early life exposures as “causes” of asthma/atopic phenotypes: key questions

Early Life Exposures as “Causes” of Asthma/Atopic Phenotypes:

Key QuestionsAnita L Kozyrskyj, PhD,

Research Chair & Associate Professor Dept Pediatrics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, CanadaThe Genesis of Allergy and Asthma Workshop

Vancouver, March 2009

Innovation from cell to society

Objectives

List key questions/issues Identify opportunities for

investigation


Key Questions/Issues in Early Life Exposure Measurement

Timing of exposure Is there a critical window: early pregnancy, late pregnancy, first Is there a critical window: early pregnancy, late pregnancy, first

year of life, first 3 years?year of life, first 3 years?

Persistence of exposure Persistence of exposure All or nothing phenomenon during a critical time period or first All or nothing phenomenon during a critical time period or first

exposure followed by continued exposure?exposure followed by continued exposure?

Accumulation of exposureAccumulation of exposure One key exposure or a combination of exposures?One key exposure or a combination of exposures? Is there an additive risk in high risk children?Is there an additive risk in high risk children?

Validity of exposure measurementValidity of exposure measurement Are we measuring what we think we are (and does it matter)?Are we measuring what we think we are (and does it matter)?


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Social and Economic Policies

Neighborhoods/Communities

Institutions

Living ConditionsSocial Relationships

Nutrition/care

Environment

Child at birth

Life

cour

se

Genetic Factors


SAGE: Maternal distress measure postpartum time period only one and 1-5 years (short-term) persistent over 1-7 years of child’s life late onset (after postpartum period)

Continued exposure to maternal distress in early life is associated with an increased risk of Continued exposure to maternal distress in early life is associated with an increased risk of childhood asthma.childhood asthma. Kozyrskyj AL, Mai XM, McGrath P, HayGlass KT, Becker AB, MacNeil B. Kozyrskyj AL, Mai XM, McGrath P, HayGlass KT, Becker AB, MacNeil B. Am J Respir Crit Care Med 2008; 177:142-7.Am J Respir Crit Care Med 2008; 177:142-7.


Risk of asthma following adjustment Risk of asthma following adjustment for additional confounding factorsfor additional confounding factors

1.00 1.05 1.001.25

0.00

0.50

1.00

1.50

2.00

No distress 1st year only Short-term 1st-7th yr

Persistent 1st-7th yr

Odd

s R

atio

Child sex, maternal asthma, urban/rural, health care visits, number siblings,lower respiratory and non-respiratory tract infections, antibiotic use in 1st yr


Maternal Distress: Phenomena in the 1Maternal Distress: Phenomena in the 1stst year of life or persistent exposureyear of life or persistent exposure

Number of health care visits

Number of prescriptions

Mean Mean Postpartum distress only

1.2 0.2

Short-term distress

1.7 0.5

Persistent distress

2.5 1.2


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


Family Income Trajectories• Rather than pre-determined categories, maximum-

likelihood longitudinal (latent class) modeling techniques classified children on the basis of their family’s movements in and out of low income over the child’s 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 Bayes’s theorem to assign children to the income trajectory group for which they had the highest probability of belonging.


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


Odds ratio for asthma subsequent to chronic low income vs not, by age

0

0.5

1

1.5

2

2.5

3

Age 6 Age 14

GirlsBoys


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.


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.


SAGE: Absence of additive risk?

Increased risk of childhood asthma from antibiotic use in early life. Increased risk of childhood asthma from antibiotic use in early life. Kozyrskyj AL, Ernst P, Becker AB. Chest 2007: 131: 1-7.


Key Questions/Issues in Early Life Exposure Assessment

Indoor environment Is endotoxin exposure in later life a valid exposure for early life?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 What are the important questions to ask: living on a farm or exposure to

farm animals?farm animals? How do you disentangle reverse causation for antibiotic use?How do you disentangle reverse causation for antibiotic use?

Psychosocial environment What is it about socioeconomic status that is associated with asthma?What is it about socioeconomic status that is associated with asthma? What types of exposures are important, ie. depression vs anxiety?What types of exposures are important, ie. depression vs anxiety? How do you disentangle reverse causation for exposure maternal distress How do you disentangle reverse causation for exposure maternal distress

(“living” exposure which can change in response to the child)?(“living” exposure which can change in response to the child)?

Outdoor environment Why measure outdoor environmental exposures when the infant/toddler Why measure outdoor environmental exposures when the infant/toddler

spends most of her/his time indoors?spends most of her/his time indoors? Do exposures during pregnancy matter and how can they be measured?Do exposures during pregnancy matter and how can they be measured?


Key Questions/Issues in Early Life Exposure Assessment

Indoor environment

Psychosocial environment


Key Questions/Issues in Gene-Environment Interactions

Indoor environment

Psychosocial environment

early life exposures as “causes” of asthma/atopic phenotypes: key questions

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