The
C anadian
H ealthy
I nfant
L ongitudinal
D evelopment
Study – Preliminary data
November 27, 2015
Padmaja Subbarao, MD, MSc FRCP(C)
Clinician-Scientist
Co-Director, CHILD Study
Hospital for Sick Children
University of Toronto
Toronto, Canada
Disclosures
No commercial or other
interests other than a
bias towards pulmonary
function outcomes!
Objectives
• to review the CHILD study pulmonary function
measures
• to discuss the Toronto subcohort infant pulmonary
function measures
• to present preliminary data from the Toronto
subcohort pulmonary function group
N Engl J Med 2003; 349: 1414-1422
Longitudinal lung function by asthma outcome at age 26
Sears MR, et al. N Engl J Med 2003;349:1414-22
Males
Males
It all happens
in early
Re
childhood
Canadian Healthy Infant Longitudinal Development Study
Exposures
Pollution
Work & School
environment
Home
environment
Genetics
Immune phenotypes
Clinical phenotypes
Infant Pulmonary Function
Microbiome
Stress
Diet
Viruses
SES
Pets
Recruitment of a general population cohort
Inclusion criteria
Exclusion criteria
• Pregnant women aged >18
years (19in Vancouver)
• Residential proximity (<50km)
to participating delivery
hospital
• Able to read, write and speak
English
• Willing to donate cord blood
• Planning to deliver at a
designated recruitment centre
participating hospital
• Infant born at or after 35
weeks
• Children born with major
congenital abnormalities or
respiratory distress syndrome
• Expectation of moving away
from a recruitment centre
within 1 year of recruitment
• Children of multiple births
• Children resulting from in-vitro
fertilization
• Children who will not spend at
least 80% of nights in the
index home
Current recruitment sites for CHILD
National
Coordinating
Centre
Key variables obtained by questionnaires
HOME
MOTHER
FATHER
CHILD
Current residence
Maternal demographics
Paternal demographics
Mode of delivery
Previous residences (12 mo)
Maternal health
Paternal health
Medications around birth
Changes of residence
Maternal medications
Paternal medications
Sleeping arrangements
Type and age of home
Maternal smoking
Paternal smoking
Activities outside home
Characteristics of home
Maternal respiratory symptoms
Paternal respiratory symptoms
Colds and infections
Attached garage
Maternal diagnosed asthma
Paternal diagnosed asthma
Coughing episodes
Heating and cooling systems
Maternal allergies
Paternal allergies
Wheezing episodes
Humidifiers
Maternal occupation
Paternal occupation
Medications
Basement/crawl space
Health of other children
Hobbies and activities in home
Food allergy
Water leaks and mold
Health during pregnancy
Atopic dermatitis / eczema
Swimming pool, spa
Diet before and in pregnancy
Doctor visits
Renovations
Vitamins and supplements
Hospital/ER visits
Furniture
Prenatal/postnatal maternal stress
Breastfeeding
Cooking systems
Socioeconomic status
Introduction of milk, solids
Cleaning habits
Depression module
Vaccinations
Chemicals used in home
Labor and delivery
Time/activity/locations
Smoking in the home
Post-partum health
Travel times and exposures
Characteristics of bedroom
Post-partum stress
Daycare arrangements
Animals in home (pets)
Breastfeeding
Insects and pests in home
Parenting stress
Model of genetic and environmental determinants of lung function
PRENATAL EXPOSURE
ASSESSMENT
POSTNATAL EXPOSURE ASSESSMENT
ETS
Air Pollution (GIS Modelling)
Child Nutrition
Maternal
Nutrition
Breastfeeding
Viral infection
PFT (Entire
cohort)
3 year
5 year –
complete
2019
PFT (Toronto)
PFT (Toronto)
18 month
PFT (Toronto)
12 month
PFT (Toronto)
3 month
PFT (Toronto)
Nasal
microbiome
Birth
Mould*
(28-32 weeks)
Dust allergen &
Microbiome*
Nasal
microbiome
Birth weight
Prenatal
*From standardized
home assessment
Diagnosis of Asthma in > 8
• 3 features must be considered:
1. Symptoms.
2. Variable airflow obstruction.
a) Spirometry: >12% BDR, >20% FEV1
b) PEF: >20% variability
c) Methacholine challenge: <8mg/mL
3. Airway inflammation (not required for
diagnosis).
Canadian Asthma Consensus Guidelines, 1999
Preschool Asthma Diagnosis
Ducharme CRJ 2015
Preschool prediction rule
Frequent wheezing < 3y AND:
Minor Criteria
Major Criteria
1. Parental MD asthma
2. MD eczema
3. Sensitivity to
aeroallergen
1.
2.
3.
4.
MD allergic rhinitis
Wheezing apart from colds
Eosinophilia ≥ 4%
Sensitivity to egg, milk or
peanut
1/2 Major + 2/3 Minor: 97% sensitivity but PPV 47%.
Castro-Rodriguez, AJRCCM, 2000
Guilbert, Cont Clin Trials, 2004
Pulmonary Function Measures
1. Spirometry – infancy, 3 & 5 years
2. Multiple Breath Washout – infancy, 3 & 5 years
3. Forced Oscillation tests – 3 & 5 years
*In the full cohort only spirometry at 5 years
SPIROMETRY
FVC
FVC
Spirometry in Preschool
• Tracking
• 73% success rate in 2-4
year olds if accept
FEV0.5
• Need to have incentive
programs
• Technical aspects
• End of test criteria
Raised Volume Rapid Thoracoabdominal Compression
• Sedated infant
• Mask applies extra
volume
• Jacket provides assisted
expiration
Journal of Applied Physiology 1998
Pre 1
**
*
*
Pre 2
Post
Multiple Breath Washout (MBW)
• An inert gas washout test – first described 60
years ago – repurposed for modern use
• Tidal breathing measure, requires virtually no
effort and thus is possible in all ages.
• Sensitive measure of gas mixing in the small
peripheral airways.
• Add complementary information to
spirometry.
Multiple Breath Washout (MBW)
- an inert gas washout test Inert gases
Do not participate in gas exchange
Low solubility in blood and tissue
Resident inert gases: Ar (40), N2 (28)
Extrinsic inert gases: CH4 (16), He (4), SF6 (146)
(MM) = Molecular Mass
Ventilation distribution homogeneity
The efficiency with which inspired gas mixes
with the resident gas in the lungs
Tidal volume
Ventilation
distribution
Nitrogen Washout
Factors and mechanisms involved
in the gas exchange
IV
III
II
I
Expired Gas Volume
Airway
resistance
Diffusion
V´A/Q´matching
Lung
elasticity
Tidal volume
Ventilation
inhomogeneity
Nitrogen Washout
Factors and mechanisms involved
in the gas exchange
IV
III
II
I
Expired Gas Volume
Airway
resistance
Diffusion
V´A/Q´matching
Lung
elasticity
Tidal volume
Ventilation
inhomogeneity
Nitrogen Washout
Factors and mechanisms involved
in the gas exchange
IV
III
II
I
Expired Gas Volume
Airway
resistance
Diffusion
V´A/Q´matching
Lung
elasticity
Multiple Breath Washout (MBW) SF6
Gas
Supply
4% SF6
Flow
Analyzer
Mass Spec
Wash-in Phase
26
Multiple Breath Washout (MBW) SF6
[SF6]
4%
4% SF6
Sample time
Flow
Analyzer
Mass Spec
Wash-out Phase
Expiration
27
Multiple Breath Washout (MBW) SF6
[SF6]
4%
Room Air
4% SF6
Sample time
Flow
Analyzer
Mass Spec
Wash-out Phase
Inspiration
28
Multiple Breath Washout (MBW) SF6
[SF6]
4%
4% SF6
Sample time
Mass Spec
Wash-out Phase
Expiration
29
Multiple Breath Washout (MBW) SF6
Healthy Infant
Healthy infant
Infant with cystic fibrosis
Parameters from MBW
Lung Clearance Index
• Most commonly reported parameter
• Measures ventilation distribution homogeneity (the efficiency with
•
which inspired gas mixes with the resident gas within the lung).
The number of FRC lung volumes to reduce the inert tracer gas to 1/40th
(2.5%) of its initial starting concentration.
LCI = Cumulative Expired Volume
FRC
A higher LCI = “worse” lung disease
Data from CHILD
Infant Pulmonary Function (IPFT) Subcohort
Toronto Cohort
N= 768
231 Infants
430 Infant Test visits
IPFT Cohorts:
1. Tucson – 127
2. Perth – 250
3. COPSAC (hi-risk) – 400
None have longitudinal data
in preschool.
Early Infant visit
N = 132
Mid Infancy
N = 221
Late Infancy
N = 77
109 MBW
75 Pleth
50 RVRTC
183 MBW
165 Pleth
107 RVRTC
59 MBW
38 Pleth
28 RVRTC
IPFT & Preschool Subcohort
Toronto Cohort
N= 768
231 Infants
430 Infant Test visits
635 (82%) 3 year visits
completed
Still on going
177 (77%) F/U from IPFT
523 (80%) acceptable PFT
369 (70%) MBW
348 (66%) Spiro
IPFT Cohorts:
1. Tucson – 169 – F/U 11y (74%)
2. Perth – 243 – F/U 6 y (48%)
3. COPSAC (hi-risk) – 400 – F/U – 7
years (77% f/u)
None have longitudinal data in
preschool.
Demographics of the full dataset
3 Month
N
Mean
Std
1 year
N
Mean
Std
18 month
N
Mean
Std
Birth weight (gram)
118
3432.16 447.9
182
3421
488
85
3297
464.7
Birth length (cm)
Weight (kg)
Height (cm)
Age (year)
Calulated BMI=weight /
squared(_CLENHEI)
BMI-for-age z-score
Length/height-for-age zscore
Weight-for-age z-score
Weight-for-length/height zscore
Age in months
78
119
119
119
51.79
7.56
66.05
0.5
5.83
1.22
3.36
0.14
124
184
184
184
50.82
9.76
75.34
1.08
2.88
1.2
3.54
0.15
52
85
85
85
51.01
11.09
81.25
1.61
2.51
1.34
4.3
0.16
119
17.25
1.87
184
17.17
1.51
85
16.81
1.93
112
0.04
1.21
181
0.4
0.99
85
0.63
1.23
112
-0.27
1.09
181
-0.26
1.12
85
-0.53
1.36
112
-0.12
1.01
181
0.14
0.96
85
0.11
0.91
112
0.11
1.22
181
0.36
0.97
85
0.52
1.18
119
6.03
1.71
184
12.94
1.85
85
19.28
1.89
In conclusion
• Very little is known about the early life lung
function trajectories.
• We found that many factors impact lung
function and some differentially.
• The interaction of the microbiome and virome
with diet and dust and its associations with
pulmonary function is a key area of interest
for CHILD.
Strategic Focus of CHILD Research
• To understand key relationships and interactions among the many
genetic determinants and environmental exposures associated
with the development of asthma, and use this understanding to
prevent it and improve its treatment.
• Multiple asthma/allergy hypotheses related to:
Innate immunity
Genetic risk, epigenetic effects
Microbiome
Nutrition
Infant lung function
Viral infections
Psychosocial effects, stress Environmental exposures
• Data collection has been expanded to provide for the study of
development of other chronic non-communicable diseases
including metabolic (obesity, diabetes) and cardiac disorders.
38
CHILD Study Funding
Private donors –
Sick Kids Foundation