Alexandria Egypt Sepsis 02-04-09
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Transcript of Alexandria Egypt Sepsis 02-04-09
Prof. Christian P. Speer, MD, FRCPE
Director and Chairman
University Children’s Hospital Würzburg, Germany
April 2 - 4, 2009 Alexandria, Egypt
2nd International Neonatology Conference
Neonatal septicemia: Current concepts andthe role of neonatal host defense
Neonatal Sepsis
• Incidence 1- 4 Newborns /
1000 LB / Year• Meningitis 5 - 25 %• Case fatality ~ 25 % (5 - 60%)
Mortality• 1.6 Million Deaths / Year1
• Infections as cause of death in > 50 % of extremely LBW infants on autopsy2
Morbidity • Association between chorioamnionitis and cerebral palsy in mature
infants (odds ratio 9.3, CI 2.7-31)3
• Qualitative MRI in extremely LBW infants: Association between non-cystic white mater injury (oligodendroglial specific injury) and perinatal infection (maternal fever, proven neonatal sepsis at delivery4)
• Adverse neurodevelopmental outcome in preterm infants with postnatal sepsis or NEC is mediated by white matter abnormalities on MRI 5
Neonatal Sepsis
1Vergnano et al, Arch Dis Child Fetal Neonatal Ed 2006; 2 Barton et al, Pediatrics 1999;3 Grether and Nelson, JAMA, 1997; 4 Inder et al, J Pediatr 2003; 5 Shaw et al, J Pediatr 2008
Descending infection
Ascending infection
Risk Factors of Early Onset Sepsis
• Prolonged rupture of membranes >18 hours• Preterm premature rupture of membranes• Maternal amnionitis• Fever, bacteremia of the mother• Prematurity
Bacterial Colonization of Pregnant Women and Newborns in European Countries
Bacteria Rectal-Vaginal Colonization Attack Colonization of the Newborn Rate
GBS* 8 - 36 % 40 - 70 % ~ 1:100
E. coli 32 - 50 % 30 - 70 % ~ 1:200
*GBS: Group B-StreptococciBarcaite et al Acta Obstet Gynecol 2008 (Review)
• Women colonized with GBS* prenatally have a 25 fold higher risk of delivering a baby with
early onset GBS compared with non-colonized women
Mikroorganismen
Route of Infection
Spectrum of GBS Infection
● Pneumonia 35 - 55 %
● Sepsis 25 - 40 %
● Meningitis 4 - 10 %
● ~ 75 % of cases with GBS infection are
early onset (within the first days of life)
● Most affected infants become ill within
the first 24 hours
Tumbaga, Philip, NeoReviews 2003
S Hakansson, K Källén, BJ0G 2006
Impact and risk factors for early-onset group B streptococcal disease: analysis of a national, population-
based cohost in Sweden 1997-2001, 435 070 live births
Tentative risk factor Verified sepsis n=174
Gestational age OR 95% CI(completed weeks)
< 28 22 8.5-5728-31 34 18-6232-34 11 6-2135-36 5 2- 937-41 3.5 2-6.5≥ 42 1.9 1-3.7
Schrag SJ et al, NEJM 2000
Case Fatality Rates of Neonates withEarly-Onset GBS-Sepsis in the United Sates,
1993 – 1998n = 1584
Gestational Age Case Fatality
< 33 wk 30 %
34 – 36 wk 10 %
> 37 wk 2 %
Case fatality rates for E. coli sepsis
Birthweight Case fatality rates
<1500g 33/66 (50%)
>1500g 2/30 (7%)
Daley AF et al. Pediatr Infect Dis J 2004
(Australasia, 1992 – 2001)
Banerjea, Speer, Pädiat Prax, 2002
Predominant Microorganisms Responsible for Septicemia
0
10
20
30
40
50
60
USA2000
Germany1997
Spain2000
Israel1997
Nigeria1999
Pakistan2000
Panama1994
(%)
GBS coag.-neg. Staphylococci Klebsiella Species E.coli
Zaudu AKM et al. Lancet 2005
0
10
20
30
40
50
60
Africa
(n=110)
Pro
po
rtio
n (
%)
70
Middleeast
(n=27)
SouthAsia
(n=239)
SoutheastAsia
(n=91)
Latin Am/Caribbean
(n=41)
Alldeveloping
regions(n=508)
Causes of serious bacterial infections in babies aged 0-3 days in hospitals of developing countries (1990-2004)
GBS E.coliKlebsiella spp, Pseudomonas spp, Acinetobacter spp,and other gram negative rods
S aureus Others
Neonatal Infections in AsiaIran, Thailand, China, Malaysia, Hong Kong, India, Australia
Organisms causing early-onset sepsisOrganism n (%)
Group B streptococcus 18 (38)Coagulase-negative staphylococcus 8 (17)Escherichia coli 6 (13)Staphylococcucs aureus 2 (4) Other Gram-negative bacilli 11 (23)Other Gram-positive cocci 2 (4)
Total 47 (100)Tiskumara, Arch Dis Child Fetal Neonatal Ed 2009
Isaacs et al, Arch Dis Child Fetal Neonatal Ed 2003
Day of first positive culture of coagulase negative staphylococci from blood or cerbrospinal fluid
Day of first positive culture
Nu
mb
er
of
infe
cte
d b
abie
s
3 5 7 9 11 13 15 17 19 21 23 25 27 290
10
100
20
30
40
50
60
70
80
90
Preterm infant/Newborn Microorganisms
Cellular and Factors of virulencehumoral defense - adherence - capsules
- biofilm- endotoxin (LPS)- lipoteichoic acid (LA)
LA: cell wall constituent of Gram-positive bacteria
Innate immunity
Granulopoesis in Newborns and Adults Newborns Adults
CFU - GM (%) 10 100Proliferation (%) 80 25Bone marrow reserve (%) 25 100Neutrophil releaseduring sepsis
Christensen et al, 1986, 1988; Cairo et al, 1990 Banerjea, Speer, Semin, Neonatol, 2002Manroe et al., J Pediatr 1977
Total Number of Neutrophils
15000
10000
25000
20000
5000Neu
trop
hils
(m
m³)
12 24 36 48 60 5 10 15 20 25 80hours days
Postnatal Age
Contact Rolling Firm Adhesion Diapedesis
Shedding
E-selectinP-selectinReceptor
L-selectins-Lex PSGL-1
LFA-1
LFA-1
CR-3
CR-3
ICAM-1 ICAM-2
Capillary
Tissue
Urlichs, Speer NeoReviews 2004
Adherence and Receptor Expression by Neutrophils From Pretern and Term Infants Compared With
Cells From Adults
Preterm TermGeneral adherence
"Rolling"
L-selectin (CD62L) expression
L-selectin shedding
CR3 (CD11b/CD18)- surface expression
- upregulation
LFA-1 (CD11a/CD18) expression N N
NN
N = normal; = decreased
Urlichs, Speer NeoReviews 2004
Circulation
Deformability Deformability
Chemotaxis Chemotaxis
Phagocytosis
Killing
Apoptosis
Capillary Tissue
Microorganism
Chemi-luminescence
O2
H2O2
OH
Degranulation Adherence Adherence
Ser
um
- G
Glu
bo
lin
( m
g p
er 1
00
ml )
Hobbs, Davis, Lancet 1967
Serum G-globulin levels on logarithmic scale plotted against gestational age on linear scale
Estimated Gestation (weeks)
2000
1000800
600
400
300
200
100
5020 25 30 35 40
C 3bspecific IgG
opsonisedbacterium
Fc-receptor C3b-receptor
Lysosome
cellmembrane
Phagocytosis
CD 14
NF-kB
TRAF-6
TRIF
MyD88
Mal
Recognition of cell wall components of Gram-positive andGram-negative bacteria by Toll-like recepors TLR2 and TLR4
Transcription of
inflammatory cytokines
MyD88
Mal
TLR2 TLR4
PeptidoglycansLipopeptides
LPSLipoteichoicacid
Cell
LPS
Toll-like receptors
Concentrations TNF-α
low ● adhesive molecules● activation of neutrophils, monocytes , macrophages
high ● massive release of proinflammatory cytokines● activation of clotting- and complement system
very high ● hypotension● myocardial depression● DIC
Activation of Immune Cells by LPS and by GBS Cell Wall Constituents
GBS (cell wall, soluble factors)
Berner et al, Pediatr Res 2001, Henneke et al, J Immunol 2002
Different GBS-Strains and Platelet Aggregation
-20
Pla
tele
t A
gg
reg
atio
n 0
20
40
60
80
100
0 6 12 18 24 30
GBS-strain (GS130903);
colonization of skin
Platelets (no bacteria)
GBS-referencestrain(ATCC13813)
GBS-strain (SJ250903);Neonatal Sepsis
minutesSiauw, Speer; Thromb Hemost, 2006
Partial Systemic Immunodeficienciesof Preterm and Term Infants
● IgG-concentrations in preterm infants
● Specific antibodies
● Complement activity in preterm infants
● Opsonin-dependent phagocytosis
● Bone marrow reserves
● Phagocyte functions- adherence- chemotaxis
● Myd88 expression in neonatal monocytes
following TLR2 and TLR4 stimulation
● Production of IFN-γ by neonatal lymphocytes
● Activation of macrophages
Immune Therapies
• Exchange transfusion No benefit
• Granulocyte transfusion Insufficient evidence 1
• G-CSF, GM-CSF Insufficient evidence 2
• Immunoglobulins Insufficient evidence 3
1 Mohan, Brocklehurst, Cochrane Database 20032 Cars et al, Cochrane Database 20033 Ohlsson, Lacy, Cochrane Database Syst Rev 2004;
Prevention of Sepsis by Immunoglobulins
Randomized contr. double-blinded multicenter trial:Preterm infants 500 - 1500 g (n = 2416)
Sepsis Nosocomial MortalitySepsis
IgG 16 % 17 % 11 %
Placebo 17 % 19 % 11 %
Fanaroff et al, NEJM, 1996
Meta-Analysis of Intravenous Immunoglobulins (IVIG)
• Prophylaxis1
- 3 % reduction in sepsis (p < 0.02)- No reduction in mortality or other severe outcomes
(IVH, NEC etc.)
• Therapeutic administration2
- inconsistent effects
• Conclusion:
There is currently insufficient evidence to support prophylactic or therapeutic IVIG to prevent mortality in infants with neonatal sepsis3
1 Ohlsson, Lacy, Cochrane Database Syst Rev 2004;2 Ohlsson, Lacy, Cochrane Database Syst Rev 2004; 3 Suri, Cairo, Curr Opin Pediatr 2003
● Universal screening of all pregnant women at 35 to 37 weeks’ gestational age is the proposed standard of care. It prevents more cases of early onset disease than the risk-based approach.
● Intrapartum prophylaxis has decreased the incidence of early-onset GBS sepsis by 70 %.
● Penicillin G remains the drug of choice for intrapartum prophylaxis
● For patients who are allergic to penicillin but do not have a history of anaphylaxis,cefazolin is the preferred
choice
Schrag et al, NEJM 2002; Tumbage, Philip, NeoReviews 2003
New Guidelines for GBS Prevention-American Academy of Pediatrics and
American College of Obstetricians and Gynecologists -
Rate of early-onset and late-onset invasivegroup B streptococcal disease in infants, by year
United States, 1996-2004
Cas
es p
er 1
000
Liv
e B
irth
s
1996 1997 1998 1999 2000 2001 2002 2003 20040.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Year
Early-onset diseaseLate-onset disease
Prophylaxis protocolimplemented
De Gueto et al, Obstet Gynecol, 1998
Timing of Intrapartum Ampicillin Administration
and Rate of Vertical Transmission
< 1 h 24 11 (46)
1 to 2 h 21 6 (28)
> 2 to 4 h 70 2 (2.9)
> 4 h 86 1 (1.2)
Control group 253 120 (47)(no ampicillin)
Time Between Ampicillin Administration and Delivery
Number of Group B Streptococci Carriers
Number of Colonized Newborns (%)
● Pediatric recommendations suggest a 48-hour
observation period for infants whose mothers
received antibiotics
● With the exception of maternal chorioamnionitis
routine use of antibiotics in infants whose mothers
have received adequate treatment is not indicated
● Postnatal penicillin prophylaxis in infants has been
associated with an increased mortality and is not
recommended
Tumbaga, Philip, NeoReviews 2003
Intrapartum Antibiotics and Consequences on Newborn Treatment
Maternal Antibody to Capsule
Health Disease
Gestation > 37 weeksPROM < 12 hoursLess virulent GBS
Low inoculum
Gestation < 37 weeksChorioamnionitisPROM > 18 hours
Virulent GBSHigh inoculum
Exposure
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
His
tolo
gic
al c
ho
rio
am
nio
nit
is %
Gestational Age (completed weeks)
n=261 n=
139
n=200
n=164
n=236
n=284 n=
375 n=380
n=539
n=580 n=
770
Frequency of a positive amniotic fluid (AF) culture and intraamniotic inflammation
Shim et al, Am J Obstet Gynecol, 2004
%
80
60
40
20
020-27 27-30 30-33 33-35
Gestational age (weeks)
intra-amniotic inflammation (P< .001) positive AF culture (P< .05)
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 from neonates delivered between 23 – 27 weeks was cultured and tested by PCR , n = 1365
Results: Culture positive68% of vaginal deliveries41% of caesarean sections
30% had only aerobic bacteria21% had only anaerobic bacteria9% had Mycoplasma / Ureaplasma
Conclusion: Approximately half of second – trimester placentas harbour organisms within the chorionic plate
Intrauterine Cytokine Exposure
Systemic Fetal Inflammatory Response
Elevated IL-6 concentrations in
umbilical cord blood
Yoon et al, Am J Obstet Gynecol, 1999
TNF-IL-1IL-8
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
ResultsU. urealyticum an for M. hominis were present in 23% of cord blood 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).
Twenty percent of very preterm neonates(23-32 weeks of gestation) are born with
bacteremia caused by genital Mycoplasmas
Romero, Garite, AJOG, 2008
Yoder, Coalson et al, Pediatr Res 2004
Colony forming units for Ureaplasma urealyticum at delivery and postnatal
tracheal aspirates in premature baboons
CF
U`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=5Animals with persistently positive cultures (Uu+), n=4
(amniotic fluid)
Effects of antenatal colonization with Ureaplasma 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
Increased risk for VLBW infants to develop
- Neonatal sepsis 1, 2, 3, 4, 5,6
- Severe intracerebral hemmorhage (ICH) 1, 3, 5
- Periventricular leukomalacia (PVL) 1, 3, 5
1 Alexander et al, Obst Gynecol 1998; 2 Dexter et al, Obstet Gynecol 1999; 3 Morales, Obstet Gynecol 19874 Beazley, Am J Obstet Gynecol 1998; 5 Ramsey et al, Am J Obstet Gynecol 2005;6 Constantine et al, Am J Obst Gynecol 2007; 7 Stoll et al JAMA 2004
Premature Ruptureof Membranes
Maternal Amnionitis
Neurodevelopmental and growth impairment among extremely LBWI with neonatal infection7
- Bronchopulmonary dysplasia 1-7
Clinical Signs of Sepsis
•Respiratory distress
• Thermal instability
- hyperthermia
- hypothermia
• Pallor, peripheral vasoconstriction
• Abdominal distension, vomiting, poor feeding
• Irritability
• Lethargy
• Apnoea
Early Identification and Alarm Signs of Sepsis
• Obstetrical risk factors• Clinical symptoms• Markers of inflammation
- leucocytes- total number of neutrophils (T)- total number of immature neutrophils (I)- I/T-ratio- CRP- IL-6- others
• Identification of microorganisms; blood culture 0.5ml; frequently an insufficient amount of blood is drawn
Time (hours)
Microbial invasion
Symptomatik
Recruitment and activation of neutrophilis and macrophages
Mediator release by macrophages
TNF-
IL-1
Organ ReactionLiver: akute Phase-Reaction
CRP
IL-6
Hours after challenge
Pla
sma
leve
ls (
Arb
ittr
ay U
nit
s)Cytokine profile kinetics after
experimental endotoxemia
Abbas AK: Cell Mol Immunol, 1994
0 1 2 3 4 5
LPS
TNF
IL-1
IL-6CRP
Diagnostic Tests for “Early Identification” or “Ruling out” of Sepsis
Conclusion
• No single individual test or combination of tests has a positive predictive accuracy of sepsis more than 40 %
• Serial CRP determinations or sepsis screens (WBC, neutrophil counts, CRP, IL-6) have an extremely high negative predictive accuracy of sepsis (> 99 %) and can be helpful in ruling out infection
Polin, J Pediatr 2003
Empiric use of ampicillin and cefotaxime, compared with ampicillin and gentamicin, for neonates at risk for sepsis is associated with an increased risk of neonatal death.
Clark RH, Bloom BT, Spitzer AR, Gerstmann DR
BACKGROUND: Use of cephalosporins among premature neonates increased the risk of subsequent fungal sepsis. As a result, it is recommended that ampicillin and gentamicin be used as empiric coverage for early-onset neonatal sepsis while culture results are awaited.RESULTS: There were 128,914 neonates selected as the study cohort; 24,111 were treated concurrently with ampicillin and cefotaxime and 104,803 were treated concurrently with ampicillin and gentamicin. Logistic modeling showed that neonates treated with ampicillin/cefotaxime were more likely to die :adjusted odds ratio: 1.5; 95% confidence interval: 1.4-1.7
Pediatrics, 2006;117:67-74