Summer Conference on NeonatologyAvignon – Sept. 2017

Postnatal Risk Factors for BPD

Alan H. Jobe, MD, PhD

Cincinnati Children’s Hospital

University of Cincinnati

Cincinnati, Ohio

Conflicts of Interest DeclarationSource: Purpose:

Grants B&M Gates Foundation Antenatal steroid studies

GSK (Matt Kemp) Steroid Pharmacokinetics

Gifts for Research Chiesi Surfactant

Merck Betamethasone

Consulting B&M Gates Foundation Infant mortality in low resource environments

Chiesi New treatments for BPD

The Big Picture – Developmental Exposures that Degrade Lung Function in Later life

9 mos

Conception

Preconceptional

Exposures

Fetal

Exposures

Birth

Early Childhood

Exposures

Compounding Effects: Pre-conceptional + Fetal + Early

Childhood – Single Exposure – Different Exposures

Outcome

Fetal Lung Development/Injury

- Prematurity

- Inflammation

- SGA

- Induced maturation, ANS

Injury

Repair

“Normal”

BPD

Oxygen

Inflammation

Ventilation

Fetal

Events

Resuscitation

Injury

Ongoing Injury Outcome

Months Minutes Months Years

What is BPD?

BPD Pathogenesis - Complex

Wright & Kirpalani, Pediatrics, 2011

Lung

Development

Injury

Repair

“Normal”

BPD

BPD is a Collision of 3 Programs

• Genetics

• Developmental Programming – epigenetics

• Stem cell populations

• Preconditioning to modulate response to a stimulus

• Systemic immune modulation

• Postnatal drug effects

• Nutrition

• Microbiome at Birth

BPD by NIH Workshop Definition

Prediction of BPD by Postnatal Age

• Postnatal risk factors• Gestational age

• Birth weight

• Sex

• Race and ethnicity

• Respiratory support

• FiO2

at 6 ages after birth

*Prediction improved with postnatal age

Web based model: https://neonatal.rti.org

Laughon, et al., AJRCCM, 2011

https://neonatal.rti.org/

FiO2 to Day 14, and Frequency of BPD in 1340

Infants with GA

A Brief Summary of the Clinical Landscape for Infants with GA

What type of BPD do I want to prevent / treat?

• BPD is a continum of severity from “normal” lungs of VLBW infants at term to death before 36 weeks of respiratory failure.

• Definitions do not capture severity well.

Proportionate Mortality at Postnatal

Ages for 22-28 Week GA Infants

Patel, et al., NEJM, 2015

Conclusions First:

• Definition of BPD confounds insights into pathophysiology

• Variability in antenatal/postnatal exposures in infants confounds single therapies derived from animal models

• BPD in VLBW infants is much more complex than any of the animal models.

• Preconditioning phenomena contribute to variability in infants.

Animal Models of Pathophysiology

of BPD

Elements of BPD that are the Focus of Animal Model Research

• Pathology• Septation abnormalities/alveolar simplification

• Microvascular injury and attenuation

• Pulmonary hypertension

• Primary Causes of Pathology• Oxygen

• Ventilation

• Inflammation

Animal Models of BPDIntervention Weakness

Term rats and

mice

Preterm sheep

Preterm

monkeys/baboons

O2 or bleomycin causes

inflammation, septation

inhibition, and vascular

injury/pulmonary

hypertension

Can test mechanistic

pathways

Inexpensive and available

Can ventilate and expose to

oxygen – mimic clinical care

Can use fetal exposures

Can ventilated and expose to

oxygen – mimic clinical care

Primarily an oxidant injury

Chronic models are expensive

with limited availability

Acute and chronic models are

very expensive with very

limited availability

Ethical constraints

Drug Therapies that Reverse Most of the Abnormalities of BPD in Animal Models

Agent/Intervention Clinical

Testing/Effectiveness

Growth factors – VEGF, KGF

Hepatocyte growth factor, anti-bombesin

Cox-2 inhibitors

Anti-TNF- antibodies

Elafin – elastase inhibitors

-catenin inhibitor

Stem cells

NT

No effect – not directly tested

NT

NT

NT

Possibly effective

Drug Therapies that Reverse Most of the Abnormalities of BPD in Animal Models

Agent/Intervention Clinical

Testing/Effectiveness

Anti-inflammatory

Glucocorticoids

Granulocyte inhibitors –

CINC-1, Anti-CD-18, IL-1ra

Block Macrophages

Decrease BPD

NT

NT

*NT = Not Tested

Drug Therapies that Reverse Most of the Abnormalities of BPD in Animal Models

Agent/Intervention Clinical

Testing/Effectiveness

Antioxidants -

Vitamin A

N-acetyl Cysteine

Small MW antioxidants – baboons

Peroxynitrite decomp. catalyst

Superoxide Dismutase

Inhaled NO- rodents, sheep, baboons

Modest decrease in BPD

No benefit

NT

NT

Possible benefit

No benefit

Oxygen is harmful, but injury is decreased in:

• Newborns relative to adults

• Animals exposed to inflammation

• Animals pre-exposed to oxygen

• Corticosteroid treatment

Injury is increased by:

• Calorie deprivation

[All associations in animal models]

Sensitivity to oxygen is probably quite

variable in preterm infants

Thoughts About Targeted Treatments for BPD Based on Animal Models

• Multiple pathways can be manipulated in animal models to decrease the BPD phenotype:• Block inflammatory cell recruitment to lung/inflammation• Antioxidants• iNO• Growth factors• Others

• Positive clinical results: Vit A and corticosteroids

• Targeting specific pathways may be ineffective (complex pathophysiology)

• Antioxidants may be of marginal benefit – corticosteroid effects are proof of principal that inhibition of inflammations can decrease BPD.

Definitions of BPD - Clinical

• Supplemental O2 at 28d or for 28d

• Supplemental O2 at 36 wks (Shennan)

• Mild – 28d O2• Moderate – O2 use at 36 wks

• Severe - >30% O2 + Positive

Pressure

• Challenge of O2 need or Flow at 36 wks

NIH

Workshop

22

Limitations to Definitions –“Facts” often Overlooked

• Preterm infants are abnormal.

• The lungs of VLBW infants develop abnormally. –independent of BPD

• The lungs of VLBW infants are abnormal at 36 weeks / term. – independent of BPD

• Comparison populations for incidence of BPD are abnormal – no “control” group.

23

Problems with Definitions

• 36 wks is an arbitrary time on a continuum of disease.

• Defined by O2 or positive pressure – not pathophysiology, lab, radiology.

• Diagnosis occurs months after opportunities to prevent or treat.

• Patients are unclassifiable with newer therapies. • High flow nasal cannula – No O2• Very low flow - 100% O2

• Diagnosis poorly predicts long term outcomes.

24

Poindexter, Annals ATS, 2015

Severe Chronic Respiratory Disease of Prematurity

Primary Abnormalities:

• Parenchymal injury

• Airway injury

• Control of breathing abnormalities

• Pulmonary hypertension

• Others – Aspiration

26

3 Populations to ConsiderRelative to a BPD Diagnosis

1. Infants that die of RDS + BPD before 36 wks.

2. Infants with “severe” BPD.

3. Infants that die with BPD after 36 wks

• Target populations for innovative therapies

• Who are these infants and how many are there?

27

Associations of 6 Traditional Bronchopulmonary Dysplasia (BPD) Definitions With Adverse Outcomes at 18 to 21 Months of Age

Serious respiratory morbidity

Serious neurosensory impairment

28

Association of Oxygen Use or Respiratory Support at 34 to 40Weeks’ Postmenstrual Age With Adverse Outcomes at 18 to 21 Months of Age

Serious respiratory morbidity Serious neurosensory impairment

29

New Definitions of BPD

• International Neonatal Consortium – INC

• NICHD Workshop

• PROP Cohort – Judy Aschner

• Others

30

Variables that Contribute to a BPD Diagnosis

31

Variables that Contribute to a BPD Diagnosis

32

Scoring for BPD at 36 or 40 weeks

Oxygen Use Respiratory Support

21% 0 None 0

21-30% 1 CPAP/Nasal Cannula 1

31-50% 2 Non-invasive Vent 2

>50% 3 Invasive Vent-PIP 20 4

My unvalidated attempt to quantify severity

33

Conclusion: No BPD definition will meet all needs

• Define a population of interest

• Define the endpoints of interest

• Define a 36 or 40 week outcome –Primary outcome

• Define a 1 year respiratory outcome –Secondary outcome

34

Summary of Recent Early Steroid Trials:

Inhaled SteroidBassler - 2015

10 day Hydrocortisone

Baud - 2016

Steroid + SurfYeh - 2016

Steroid Exposure Relatively targeted to lung, but higher dose

Very low dose,but systemic

Targeted to lung

Duration of Treatment Off support or 32 weeks

10 days Surfactant Treatments

Death Increased 3.3% Decreased 5 % Decreased 3 %

BPD Decreased 10.2 % Decreased 4 % Decreased 21 %

These results are a convincing proof of principle that early steroid treatments are effective.

Which treatment strategy do you prefer?

BPD is 50 Years Old!