MCAN Meeting

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Asthma, Outdoor Air Pollution and Genetic
Susceptibility
Frank D. Gilliland, M.D., Ph.D. Keck School of
Medicine University of Southern California
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Take Home Points

• There are important adverse impacts of outdoor
  air pollutants on children, especially those with
  asthma
• Interventions that reduce genetic susceptibility
  to air pollution will likely have a role in
  personalized asthma management

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Overview

• Outdoor air pollution and new onset asthma
• Air pollution effects in children with asthma
• Genetic susceptibility new opportunities for
  personalized asthma care
• Recommendations clinical and research

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Outdoor Air Pollutants Regional Pollutants

Ozone Nitrogen dioxide Particulate matter Acids
and organics
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Outdoor Air PollutantsLocal Exposures
Traffic - the major source Ultrafine
particles Reactive gases High local concentrations
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Asthma in Southern CaliforniaCalifornia Health
Interview Survey 2001

• Large population of children exposed to elevated
  levels of air pollution
• 12.1 lifetime prevalence
• 400.000 children in LA and SD counties
• 10 of asthmatic children have severe asthma
• daily or weekly symptoms
• 11 had an asthma-related emergency department
  (ED) visit or hospitalization in the year prior
  to the interview
• Does the evidence support outdoor air pollution
  as an important contributor to the burden of
  asthma?

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Air pollution and New-onset Asthma

• Conventional Wisdom
• outdoor air pollution does not cause asthma, but
  makes it worse
• New studies indicate an important role when key
  factors are considered
• air pollution dose
• traffic-related pollution
• genetic susceptibility

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The USC Childrens Health Study
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Ozone, Exercise and Asthma IncidenceUSC
Childrens Health Study
Number of team sports
Community Ambient O3
Community Ambient PM
McConnell et al., Lancet 2002359386-91
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Traffic-related Pollutants and Asthma USC
Childrens Health Study
McConnell et. al 2005
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Overview

• Outdoor air pollution and new onset asthma
• Air pollution effects in children with asthma
• Susceptibility to air pollution
• Genetic susceptibility new opportunities for
  personalized asthma care
• Recommendations

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Adverse Effects of Regional and Traffic-related
Air Pollutants on Children with Asthma

• Pollutants
• Ozone
• Nitrogen oxides (NO2)
• Respirable particulate matter
• PM10, PM2.5
• Vehicle exhaust

• Effects
• Respiratory symptoms
• Acute - wheezing
• Chronic - bronchitis
• Medication use
• Decreased lung function
• Emergency Dept visits
• Hospitalizations
• School absences

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Air Pollution and Bronchitis Symptoms PM and
NO2 USC Childrens Health Study
McConnell et al, EHP 1999197757-60
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Residential Traffic and ED/hospitalization in
Children with AsthmaCHIS 2001
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Overview

• Outdoor air pollution and new onset asthma
• Air pollution effects in children with asthma
• Genetic susceptibility new opportunities for
  personalized asthma care
• Recommendations

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Genetic Susceptibility to Air Pollution Diesel
Exhaust and Ozone as Models

• Diesel exhaust and ozone are model local and
  regional air pollutants
• Studies show that DEP and ozone have adverse
  effects in model systems and children
• enhancement of allergic responses to allergens
• mechanism appears to involve oxidative stress and
  GSTM1
• Do these effects vary by genotype and can they be
  blocked by increased antioxidant defenses?

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GSTM1 and Diesel Exhaust Particle Enhancement of
Allergic Responses

• Crossover trial design using nasal challenge
  model with DEP and ragweed allergen
• 19 ragweed allergic subjects aged 20-34 yrs
• Random assignment of order
• Allergen plus clean air
• Allergen plus DEP
• Responses
• Allergen-specific IgE, histamine, INFg, IL-4
• GSTM1 genotype (null vs present)

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Diesel Exhaust Particle Enhance Allergic Responses
Gilliland et all, 2003
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Nasal IgE Response to Allergens and Allergen Plus
DEP GSTM1 null vs present
IgE (U/mL)
IgE (U/mL)
GSTM1 (-)
GSTM1 ()
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Interventions and Genetic Susceptibility

• Can the adverse effects of air pollution be
  reduced by interventions tailored to individual
  genetic susceptibility?
• Approach increase antioxidant defenses to reduce
  air pollution susceptibility associated with
  GSTM1 null
• Supplemental antioxidants
• Induction of enzymatic antioxidant defenses

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Vitamins E and C Supplement Trial
Vitamin E (50 mg/day) Vitamin C (250 mg/day)
12 week follow-up
Mexico city Asthmatic children
Random Assignment
Placebo

• Can vitamins E and C supplementation reduce the
  effects of ozone on chilren with asthma?
• Does GSTM1 genotype affect responses to
  treatment?

Romieu et al. 2003
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Change in FEF25-75 per 50 ppb of O3, by GSTM1
Genotype and Antioxidant Supplementation Group
Change FEF
GSTM1 -
GSTM1
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Sulforaphane
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Dietary Sulforaphane Increases Phase II Enzyme
Expression in Nasal Cells
Wan, Diaz-Sanchez et al. , 2006
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Wan Diaz-Sanchez., J. Immunol, 2006
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Research Recommendations

• Develop personalized interventions that target
  antioxidant defense in genetically susceptible
  groups to reduce the adverse effects of air
  pollution
• Supplements
• Diet
• Chemopreventive medications

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Recommendations for Reducing the Burden of Asthma

• Incorporate control of air pollution exposures as
  an integral component of clinical asthma
  management
• Recognize and foster the critical role of
  physicians and other providers in addressing the
  adverse effects of air pollution
• clinical care
• patient advocacy
• policy making
• standard setting for air pollution

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Practical Advice for Our Patients

• Explain AQI and daily ozone patterns Reduce
  outdoor activities at times when in unhealthy
  range
• Increase PEF checks during poor AQI
• Exercise away from major roads

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Reductions In Pollution Decrease or Eliminate
Adverse Effects on Childrens Respiratory Health
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Vitamins E and C Supplement Trial

• Can vitamins E and C Supplementation redcue teh
  effects of ozone on chilren with asthma?
• Does GSTM1 genotype affect response to treatment?
  

Romieu et al. 2003
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Vitamins E and C Supplement Trial
Vitamin E (50 mg/day) Vitamin C (250 mg/day)
Asthmatic children
Random Assignment
Placebo
3rd group n40
1st group n40
2nd group n40
4th group n40
12 weeks
12 weeks
12 weeks
12 weeks

• Monitoring
• Network data O3, PM10, NO2
• Personal monitoringO3, PM10
• Biomarkers of inflammation
• Biomarkers of antioxidant status

• Baseline
• Gn questionnaire
• FFQ
• Blood samples
• Spirometry

• Activities
• Vitamin supplementation
• Spirometry twice a week
• Symptoms diaries Nasal lavages
• Blood samples

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