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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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