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WHY DO FORMER PREMIES WHEEZE?
Richard J. Martin, M.D.Drusinsky-Fanaroff Chair in Neonatology
Rainbow Babies & Children’s Hospital
Professor, Pediatrics
Case Western Reserve University
Cleveland, Ohio
Advice for an Entry Level Neonatologist in the 1970s
“A solution for prematurity is at hand”. Implication: this is a risky career move
“All the respiratory problems have been solved”. Implication: avoid respiratory research
Respiratory Morbidityin Former Preterm Infants
Preterm birth and low birth weight as risk factors for later morbidity
How much is attributable to BPD?
What about the later preterm?
Proposed biologic mechanisms
The clinical challenge
“Intrauterine influences which retard fetal weight gain may irrevocably constrain the growth of the airways”.
BMJ, 1991
Risk Factors for Childhood AsthmaDiagnosed before 3 Years:
Population Based Study in Finland
0
0.5
1
1.5
2
2.5
3
3.5
4
Prematurity SGA Maternal Asthma
Odds
Rati
o(c
om
pare
d t
o t
erm
)
CI(2.5-3.0)
CI(1.7-2.3)
CI(3.0-3.7)
Metsälä J: Am J Epidemiol 2008
Odds of Recurrent Wheezing [mean age 2 yrs], Chorioamnionitis and Prematurity
ChorioamnionitisGestation[weeks]
OR[95%CI]
p value
No>37
33 – 37<33
>3733 – 37
<33Yes
1.01.7 [1.0-2.9]2.7 [1.3-5.5]
2.0 [1.1-3.8]1.3 [0.4-3.6]4.0 [2.0-8.0]
-.03
.005
.03
.67.0001
Boston data: Kumar R: J Allergy Clin Immunol 2008
Risk for Recurrent Wheezingin Former Preterm Infants
Choriamnionitis
PrematurityRecurrent
Wheezing
Risk for Recurrent Wheezing in Former Preterm Infants
Choriamnionitis
PrematurityRecurrent
WheezingViral infection
[rhinovirus, RSV]
Asthma at School Age inELBW Infants Born in the 1990’s
0
10
20
30
40
50
ELBW(n=219)
TERM CONTROLS(n=176)
OR 3.0, 95% CI 1.6-5.6, p=0.001
Ast
hm
a
Rate
* (
%)
Hack et al: JAMA 2005* need for medication
Does the asthma phenotype
differ between former preterm
and term infants?
0
10
20
30
8 Years 14 Years
ELBW NBW
Prevalence of Asthma* betweenChildhood and Adolescence
Hack et al: JAMA 2011* need for medication
Su
bje
cts
wit
h A
sth
ma
(%
)
Adult Progression of Bronchial Responsiveness after Term and Extremely Preterm [EP] Birth
TERM
EP
Vollsæter M: Ann Am Thorac Soc, 2015
Respiratory Morbidityin Former Preterm Infants
Preterm birth and low birth weight as risk factors for later morbidity
How much is attributable to BPD?
What about the later preterm?
Proposed biologic mechanisms
The clinical challenge
“Most adolescents and young adults who had bronchopulmonary dysplasia in infancy have some degree of pulmonary dysfunction, consisting of airway obstruction, airway hyperreactivity, and hyperinflation. The clinical consequences of this dysfunction are not known.”
W. H. Northway Jr.: et al. NEJM 1990
Ventilation
(baro/volutrauma)
Oxygen
(oxidant/antioxidant balance)
Infection
(pre/postnatal)
Altered pulmonary
vasculatureAlveolar remodeling
Structural
Immaturity
Inflammatory
Response
Biochemical
Imbalance
Ventilation
(baro/volutrauma)
Oxygen
(oxidant/antioxidant balance)
Infection
(pre/postnatal)
Impaired Airway Structure and Function
Altered pulmonary
vasculature
Alveolar remodeling
Structural
Immaturity
Inflammatory
Response
Biochemical
Imbalance
160
140
120
100
80
60
40
20
0
FE
V1%
p<0.0001 p<0.0001
Airway Hyperresponsiveness inSchool Children Born Very Preterm
Pelkonen AS: Am J Resp Crit Care Med 1997
Non-BPDBPD Controls
Respiratory Morbidityin Former Preterm Infants
Preterm birth and low birth weight as risk factors for later morbidity
How much is attributable to BPD?
What about the late preterm?
Proposed biologic mechanisms
The clinical challenge
Am J Respir Crit Care Med 2013
Preterm Birth and Childhood Wheezing: Meta-analysis
Moderately preterm
[≥32 wk]
Very preterm
[<32 wk]
Been JV et al: PLOS 2014
1.49 [1.34-1.66]
2.81 [2.52-3.12]
<0.001
<0.001
Adj OR [95%CI] p
Respiratory Morbidityin Former Preterm Infants
Preterm birth is a risk factor for longer term airway hyperreactivity
Much, but by no means all, of this is attributable to BPD
The later preterm without significant neonatal lung disease is also at risk
Resolved:
Respiratory Morbidityin Former Preterm Infants
Preterm birth and low birth weight as risk factors for asthma
How much is attributable to BPD?
What about the late preterm?
Proposed biologic mechanisms
The clinical challenge
Neonatal Contributors to Altered Airway Function
Modulated neural output
Parenchymal [alveolar] injury
Airway dysfunction
Imbalance of Neural Regulation of Airway Caliber
cAMP/cGMP
mAchRairway smooth
muscleepithelium
mAchR
vagus
vagal postganglionic neuron
Ach
Ach
NOS NOS
ContractionRelaxation
PG
Neonatal Contributors to Altered Airway Function
Modulated neural output
Parenchymal [alveolar] injury
Airway dysfunction
Altered Neonatal Airway Function: Lung Parenchymal Injury
Colin, A. A. et al. Pediatrics 2010
Airway
PleuralSpace
Neonatal Contributors to Altered Airway Function
Modulated neural output
Parenchymal [alveolar]
injury
Airway dysfunction
Developmental Progression of
Airway Vulnerability
INCREASED
EXTRACELLULAR
MATRIX
PASSIVE
COLLAPSE
ACTIVE
BRONCHOSPASM
Hypothesis
Modest therapeutic interventions,
such as low supplemental oxygen
and/or CPAP, may elicit longer term
airway hyperreactivity in former
preterm infants
Ventilation in Extremely Preterm Infants and Respiratory Function at 8 Years
Lex W. Doyle, M.D., Elizabeth Carse, M.D., Anne-Marie Adams, Ph.D., Sarath Ranganathan, Ph.D., Gillian Opie, M.B.,
B.S., Jeanie L.Y. Cheong, M.D., for the Victorian Infant Collaborative Study Group
N Engl J MedVolume 377(4):329-337
July 27, 2017
Days of Respiratory Support in Extremely Preterm Inants [<28 wk]
Doyle LW: NEJM 2017
1997 [n=151]
2005 [n=170]1997
[N=112]
2005
[N=123]
Expiratory Flows at 8 Years of Age in Each Period
Doyle LW: NEJM 2017
PROS
Very immatureGrows up fastSurvivable Amenable to geneticsInexpensive
CONS
Very smallNot a human infant
Airway Reactivity in Mice is Delayed after Neonatal Hyperoxia [day 21]
Onugha H: Neonatology 2015
Effect of Oxygen Exposure on ASM Proliferation and Apoptosis
Hartman WR et al: Am J Physiol: Lung Cell Mol Physiol 2012Hartman WR, et al: Am J Physiol Lung Cell Mol Physiol, 2012
Rainbow Mouse Pup NICU
Courtesy: PM MacFarlane, Ph.D.
Increased Airway Reactivity in a Neonatal Mouse Model of CPAP: data from male pups at day 7
Methacholine [mol/l]
Large airwaysSmall airways
Mayer CA: Pediatr Res 2015
CPAP
Control
Conclusion
Mild postnatal oxygen exposure and CPAP both cause airway smooth muscle proliferation and airway hyperreactivity in a neonatal rodent model
This may contribute to the increased incidence of wheezing observed in former preterm infants, many of whom may not manifest BPD
Respiratory Morbidityin Former Preterm Infants
Preterm birth and low birth weight as risk factors for later morbidity
How much is attributable to BPD?
What about the late preterm?
Proposed biologic mechanisms
The clinical challenge
Bronchodilators for the Prevention and Treatment of Chronic Lung Disease in Preterm
Infants (Review)
Ng G, da Silva O, Ohlsson A
“…no evidence that salbutamol reduces mortality or CLD at 28 days in preterm
infants at risk of developing CLD.”
2009
Effect of Smoking on Age-related Decline in Airway Function
Parkes G et al: BMJ 2008
*
Potential Maturational Parallels?
Apnea of Prematurity
BPD
Adverse Outcomes
OSA COPD
Adverse Outcomes
Peter MacFarlane
NHLBI, NICHD
Thank you to My Research Lab Collaborators
Catherine Mayer
Thomas RaffayYS Prakash
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