early life origin of chronic obstructive …predispose to chronic respiratory disease syndromes....
TRANSCRIPT
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EARLY LIFE ORIGIN OF CHRONIC OBSTRUCTIVE LUNG DISEASES
Eugenio Baraldi, MDWomen’s and Children’s Health DepartmentUniversity of Padova
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MODEL OF CHANGES OF LUNG FUNCTION ACROSS THE LIFE
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COPD
Lung immaturity
Infections (VRS, HRV)
Allergy
Passive smoking
Lung immaturity
Viral infections (RSV,HRV)
Atopy
Passive smoking
Baraldi & Filippone NEJM 2007
EARLY INSULTS MAY CAUSE FAILURE TO ACHIEVE MAXIMAL LUNG FUNCTION AND EXPOSE INDIVIDUALS TO THE RISK OF CHRONIC RESPIRATORY DISEASES LATER IN LIFE
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Carraro S, Scheltema N, Bont L, Baraldi E
ERJ 2014
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Carraro S, Scheltema N, Bont L, Baraldi E
ERJ 2014
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FACTORS ACTING IN THE INTRAUTERINE LIFE MAY HAVE EFFECTS ON LIFELONG RESPIRATORY HEALTH
It may be necessary to intervene in utero or in early postnatal life
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‘80-’90 Barker: link between events occurring in the fetal environmentand long-term health and lifespan consequences in adults
«FETAL PROGRAMMING THEORY»
Barker DJ et al Lancet 1986
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Holt & Sly CEA 2009 modified
premature birth
(1st, 2nd hand)
Commongenotype
SusceptibilityInception
THE “FAMILY TREE” OF CHRONIC RESPIRATORY DISEASE SYNDROMES
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COPD
Lung immaturity
Infections (VRS, HRV)
Allergy
Passive smoking
COPD
Lung immaturity
Infections (RSV, HRV)
Atopy
Passive smoking
EARLY INSULTS MAY CAUSE FAILURE TO ACHIEVE MAXIMAL LUNG FUNCTION
AND EXPOSE INDIVIDUALS TO THE RISK OF COPD LATER IN LIFE
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TOBACCO SMOKE EXPOSURE AND CHANGES OFLUNG FUNCTION ACROSS THE LIFE
COPD
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COPD
TOBACCO SMOKE EXPOSURE AND CHANGES OF LUNG FUNCTION ACROSS THE LIFE
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Smoking in pregnancy is associated with an increased risk for asthma and lower lung function at age 14.
Hollams AJRCCM 2014
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Uso in aumento – percezione che sono sicure (meno catrame) – aumento accettabilità sociale del fumo
L’aerosol di e-cig non è solo "vapore acqueo", come viene affermato nella commercializzazione. Effetti dannosi della nicotina
Prove insufficienti a concludere che le e-cigarettes aiutino gli utenti a smettere di fumare.
Il loro uso puo’ essere una minaccia per i bambini e per il feto di madri incinte.
E’ necessario impedire la promozione delle e-cigarettes tra i non fumatori e i più giovani.
July 2014
AJRCCM 2014
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Model of changes of lung function across the life
COPD
Lung immaturity
Infections (VRS, HRV)
Allergy
Passive smoking
COPD
Lung immaturity
Infections (RSV, HRV)
Atopy
Passive smoking
EARLY INSULTS MAY CAUSE FAILURE TOACHIEVE MAXIMAL LUNG FUNCTION
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PREMATURITY IS A MAJOR HEALTH PROBLEM
IN THE DEVELOPED COUNTRIES
Preterm delivery rate: 5-9% Europe
12-13% USA
PRETERM DELIVERY RATE IS INCREASING
Goldenberg, Lancet 2008
30%
Year
Pro
port
ion o
f
pre
term
bir
th (
%)
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Premature
delivery
Canalicular stageSaccular stage
Alveolar stage
32 w23 w16 w 38 w
Normal
development
Structural injuryDevelopmental arrest/delay
New BPD
Baraldi & Filippone NEJM 2007
BPD: Any form of lung injury of the newborn determining the needfor supplemental O2 at 36 weeks’ postmenstrual age
Stages of lung development
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Despite the huge improvement in neonatalintensive care BPD remains a major cause ofmorbidity and mortality among premature infants
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LUNG FUNCTION IN BPD SURVIVORS (age 6-19 years)
CHILDREN ADOLESCENTS ADULTS
Baraldi & Filippone NEJM 2007
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BPD group
Born 1964-2000Ages 5-23 yearsG.A. 24-36 weeks
-16.2% -7.2%
59 studies : 28 preterm-born,24 with BPD28
PRETERM group
Kotecha Thorax 2013
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INDIVIDUAL WHO ENTER ADULT LIFE WITH LUNG-FUNCTION DEFICITS ARE AT RISK OF CHRONIC
OBSTRUCTIVE PULMONARY DISEASE LATER IN LIFE
Baraldi & Filippone NEJM 2007
Concern that a subset of BPD survivors may be susceptible to
a new COPD-like phenotype
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When Does BPD Start ?
BIR
TH
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„-OMIC‟ SCIENCES
Carraro J Pediatr 2009
“SYSTEMS BIOLOGY”
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J Pediatr 2009;154:638-44
METABOLITE FINGERPRINTING
Metabolomics allows the characterization of the
metabolite fingerprint of a biological sample
without any “a priori” hypothesis allowing
hypothesis free profiling of biomarkers, rather
than a traditional hypothesis-driven approach.
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METABOLIC PROFILING OF THE AMNIOTIC FLUID PREDICTSTHE RISK OF PRETERM DELIVERY AND BPD DEVELOPMENT
Amniotic fluid
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IRP – Istituto di Ricerca Pediatrica Città della Speranza - Padova
MS and Metabolomic Lab
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group R2 Q2
BPD 0.71 0.37
CMPD 0.80 0.62
CMTD 0.81 0.59
METABOLIC PROFILING OF THE AMNIOTIC FLUID PREDICTSTHE RISK OF PRETERM DELIVERY AND BPD DEVELOPMENT
Baraldi et al ERS 2014
AF collected between the21th-28th week of gestation
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METABOLIC PROFILING OF THE AMNIOTIC FLUID PREDICTSTHE RISK OF PRETERM DELIVERY AND BPD DEVELOPMENT
Baraldi et al ERS 2014
Suggesting that BPD begins during fetal life
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• Prematurity and BPD
• Recurrent wheezing and asthma
• Viral infections and subsequent airway obstruction
• COPD?
EARLY LIFE ORIGIN OF
CHRONIC RESPIRATORY DISEASE
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ATOPIC CHILDREN ARE MORE LIKELY TO CONTINUE WHEEZING BY THE TIME THEY REACH ADOLESCENCE
MAS study – Illi et al Lancet 2006
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INTERACTION BETWEEN ASTHMA AND LUNG FUNCTION GROWTH IN EARLY LIFE
Bisgaard AJRCCM 2012
Prospective clinical study of a birth-cohort of 411 at-risk children. Spirometry was completed in 403 neonates and again by age 7 in 317 children (77%)
Neonatal FEF50-Child FEF50
Airflow limitation in asthma is related to 2 components:• congenital (1/3) • acquired (2/3) This leaves open a “window of opportunity” to prevent the acquired component
Asthma
1 month
FE
F50
z-s
core
Age years
Controls
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INTERACTION BETWEEN ASTHMA AND LUNG FUNCTION GROWTH IN EARLY LIFE
Bisgaard AJRCCM 2012
Prospective clinical study of a birth-cohort of 411 at-risk children. Spirometry was completed in 403 neonates and again by age 7 in 317 children (77%)
Neonatal FEF50-Child FEF50
Airflow limitation in asthma is related to 2 components:• congenital (1/3) • acquired (2/3) This leaves open a “window of opportunity” to prevent the acquired component
Asthma
1 month
FE
F50
z-s
core
Age years
Controls
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R2=0.80 Q2=0.48
Baraldi & Bont
At birth, different metabolic profiles characterize AF of children who will or won’t
develop recurrent wheezing
WHEEZING CHILDREN: METABOLOMIC ANALYSIS OF
AMNIOTIC FLUID COLLECTED AT BIRTH
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COPD
Lung immaturity
Infections (VRS, HRV)
Allergy
Passive smoking
COPD
Lung immaturity
Infections (RSV, HRV)
Atopy
Passive smoking
EARLY INSULTS MAY CAUSE FAILURE TO ACHIEVE MAXIMAL LUNG FUNCTION
AND EXPOSE INDIVIDUALS TO THE RISK OF COPD LATER IN LIFE
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Post-RSV-bronchiolitis
recurrent wheeze
RSV
A UNIQUE MODEL!
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0
5
10
15
20
25
30
35
40
45
50
As
thm
a &
re
cu
rre
nt
wh
ee
ze
39%
9%
RSV(n=46)
Control(n=92)
Ato
py
0
5
10
15
20
25
30
35
40
45
50
43%
17%
Infants hospitalized for RSV bronchiolitis:
18 years follow-up
Sigurs, Thorax 2010
RSV(n=46)
Control(n=92)
n=46
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ASTHMA 30 YEARS AFTER HOSPITALIZATION
FOR BRONCHIOLITIS
Backman Ped Pulm 2013
• 70 bronchiolitis children enrolledin 1981-1982 evaluated at the age of 28-31 years (Finland)
• 138 matched controls
Bronchiolitis Control0
5
10
15
20
25
30
35
40
45
50
Ast
hm
a
n=46
32%
11%
Asthma was present in 1/3 of the former bronchiolitis patients
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Blanken NEJM 2013
Healthy preterm (33-35 ga) infants “late preterm”
214 Palivizumab vs 215 placebo
61% reduction in then°of wheezing days in the first year of life
(hospitalization 12% vs 22%)
61%
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• Prematurity and BPD
• Recurrent wheezing and asthma
• Viral infections and subsequent airway obstruction
• COPD?
EARLY LIFE ORIGIN OF
CHRONIC RESPIRATORY DISEASE
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Chronic Obstructive Pulmonary Disease COPD
GOLD
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COPD Journal 2008:5:53-67
“Any model of COPD which does not take into account
early life influences is likely to be fatally flawed”
“COPD is a disease of childhood that becomes manifest in adults”
Manninio Thorax 2010
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COPD – RISK FACTORS
GOLD
CIGARETTE SMOKING
SECOND HAND SMOKE
MATERNAL SMOKING
POLLUTION
OCCUPATIONAL EXPOSURE
LUNG GROWTH
NUTRITION
RESPIRATORY INFECTIONS
ALFA1-AT DEFICENCY
OXIDATIVE STRESS
LOW BIRTH WEIGHT
REDUCED LUNG FUNCTION IN
THE FIRST MONTHS OF LIFE
ENVIRONMENTAL FACTORS INDIVIDUAL FACTORS
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People with early life disadvantages (asthma, respiratory
infections < age 5, maternal smoking…) have low lung
function when adults, no catch-up with age and an
increased COPD risk.
Follow-up study from general population (7.738 subjects)
Enrolled at 20-45 yrs – followed 9 years
Svanes et al. Thorax 2010
Early life disadvantages
HeavysmokingThe impact of childhood disadvantages
was as large as that of heavy smoking !!
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• COPD smokers
• COPD-Asthma
• Poor lung function at birth and in the
first years of life (transient wheeze ?)
• Prematurity and BPD
• Recurrent respiratory infections in infancy
COPD PHENOTYPES
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Viral30%
Atopic10-15%
0 10 20 30 40 50 60 70 80
Pre
vale
nce o
f w
heezin
g
Age (years)
NATURAL HISTORY OF WHEEZING
ACROSS THE LIFE
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A common “at risk” genotype probablypredispose to chronic respiratory disease syndromes.
Deficit in airway function shortly after birth predisposesto flow limitation in adult life.
Environmental experiences during infancy (prematurity, respiratory infections, allergy, smoking exposure) may determine the progression towards specific phenotypes.
CONCLUSIONS
EARLY LIFE ORIGIN OF CHRONIC RESPIRATORY DISEASE
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EARLY LIFE EVENTS ARE CRUCIAL IN THE GENERATION
OF CHRONIC OBSTRUCTIVE LUNG DISEASES
Investment in Paediatric Research
warrants to save lives (and money) for adult
respiratory health