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