Central Annals of Clinical and Medical Microbiology

Review Article *Corresponding author

Biomarkers in early-Onset
Athis Arunachalam, Department of Pediatrics, Texas
Children’s Hospital & Baylor College of Medicine,
Houston, TX 77030, USA, Tel: 832-826-1380; Fax: 832-825-

Neonatal Sepsis: An Update

2799; E-mail:
Submitted: 19 February 2015
Accepted: 24 July 2015
Athis Rajh Arunachalam* and Mohan Pammi Published: 11 September 2015
Department of Pediatrics, Texas Children’s Hospital & Baylor College of Medicine, Copyright
USA © 2015 Arunachalam et al.

OPEN ACCESS
Abstract
Globally, an estimated 500,000 newborns die each year from serious neonatal Keywords
infections, which account for about 15% of all neonatal deaths. “Suspected sepsis” • Early- onset neonatal sepsis
is one of the most common reasons for admission to the neonatal intensive care • Biomarkers
unit (NICU). The challenge to the physician has always been trying to differentiate
newborns with early onset sepsis from other non-infectious pathology whose clinical
features overlap with sepsis. Current diagnosis of early onset sepsis is a combination of
clinical presentation, non-specific biomarkers and blood culture. Traditional biomarkers
such as complete blood count (CBC) and C-reactive protein (CRP) have poor sensitivity
and positive predictive value. Current literature suggests the potential utilities of novel
biomarkers such as cell surface markers (CD11B, CD64), genomics, proteomics and
advanced molecular techniques in the diagnosis of neonatal sepsis. An ideal biomarker
or a combination of biomarkers will help clinicians in the judicious use of antibiotics in
early onset sepsis.

ABBREVIATIONS
EOS: Early Onset Sepsis; CRP: C - reactive protein; PCT:
Procalcitonin
INTRODUCTION
Sepsis continues to present a significant problem in the
neonatal intensive care units (NICU) worldwide [1]. Especially,
in this age of advanced neonatal care, sepsis burden assumes
even greater significance as extremely preterm infants are
increasingly being cared for in the NICUs. Sepsis in premature
infants is an important cause of morbidity and mortality [2,3]. The
risk of sepsis increases with decreasing gestational age and birth
weight. Neonatal sepsis has traditionally been classified as early-
onset sepsis (EOS), if the onset of infection is in the first 72 hours,
and late-onset sepsis (LOS) if the onset of infection occurs after
the first 3 days of life. This classification is helpful in targeting
the presumed bacterial pathogens based on the timing of their
acquisition. Typically, EOS is attributed to pathogens acquired by
vertical transmission from the maternal genital tract and LOS is
caused by pathogens acquired by horizontal transmission from
the caregivers and environment.
Epidemiology
Neonatal infections account for the majority of neonatal
deaths worldwide [1]. Globally, an estimated 500,000 newborns
die each year from serious neonatal infections, which account
for about 15% of all neonatal deaths [4]. The incidence of EOS
is ~ 0.7-1/1000 live births in developed world [5,6]. Based on
few hospital based studies performed in developing countries,
the incidence of EOS ranges anywhere from 2.2 to 9.8 per
1000 live births [7,8]. Neonatal sepsis also increasesshort term
and long term morbidities such asnecrotizing enterocolitis
(NEC), bronchopulmonary dysplasia (BPD), patent ductus
arteriosus (PDA), prolonged ventilation, neurodevelopmental
impairment and prolonged hospital stay [9-12]. Shatrov et al
in their meta-analysis showed significant association between
chorioamnionitis (clinical or histological)and cerebral palsy in
preterm and term children [13].
Enigma of “Suspected Sepsis”
“Rule out sepsis” or “Suspected sepsis” is one of the most
common reasons for admission to a NICU. The challenge to the
physician has always been trying to differentiate newborns with
sepsis from other non-infectious pathology whose clinical features
overlap with sepsis. Given the morbidities associated with
delayed identification of sepsis, the number of sepsis evaluations
performed in this population is very high. Several studies have
attempted to identify neonates who are infected at birth [14-17].
These studies focused on laboratory tests, including total and
differential white blood counts (WBC), C-reactive protein (CRP),
erythrocyte sedimentation rate and clinical symptoms to select
infants at high risk for sepsis. Similar to clinical signs of sepsis,
the conventional laboratory tests are also less reliable in the
newborn period. In the absence of an unequivocal evidence to
prove or disprove infection, empirical use of antibiotics is widely
prevalent. But widespread use of antibiotics is not without
potential adverse effects. In a study from the Neonatal Research
Network, prolonged empirical antibiotic use in extremely low
birth weight infants (ELBW) was associated with NEC and

Cite this article: Arunachalam AR, Pammi M (2015) Biomarkers in early-Onset Neonatal Sepsis: An Update. Ann Clin Med Microbio 1(2): 1007.

Central
death [18]. The other major problem worldwide as a result of
a widespread antibiotic use is antimicrobial resistance [19,20]
and hence there is an increased focus on antibiotic stewardship.
American Academy of Pediatrics (AAP) in its latest guidelines
has advocated withholding antibiotics in low risk neonates
pending blood culture results [21].A myriad of studies have been
conducted on various biological markers that may be useful in
the early diagnosis of sepsis [17,27,43,45,46]. This review will
focus on the utility of the biomarkers that have been investigated
in early onset sepsis in neonates.
Biomarkers
The sepsis work upon neonates includes complete blood
count (CBC), blood culture, and lumbar puncture [22]. Acute
phase reactants, especially CRP and procalcitonin are also part
of the sepsis workup in some units. Depending on the clinical
scenario, tracheal aspirate culture in intubated patients, urine
culture and chest x-ray are also used in the evaluation of EOS.
Complete Blood Count: WBC counts and the components of
WBC, absolute neutrophil count (ANC), absolute band count and
the ratio of immature to total neutrophils (I/T) in the blood are
parameters that are commonly used as screening tests for the
diagnosis of sepsis.
Total leukocyte counts (5000/mm3 to 30000/mm3) although
commonly used have a poor positive predictive value and have
poor diagnostic accuracy (low sensitivity and specificity) in sepsis,
[23,24]. Neutropenia is a more reliable marker for neonatal sepsis,
but the definition of neutropenia is dependent on gestational age,
delivery method (cesarean delivery without labor result in lower
counts than vaginal delivery) and altitude (elevated altitudes
have higher total neutrophil counts), [14,25,26]. The definition
of neutropenia in term and late preterm infants is a neutrophil
count<1800/mm3 at birth and <7800/mm3 at 12–14 hours of age
based on Manroe et al. [14]. Based on Schmutz et al, neutrophil
counts increased over the first several hours following delivery,
with peak values occurring between 6 and 8 h for infants more
than 28 weeks gestation and between 12 and 24 h for infants
delivered at less than 28 weeks [25].
Immature to total neutrophil count (I/T) ratio is considered to
be more specific than total leukocyte count in sepsis. In contrast
to absolute neutrophil count (ANC) and band count, I/T ratio is
at its peak (0.16) at birth and decreases to 0.12 with increasing
postnatal age. A single cut off value of 0.3 has a high negative
predictive value (NPV)(99%) but a poor positive predictive value
(25%)(27).I/T ratio of >0.2 is suspicious for sepsis. Notable inter-
reader differences in identification of bands in the blood smear
decreases its reliability in clinical practice. A retrospective study
by Murphy et al. showed that a negative blood culture at 24h of
age along with two serial normal WBC screens separated by 8
to 12 hours had a very high negative predictive value(100%) in
neonates empirically started on antibiotics at birth [28]. Overall,
low ANC, high band count and high I/T ratio are associated with
an increased risk of infection. In practice, it may be advantageous
to wait at least 6h after birth to obtain CBC, as multiple studies
have shown WBC and ANC to increase for the first 6h after birth
and also an established inflammatory response is a requisite
for inducing a noticeable leftward shift in the WBC [14,29,30].
Ann Clin Med Microbio 1(2): 1007 (2015)
Arunachalam et al. (2015)
Email:
In reality, components of WBC, i.e. ANC and I/T ratio have been
shown to be more useful for excluding infants without infection
rather than identifying newborns who are infected [21].
Platelet counts: Platelet counts are characterized by poor
sensitivity and specificity for the diagnosis of neonatal sepsis and
hence are unreliable for initiating or discontinuing antibiotics
[31,32].Mean platelet volume is also a poor marker of neonatal
sepsis [33].
C-reactive protein (CRP): CRP is an acute phase reactant
produced in the liver and an extensively studied biomarker in
neonatal sepsis. Inflammatory triggers like sepsis induces the
release of the cytokine IL-6 from various immune cells which in
turn stimulates the release of CRP. This increase in CRP is noted
within 8 h of infection and peaks at 24 h [34,35]. CRP levels change
significantly from baseline at 10-12h after onset of infection.
Hence a rising CRP is a strong predictor of infection.CRP should
be obtained 12-24h after onset of infection. Most studies use a
value of 10mg/L as a cut-off [36-38]. In viral infections the levels
usually do not rise above 5mg/l [38,39]. A low CRP [< 10mg/L]
at 18 h has a negative predictive value of 93% in EOS [40]. Benitz
et al. showed that serial normal CRP values are a strong evidence
to rule out bacterial sepsis [38]. The pitfalls of using CRP are; it
is a “late” marker of sepsis and it is elevated innumerous non-
infective conditions like meconium aspiration, hemolysis and
ischemia. In preterm infants, baseline CRP values are lower than
term infants [41].
Procalcitonin: Procalcitonin (PCT) is a propeptide of
calcitonin, produced by macrophages and hepatocytes. Serum
PCT levels increase rapidly in 2-4h and peaks at 6-12h in response
to bacterial infection [42]. PCT levels are elevated in early and
late onset neonatal sepsis and necrotizing enterocolitis [43]. A
meta-analysis of 29 studies revealed a sensitivity of 81% (74–
87%) and specificity of 79% (69–87%) [44]. The advantages of
PCT over CRP in sepsis include: rapid rise in response to infection
(useful in EOS), levels decline with control of infection (half life
is 24h), not typically affected by viral infections (specific for
bacterial sepsis) and it correlates with severity of infection [45].
PCT also has its own limitations. PCT is increased in newborns
requiring neonatal resuscitation,maternal GBS colonization and
prolonged rupture of membranes ≥18 h [43,46]. PCT in healthy
neonates increases gradually from birth to its peak at 24h and
decrease by 48h [43]. Therefore, to improve its diagnostic
accuracy, specific cutoff values needs to be established with
respect to different gestational age and postnatal age. Overall, in
EOS, PCT might be a better biomarker than CRP [47,48].
Cytokine Profile: Cytokines play a vital role in sepsis. They
are produced by neutrophils and various other immune cells in
response to sepsis. It is well established that levels of cytokines
such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6
and IL-8 are elevated in the serum in sepsis. Studies in neonates
have shown that proinflammatory cytokines such as IL-6, IL-8,
and TNFα level were higher in septic neonates than controls
[49,50]. IL-6 is an inducer of CRP and has been extensively
studied among all the cytokines in sepsis.IL-6 is a very early
marker with a very high sensitivity (75-90%) in EOS [51,52].
The limitation is that it has short half-life and hence less useful
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if not obtained within the first few hours of life [51].In current
scenario, measuring cytokines for diagnosis of EOS may not
be practical or cost-effective because enzyme immunoassay is
expensive and time consuming. An easily available, inexpensive
automated assay in the future might make cytokines an
attractive tool in the evaluation of neonatal sepsis. Evaluation
of a composite set of markers involving acute phase reactants,
leukocytes and cytokines/chemokines may increase sensitivity
and specificity in the diagnosis of sepsis, for e.g. CRP and IL-6
[53], CRP and leukocyte indices [54]. The lack of widespread
hospital laboratory availability of the tests and the need for serial
measurements may be limiting issues for their routine use.
Cell surface markers (Neutrophil CD64 and Neutrophil/
Monocyte CD11b): Various cell surface antigen markers are
activated by infection and their detection is made possible by
advances in flow cytometry technologies [55,56]. Neutrophil
CD64 and neutrophil/monocyte CD11b are such cell surface
antigenic markers that are activated by bacteria and therefore
could be a potential tool in the diagnosis of neonatal sepsis. A
recent study by Genel et al. showed that the expressions of CD64
and CD11b were significantly enhanced in the infection group
compared to the non-infective group and the controls. There was
no difference between the non-infected and control groups [57].
There may be several advantages in using CD64: a) Studies require
minimal blood (50 µL of whole blood), b) results are obtained in
(few hours within 4 hours), c) the persistent expression of CD64
for at least 24 hours gives the marker a wide diagnostic window
(in contrast to IL-6) and d) reliability is proven in neonatal sepsis
[58,59]. High cost and availability of resources are likely the
barriers for its use in clinical practice.
Molecular Techniques for Early Detection of Neonatal
Sepsis: Molecular techniques for diagnosis of infection may be
useful in infants whose mothers have received intrapartum
antibiotics, may provide rapid results and have better sensitivity
compared to blood cultures. Amplification methods such as
polymerase chain reaction (PCR) for the bacterial 16S rRNA
gene or hybridization methods such as microarrays have been
evaluated in clinical studies in neonates. In a meta-analysis of 23
included studies on PCR-based molecular methods, the summary
estimates of sensitivity and specificity with 95% CI intervals were
generated using the bivariate random effects model [60]. Mean
sensitivity and specificity were 0.90 (95% CI, 0.78 to 0.95) and
0.96 (95% CI, 0.94 to 0.97) respectively. The authors conclude
that molecular assays do not have sufficient sensitivity to replace
microbial cultures in the diagnosis of neonatal sepsis but may
perform well as ‘add on’ tests.
Genomics and Proteomics: In the quest to discover novel
biomarkers with high sensitivity and specificity in sepsis, the
fields of proteomics and genomics are helping us understand the
fundamental mechanisms of sepsis. In sepsis, genomics is used
to identify genes that are preferentially up regulated in infection
using sophisticated DNA sequencing methods and bioinformatics
[61]. Host genetic background is an important factor influencing
the host response to infection. Genomics potentially could
uncover this host genetic variability that likely results in the
variable clinical presentation and outcome of neonates infected
with similar pathogens [62]. Proteomics is used to analyze the
Ann Clin Med Microbio 1(2): 1007 (2015)
Arunachalam et al. (2015)
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structure, function and interaction of specific proteins that
are elevated in blood or other samples as a result of infection
using mass spectrometric methods. Proteomic methods have
identified several proteins, that are increased in neonatal sepsis
[63]. Proteomic analyses of amniotic fluids have also provided
useful information regarding the fetal response to intra-amniotic
inflammation [64]. Currently, novel methods using genomics and
proteomics are being researched that can be translated to the
bedside in the future, to guide therapy decisions.
Suggested pragmatic approach to common clinical
scenarios in EOS [65]
[i] Asymptomatic neonates born to mothers diagnosed and or
treated for chorioamnionitis:
Intervention: Obtain CBC, CRP/PCT (optional) at 6-12h after
birth and blood culture. Start empirical antibiotics based on
institutional antibiotic protocols.
a) If normal labs, negative blood culture and well
appearing newborn: Discontinue antibiotics at 48 h. In preterm
infants, consider discontinuing antibiotics after 48-72h, given the
higher risk of infection in premature infants.
b) If abnormal labs, negative blood culture and well
appearing newborn: There is a dichotomy in expert opinion
in this scenario due to paucity of scientific evidence. The two
approaches are as follows.
- Physician may elect to continue antibiotics for a
longer period of time (5-7 days) if there are strong risk factors
for infection, especially in the setting where mothers received
antibiotics, which make postnatal blood cultures less sensitive.
Some clinicians may choose to discontinue antibiotics
after 48-72 h. The rationale to discontinue antibiotics despite
‘abnormal’ labs is that the supplementary tests for neonatal
sepsis are better at excluding sepsis but not very reliable in
predicting the presence of sepsis (40% or less) [54]. Although
a 40% risk of sepsis cannot be written off, it is highly unlikely
for a well appearing newborn who is feeding well with normal
physical examination at 48 h to have sepsis [66, 67].
ii] Asymptomatic term and late preterm neonates with
antenatal risk of infection (prolonged rupture of membranes>18h,
foul smelling liquor) may be observed for 48h with no antibiotics
after obtaining blood culture at birth. Infants not started on
antibiotics must be monitored closely for at least 48 hours (vitals
check every 2-4h) before discharge.
iii] Symptomatic term neonates with no antenatal risk of
infection and with evidence of rapidly improving symptoms in
the first few hours of life (4-6h), may have their antimicrobial
therapy withheld and monitored clinically. As mentioned above,
clinical features of neonatal sepsis at birth, such as tachypnea
overlap with those of non-infectious etiologies such as transient
tachypnea of newborn (TTN).
SUMMARY AND CONCLUSION
Despite several studies on various diagnostic markers, further
research is needed to identify a rapid, reliable and an inexpensive
biomarker. CBC, CRP and procalcitonin are currently the most
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commonly used biomarkers in clinical practice in the setting of
EOS. In the absence of an ideal marker to rule in or rule out an
infection, physicians need to rely on clinical symptomatology
and temporal course of the symptomatology and monitoring.
More reliable biomarkers will help clinicians in the judicious
use of antibiotics that will decrease antimicrobial resistance.
The goal of sepsis evaluation is not only to avoid sepsis related
morbidity and mortality but also to avoid the unwanted exposure
to antibiotics.
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Cite this article

Arunachalam AR, Pammi M (2015) Biomarkers in early-Onset Neonatal Sepsis: An Update. Ann Clin Med Microbio 1(2): 1007.

Ann Clin Med Microbio 1(2): 1007 (2015)

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