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2nd International Neonatology Conference

April 2 - 4, 2009 Alexandria, Egypt

Neonatal septicemia: Current concepts and


the role of neonatal host defense

Prof. Christian P. Speer, MD, FRCPE


Director and Chairman
University Children’s Hospital Würzburg, Germany
Neonatal Sepsis

• Incidence 1- 4 Newborns /
1000 LB / Year
• Meningitis 5 - 25 %
• Case fatality ~ 25 % (5 - 60%)
Neonatal Sepsis
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
1
Vergnano 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
• Women colonized with GBS* prenatally have a
25 fold higher risk of delivering a baby with
early onset GBS compared with non-colonized
women
Barcaite et al Acta Obstet Gynecol 2008 (Review) *GBS: Group B-Streptococci
Route of Infection
Mikroorganismen
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


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 8.5-57
28-31 34 18-62
32-34 11 6-21
35-36 5 2- 9
37-41 3.5 2-6.5
≥ 42 1.9 1-3.7

S Hakansson, K Källén, BJ0G 2006


Case Fatality Rates of Neonates with
Early-Onset GBS-Sepsis in the United Sates,
1993 – 1998
n = 1584

Gestational Age Case Fatality

< 33 wk 30 %

34 – 36 wk 10 %

> 37 wk 2%

Schrag SJ et al, NEJM 2000


Case fatality rates
for E. coli sepsis
(Australasia, 1992 – 2001)

Birthweight Case fatality rates

<1500g 33/66 (50%)

>1500g 2/30 (7%)

Daley AF et al. Pediatr Infect Dis J 2004


Predominant Microorganisms
Responsible for Septicemia
60

50

40
(%)

30

20

10

0
USA Germany Spain Israel Nigeria Pakistan Panama
2000 1997 2000 1997 1999 2000 1994

GBS coag.-neg. Staphylococci Klebsiella Species E.coli

Banerjea, Speer, Pädiat Prax, 2002


Causes of serious bacterial infections in babies aged 0-3
days in hospitals of developing countries (1990-2004)
70
60
Proportion (%)

50
40
30
20
10
0 All
Africa Middle South Southeast Latin Am/ developing
east Asia Asia Caribbean regions
(n=110) (n=27) (n=239) (n=91) (n=41) (n=508)

GBS E.coli S aureus Others


Klebsiella spp, Pseudomonas spp, Acinetobacter spp,and other gram
negative rods

Zaudu AKM et al. Lancet 2005


Neonatal Infections in Asia
Iran, Thailand, China, Malaysia, Hong Kong, India, Australia

Organisms causing early-onset sepsis


Organism 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
Day of first positive culture of coagulase negative
staphylococci from blood or cerbrospinal fluid

100
Number of infected babies

90
80
70
60
50
40
30
20
10
0
3 5 7 9 11 13 15 17 19 21 23 25 27 29
Day of first positive culture

Isaacs et al, Arch Dis Child Fetal Neonatal Ed 2003


Preterm infant/
Newborn Microorganisms

Cellular and Factors of virulence


humoral defense - adherence
- capsules
Innate immunity - biofilm
- endotoxin (LPS)
- lipoteichoic acid (LA)

LA: cell wall constituent of Gram-positive bacteria


Total Number of Neutrophils
25000
Neutrophils (mm³)

20000

15000

10000

5000

12 24 36 48 60 5 10 15 20 25 80 Postnatal Age
hours days
Granulopoesis in Newborns and Adults
Newborns
Adults
CFU - GM (%) 10
100
Proliferation (%) 80
25
Bone marrow reserve (%) 25
100
Manroe et al., J Pediatr 1977
Neutrophil
Christensen release
et al, 1986, 1988; Cairo et al, 1990 Banerjea, Speer, Semin, Neonatol, 2002
Capillary
LFA-1 CR-3

LFA-1 Shedding
CR-3

L-selectin PSGL-1
s-Lex
Receptor P-selectin
E-selectin

ICAM-1 ICAM-2

Tissue

Contact Rolling Firm Adhesion Diapedesis


Urlichs, Speer NeoReviews 2004
Adherence and Receptor Expression by Neutrophils
From Pretern and Term Infants Compared With
Cells From Adults

Preterm Term
General adherence
"Rolling"
L-selectin (CD62L) expression
L-selectin shedding
CR3 (CD11b/CD18)
- surface expression N N
- upregulation
LFA-1 (CD11a/CD18) expression N N
N = normal; = decreased
Urlichs, Speer NeoReviews 2004
Circulation Apoptosis

O2
H2O2
Chemi- OH
Killing
Adherence luminescence
Degranulation

Microorganism

Phagocytosis
Deformability
Chemotaxis

Capillary Tissue
2000

1000
800
Serum-γ G Glubolin

600
( mg per 100 ml )

400
300

200

100

20 25 30 35 40
50
Estimated Gestation (weeks)
Serum γ G-globulin levels on logarithmic scale plotted against
gestational age on linear scale

Hobbs, Davis, Lancet 1967


C 3b
specific IgG
opsonised
bacterium

Fc-receptor C3b-receptor

cell
membrane
Lysosome

Phagocytosis
Recognition of cell wall components of Gram-positive and
Gram-negative bacteria by Toll-like recepors TLR2 and TLR4

Peptidoglycans LPS
Lipopeptides 1 4 Lipoteichoicacid
CD

TLR2 TLR4

Mal Mal
TRAF-6
MyD88 MyD88
TRIF
Cell NF-kB

Transcription
of
inflammatory cytokines
Activation of Immune Cells by LPS
and by GBS Cell Wall Constituents
LPS GBS (cell wall, soluble factors)

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

Berner et al, Pediatr Res 2001, Henneke et al, J Immunol 2002


Different GBS-Strains and Platelet Aggregation

GBS-strain (GS130903);
-20 colonization of skin

0
Platelet Aggregation

Platelets (no bacteria)

20

40

60

80 GBS-
reference
100 strain GBS-strain (SJ250903);
(ATCC13813) Neonatal Sepsis
0 6 12 18 24 30
Siauw, Speer; Thromb Hemost, 2006
minutes
Partial Systemic Immunodeficiencies
of 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 2003
2
Cars et al, Cochrane Database 2003
3
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 Mortality


Sepsis

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
New Guidelines for GBS Prevention
-American Academy of Pediatrics and
American College of Obstetricians and Gynecologists -

● 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
Rate of early-onset and late-onset invasive
group B streptococcal disease in infants, by year
United States, 1996-2004
Cases per 1000 Live Births

1.0 Prophylaxis protocol


implemented
0.9
0.8
Early-onset disease
0.7 Late-onset disease
0.6
0.5
0.4
0.3
0.2
1996 1997 1998 1999 2000 2001 2002 2003 2004
Year
Timing of Intrapartum Ampicillin
Administration
and Rate of Vertical Transmission

Time Between Ampicillin Number of Group Number of


Administration and B Streptococci Colonized
Delivery Carriers Newborns (%)

<1h 24 11 (46)
1 to 2 h 21 6 (28)
> 2 to 4 h 70 2 (2.9)
>4h 86 1 (1.2)
Control group 253 120 (47)
(no ampicillin)

De Gueto et al, Obstet Gynecol, 1998


Intrapartum Antibiotics and Consequences
on Newborn Treatment

● 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


Exposure

Gestation < 37 weeks


Gestation > 37 weeks Chorioamnionitis
PROM < 12 hours PROM > 18 hours
Less virulent GBS Virulent GBS
Low inoculum High inoculum

Health Disease

Maternal Antibody to Capsule


Histologic Chorioamnionitis

70 n=
261 n=
n=
Histological chorioamnionitis %

200
60 139
n=
164
50
n= n=
236 284
40 n=
375 n=
380
30 n=
n=
539
580 n=
20 770

10

0
20-24 25 26 27 28 29 30 31 32 33 34
Gestational Age (completed weeks)

Lahra and Jeffrey, AJOBGYN, 190:147, 2004
Frequency of a positive amniotic fluid (AF) culture
and intraamniotic inflammation

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)

Shim et al, Am J Obstet Gynecol, 2004


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 positive


68% of vaginal deliveries
41% 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

Onderdonk et al AJ0G 2008


Intrauterine Cytokine
Exposure
TNF-
α
IL-1
IL-8
Systemic Fetal
Inflammatory Response

Elevated IL-6
concentrations in
umbilical cord blood
Yoon et al, Am J Obstet Gynecol, 1999
The Alabama Preterm Birth Study: Umbilical cord blood
Ureaplasma urealyticum and Mycoplasma hominis cultures
in very preterm newborn infants
Study
351 mother / infant dyads with deliveries between 23 and 32
weeks’ gestational age
Results
U. 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).

Goldenberg et al, AJOG 2008


Twenty percent of very preterm neonates
(23-32 weeks of gestation) are born with
bacteremia caused by genital Mycoplasmas

Romero, Garite, AJOG, 2008


Colony forming units for Ureaplasma
urealyticum at delivery and postnatal
tracheal aspirates in premature baboons
10.000.000

1.000.000
CFU`s

100.000
10.000

1.000

100

10
1
AF 24 hr 72 hr 144 hr 240 hr 336 hr
(amniotic fluid)

Animals with negative culture at 14 days of postnatal age (Uu -), n=5
Animals with persistently positive cultures (Uu+), n=4
Yoder, Coalson et al, Pediatr Res 2004
Effects of antenatal colonization with
Ureaplasma urealyticum on pulmonary disease
in the immature baboon

Uninfected Uu - negative Uu - positive


animals ventilated animals at 14 animals at 14
for 14 days days of age days of age
Yoder, Coalson et al, Pediatr Res 2004
Premature Rupture
Maternal Amnionitis
of Membranes

Increased risk for VLBW infants to develop


- Neonatal sepsis 1, 2, 3, 4, 5,6

- Bronchopulmonary dysplasia 1-7

- Severe intracerebral hemmorhage (ICH) 1, 3, 5


- Periventricular leukomalacia (PVL) 1, 3, 5
Neurodevelopmental and growth impairment
among extremely LBWI with neonatal infection7
1
Alexander et al, Obst Gynecol 1998; 2 Dexter et al, Obstet Gynecol 1999; 3 Morales, Obstet Gynecol 1987
4
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
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
Microbial invasion

Recruitment and activation of neutrophilis and macrophages

Mediator release by macrophages

TNF-α
IL-1

IL-6

Organ Reaction
Liver: akute Phase-Reaction
CRP

Symptomatik

Time (hours)
Plasma levels (Arbittray Units) LPS Cytokine profile kinetics after
TNF experimental endotoxemia

IL-1

IL-6
CRP

0 1 2 3 4 5
Hours after challenge
Abbas AK: Cell Mol Immunol, 1994
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