Professional Documents
Culture Documents
• 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
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
< 33 wk 30 %
34 – 36 wk 10 %
> 37 wk 2%
50
40
(%)
30
20
10
0
USA Germany Spain Israel Nigeria Pakistan Panama
2000 1997 2000 1997 1999 2000 1994
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)
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
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
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
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
GBS-strain (GS130903);
-20 colonization of skin
0
Platelet Aggregation
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
• 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
IgG 16 % 17 % 11 %
Placebo 17 % 19 % 11 %
<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)
Health Disease
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)
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).
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
•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
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 %