Infection in neonates continues to be a global problem with signicant morbidity and mortality. The diagnosis of
neonatal sepsis is complicated by nonspecic clinical symptomatology, a high-false negative rate, and a delay in
obtaining blood culture results. An ideal biomarker needs to have a high degree of accuracy in recognizing the
presence or absence of denite infection at an early stage, to guide the initiation and duration of antibiotic
therapy. The diagnostic utility of the following biomarkers seems to be most practical in the early (interleukin
[IL]-6, IL-8, tumor necrosis factor-alpha, neutrophil CD64), mid ( procalcitonin) and late (C-reactive protein)
phases of neonatal sepsis. Future research studies to assess reliability of these biomarkers should be (1) adequately
powered for sample size and (2) use the gold-standard denition of blood-culture proven pathogen-specic
sepsis. Signicant advances in diagnostic accuracy of novel biomarkers to allow early, accurate, and cost-effective
identication of pathogens responsible for neonatal sepsis is anticipated in the next 5 years.
Key words.
Journal of the Pediatric Infectious Diseases Society, Vol. 3, No. 3, pp. 23445, 2014. DOI:10.1093/jpids/piu063
The Author 2014. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society.
All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
volumes taken from neonates and exposure to antenatal antibiotics (to mention 2 reasons), the chances of getting a positive blood culture (considered the gold-standard for
diagnosis of sepsis) are markedly reduced. There is no standard denition of clinical sepsis in neonates (which can vary
from relying on limited clinical symptomatology to including selective laboratory and radiological investigations),
and this inconsistency adds another confounding variable
when assessing biomarker studies in neonatal sepsis.
The search strategy utilized PubMed, focusing on published studies restricted to those in English and after
2008, using the search words newborn or neonatal,
and sepsis, and biomarkers. Further selection was
done to restrict to the most promising and novel biomarkers. Earlier (before 2008) original and review studies were
accessed and referred to wherever appropriate. The present
review will be mostly limited to studies related to identication and testing of the clinical utility of select biomarkers
of neonatal sepsis in the last 5 years, primarily in the neonatal intensive care unit (NICU) population. The focus will
be on biomarkers with reporting of details noted above, as
available. Most cytokine levels are not expected to be normally distributed in studies done in the neonatal population. Although in some studies the actual cytokine levels
have been used to run the analyses, in others receiver operator characteristic (ROC) curves were used to generate the
cutoff values. The latter approach will be used in this manuscript, unless otherwise explicitly stated. The primary
objective of the present review is to summarize the information about biomarkers that have been reported in reallife NICU settings, in order for a list of selected biomarkers be generated, which would be the focus of further testing in a prospective manner with adequately powered
sample sizes using the gold-standard test of positive
blood culture as the reference point. The majority of the
studies reported in this review have been prospectively
done in the NICU setting. Although methodological differences do exist among studies (for example, in the diagnosis
of presumed or clinical sepsis) and could account for some
of the variability of the results, if a biomarker is going to be
potentially clinically useful in the NICU setting, there should
be enough of a signal from multiple studies for it to stand
out. This method was a practical approach that I believe
would narrow down the eld to selective biomarkers for investigators to focus their energies upon in the next 5 years.
preterm, access to the amniotic uid (AF) provides an opportunity to search for biomarkers [19]. Although AF collection is not routinely practiced for detection of EOS in
some centers and is associated with the inherent risks
(for example, bleeding) of being an invasive procedure, it
does allow unique access to the intrauterine environment.
Although earlier studies assessed specic cytokines [20,
21], recent investigations into the application of proteomic
analyses of the AF have shown signicant promise [22].
The Mass Restricted (MR) score was generated from the
AF using a single surface-enhanced laser desorption ionization time-of-ight mass spectrometer instrument [22].
Surface-enhanced laser desorption ionization time-of-ight
outputs are sequences of values with the molecular weight
on the horizontal axis and normalized peak intensity on
the vertical axis; the MR score was devised using a stepwise
strategy based on lter preferences applied in a sequential
manner to result in a numeric score [19]. A priori a categorical value of 1 was assigned if a particular peak was present
and 0 if absent. Proteomic mapping of the AF revealed a
characteristic ngerprint generating a MR score utilizing
the presence of 4 biomarkers: neutrophil defensin-1 and
defensin-2, along with calgranulins A (S100A8) and C
(S100A12). The study specied that a score of 34 indicated the presence of inammation, whereas a score of 02
excluded it. Thus, the population was stratied based on
the severity of inammation (MR = 0 indicated no inammation; MR = 12 indicated minimal inammation;
and MR = 34 indicated severe inammation) [22].
Women with MR scores of 34 were more likely to deliver
neonates with EOS [2224]. These studies were conducted
with a prospective collection of consecutive samples, with
the neonates being admitted to and monitored in the
NICU. Early-onset sepsis was dened as being conrmed
(culture positive) or suspected (based on presence of validated hematologic criteria when 2 or more of the following
were observed: absolute neutrophil count [ANC] <7500/
mL or >14 500/mL, absolute band count [ABC] >1500/
mL, immature/total neutrophil ratio [I:T ratio] >0.16,
platelet count <150 000 cells/mm3, or an abnormal spinal
tap, if done) [2224]. Neonatal hematological indices and
EOS signicantly correlated with the MR score, even after
adjusting for GA [22]. Although clinicians are likely to
treat a symptomatic infant, given a history of clinical chorioamnionitis, if data on AF biomarkers (as noted above)
could be made available with a short turn-around time
(TAT), it would be an important step towards a more rational use of antibiotics.
It is well known that using traditional culture methods
underestimates the infectious etiology of intra-amniotic
inammation (IAI). Towards that end, metagenomic
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Bhandari
techniques and sequencing technology for specic identication of species of microorganisms that do not grow in
culture, by sequencing 16S ribosomal RNA (rRNA), is
now possible [25]. Samples were obtained from a cohort
of consecutive patients enrolled at Yale-New Haven
Hospital who had paired AF and cord blood available
for analysis (n = 161). To avoid selection bias, cases fullling the clinical group requirements were selected consecutively based on the availability of at least 1 mL of umbilical
vein cord blood for DNA extraction and other research
analyses. The study groups were designed using the results
of AF and neonatal blood bacterial cultures as reported by
the microbiology laboratory. The following groups were
studied: Group 1: premature newborns with neonatal
blood culture conrmed early-onset neonatal sepsis (median GA at delivery, 25 weeks; n = 6); Group 2: premature
newborns with negative neonatal blood culture but presumed EOS and positive IAI (27 weeks; n = 16); Group
3: premature newborns with negative neonatal blood culture but presumed EOS and negative IAI (32 weeks; n = 7);
Group 4: premature newborns without EOS and no IAI
(32 weeks; n = 7); Group 5: term healthy newborns (39
weeks; n = 8) delivered by elective Cesarean within the
same time period. This last group served as a technical control for handling and analysis of the samples. Six, 15, 5,
and 1 patient had histological chorioamnionitis in
Groups 1 to 4, respectively, with all 21 samples in
Groups 1 and 2 only having positive results with the
culture-independent method from AF or cord blood
samples. Five (of 6 in Group 1 only) neonatal blood cultures correlated with positive results with the cultureindependent method from AF or cord blood samples. It
was noted that 72% of the microbial species identied
(Escherichia coli and Fusobacterium nucleatum being the
most common) in the cord blood matched those in the
AF. Using the16S rRNA sequencing approach, the paired
samples were 99.9%100% identical [25]. Thus, the
strength of this technique to recognize unique microorganisms that are otherwise difcult to detect using conventional culture approaches provides us with the potential for an
early diagnosis of EOS [25].
Source
Sample Size*
Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
MR Score [23]
TBARS [29]
SAA [101]
nCD64 [43, 81]
AF
Cord blood
Peripheral blood
Peripheral blood
22 of 97
40 of 120
23 of 104
207 of 623
Presence of 1 of 4 components
0.88
8 mg/L / 0.987
1.63%2.38% / 0.720.89
5586
96
67100
2880
95
6768
2644
85
250
8688
99
80100
Abbreviations: AF, amniotic fluid; AUC, area under the receiver operating characteristic curve; EOS, early-onset sepsis; MR, mass restricted; nCD64, neutrophil CD64;
NPV, negative predictive value; PPV, positive predictive value; SAA, serum amyloid A; TBARS, thiobarbituric acid reactive substances.
*Confirmed or suspected sepsis/total number of infants.
Calgranulin A, C, Defensin 1, 2.
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238
Bhandari
culture-proven LOS, the CD64 index with a derived cutpoint value of 3.62 had sensitivity, specicity and NPV
of 75%, 77%, and 96%, respectively, in a prospective
NICU-based study enrolling consecutive infants (n = 417,
evaluated for LOS) [43]. In a recent study, with a derived
cutoff of 2.85, the sensitivity was 87.5% and specicity of
100% for nCD64 index in blood-culture proven LOS [49].
Among noninvasive approaches, using a heart rate characteristics index was shown to be useful for detecting LOS
[50]. In a randomized clinical trial utilizing this approach,
there was a reduction in mortality from 10.2% to 8.1%
(P = .04) in infants who had the heart rate characteristics
index visible to clinicians [51]. However, this approach
led to 10% more blood cultures being sent and 5% more
days on antibiotics in the group with the heart rate characteristics index display [51].
An under-utilized, noninvasive approach is to monitor
core-peripheral temperature differences in neonates at risk
for sepsis. This has been shown to be a fairly accurate predictor of LOS (culture proven or necropsy ndings) in developed [52] as well as in resource-limited countries [53]. There
was signicant widening of the rectal-sole and axillary-sole
temperatures in the preterm neonates with sepsis
(culture-proven or based on clinical or laboratory criteria)
(P < .001) [53]. With an overall accuracy of 90.9%, a rectalsole temperature difference of 2.3C (100% sensitivity) or
3.2C (100% specicity) was a useful marker to differentiate normothermic preterm neonates with or without sepsis. Using the axillary-sole temperature difference, the
respective values were 2.2C and 3.0C [53]. These results have been recently replicated in a prospective observational study with proven or probable LOS [54].
Early- and Late-onset Sepsis: Peripheral Blood
Molecular Assays. Using mass spectrophotometric techniques
to identify bacteria have the possibility of earlier identication (within 1 hour) of pathogens but modest
sensitivities (66%80%), poor yield when there is low
bacterial density, and risk of misidentication of pathogens, especially in situations of polymicrobial growth
are signicant limitations [55, 56]. The commonly used
approach is that of matrix-assisted laser desorption
ionization time-of-ight mass spectrophotometry (MALDITOF MS). In this process, ionization of a specic sample
(in this case, the pathogen that can be detected in a positive
blood culture) results in a specic mass spectrum plot
(intensity vs mass-to-charge ratio) that determines its identity. Additional details of the sample preparation and the
MALDI-TOF MS technique have been published [57, 58].
Molecular techniques to detect the presence of bacterial
DNA have been utilized to enhance the diagnostic yield in
that TNF- was the best diagnostic test for sepsis in the
NICU (11 with positive cultures, 4 clinical criteria)
[62], whereas others evaluating IL-6 on the 1st day of
symptoms with CRP-positive (measured after 4872
hours) sepsis cases noted a sensitivity of 77%, specicity
of 74%, PPV of 80%, and NPV of 70% [63]. Fungal
infections in neonates resulted in signicantly higher IL-6
and CRP levels, compared with those with bacterial
sepsis [64]. In a NICU study evaluating CRP, IL-6 and
immunoglobulin (Ig)M as diagnostic markers for
neonatal sepsis (culture-proven or suspected based on
clinical and laboratory criteria), it was reported that a
CRP of >4 mg/dL gave the best derived cutoff value with
95.7% sensitivity, 88.9% specicity, 78.6% PPV, and
98% NPV [65]. The sensitivity of IgM as a single test at
a cutoff derived value of 10 mg/dL was 91.3%, with a
low specicity of 45% [65]. Likewise, the IL-6-derived
cutoff value of 18.2 pg/mL was associated with sensitivity
and specicity of 87% and 50%, respectively [65].
C-reactive protein continues to be used as a biomarker
for sepsis in multiple studies. It is a late biomarker with
a high specicity but poor sensitivity [15, 45]. All studies
on severe, invasive bacterial infections in children report
higher sensitivities and specicities of PCT than for CRP
[66]. C-reactive protein decreases to its normal values
after 37 days [66]. C-reactive protein levels have been
reported to be inuenced by GA and noninfectious
conditions [67].
Procalcitonin is another extensively studied acutephase reactant with the advantages of quickly increasing
within 4 hours of exposure to bacterial products, peaking
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Bhandari
Antibiotic Stewardship
Prompt diagnosis of sepsis and initiation of antibiotic (and
appropriate supportive) therapy are critical in the neonatal
population because delays can worsen outcomes [83]. It is
routine practice in the NICU to start broad-spectrum antibiotics, after a sepsis work-up, while awaiting results of the
blood cultures sent [8385]. Antibiotic use, whether measured in courses or days of antibiotic treatment, was 9- to
14-fold higher in neonates worked up for sepsis compared
with those treated for central-line-associated blood stream
infections [86]. This increased exposure of antibiotics to
neonates in the NICU is not without consequences.
Besides separating infants from the parents (while admitted
to the NICU), there is also the potential risk for development of antibiotic resistance and changes in the microbiome of these neonates [83, 87, 88]. In fact, prolonged
antibiotic exposure has been associated with the development of antimicrobial resistance [87], necrotizing enterocolitis [8890], LOS [90], prolonged hospitalization with its
attendant expenses [91], and increased mortality [90].
Although it has been suggested that serial measurements
Sample Size*
Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
204 of 533
123 of 163
42 of 73
17 of 44
62 of 201
45 of 573
65 of 77
2.19%3.62% / 0.730.83
> 6.8 mg/dL / 0.710.88
0.199
> 92.2 ng/mL
1.7 g/mL
177 mg/L / 0.94
290 fluorescent units
7578
44.776.4
100
76
89
89.5
75
5977
100
61
100
96
99
100
2954
100
75
100
98
95
100
8196
38.858
100
87
80
98
86
Abbreviations: AUC, area under the receiver operating characteristic curve; CD11b, cell surface marker on neutrophils; EOS, early-onset sepsis; IaIp, interalpha
inhibitory proteins; LOS, late-onset sepsis; nCD64, neutrophil CD64; NPV, negative predictive value; PPV, positive predictive value; SAA, serum amyloid A.
*Confirmed or suspected sepsis/total number of infants.
Composite score using proapolipoprotein CII and the des-arginine variant of SAA.
of CRP may dictate the duration of antimicrobial therapy in the NICU [15, 45], it has not yet been proven to
do so [66].
Among the most promising biomarkers of neonatal sepsis that have strong potential to reduce unnecessary antibiotic use are PCT and nCD64. Use of PCT has been shown
to decrease the duration of antimicrobial treatment by 24
days, in a meta-analysis of randomized controlled trials in
intensive care units, which did include neonates (n = 121),
with no apparent adverse clinical outcomes [92]. A pilot
study using PCT to guide treatment has reported a signicant absolute risk reduction of 27% (P = .002) in neonates
treated for 72 hours, with an average decrease of 22.4
hours for the duration of antibiotic therapy [93]. A multicenter, randomized trial on the efcacy and safety of
PCT-guided treatment in neonates is ongoing (clinical
trials.gov: NCT00854932) [66].
As regards nCD64, its high NPV and decrease in concentration on sequential measurements in blood culturepositive cases on treatment suggest the potential for its
use in deciding the initiation and duration of antibiotic
use [43, 76, 81]. Currently, a single-center randomized controlled trial using sequential nCD64 concentrations for decision making to stop antibiotics early in EOS and LOS in
neonates is planned (clinicaltrials.gov: NCT01825421).
Expert Commentary
From the practical viewpoint, 1 approach would be to categorize the biomarkers of neonatal sepsis based on the
detection time from the perspective of point-of-care diagnostics into early, mid, and late phases [14]. Dening the
phase is complicated by the fact that it is dependent upon
when the sample was collected and analyzed during the
course of the neonatal sepsis. Thus, the start point
could be the time when the clinical suspicion of sepsis
was initially triggered or when the neonate was rst
brought to the attention of the medical team. In the latter
scenario, this may not coincide with the onset of illness and
Table 3. Diagnostic Clinical Utility of Selective Biomarkers At Different Phases of Neonatal Sepsis*
Phase
Biomarker
Cutoff Values
Turnaround Time
Early (212 h)
IL-6
IL-8
TNF-
nCD64
PCT
CRP
10150 pg/mL
60300 pg/mL
1290 pg/mL
2.43.6%
0.55.75 ng/mL
410 mg/L
2100 L
250 L
2200 L
50 L
20200 L
520 L
1.56 h
1.56 h
1.56 h
12 h
20 min5 h
14 h
Mid (1224 h)
Late (>24 h)
Abbreviations: CRP, C-reactive protein; IL, interleukin; LOS, late-onset sepsis; nCD64, neutrophil CD64; PCT, procalcitonin; TNF, tumor necrosis factor.
*See text for more details.
For EOS.
For LOS.
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Bhandari
blood volumes for sample collection and quick TAT for diagnostic tests are always critical factors for the neonatal
population. In addition, the utility of serial measurements
of such biomarkers should be assessed for antibiotic stewardship in the neonatal population.
Five-Year View
One would anticipate that given the strength of the evidence noted in the preceding pages, nCD64 and PCT
would emerge as the best combination of biomarkers for
diagnostic accuracy of neonatal EOS and LOS as well as
for deciding upon the initiation and duration of antibiotic
therapy. In nurseries where the access to the above resources is limited or unavailable, CRP measurements would be
preferred or continue to be used for the same purposes.
In terms of newer biomarkers, those listed in Tables 1
and 2 would have additional data generated that would
help sort out if they actually are going to be useful as diagnostic markers for neonatal sepsis. Among those listed as
having little or no neonatal data available, angiopoietin 2
would be the one most aggressively pursued given the experimental data supporting a signicant role in the pathogenesis of sepsis and the wealth of data reporting it to be a
promising biomarker for sepsis in adults and children. In
addition, one would expect signicant advances to be
made in the molecular assays for diagnosing EOS and
LOS, with further renements to allow early, accurate,
and cost-effective identication of pathogens responsible
for neonatal sepsis.
Key Issues
nonspecic clinical symptomatology, a high-false negative rate, and a delay in obtaining positive blood culture
results.
An ideal biomarker for neonatal sepsis needs to have a
high degree of accuracy in recognizing the presence (or
absence) of denite infection at an early stage, with results being available with a short TAT, for it to be useful
to guide the initiation and duration of antibiotic therapy.
Amniotic uid, cord and peripheral blood have
been used as sources to detect biomarkers for neonatal
sepsis.
Promising early-phase biomarkers would be IL-6, IL-8,
nCD64, TNF-, whereas mid phase would be PCT,
and the late phase being CRP.
Among noninvasive biomarkers for neonatal sepsis, the
heart rate characteristics index and core-peripheral temperature differences show promise.
Novel biomarkers of neonatal sepsis that require additional research include MR score, haptoglobin, serum
amyloid A, hepcidin, interalpha inhibitory proteins
(IaIp), MBL, angiopoietin 2, sTREM, and soluble uPAR.
The utility of serial measurements of such biomarkers
should be assessed for antibiotic stewardship in newborns.
Renements to allow early, accurate, and cost-effective
identication of pathogens responsible for neonatal sepsis would be anticipated in the next 5 years.
Acknowledgments
Potential conicts of interest. Author: No reported conicts.
Author has submitted the ICMJE Form for Disclosure of Potential
Conicts of Interest.
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