Ear ly -onse t sepsis :cl in ica l a nd

la bo ra tor y c hal le ng e

By
Shadia El Sallab
Prof. of pediatrics
Mansoura
University
A pretem baby 34w
gestation,1.5 kg
Presented 4h after
birth with severe R.D

What is your diagnosis ?

RDS
 Baby put on ventilator
Given surfactant

with clinical deterioration

x-ray was repeated

A 2nd dose of surfactant was

given
6h later , as there is no clinical
improvement
A sepsis work-up was done
The diagnosis is changed to
probably

EARLY-ONSET PNEUMONIA

Antibiotics was instituted , but the baby

deteriorated with poor perfusion and
hypotension & Death occurs at 24 h of life
WHAT IS EARLY-
ONSET SEPSIS
Definition of early –onset sepsis

Sepsis appearing within 72 h of life

50% appear within 6h. of birth , 85% within

24h.
Causative organisms:
EOS is usually due to organisms transmitted
from mother to baby

GBS & gram-ve enteric organisms

(predominantly E.Coli) accounts for 70% of early-
onset sepsis

H.influenza , klebsiella

Listeria monocytogenes ,Enterococci ,Staph.

Clinical presentation
Most neonates with early onset sepsis presents with
respiratory distress (fulminant pneumonia):90%
Temperature instability ,Poor perfusion ,hypotension
and shock
Meningitis is very rare
Mortality rate even with treatment is 15-50%

Sometimes ,the signs and symptoms are

inconspicuous and can be easily confused with other
non-infective causes :
D.D. of EOS
Asymptomatic newborns at birth with risk
factors
3groups

1-asymtomatic babies with maternal risk factors

2- symptomatic babies at or shortly after birth
3-babies with equivocal signs and symptoms;
suspected infection
In view of the potentially serious outcome
associated with delayed treatment and the
difficulty in distinguishing infected from
non-infected cases, it has become
common practice to prescribe antibiotics for :
So the current practice is characterized by
frequent antibiotic treatment despite low
incidence of true infection
Why empiric antibiotic therapy is dangerous ?

The high prevalence of unnecessary antibiotic therapy

augments the risk of emerging resistant bacterial
strains

Prolonged duration of initial empiric antibiotic therapy

> 5days started in in the 1st 3days of life is associated
with increased rate of NEC& death for extremely low
birth weight and should be used with caution .
(a retrospective cohort study by COTTON et al .pediatrics
(January 2009 )
Diagnostic challenge

Accurate and timely diagnosis of early –onset

sepsis remains challenging to the clinician and
laboratory as if patient escapes early diagnosis
EOS may progress to septic shock

So a test with rapid turnaround time with100% sensitivity

,rather than high specificity which allows accurate
diagnosis and appropriate antimicrobial treatment or
which allow antibiotics to be safely withheld in non-
infected infants,,is desirable
Sepsis work-UP
 CBC
CDC in 1996 recommended obtaining CBC from all
clinically septic & asymtomatic at risk newborns

Total WBCs >.30.000 or <5000/mm3

Absolute neutophil count (ANC) :<1500/mm3
Band /Neutophil ratio (I:T ) >0.2
Thrombocytopenia

Sensitivity & specificity of WBCs in predicting which newborns

would develop sepsis were 41% and 73%respectively
Limited accuracy of WBCs
large overlap with normal values for WBCs
33% of septic infants had normal I:T initially but all
septic infants had abnormal I:T ratio at 12-24h

36% of healthy neonates at 4h of age have

abnormal leukocyte indices

The sensitivity of physical examination and

symptoms is greater than that of I/T ratio or
ANC
Blood culture
Culture –proven sepsis: symptoms of bacterial
infection + positive blood culture
Culture- negative : (blood culture misses 18% of
sepsis)
1- probable sepsis :clinical symptoms + host
response
2- possible sepsis :equivocal clinical findings
Value of Bc in asymptomatic at risk

Non of the babies at risk who remained

asymptomatic had +veblood culture (ortollani et
al 1999)

blood culture did not aid in diagnosis of sepsis

among asymptomatic at risk newborns and
24h of close observation is mandatory
lumbar puncture
Menigitis is rare & non is asymtomatic
LP is Controversial

L.P. may be postponed or excluded from the

evaluation of infant with suspected EOS

Meningitis cannot be diagnosed or excluded

solely on the basis of CNS symptoms and so LP
is mandatory in symptomatic EOS
 CRP
Is produced by the liver under the influence of IL-1 &TNF-
alpha when inflammation is present. rise begins in 4-6h
peaks at 2-3 days , remain elevated with ongoing
inflammation but with resolution they decline rapidly due to
short half life

A single normal value cannot rule out infections because

the sampling may have preceded the rise in CRP, serial
determination are therefore indicated at 12,24 &48h
(Benitz et al 1998)

3 serial CRP had sensitivity of 97.8% & specificity of

98% for proven or probable sepsis
Value of CRP
2 CRP under 10mg/l 24hs apart make sepsis
highly unlikely
False positive rate of 8% is found in healthy
neonates
CRP is a valuable adjuncts
1. in the diagnosis of sepsis ,
2. In monitoring the response to treatment
3. guiding the duration of treatment
NPV is 97-99% so can be used to determine
when antibiotics can be safely discontinued
New markers
Many new markers,including cytokines and
cell surface markers have been suggested to
improve decision making ,but the clinical
efficacy of these techniques remain uncertain
and combination of markers will ensure
greater diagnostic accuracy
cytokines

IL-6 and TNF-alpha :

Giardian&collegues: European j.ped.149:1990
when both tests are positive ,the diagnosis of
neonatal sepsis is almost certain.

sensitivity is 60% ,specificity is 100%

Ng (2004 )
:
IL-6&CRP:
Buck& co-workers : ped.93,1990:
The combination of both may be helpful in early
diagnosis of sepsis while awaiting for culture
results

G-CSF
Russel et al BR.j.Hematology 86 1994
Infected newborns had a much peak conc.than
non-infected infants
G-CSF and IL-8
(Fisher et al. intensive care medicine 2002)
High level is associated with likely sepsis

Tracheal aspirate levels of G-CSF

(Fisher et al :lancet 1998)
Used to diagnose localized lung infection as
localized infections cannot be diagnosed on
basis of blood- derived cytokines
A study comparing CRP, TNF receptors and
soluble adhesion molecules (ICAM-1,E-Selectin)
Hench&et al(j.clinical epidemiology December2001)
concluded that
CRP was the best simple test to predict sepsis
Diagnostic accuracy was improved by combining
IL-6 to CRP whereas the other parameters added
no further diagnostic information
IL-6 and IL-10
(Ehab khairy et al , egyptian j.of neonatology vol 8,,may 2007)
(Ng et at al(2003) archives of disease in , fetal & neonatal
ed.88:F209)

Early estimation of IL-6 & IL-10 in neonates with

suspected sepsis is of diagnostic value and
increased IL-6/IL-10 ratio is correlated with poor
outcome and with prolonged hospital stay
CRP,IL-6,and Procalcitonin
(Chiesa et al,clinical chemisty 2003,49:60-68)

Increased levels in the presence of bacterial

infections and that the increase is
independent of illness severity
cell surface markers
Surface neutophil CD11 (Ng 2004)
Has been shown to be an excellent marker of
early infection that correlates well with CRP
but peaks earlier
Surface neutrophil CD64 (Safaa Meneza et al .thesis
2009):
Was found as useful marker to differentiate
infectious from non-infectious causes of RD
In most tests ,evaluation of the results have
been conflicting and the results of diagnostic
tests must be evaluated in the light of clinical
condition of the baby
conclusion
In all symptomatic cases ,start empiric antibiotic
therapy &-ve WBCs &CRP screen do not overrule
symptoms

Asymtomatic at risk of EOS : WBCs &CRP

at 12, 24 & 48h of age
-ve diagnostic screen : clinical observation
+ve diagnostic screen empiric antibiotic
therapy for 48-72h pending -ve blood culture
THANK
YOU