Early-onset Sepsis :clinical And Laboratory Challenge

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 EARLYONSET 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 earlyonset 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 noninfected 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 &TNFalpha 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