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Neonatal sepsis
a b
Birju A Shah & James F Padbury
a
Instructor of Pediatrics; Neonatal-Perinatal Medicine; Warren Alpert Medical School of
Brown University; Women & Infants Hospital of Rhode Island; Providence, RI USA
b
Pediatrician-in-Chief, Professor of Pediatrics; Warren Alpert Medical School of Brown
University; Women & Infants Hospital of Rhode Island; Providence, RI USA
Published online: 01 Nov 2013.
To cite this article: Birju A Shah & James F Padbury (2014) Neonatal sepsis, Virulence, 5:1, 170-178, DOI: 10.4161/viru.26906
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ReviewReview
Virulence 5:1, 170–178; January 1, 2014; © 2014 Landes Bioscience
Neonatal sepsis
An old problem with new insights
Birju A Shah1 and James F Padbury2,*
1
Instructor of Pediatrics; Neonatal-Perinatal Medicine; Warren Alpert Medical School of Brown University; Women & Infants Hospital of Rhode Island; Providence, RI USA;
2
Pediatrician-in-Chief, Professor of Pediatrics; Warren Alpert Medical School of Brown University; Women & Infants Hospital of Rhode Island; Providence, RI USA
Keywords: neonatal sepsis, epidemiology, microbiology, biomarkers, algorithms, newer tests, screening, group B streptococcus,
antibiotic prophylaxis
Abbreviations: CDC, Centers for Disease Control and Prevention; GBS, group B streptococcus; EOS, early-onset sepsis; IAIP,
inter alpha inhibitor protein(s); LOS, late-onset sepsis; NEC, necrotizing enterocolitis; NICHD, Eunice Kennedy Shriver National
Institute of Child Health and Human Development; NICU, neonatal intensive care unit; VLBW, very low birth weight
Downloaded by [Michigan State University] at 12:43 17 February 2015
Based on the timing of the infection neonatal sepsis has been about 70% of cases of EOS in the neonatal period.2,26 Although
classified into early-onset sepsis (EOS) and late-onset sepsis less common, Listeria monocytogenes is associated with invasive
(LOS).2 This classification helps to guide antibiotic therapy as disease in the newborn, spontaneous abortions or stillbirth if
it implies differences in the presumed mode of transmission and acquired during pregnancy.
predominant organisms. EOS is defined as onset of sepsis in the Organisms associated with late-onset sepsis (LOS)
first 3 d and is mostly the result of vertical transmission of bac- With improved survival of preterm infants, LOS has become
teria from mothers to infants during the intrapartum period.21 an important cause of morbidity and mortality among low birth
LOS is defined as infection occurring after 1 week of life is attrib- weight infants.27 LOS is mainly associated with the organisms
uted to the horizontal transmission of pathogens acquired post- acquired from the environment after birth. In a study on 6215
natally and is often more insidious in onset.2 One investigative infants admitted to National Institute of Child Health and
group classified neonatal sepsis into early-onset (≤4 d), late-onset Human Development (NICHD) Neonatal Research Network
(5–30 d), and late, late-onset (>30 d) according to the infant’s age (NRN) centers, 70% of first episode late-onset infections were
when positive blood culture obtained.2 VLBW preterm infants caused by gram-positive organisms, with coagulase-negative
are at particularly high risk for LOS in part because of imma- staphylococci accounting for 48% of the infections.22 Death rates
turity of the immune system, prolonged mechanical ventilation, were highest for infants infected with Pseudomonas aeruginosa,
prolonged hospitalization, use of indwelling catheters, endotra- Candida albicans, Serratia marcescens, and E. coli.28 The incidence
cheal tubes, and other invasive procedures.22 of late-onset GBS disease has remained unchanged despite intra-
partum antibiotic prophylaxis. Meningitis remains a common
Microbiology of Neonatal Sepsis presentation of late-onset GBS disease, with serious neurologic
sequelae and permanent impairment among many survivors.29,30
Longitudinal trends in the demographics, pathogens, and The microbial pathogens and risk factors associated with neona-
outcome were observed in a single-center database on neonatal tal sepsis are shown in Table 1.
sepsis at Yale–New Haven Hospital from 1928.2 Streptococcus
pneumoniae and group A streptococci were the major causes of Prevention of Early-Onset Group B Streptococcal
neonatal sepsis from 1933 to 1943. From the late 1940s to the (GBS) Disease
mid-1960s, Gram-negative organisms, especially Escherichia
coli (E. coli), were the most common causes of neonatal sepsis.23 Early onset GBS infection has a case fatality of 5–20%; a mul-
Thereafter, group B streptococci infections emerged as the fore- tistate active surveillance system demonstrated that 6% of early-
most cause of EOS in the1970s.1 onset GBS infections resulted in death.31 Neonatal infection can
Organisms associated with early-onset sepsis (EOS) occur when GBS ascends from the vagina to the amniotic fluid
Group B streptococcus (GBS, Streptococcus agalactiae) is a after the onset of labor or rupture of membranes.32,33 It is more
gram-positive encapsulated bacterium and remains the leading commonly the result of vertical transmission from mother to
cause of neonatal sepsis and meningitis in the United States. infant in women with recto-vaginal colonization. Colonization
Stoll et al. has recently described Escherichia coli (E. coli) to have with GBS occurs in roughly 10–30% of pregnant woman in their
emerged as the major pathogen of neonatal sepsis in preterm vagina or rectum.34
infants and the second most common cause in term infants.24 The only intervention proven to decrease the incidence of
E. coli is frequently associated with severe infections and men- early-onset neonatal GBS sepsis is maternal treatment with intra-
ingitis and is the leading cause of sepsis related mortality among partum intravenous antibiotics. Adequate prophylaxis is expo-
VLBW infants (24.5%).25 GBS and E. coli together account for sure to penicillin (preferred agent), ampicillin, or cefazolin given
>100.4 °F (>38 °C), of E. coli infections among VLBW infants.23 Though there has
3) GBS bacteriuria during current pregnancy, been a dramatic decline in the incidence of EOS due to GBS,
4) Previous infant with invasive GBS disease. the increasing incidence of ampicillin-resistant neonatal sepsis
among VLBW infants is concerning.39 Nonetheless, the benefits
Risk-Based Approach vs. Universal Screening from the use of antepartum antibiotic chemoprophylaxis still off-
Approach set the risks of resistant bacterial infections.36
The epidemiology and management of neonatal GBS dis- Neonatal Early-Onset Sepsis Risk Algorithms
ease has evolved significantly over the last two decades. Initially,
screening approaches based on risk factors for EOS were tested. Pediatricians currently use the CDC 2010 and American
Later, the effectiveness of universal screening was compared with Academy of Pediatrics Committee on the Fetus and Newborn
risk-based approaches in preventing early-onset GBS disease in a (COFN) 2012 algorithms for evaluation and management of
multistate retrospective cohort study. The risk of early-onset GBS infants at risk for EOS born at or near term gestation.35,40 While
sepsis was notably lower in the infants of women who underwent both sources acknowledge maternal chorioamnionitis as a signifi-
universal screening than among those in the risk-based group.36 cant risk, they do not offer a standard definition of this clinical
With universal screening, it is possible to identify GBS colonized diagnosis.24 Additionally, there are differences in their recom-
woman even without obstetric risk factors and reach more of the mendations for the evaluation of infants who received inadequate
population at risk than with the risk based approach. After con- intrapartum GBS prophylaxis and with the rupture of mem-
trolling for risk factors associated with early-onset GBS disease branes at least equal to 18 h. Puopolo et al. proposed a multivari-
(preterm delivery, prolonged ROM, young maternal age, black ate predictive model of EOS risk developed for infants born at or
race), the protective effect of the universal screening approach above 34 weeks’ gestation based on objective clinical data avail-
has been shown to be robust in subsequent prospective studies.37 able at the time of birth.41,42 This could decrease the number of
Intrapartum antibiotic prophylaxis is approximately 90% effec- infants evaluated and empirically treated for EOS but studies are
tive in preventing early-onset GBS disease.37 needed for validation of this computational model.
respectively).44 However, the sensitivity for detection of sepsis is CRP elevations, the influence of gestational age and birth weight
low. Two serial normal CBCs, performed 8 to 12 h apart, and a on kinetics of CRP, and the lack of reliable age specific reference
negative blood culture at 24 h improve the predictive power to values, the use of CRP requires further research to cover these
rule out EOS in the first 24 h after birth.49 This strategy has been pitfalls and falls short as an ideal marker.
associated with a negative predictive value as high as 100%, but Procalcitonin (PCT)
the specificity and positive predictive values may be too low to PCT is an acute phase reactant produced both by hepatocytes
guide therapy decisions.49 Components of the white cell count, and macrophages that has been studied since the mid-1990s.
including absolute neutrophil count (ANC) and immature to Serum concentrations of PCT begin to rise 4 h after exposure to
total neutrophil ratio (I:T) have also been shown to be more use- bacterial endotoxin, peak at 6 to 8 h, and remain elevated for at
ful for excluding infants without infection rather than identifying least 24 h.58 The half-life is about 25–30 h, and the serum con-
newborns who are infected.40 The maximal (I:T) ratio in unin- centration is not affected by gestational age. Nonetheless, in non-
fected newborns is 0.16 in the first 24 h, which by 120 h decreases infected newborns, serum PCT concentrations vary widely. It is
to 0.12.50 I:T ratio of >0.2 is suggestive of sepsis. However, the I:T low soon after birth, rises to a peak at 24 h and returns to baseline
ratio can be affected by various noninfectious processes like labor, at 48 h.56 Serum PCT concentrations increase appreciably in the
prolonged induction with oxytocin, and even prolonged crying.49 presence of systemic bacterial infection and necrotizing enteroco-
A total leukocyte count of <5000 to 7500/mm3 can be used to litis during early- and late-onset neonatal infection.59,60 The PCT
infer the diagnosis of neonatal sepsis.6 Many infected newborns response is more rapid than the elevation of CRP, thus it is an
may have higher counts. However, the sensitivity of a low leuko- attractive alternative for the detection of EOS. Because PCT levels
cyte count is 29%, though the specificity is as high as 91%.6 There remain high compared with TNF-α and IL-6, PCT is also useful
are important gestational age effects on the leukocyte count in in predicting severity of infection, response to treatment, and out-
the newborn period. In newborns >36 weeks gestation, the lower come.59,60 In contrast to CRP, infants with trauma, viral infections,
limit of normal for ANC at birth is 3500/mm3. The lower limit meconium aspiration, and hypoxemia have normal or minimal
of normal in infants born between 28–36 weeks is 1000/mm3 elevation in PCT.60 The sensitivity and specificity of PCT varies
and 500/mm3 in infants <28 weeks gestation.51 Total neutrophil between 83–100% and 70–100% respectively.61 The sensitivity
counts rise after birth and reach their peak levels at 6 to 8 h of life. and specificity of PCT is greater than CRP or interleukin 6 if dif-
The lower limits of normal at that time are 7500/mm3, 3500/mm3, ferent cutoff points at birth and at 24 h and 48 h of life are used.61,62
and 1500/mm3 for infants born at >36 weeks, 28–36 weeks, and Nonetheless, PCT has its own limitations as it is increased in
<28 weeks respectively.51 Thus it is more effective to obtain total newborns requiring neonatal resuscitation and in infants born
leukocyte counts at 6–12 h after birth, as they are more likely to mothers with chorioamnionitis in the absence of neonatal
to be reliable. Factors such as maternal hypertension or perinatal infection.61 In healthy neonates it has been shown that PCT con-
asphyxia may cause neutropenia or an elevated I/T ratio.50 Also, centrations are affected by maternal GBS colonization and pro-
leukocyte counts may be normal in the early course of neonatal longed rupture of membranes ≥18 h.63 Therefore, PCT needs to
sepsis. In summary, the WBC, ANC, and I/T ratio have signifi- be studied further in larger groups of infants so as to improve its
cant limitations in the diagnosis of neonatal sepsis. diagnostic accuracy.
C reactive protein (CRP) Cytokines
CRP is one of the most extensively studied, most available, and Changes in the blood levels of cytokines occur rapidly in the
most frequently used laboratory tests for the diagnosis of neonatal setting of neonatal sepsis even before that of acute phase reac-
sepsis.52 CRP is an acute phase reactant synthesized by the liver. tants. Several cytokines like interleukin-1β (IL-Iβ), interleu-
It has a half- life of 24–48 h. It takes 10–12 h for CRP to change kin-6 (IL-6), interleukin-8 (IL-8), interleukin-2 soluble receptor
significantly after onset of infection. Serial determination of CRP (SIL2R), and tumor necrosis factor α (TNF-α) have been shown
thus sensitivity falls at 24 and 48 h (67% and 58% respectively).71 late-onset neonatal sepsis.56 The variable diagnostic accuracy of
Therefore, IL-6 can be considered as an early and sensitive marker CD11β in late-onset neonatal sepsis may be related to different
of neonatal infection.56 Diagnostic accuracy is further improved infant population being evaluated, time interval between phle-
by combining IL-6 (early and sensitive) and CRP (late and spe- botomy and sample processing and at which phase of infection
cific) in first 48 h of presumed clinical sepsis.72 blood is obtained.82,83
TNF-α CD64
The concentrations of TNF-α were shown to be significantly The high affinity antibody receptor CD64 is expressed at a
higher in infected as compared with non-infected newborns in very low level on the surface of neutrophils in the absence of an
multiple studies.71,73,74 TNF-α has very similar kinetics to IL-6.67 infection.84,85 The expression of CD64 on activated neutrophils
Silveira et al. observed the diagnostic accuracy of TNF-α was markedly increases after an episode of bacterial infection.86-88
equivalent to PCT.74 Sensitivity and specificity increases to 60% CD64 has a sensitivity of 95–97% and a negative predictive
and 100% respectively when TNF-α and IL-6 levels are com- value of 97–99%.56,73 The addition of IL-6 or C-reactive protein
bined for the diagnosis of neonatal sepsis.75 to CD64 further enhances its sensitivity and negative predictive
IL-8 value to 100%, with the specificity and positive predictive value
IL-8 is a pro-inflammatory cytokine which aids in the acti- exceeding 88% and 80%, respectively.82 With the use of CD64
vation and chemotaxis of neutrophils.76 IL-8 not only serves as it may be possible for clinicians to discontinue antibiotics within
a marker for sepsis but is also associated with severity of infec- 24 h in non-infected newborns.82
tion. It is produced as a result of infection by monocytes, macro- In a prospective study performed by Streimish et al. at Yale
phages, and endothelial cells with kinetics similar to IL-6.76 IL-8 University, using a cut-point CD64 index value of 2.38 for EOS,
has sensitivity and specificity ranging from 80 to 91% and 76 to the test had a sensitivity of 100%, a specificity of 68%, and an
100% respectively.67,70 In a study performed by Boskabadi et al. NPV of 100%; while using a cut-point value of 3.62 for LOS
in 93 neonates greater than 72 h of age, serum concentrations sepsis, the test had a sensitivity of 75%, a specificity of 77%, and
of IL-8 in non-surviving neonates were 3.3 times higher than an NPV of 96%. Due to the large sample size, this study was able
surviving neonates.77 The combination of IL-8 and CRP is more to demonstrate the potential of CD64 to influence the initiation
reliable for early diagnosis of neonatal sepsis, with a sensitivity and duration of antibiotic therapy.89 However, the cost, the need
and specificity of 91% and 73% respectively.55,65,67 Thus, combin- for sophisticated equipment and the processing time are barriers
ing CRP and IL-8 may reduce excessive use of antibiotics.55 to the use of these markers in clinical practice.
Though IL-6 and IL-8 increase very rapidly with bacte-
rial invasion, their levels promptly normalize in serum (within Genomics, Proteomics, and Nucleic Acid-Based
the first 24 h), limiting their ability to be used as ideal mark- Molecular Techniques
ers. Therefore, operational difficulties in detection of cytokines,
elevation of cytokines in non-specific settings, and lack of avail- Esparcia et al. employed a gene-based molecular technique
ability in many centers are limitations for their use in day-to- using 16S rDNA for diagnostic accuracy of bacterial meningitis
day practice.65 Studies with larger sample sizes are needed before and early-onset neonatal sepsis.90 Ng et al. used a score based
cytokines can be endorsed as valid diagnostic markers. on proapolipoprotein CII and a des-arginine variant of serum
amyloid to withhold antibiotics in 45% of infants with suspected
Cell Surface Markers infection and to discontinue antibiotics in 16%.91,92 Kasper et al.
recently found that sensitivity of multiplex real-time PCR (Roche
With the advances in flow cytometric technology, cell sur- SeptiFast®) was 0.90 (95% CI 68.2–98.3) but specificity was
face antigens can be detected in blood cells. Such tests are readily low (0.80; 95% CI 58.7–92.4%) for late-onset nosocomial sepsis
in premature infants.93 The limitations of these studies includes significantly lower in septic neonates as compared with non-sep-
failure to provide information about antibiotic resistance, inabil- tic age matched controls. Receiver operating curve analysis has
ity to differentiate the false-positive results because of potential shown IAIP measurement to have a sensitivity of 89.5%, a speci-
contamination during blood sampling or processing from true ficity of 99%, a positive predictive value of 95% and a negative
positive cases and high cost. Prospective evaluation is needed to predictive value of 98% in a pilot study of 573 neonates.98 The
determine accuracy and safety of these exciting new approaches. levels of IAIP not only decrease in neonatal sepsis but also rise in
Therefore, these are currently adjunctive methods with the excep- response to antibiotic treatment.97 Yang and colleagues showed
tion of HSV PCR, which remains gold standard for the diagnosis that low levels of IAIP are highly predictive of mortality in septic
of HSV encephalitis.1 adult patients.99 Because the levels of IAIP decrease with severe
None of the markers including hematologic indices, acute sepsis, measurement may also help to guide the prognosis as lower
phase reactants, cytokines, and cell surface markers have shown levels are associated with adverse outcome.100 Chaaban et al. dem-
sensitivity, specificity, positive and negative predictive value that onstrated that the levels of IAIP also decrease significantly in
are sufficiently powerful to guide the clinical management of neo- patients with necrotizing enterocolitis (NEC, stage II/III accord-
natal sepsis.4,94 Different biomarkers have been used to diagnose ing to modified the Bell criteria) and thus can be useful to diag-
neonatal sepsis, but with inconclusive results, because of small nose patients with NEC at an early stage.17 Singh et al. showed
sample size, lack of clear reference values and lack of homogene- an immunomodulatory and protective role of administration of
ity in the study group. Thus, there remains a need for a marker IAIP in a septic newborn mice.101 This underscores potential role
with high sensitivity, specificity, positive and negative predictive of IAIP as a theranostic marker in infants with sepsis. The diag-
accuracy which is able to detect infection at an early stage. nostic performance of IAIP and other adjunctive tests of neonatal
Inter α inhibitor proteins (IAIP) sepsis is shown in Table 2.
The inter alpha inhibitor family of proteins (IAIP) are serine
protease inhibitors which provide protection from the increased Conclusion
protease activity associated with systemic immune system acti-
vation that accompanies sepsis and inflammation. They are Systemic bacterial infection in the newborn creates a signifi-
involved in extracellular matrix stabilization, inflammation, cant burden due to its impact on neonatal mortality and long-
wound healing, and play an important anti-inflammatory and term morbidity. In spite of ongoing efforts in early diagnosis,
regulatory role in infection.95 IAIP is one of the important serine treatment, and prevention, neonatal sepsis still remains an enig-
protease inhibitors secreted by the liver. IAIP is a heterotrimeric, matic area for neonatologists due to changes in epidemiology and
250 kd protein complex composed of two heavy chains and one the lack of ideal diagnostic markers. The need for a biomarker
light chain held together by glycosaminoglycan bonds. The light with high diagnostic accuracy and reliability is paramount as a
chain, Bikunin, has a molecular weight of 30 kd and is the active, guiding tool for physicians to assess the risk of infection and need
anti-protease component. In the presence of serine proteases, for antibiotic therapy. Studies are currently ongoing in the search
Bikunin is released and it provides protective effects.95,96 The of a novel marker for neonatal sepsis. Inter α inhibitor proteins
half-life of Bikunin is very short and it is rapidly excreted by the are among the candidates with significant promise.
kidneys.
IAIP concentration is independent of gestational age, postna- Disclosure of Potential Conflicts of Interest
tal age, and is similar to adult levels.97 However, IAIP levels are No potential conflicts of interest were disclosed.
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