4
Conditions: Asthma in Children, Obesity, Childhood, Exercise Induced Bronchospasm
Sponsor: University of Nevada, Las Vegas

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Cover Page 
 
 
Official Title: Asthma and childhood obesity: Understanding potential mechanisms and identifying strategies 
to improve respiratory symptoms 
 
NCT03586544 
 
Date of Document: January 26, 2017 
Updated: June 10, 2021 
 
 

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The 2013 American Thoracic Society guidelines strongly recommend interval warm-up exercise1 to reduce EIB 
severity. This recommendation is based on studies of warm-up exercise protocols that reduce EIB severity in 
nonobese asthmatic children 2. However, no empirical data on the effects of interval warm-up exercise on EIB 
severity are available in obese asthmatic children, where excess fat exerts such an unfavorable burden on the 
respiratory system, particularly during exercise. Investigation of the effectiveness of simple EIB reduction 
strategies, such as interval warm-up exercise, in obese asthmatic children is urgently needed. Therefore, the 
objective of this study is to investigate the effects of interval warm-up exercise on EIB in obese and 
nonobese asthmatic children.  
Our approach will be to investigate EIB after an exercise challenge test (ECT) preceded by a no-treatment control 
and two randomized conditions: (1) 8x30s interval warm-up and (2) pretreatment with a bronchodilator (short-
acting beta agonist [SABA]). We will test the following aims in obese asthmatic children (n=12) compared with 
nonobese asthmatic children (n=12): 
Aim: To investigate the effects of interval warm-up exercise on EIB severity 
Hypothesis: Interval warm-up exercise will reduce EIB severity after an ECT to a similar extent as SABA 
and better than control. 
RESEARCH STRATEGY  
Study design and participants: This is a cross-sectional study. We will complete testing in 9 – 12 yr old 
nonobese and obese children with a physician diagnosis of mild asthma with a Tanner pubertal stage of ≤3. This 
approach will enable us to study and compare obese and nonobese boys and girls of similar maturation while 
pubertal effects on lung function and exercise responses are minimized. For adequate power to test the stated 
hypotheses, 12 nonobese and 12 obese asthmatic children will need to complete all five visits in this study. We 
may need to enroll up to 50 children considering possible attrition, to reach a final sample of 12 obese and 12 
nonobese asthmatic children. 
All participants will have no history of smoking, no history or evidence of heart disease, no history of uncontrolled 
hypertension, no documented and/or diagnosed sleep disorders, no diagnosed diabetes, no metabolic disorders, 
no history of significant mental illness, no dietary restrictions, no serious health conditions, or no musculoskeletal 
abnormality that would preclude exercise. Children who have been hospitalized for an asthma exacerbation or 
who have taken oral glucocorticoids for asthma in the past year and children who have been admitted to an 
intensive care unit or been intubated because of their asthma in the past five years, will be excluded to reduce 
the risk of exacerbation during the study3. 
BMI criteria: We will study nonobese children with a BMI between the 16th and 84th percentile and obese children 
with a BMI > 95th percentile but less than 170% above the 95th percentile and less than an absolute BMI of 40 
kg·m-2. Recently, there has been a shift towards classifying child BMI over the 95th percentile as a percent above 
the 95% percentile because the statistical procedures used to generate percentile curves are not accurate at the 
extreme tails of BMI distribution4. We have chosen 170% above the 95th percentile as a reasonable cut-off or 
upper-limit because it will exclude children with an average age and sex specific BMI of approximately > 40 kg·m-
2 (BMI Range 36 – 43 in boys and 37 – 45 in girls 9 – 12 yr), which roughly corresponds to Class III obesity in 
adults. Since this BMI percentile range also includes children with a BMI > 40 kg·m-2, we will further exclude any 
children with an absolute BMI > 40 kg·m-2. 
Lung function criteria: We will study children with 1) FVC ≥ 80% predicted, 2) FEV1 ≥ 75% predicted, and TLC ≥ 
80% predicted, consistent with normal pulmonary function and including participants with mild obstructive airway 
disease. Since the risk of severe EIB increases in children with moderate or severe obstructive airway disease, 
children with FEV1 < 75% predicted will be excluded from the study5. Diagnosis of asthma (i.e., airway 
responsiveness with reversible obstruction) will be established by spirometry (i.e., improvement of FEV1 of ≥8% 
after administration of SABA6). Children without reversible airway obstruction will also be excluded from the 
study. 
Aim: To investigate the effects of interval warm-up exercise on EIB severity 
Introduction: The working hypothesis is that interval warm-up exercise will reduce EIB severity to a similar extent 
as a SABA and a greater extent than control in obese asthmatic children. Furthermore, we propose that reduction 
of EIB severity in obese asthmatic children after interval warm-up exercise and/or SABA may be to a lesser 
extent than in nonobese asthmatic children. The rationale behind the proposed research centers on the fact that 

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EELV will be forced to even lower levels during exercise in an obese asthmatic child creating the potential for 
increased airway hyperresponsiveness and EIB. In this context, interval warm-up exercise and SABA may 
improve EIB as it does in nonobese asthmatic children2, but obesity-related changes in respiratory function may 
reduce the effectiveness of interval warm-up exercise and SABA in obese asthmatic children. 
Sample size estimation: Our primary variable is maximum % fall in FEV1 after interval warm-up exercise vs. no-
treatment control. Schnall and Landau7 reported maximum % fall in FEV1 after an exercise challenge preceded 
by interval warm-up of 6.9±5.2% compared to control 23.0±5.2%. Based on these data7, we would be able to 
detect a significant mean reduction in maximum % fall in FEV1 between the control and interval warm-up at 
greater than 95% power in 12 nonobese asthmatic children. While effect sizes may be lower in obese asthmatic 
children, we can detect a maximum 9.9% fall in FEV1 difference between control and interval warm-up at 80% 
power with a sample size of 12 obese asthmatic children. A sample size calculation to detect a significant group 
x treatment interaction was not possible for this aim without preliminary/published data. Nevertheless, testing 
the effectiveness of interval warm-up exercise on EIB in obese asthmatic children is itself of considerable clinical 
value and an important clinical outcome in the proposed project. 
METHODS: Over five separate visits (1.5 – 2.5 h each), we will measure respiratory function, exercise tolerance, 
and EIB after an ECT that is preceded by a no-treatment control and two randomized conditions: (1) 8 x 30 s 
interval warm-up, and (2) pretreatment with a bronchodilator (SABA). Testing that requires physician oversight 
(e.g., exercise tests) will be conducted at the Sunrise Health and Medical Center (SHMC). Testing that does not 
require physician oversight, such as plethysmography measurements for lung volumes, will be conducted at 
UNLV. 
Visit 1: We will conduct spirometry and airway resistance measurements (using FOT) before and after SABA 
(Albuterol 4 puffs, 90mcg per actuation) to assess airway hyperresponsiveness. Participants with an FEV1 < 75% 
predicted will be excluded from the study to reduce risk of severe EIB after exercise5. Lung volumes (i.e., TLC, 
FRC, RV) will be measured by plethysmography. Maximal voluntary ventilation (MVV) will be determined from a 
10 s test extrapolated to 1 min. Height, weight, circumference measurements (chest, waist, hip, and neck), and 
BMI percentile will be used to characterize body size and fat distribution. 
Visit 2: Participants will undergo maximal graded cycle ergometry to exhaustion to measure exercise tolerance. 
Graded cycle ergometry will be performed using 1-min increments of 10W on an electronically braked cycle 
ergometer (VIAsprintTM, Vyaire Medical, Yorba Linda, CA). During cycle ergometry, we will measure ventilation 
and gas exchange to assess minute ventilation (V
•
E), V
• O2, V
• CO2, respiratory exchange ratio, and ventilatory 
equivalents for V̇ O2 and V
• CO2. During cycle ergometry we will also measure exercise tidal flow-volume loops 
and participants will perform inspiratory capacity maneuvers by inhaling to TLC every minute to assess end-
expiratory lung volume (EELV). Expiratory flow limitation (EFL) will be assessed by comparing overlap of 
exercise tidal flow-volume loops with the maximal flow-volume loop. For patient safety and to monitor progress 
during the test, we will also record ratings of perceived breathlessness (RPB: 0–10 scale), ratings of perceived 
exertion (RPE: 6–20 scale), blood pressure, heart rate, breathing frequency, tidal volume, pulse oximetry (SpO2), 
and PETCO2. V̇ O2max will be confirmed by a supramaximal verification test at 105% of maximal work rate to 
exhaustion. Maximal exercise capacity will be evidenced by V̇ O2max (highest V
• O2 obtained during maximal or 
verification test)8.  
Visit 3: CONTROL VISIT We will ask participants to hold SABA for 8h, corticosteroid for 24h, and long acting 
asthma medications for 24h prior to the exercise challenge test (ECT) visits. Participants will also be asked to 
avoid exercise for 24h prior to the visit. We will measure FEV1 using spirometry, airway function using FOT and 
FeNO before starting the ECT (see Fig. 1 for timeline of ECT visits). The ECT will be performed in accordance 
with the American Thoracic Society guidelines5. Target work rate (W) will be calculated as [(53.76 × measured 
FEV1) – 11.07] 5. Work rate will be increased from 60% of target work rate in the first minute, to 75% in the 
second minute, 90% in the third minute, and 100% in the fourth minute9. We will measure HR, SpO2%, RPB, 

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and RPE during 6 minutes of cycling at 80-90% of HRmax. We will measure FEV1 using spirometry and airway 
function using FOT at 2, 5, 10, 15, and 30min after completing the ECT (see Fig. 1). SABA will be administered 
to any patient with exercise-related respiratory symptoms and the test will be stopped. Spirometry and FOT 
measurements will be conducted every 5min after SABA administration to determine whether SABA effectively 
reversed the bronchoconstriction. A decision of whether to exclude the participant from the study will be made 
after consulting the pediatric pulmonologist. 
Visits 4 and 5: ECT will completed 15 
min after two randomized conditions: 
(1) 8 x 30 s interval warm-up and (2) 
pretreatment with a SABA. We will 
conduct 
spirometry 
and 
airway 
function measurements at baseline 
prior to after interval warm-up exercise 
or SABA administration. We will also 
conduct 
spirometry 
and 
airway 
function measurements at 2, 5, and 10 
min after interval warm-up exercise or 
SABA administration and prior to the 
ECT to assess bronchodilation or 
bronchoconstriction 
resulting 
from 
interval warm-up and SABA. FeNO will 
only be measured at baseline. ECT will be performed exactly as described in Aim 2. Details regarding interval 
warm-up and SABA administration are given below. 
• Interval warm-up: eight 30 s intervals of cycling at 100% of the target work-rate calculated as [(53.76 × 
measured FEV1) – 11.07]5. 45 s of active recovery at 20W will be performed between two intervals. The interval 
warm-up protocol selected for the proposed study was based on published research by Mickleborough et al 10 
comparing the effects of interval warm-up, SABA and no warm-up on EIB in nonobese asthmatic adults. We 
will monitor HR and SpO2 during the test.  
• SABA: 4 puffs of Albuterol (90mcg per actuation). Participants will actuate the medication into the spacer, 
inhale slowly from FRC and hold their breath for 10 s before exhaling. This procedure will be repeated four 
times with 1 min between actuations. 
Statistical analysis plan: Comparisons in maximum % fall in FEV1 from baseline will be made using a mixed 
ANOVA (between effect: obese, nonobese; within effect: control, SABA, interval warm-up). Pearson product-
moment correlations will be utilized to examine associations between maximum % fall in FEV1 and airway 
function (resistance and reactance) and FeNO, measures of body composition, and fat distribution.  
 
 
Figure 1. A timeline of testing for the exercise challenge tests (ECT) in visits 3-5. FOT, 
forced oscillation technique; FeNO, fractional expired nitric oxide 

 
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