Asthma and Obesity Diet Versus Exercise
Condition: Obesity, Childhood; Asthma in Children; Inflammatory Response; Metabolic Syndrome; Nutrition Poor; Physical Activity; Behavior, Eating; Molecular Biology, Restriction Fragment Length Polymorphisms; Maternal Exposure; Genetic Change
MeSH terms: Asthma; Obesity; Metabolic Syndrome; Pediatric Obesity; Malnutrition
Study type: Interventional

Summary: 
      Obesity is recognized as a pro-inflammatory condition associated with multiple chronic
      diseases, including asthma. The specific mechanisms linking asthma and obesity remain
      hypothetical. Our primary hypothesis is that inflammatory SNPs may regulate the degree of the
      inflammatory response, with obesity modifying the severity of the disease. In this instance,
      asthma that develops in the context of obesity demonstrates the potential deleterious
      relationship between a specific proinflammatory state (obesity) and the genetic regulators of
      inflammation (SNPs). Our secondary hypothesis proposes that short-term (12-weeks) weight loss
      by diet alone, but not exercise alone, will reduce lung specific inflammation and diminish
      the pro-inflammatory responses in female African American obese adolescents with asthma
      compared to a waiting list control group who after their initial 12 weeks then receive a
      combined 12-week diet plus exercise program (waiting list control/combined). A third
      exploratory hypothesis proposes that the frequency of identified SNPs will be significantly
      related to the amount of fat loss through diet, exercise or combined program and will further
      be mediated by specific airway and, pro-and-anti-inflammatory markers.These hypotheses will
      be tested using the following Specific Aims:

        1. To determine the frequency of single nucleotide polymorphisms and SNP haplotypes in pro-
           and anti-inflammatory genes in female African American obese and non-obese asthmatic and
           non-asthmatic adolescents, 13-19 years or age.

        2. To examine the effects of diet or exercise on lung specific inflammation (exhaled nitric
           oxide, [eNO]) and pro-and-anti-inflammatory responses in female African-American obese
           asthmatic and non-asthmatic adolescents compared to a waiting list control/ combined
           group.

      In addition we will examine the following Exploratory Aim:

      To determine the effects of the inflammatory SNPs in the modulation of several inflammatory
      markers and lung specific inflammation (eNO) in female African-American obese asthmatic and
      non-asthmatic adolescents before and after weight loss through diet, exercise or both.
    

Detailed description: 
      Our primary hypothesis is that inflammatory SNPs may regulate the degree of the inflammatory
      response, with obesity modifying the severity of the disease. In this instance, asthma that
      develops in the context of obesity demonstrates the potential deleterious relationship
      between a specific proinflammatory state (obesity) and the genetic regulators of inflammation
      (SNPs).

      Our secondary hypothesis proposes that short-term (12-weeks) weight loss by diet alone, but
      not exercise alone, will reduce lung specific inflammation and diminish the pro-inflammatory
      responses in female African American obese adolescents with asthma compared to a waiting list
      control group who after their initial 12 weeks then receive a combined 12-week diet plus
      exercise program (waiting list control/combined). A third exploratory hypothesis proposes
      that the frequency of identified SNPs will be significantly related to the amount of fat loss
      through diet, exercise or combined program and will further be mediated by specific airway
      and, pro-and-anti-inflammatory markers. Specific aims include:

        1. To determine the frequency of single nucleotide polymorphisms and SNP haplotypes in pro-
           and anti-inflammatory genes in female African American obese and non-obese asthmatic and
           non-asthmatic adolescents, 13-19 years or age.

        2. To examine the effects of diet or exercise on lung specific inflammation (exhaled nitric
           oxide, [eNO]) and pro-and-anti-inflammatory responses in female African-American obese
           asthmatic and non-asthmatic adolescents compared to a waiting list control/ combined
           group.

        3. To determine the effects of the inflammatory SNPs in the modulation of several
           inflammatory markers and lung specific inflammation (eNO) in female African-American
           obese asthmatic and non-asthmatic adolescents before and after weight loss through diet,
           exercise or both.

      We will conduct a cross-sectional analysis of 4 groups of African American adolescent (13-19
      years) females as follows: Group 1A: Obese with asthma Group 1B: Non-obese with asthma Group
      1C: Obese non-asthmatics Group 1D: Non-obese, non-asthmatics

      Patients included in this part of the study will be female African American obese and
      non-obese asthmatic adolescents, 13-19 years, as defined by United States Centers for Disease
      control (USCDC 2000 sex specific Body Mass Index (BMI)-for-age growth charts. As controls we
      will include female African American obese, non asthmatic adolescents and healthy age matched
      controls (non-obese, non-asthmatics).

      Assuming a dominant model, for a haplotype of 5 SNPs, a sample of 100 individuals per group
      (matching 1:1) would achieve at least 80% power to detect an OR of 1.5 for the association of
      the haplotype with group membership (such as obese with asthma vs. non-obese with asthma), at
      0.05 significance level. All other group comparisons would assume the same conditions, thus
      samples of 100 for each of the groups are required.

      After parent/guardian has signed the informed consent, a general medical exam and history is
      taken, and spirometry testing is performed to assess the lung function of each participant,
      obesity status will be assessed. For girls found to be non-obese during visit 1,
      approximately 30 ml of peripheral blood will be obtained from 100 asthmatics and 100
      non-asthmatic healthy age matched controls. For obese participants (100 asthmatic and 100
      non-asthmatics), peripheral blood draws will be obtained during visit 2 (baseline).
      Peripheral blood will be tested for a Hemoglobin A1-C (HA1C), lipid profile and to determine
      the presence of inflammation and genetic markers. An additional blood sample from all African
      American adolescent girls participating in the study will be collected into heparin tubes (2
      10ml tubes). The mononuclear layer will be separated using density gradients and will
      characterize the circulating MDS. Flow cytometry will be used to determine the percentage of
      monocytic or granulocytic MDSC using several fluorescence-labeled antibodies, including
      anti-CD11b, CD14, CD15, CD33, CD66 and HLA-DR. The DNA will be extracted by DNAzol
      (Invitrogen Corp; Grand Island, NY). For the SNP analysis we plan to use the humanCNV370-Quad
      bead chip from lllumina (lllumina Inc, San Diego, CA). This chip allows the analysis of more
      than 370,000 SNPs simultaneously and uses only 200 ng of genomic DNA. We will initially focus
      our analysis in the pro- and anti-inflammatory cytokine gene SNPs (/LS, TNF, TGFB, ILIO, IL8,
      IL6, PTGS2, ARG1) and SNPs in leptin, leptin receptor and adiponectin (Table 11) and the
      results will be confirmed by TaqMan as follows: genomic DNA (5 ng) will be denatured at 95°C
      for 10 min and amplified for 40 cycles of 15 sec at 92°C and 1 min at 58°C, in the presence
      of 2X TaqMan Universal Master Mix (Applied Biosystems), water, and the respective primer and
      reporter probe mix (labeled with either FAM or VIC). The reaction will be analyzed using a
      7900 HT instrument (Applied Biosystems), for the presence of VIC or FAM fluorescence marker,
      or both, using the Sequence Detection System (Applied Biosystems) to determine the genotype.
      Controls will include individuals of known genotype and blanks without DNA. In addition, 15%
      of the samples will be run twice in separate assays and the allele classification compared.
      The individuals of known genotype and blanks without DNA will be included for each SNP in
      every batch.

      Chi-square, Fisher's exact, and student-t tests will be used to assess the statistical
      significance of the differences in the frequencies of the different SNPs between obese
      asthmatics, non-obese asthmatics, obese non-asthmatics and healthy controls. Haplotype
      frequencies will be inferred using log-linear modeling embedded within an
      expectation-maximization algorithm. Quality control procedures (including evaluation of
      genotyping efficiency and Hardy-Weinberg equilibrium), assessment of linkage disequilibrium
      between markers as well as haplotype association analysis will be performed separately in
      obese versus nonobese and asthmatic versus non-asthmatics.

      After enrollment, eligible participants will undergo a baseline visit to include
      approximately 30ml peripheral blood draw, Dual Energy X-RAY Absorptiometry (DEXA) scan,
      exhaled nitric oxide (eNO), and study eligibility per the study physician. Following this
      baseline visit, obese participants with and without asthma will be randomized to:

      1) diet only, 2) exercise only or 3) waiting list/combined intervention (no intervention for
      12 weeks followed by combined diet and exercise).

      Approximately 110 subjects will be recruited per treatment and control group. Assuming an
      attrition rate of 20%, we will maintain 360 subjects, 90 per group which will provide
      adequate statistical power to:

        1. detect significant differences in eNO between diet only, exercise only, combined
           program, or a waiting list control group of female African American obese asthmatics and
           non-asthmatics as per the sample size power calculations below and;

        2. as part of the exploratory aim 3, determine the effects of the inflammatory SNPs in the
           modulation of inflammatory markers and eNO in female African-American obese asthmatic
           and non-asthmatic adolescents before and after weight loss through diet, exercise or
           both as per the sample size power calculations).

      Intervention Methods:

      Treatment groups will receive the Trim Kids behavior modification program but the
      intervention materials will be specific to diet only or exercise only treatments. Non-obese
      asthmatics and non-obese, non-asthmatics will serve as controls for the exploratory aim and
      participate in a general medical exam, spirometry and blood testing only. Parents and
      children attend a weekly two-hour comprehensive session for a recommended time period.
      Medical supervision and guidance are provided by a physician or nurse at each session in
      order to increase compliance and monitor side effects.

      Management of asthma: We will exclude persons with severe or uncontrolled asthma. In the case
      of acute asthma attacks participants will be managed according to a written and reviewed
      asthma action plan, with the use of asthma medications or S-agonists like Albuterol, and if
      necessary with a short course of other medications. Asthmatic participants involved in the
      intervention group will also be required to use a pre-exercise dose of asthma medication
      before participation in each exercise session or will be excluded from that session. Any
      exacerbation will be recorded and participants will be able to contact a health provider, and
      if needed will be referred to emergency services. In case of a more severe exacerbation or
      progressive worsening, the participant will be treated according to standard of care, and
      taken off the study if chronic or prolonged anti-inflammatory treatment is considered a
      priority.

      Nutrition education includes a series of learning activities, which are specific to needs of
      each group as they progress through the different stages of the treatment program. The
      children are provided with easy-to-use food frequency checklists to fill in each week.

      The exercise protocols to be utilized in this study will be based on the Trim Kids exercise
      protocol, which tailors the recommendations to the child's medical condition (co-morbidities
      such as asthma), weight status and fitness level. All exercise recommendations will follow
      the guidelines of the American Thoracic Society (ATS), American Academy of Pediatrics (AAP)
      and American Academy of Sports Medicine (ACSM). Exercise sessions at the LSUHSC Wellness
      center will be supervised by ACSM certified instructors and personal trainers. During each
      12-week session of the program, the exercise activities correspond with the group's physical
      condition of obesity and ability to comprehend, synthesize and apply health and fitness
      Information to daily life situations. Children receive an exercise video containing an
      exercise routine to perform at home. They are also given cards to record the number of
      minutes of physical activity, they perform each week. Compliance is monitored by observing
      these physical activity record cards and monitoring of heart and breathing rate. Behavior
      modification and psychosocial education are integrated into educational sessions by a
      psychologist.

      Behavior modification skills are taught stressing how discussion, modeling, role playing and
      guided problem solving are used. Topics such as self-monitoring, commitment, limit setting,
      habit formation, goal setting and action plans, decision-making skills and assertiveness
      training are discussed.

      The intervention will be conducted at the Louisiana State University (LSU) Health Sciences
      Center Wellness Facility. Both diet and exercise groups will meet for medical monitoring and
      weigh in a clinical area adjacent to a private room with a scale during the first 30 minutes
      of each weekly class.

      The diet only group will meet in a classroom after the 30-minute medical monitoring and
      weigh-in. Behavior modification class will follow for 30 minutes and Nutrition education for
      approximately 30-60 minutes. Study participants enrolled in the diet only intervention will
      be placed on either a protein modified fast diet plus supplementation of vitamins and
      minerals, followed by a balanced, hypo-caloric diet and/or a moderate intensity, progressive
      exercise program, and given instruction on behavior modification.

      The exercise only group will meet in the large multi-purpose room after the 30 minute medical
      monitoring and weigh in. Behavior modification class will follow for 30 minutes. Participants
      will utilize the aerobic equipment, attend culturally specific dance classes, participate in
      strength training, and outdoor family field sports in an adjacent community park area for
      approximately 30-60 minutes. The participants exercise in a playful, sporadic, intermittent
      manner while the instructor discusses key concepts using symbols, music and various props.

      Following a 12 week waiting period, participants in the combined program will meet in a
      separate multi-purpose room and will participate in diet, exercise and behavior modification
      sessions once per week.
    

Intervention name(s): Lifestyle counseling
Intervention type(s): Behavioral
Intervention description(s): Inter-disciplinary, interactive, family based behavioral intervention for overweight children
Other intervention name(s): Trim Kids Behavioral Counseling Intervention
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Cross-sectional, randomized controlled trial
Masking: None (Open Label)
Primary purpose: Treatment