Early Life Exposures as

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Early Life Exposures as Causes of
Asthma/Atopic Phenotypes Key Questions

• Anita L Kozyrskyj, PhD,
• Research Chair Associate Professor
• Dept Pediatrics, Faculty of Medicine Dentistry,
  
• University of Alberta, Edmonton, Alberta, Canada
• The Genesis of Allergy and Asthma Workshop
• Vancouver, March 2009

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Objectives

• List key questions/issues
• Identify opportunities for investigation

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Key Questions/Issues in Early Life Exposure
Measurement

• Timing of exposure
• Is there a critical window early pregnancy, late
  pregnancy, first year of life, first 3 years?
• Persistence of exposure
• All or nothing phenomenon during a critical time
  period or first exposure followed by continued
  exposure?
• Accumulation of exposure
• One key exposure or a combination of exposures?
• Is there an additive risk in high risk children?
• Validity of exposure measurement
• Are we measuring what we think we are (and does
  it matter)?

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Social and Economic Policies
Institutions
Neighborhoods/Communities

Living Conditions

Social Relationships
Lifecourse
Nutrition/care
Genetic Factors
Environment
Child at birth
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SAGE Maternal distress measure

• postpartum time period only
• one and 1-5 years (short-term)
• persistent over 1-7 years of childs life
• late onset (after postpartum period)

Continued exposure to maternal distress in early
life is associated with an increased risk of
childhood asthma. Kozyrskyj AL, Mai XM, McGrath
P, HayGlass KT, Becker AB, MacNeil B. Am J
Respir Crit Care Med 2008 177142-7.
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Risk of asthma following adjustment for
additional confounding factors
Child sex, maternal asthma, urban/rural, health
care visits, number siblings, lower respiratory
and non-respiratory tract infections, antibiotic
use in 1st yr
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Maternal Distress Phenomena in the 1st year of
life or persistent exposure
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The Complexity of the Association between
Socioeconomic Status and the Development of
Childhood Asthma as revealed by trajectory
analyses Kozyrskyj AL, Kendall GE, Jacoby P, Sly
PD, Zubrick SR. Am J Pub Health 2009 in press
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Family Income Trajectories

• Rather than pre-determined categories,
  maximum-likelihood longitudinal (latent class)
  modeling techniques classified children on the
  basis of their familys movements in and out of
  low income over the childs lifetime (timing,
  duration, sequence of family low income)
• SAS PROC TRAJ program was used to create family
  income trajectories from birth until child age 6
  or 14 years. PROC TRAJ uses Bayess theorem to
  assign children to the income trajectory group
  for which they had the highest probability of
  belonging.

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The Complexity of the Association between
Socioeconomic Status and the Development of
Childhood Asthma as revealed by trajectory
analyses Kozyrskyj AL, Kendall GE, Jacoby P, Sly
PD, Zubrick SR. Am J Pub Health 2009 in press
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Odds ratio for asthma subsequent to chronic low
income vs not, by age
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Are the results biologically plausible? Stress
hypothesis

• Pregnancy, early life stress and chronic family
  stress were independently associated with asthma
  at age 6 and diminished the SES association with
  asthma
• Caregiver stress in early life has been
  associated with increased levels of
  pro-inflammatory cytokines in asthma. Infants
  (esp male) born into low income households are
  more likely to have an atopic profile at birth.
• By age 14, chronic life stress was associated
  with a two-fold increase in asthma.
• Children with asthma who experience both acute
  and chronic stress show a reduction in the
  expression of the glucocorticoid receptor, which
  can increase the airway inflammatory response to
  allergens.

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Are the results biologically plausible? Hygiene
hypothesis

• Children born to single-parents live in a SES
  environment that protects against asthma
  development. Single-parents made up 44 of
  households that moved out of poverty.
  Single-parent status diminished the inverse
  association between increasing income and asthma.
  When the increasing income trajectory was
  compared to chronic low income, asthma risk ?d
  by more than 60.
• Chen et al reported that asthma likelihood was
  lower in children whose families had moved up in
  income, than in children who continued to live in
  a low income family. Children living in
  increasing income families may experience higher
  rates of exposure to endotoxin and infections
  during early infancy, which may protect against
  asthma development. These exposures continue in
  chronic low income families and increase risk of
  asthma, as Celedon et al have found.

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SAGE Absence of additive risk?
Increased risk of childhood asthma from
antibiotic use in early life. Kozyrskyj AL,
Ernst P, Becker AB. Chest 2007 131 1-7.
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Key Questions/Issues in Early Life Exposure
Assessment

• Indoor environment
• Is endotoxin exposure in later life a valid
  exposure for early life?
• What are the important questions to ask living
  on a farm or exposure to farm animals?
• How do you disentangle reverse causation for
  antibiotic use?
• Psychosocial environment
• What is it about socioeconomic status that is
  associated with asthma?
• What types of exposures are important, ie.
  depression vs anxiety?
• How do you disentangle reverse causation for
  exposure maternal distress (living exposure
  which can change in response to the child)?
• Outdoor environment
• Why measure outdoor environmental exposures when
  the infant/toddler spends most of her/his time
  indoors?
• Do exposures during pregnancy matter and how can
  they be measured?

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Key Questions/Issues in Early Life Exposure
Assessment

• Indoor environment
• Psychosocial environment

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Key Questions/Issues in Gene-Environment
Interactions

• Indoor environment
• Psychosocial environment