Alexandria Egypt BPD 04-09

8/14/2019 Alexandria Egypt BPD 04-09

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Prof. Christian P. Speer, MD, FRCPE

Director and ChairmanUniversity Childrens Hospital Wrzburg, Germany

April 2 - 4, 2009 Alexandria, Egypt

2nd International Neonatology Conference

Pre- and postnatal risk factors in thepathogenesis of BPD: The role of infections


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Gerhardt, 1994

BPD (3/89 - 3/91)

Postnatal age (days)

%Fi

O2

0 5 10 15 20 25 3020

30

40

50

60

Low Risk (n=48)

High Risk (n=26)


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Neonatal survival and incidence of BPD defined as 28 days' duration

of oxygen dependency during hospitalization at the UM/JMC during

the period 1995 - 2000 (n = 1266 inborn infants; birthweight, 500 - 1000

g).

Bancalari E et al, Semin Neonatol, 2003

500-599 600-699 700-799 800-899 900-1000 1001-1250 1251-1500

Birth weight (g)

0%

20%

40%

60%

80%

100%

BPD Alive at 28 days Died < 28 days


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Merritt et al, J Clin Invest 1983

Infants at risk for BPD

Infants with RDSNon-pulmonary disorders

CELLN

UMBER

DAYS

Birth1 2 3 4 5 6 7 8 9 10 14

105

104

106

107

Inflammatory Cells in TAF

TAF= tracheal aspirate fluid


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Speer Biol Neon 2001; Shimotake et al Pediatr Res 2004Speer, Drug Discovery Today 2007

Hyperoxia

ChorioamnionitisMicroorganisms, LPS

Baro-/ Volutrauma

IL-1TNF-

Type II-Pneumozyt

Airway

Capillary

Interstitium

PMN

Fibroblast

IL-8

Mo


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O2 , OH

Surfactant

AveolarMacrophage

Type IIPneumocyte

Elastase

Albumin

Chem

otacti

c

Facto

rs

Permeability

Inflammatory

Mediators

AlveolarSpace

VascularSpace

Speer Biol Neon 2001; Speer, Drug Discovery Today 2007

Mo


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postnatal age (days)

%C

hangeInEnyzmeActivity

3

Groneck et al, Pediatrics, 1994

p


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26 weeks of gestation, day 10 of life


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Histologic Chorioamnionitis

Lahra and Jeffrey, AJOBGYN, 190:147, 2004

20-24 25 26 27 28 29 30 31 32 33 340

10

20

30

40

50

60

70

Histo

logicalchorio

amnionitis%

Gestational Age (completed weeks)

n=

261 n=139

n=

200

n=

164

n=

236

n=

284n=375

n=

380n=

539n=

580 n=

770


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Frequency of a positive amniotic fluid (AF) culture

and intraamniotic inflammation

Shim et al, Am J Obstet Gynecol, 2004

%

80

60

40

20

0 20-27 27-30 30-33 33-35

Gestational age (weeks)

intra-amniotic inflammation (P< .001) positive AF culture (P< .05)


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Onderdonk et al AJ0G 2008

Detection of bacteria in placental tissues obtained from

extremely low gestational age neonates

Study design: A sample of the chorionic parenchyma fromneonates delivered between 23 27 weeks was cultured and

tested by PCR , n = 1365

Results: Culture positive

68% of vaginal deliveries41% of caesarean sections

30% had only aerobic bacteria

21% had only anaerobic bacteria

9% had Mycoplasma / Ureaplasma

Conclusion: Approximately half of second trimester placentas

harbour organisms within the chorionic plate


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Intrauterine Cytokine

Exposure

Systemic Fetal

Inflammatory Response

Elevated IL-6concentrations in

umbilical cord blood

Yoon et al, Am J Obstet Gynecol, 1999

TNF-IL-1IL-8


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Neutrophil Influx in Pulmonary TissueNeutrophil Influx in Pulmonary TissueFollowing ChorioamnionitisFollowing Chorioamnionitis

Amnionitis positiveAmnionitis positive Amnionitis negativeAmnionitis negative

Schmidt, Speer.Am J Obstet Gynecol2001


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Amnionitis positiveAmnionitis positive Amnionitis positiveAmnionitis positive

Schmidt, Speer.Am J Obstet Gynecol2001

In-Situ HybridizationIn-Situ Hybridization

Expression of IL-8 in Lung TissueExpression of IL-8 in Lung TissueFollowing ChorioamnionitisFollowing Chorioamnionitis


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ICAM-expression in

endothelium of an umbilical artery

Heinrich, Kramer, Seidenspinner, Marx, Berg, Groneck, Speer Pediatr Res 2005

Chorioamnionitis, funisitis,Chorioamnionitis, funisitis,GA 26 weeksGA 26 weeks

No chorioamnionitis,No chorioamnionitis,GA 26 weeksGA 26 weeks


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Heinrich, Kramer, Seidenspinner, Marx, Berg, Groneck, Speer, Pediatr Res 2005

Soluble ICAM-1 levels in preterm infants

exposed to chorioamnioitis

70

100

300

500

700 p = 0.0006p = 0.004

ICA

M

1(n

g/ml)

Control Chorioamn. Chorioamn.

& Funisitis


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Apoptotic indices in lungs of stillborn

fetuses

131012N =

AI

20

15

10

5

0

*

***

stillborn stillborn

+maternal

chorioamnionitis

stillborn

+maternal

chorioamnionitis

+pneumonia

*p


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50 mMay, Marx, Seidenspinner, Speer, Histopathology 2004


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Chorioamnionitis, mechanical ventilation, and

postnatal sepsis as modulators of CLD

Greatest risk for CLD

exposure to chorioamnionitis

and / eithermechanical ventilation > 7 days

or

postnatal infection

Conclusion:These 2 postnatal factors interact with antenatal

infection to further increase the risk of

CLDVan Marter et al, Pediatrics 2002


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Groneck, Schmale, Soditt, Sttzer, Gtze-Speer, Speer,Pediatr Pulmonol 2001

postnatal age (days)

Interleukin-1

(pg/gSC)

1 3 5 70

10

20

30

40

50

60

70

80

*

*

*

*

*

*

*p


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Goldenberg et al, AJOG 2008

The Alabama Preterm Birth Study: Umbilical cord blood

Ureaplasma urealyticum and Mycoplasma hominis cultures

in very preterm newborn infants

Study351 mother / infant dyads with deliveries between 23 and 32

weeks gestational age

Results

U. urealyticum an forM. hominis were present in 23% of cordblood cultures

Intrauterine infection and inflammation were more common

among infants with positive U. urealyticum and M. hominis

cultures

Infants with positive cord blood U. urealyticum and M.

hominis cultures were more likely to have neonatal systemic

inflammatory response syndrome (SIRS) and probably

bronchopulmonary dysplasia (BPD).


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Twenty percent of very preterm neonates

(23-32 weeks of gestation) are born with bacteremia

caused by genital Mycoplasmas

Romero, Garite, AJOG, 2008


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Yoder, Coalson et al, Pediatr Res 2004

Colony forming units for Ureaplasma

urealyticum at delivery and postnatal

tracheal aspirates in premature baboons

CFU

`s

10.000.000

1.000.000

100.000

10.000

1.000

100

10

1AF 24 hr 72 hr 144 hr 240 hr 336 hr

Animals with negative culture at 14 days of postnatal age (Uu -), n=5

Animals with persistently positive cultures (Uu+), n=4

(amniotic fluid)


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Effects of antenatal colonization withUreaplasma urealyticum on pulmonary disease

in the immature baboon

Uninfected

animals ventilated

for 14 days

Uu - negative

animals at 14

days of age

Uu - positive

animals at 14

days of age

Yoder, Coalson et al, Pediatr Res 2004

I b l b t P i fl t


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Jones et al.Pediatr Res, 1996

Neonatal Lung Lavage

Immature Macrophage

IL-10

TNF-IL-1IL-8

Leukocyte

Endothelium

Mature Macrophage

TNF-IL-1IL-8

IL-10

Imbalance between Proinflammatory

and Antiinflammatory Cytokines


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24 hoursCD 68 and

TNF-a positive cells


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urch et al, Pediatr Res, 1996

TNF-+ cellsSulphated GAGs

Interstitialdensity(mm

2)

0

100

200

300

400

500

600

700

Stillborn

n=5


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Relative mRNA expression of genes to inflammation (TNF-, IL-6,MCP-1) in rat pups exposed to 100% oxygen or control pups

Wagenaar et al, Free Radic Biol Med, 2004

0.0

Foldchan

ge3RA

Neonatal age (days)

* p


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Ventilation Strategy on BALFCytokine Concentrations

-Isolated Rat Lung Model-

Tremblay et al, JCI 1997

C: Control

MVHP: moderate volumehigh PEEP

MVZP: moderate volume

0 PEEP

HVZP: high volume0 PEEP

C

MVHP

MVZP

HVZP

0

100

200

1200

1400 TNF-

C

MVHP

MVZP

HVZP

0

100

200

1200

1400 IL-1


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Tsuchida, Post et al , Am J Physiol Lung Cell, 2005

Continuous Positive Airway Pressure causes Lung

Injury in a Rat Model of Sepsis

+CPAP: 4cm H2O

1000

800

600

400

200

0SALINE

-CPAP

SALINE

+CPAP

LPS

-CPAP

LPS

+CPAP

IL-1

(pg/mL)

1000

800

600

400

200

0SALINE

-CPAP

SALINE

+CPAP

LPS

-CPAP

LPS

+CPAP

TNF-

(pg/mL)

i.v. LPS was given prior to initiation of experiments.

Animals were observed for 3 hours

C ti P iti Ai P L


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Tsuchida, Post et al , Am J Physiol Lung Cell, 2005

Continuous Positive Airway Pressure causes Lung

Injury in a Rat Model of Sepsis

Intravenous saline with CPAP (4cm H2O) Intravenous LPS with CPAP

i.v. LPS was given prior to initiation of experiments.

Animals were observed for 3 hours


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Chorioamnionitis

- Cytokineexposure of the

fetus-

+ Resuscitation

+ Oxygen toxicity

+ Mechanical ventilation

+ Pulmonary and / or

systemic infection

+ PDA

Pulmonary inflammatory response

Aberrant wound healing

Inhibition of alveolarization and vascular development

New BPD

Sequential

lung injury

Prenatal events Postnatal events

SSt t i


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Use lower SaO2 , FiO2

Reduce mechanical ventilation, reduce

suctioning, extubate early

Use surfactant as early as possible

Close PDA: Prolonged PDA and lateclosure are associated with an increased

risk of BPD

StrategiesStrategieshow to reduce inflammation in thehow to reduce inflammation in the

airways and pulmonary tissueairways and pulmonary tissue

Thomas, Speer, J Perinatol 2007, Neonatology 2008;Aly, Pediatrics 2007; Geary et al, Pediatrics 2008

S iSt t i


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Treat sepsis and pulmonary infections

properly

Early nutrition, early amino acidadministration

Caffeine

Vitamin A

Dexamethasone and other

glucocorticoids cannot currently be

recommended for prevention of BPDThomas, Speer, J Perinatol 2007 , Neonatology 2008;Aly, Pediatrics 2007; Geary et al, Pediatrics 2008

StrategiesStrategieshow to reduce inflammation in thehow to reduce inflammation in the

airways and pulmonary tissueairways and pulmonary tissue


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Alexandria Egypt BPD 04-09

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