ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد ایتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants

Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants
Author:
Morven S Edwards, MD
Section Editors:
Sheldon L Kaplan, MD
Joseph A Garcia-Prats, MD
Deputy Editor:
Carrie Armsby, MD, MPH
Literature review current through: Mar 2022. | This topic last updated: Apr 30, 2021.

INTRODUCTION — Sepsis is an important cause of morbidity and mortality among newborn infants. Although the incidence of sepsis in term and late preterm infants is low, the potential for serious adverse outcomes is of such great consequence that caregivers should have a low threshold for evaluation and treatment for possible sepsis in neonates.

The epidemiology, clinical features, diagnosis, and evaluation of sepsis in term and late preterm infants will be reviewed here. The management and outcome of sepsis in term and late preterm infants, neonatal sepsis in preterm infants, and evaluation of febrile and ill-appearing neonates after discharge from the birth hospitalization are discussed separately:

(See "Management and outcome of sepsis in term and late preterm infants".)

(See "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation".)

(See "Treatment and prevention of bacterial sepsis in preterm infants <34 weeks gestation".)

(See "The febrile infant (29 to 90 days of age): Outpatient evaluation".)

(See "Approach to the ill-appearing infant (younger than 90 days of age)".)

TERMINOLOGY — The following terms will be used throughout this discussion on neonatal sepsis:

Neonatal sepsis is a clinical syndrome in an infant 28 days of life or younger, manifested by systemic signs of infection and isolation of a bacterial pathogen from the bloodstream. A consensus definition for neonatal sepsis is lacking [1]. (See 'Diagnosis' below.)

Term infants are those born at a gestational age of 37 weeks or greater.

Late preterm infants (also called near-term infants) are those born from 34 through 36 completed weeks of gestation [2]. (See "Late preterm infants".)

Preterm infants are those born at less than 34 weeks of gestation [2].

Sepsis is classified according to the infant's age at the onset of symptoms.

Early-onset sepsis is defined as the onset of symptoms before seven days of age, although some experts limit the definition to infections occurring within the first 72 hours of life [3].

Late-onset sepsis is generally defined as the onset of symptoms at ≥7 days of age [3]. Similar to early-onset sepsis, there is variability in the definition, ranging from an onset at >72 hours of life to ≥7 days of age [3,4].

Infants with early-onset sepsis typically present with symptoms during their birth hospitalization. Term infants with late-onset sepsis generally present to the outpatient setting or emergency department unless comorbid conditions have prolonged the birth hospitalization. The approach to evaluation of neonates in the outpatient setting is discussed separately. (See "Approach to the ill-appearing infant (younger than 90 days of age)" and "The febrile infant (29 to 90 days of age): Management".)

PATHOGENESIS — The pathogenesis differs based on the timing of onset:

Early-onset infection – Early-onset infection is usually due to vertical transmission by ascending contaminated amniotic fluid or during vaginal delivery from bacteria in the mother's lower genital tract [5]. Maternal chorioamnionitis (or intraamniotic infection) is a well-recognized risk factor for early-onset neonatal sepsis [6,7]. Maternal group B streptococcal (GBS) colonization is another important risk factor. (See 'Maternal risk factors' below and "Group B streptococcal infection in neonates and young infants", section on 'Risk factors'.)

Use of forceps during delivery and electrodes placed for intrauterine monitoring have been implicated in the pathogenesis of early-onset sepsis because they penetrate the neonatal defensive epithelial barriers [8].

Late-onset infection – Late-onset infections can be acquired by the following mechanisms:

Vertical transmission, resulting in initial neonatal colonization that evolves into later infection

Horizontal transmission from contact with care providers or environmental sources

Disruption of the intact skin or mucosa, which can be due to invasive procedures (eg, intravascular catheter), increases the risk of late-onset infection. Late-onset sepsis is uncommonly associated with maternal obstetrical complications.

Metabolic factors, including hypoxia, acidosis, hypothermia, and inherited metabolic disorders (eg, galactosemia), are likely to contribute to risk for and severity of neonatal sepsis (including both early- and late-onset). These factors are thought to disrupt the neonate's host defenses (ie, immunologic response) [8].

EPIDEMIOLOGY — The overall incidence of neonatal sepsis ranges from 1 to 5 cases per 1000 live births [9-11]. Estimated incidence rates vary based on the case definition and population studied. In a systematic review and meta-analysis of population-based studies from around the world, the estimated pooled incidence of neonatal sepsis was 22 per 1000 live births, with an associated mortality rate of 11 to 19 percent [12]. This translates to a global incidence of 3 million cases of neonatal sepsis per year [12]. Globally, neonatal sepsis and other severe infections were responsible for an estimated 430,000 neonatal deaths in 2013, accounting for approximately 15 percent of all neonatal deaths [13].

Rates of neonatal sepsis increase with decreasing gestational age:

Term neonates (≥37 weeks gestational age) – The estimated incidence of sepsis (both early- and late-onset) in term neonates is 1 to 2 cases per 1000 live births [9,10]. In a prospective national surveillance study (2006 to 2009), the incidence of early-onset sepsis (defined as positive blood or cerebrospinal fluid cultures) was 0.98 cases per 1000 live births; the rate among infants with birth weight >2500 g was 0.57 per 1000 [11].

Late preterm neonates (34 through 36 weeks gestational age) – The incidence is higher in late preterm than term infants. In an observational cohort study (1996 to 2007), the reported incidences of early- and late-onset sepsis (defined as positive blood culture) in late preterm neonates were 4.4 and 6.3 per 1000, respectively [14].

Preterm neonates <34 weeks gestational age – The incidence of sepsis in preterm neonates is discussed separately. (See "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Incidence'.)

The incidence of early-onset sepsis in the United States has decreased, primarily due to reduction in group B streptococcal (GBS) infections, owing to the use of intrapartum antibiotic prophylaxis (IAP) [15-19]. Early-onset GBS infection rates in the United States reported through the Centers for Disease Control and Prevention's Active Bacterial Core Surveillance Report have declined from 0.6 per 1000 live births in 2000 to 0.25 per 1000 live births in 2018 [20,21]. Late-onset GBS infection rates have remained relatively stable in the same interval (0.4 per 1000 live births in 2000 and 0.28 per 1000 live births in 2018). (See "Group B streptococcal infection in neonates and young infants", section on 'Epidemiology'.)

ETIOLOGIC AGENTS — Group B Streptococcus (GBS) and Escherichia coli are the most common causes of both early- and late-onset sepsis, accounting for approximately two-thirds of early-onset infections [16,22-24].

Other bacterial agents associated with neonatal sepsis include (table 1):

Listeria monocytogenes, although a well-recognized cause of early-onset sepsis, only accounts for rare sporadic cases of neonatal sepsis and is more commonly seen during an outbreak of listeriosis [25,26].

Staphylococcus aureus, including community-acquired methicillin-resistant S. aureus, is a potential pathogen in neonatal sepsis [27]. Bacteremic staphylococcal infections in term infants usually occur in association with skin, bone, or joint sites of involvement.

Enterococcus, a commonly encountered pathogen among preterm infants, is a rare cause of sepsis in otherwise healthy term newborn infants.

Other gram-negative bacteria (including Klebsiella, Enterobacter, and Citrobacter spp) and Pseudomonas aeruginosa are associated with late-onset infection, especially in infants admitted to neonatal intensive care units [28].

Coagulase-negative staphylococci often are a cause of hospital-associated infection in ill infants (primarily in premature infants and/or infants who have indwelling intravascular catheters). Coagulase-negative staphylococci may be considered a contaminant in otherwise healthy term infants who have not undergone invasive procedures.

The patterns of pathogens associated with neonatal sepsis have changed over time, as reflected by longitudinal databases from single tertiary centers [16,17]. The incidence of early-onset GBS has declined by 80 percent in the United States with the use of intrapartum antibiotic prophylaxis (IAP). GBS prevention efforts have not led to an increasing burden of early-onset E. coli infection [23]. (See "Prevention of early-onset group B streptococcal disease in neonates".)

Common nonbacterial agents associated with neonatal sepsis include (see 'Differential diagnosis' below):

Herpes simplex virus (see "Neonatal herpes simplex virus infection: Clinical features and diagnosis")

Enterovirus and parechovirus (see "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention", section on 'Neonates' and "Nosocomial viral infections in the neonatal intensive care unit", section on 'Sepsis-like illness and meningitis/encephalitis')

Candida (see "Clinical manifestations and diagnosis of Candida infection in neonates", section on 'Invasive infection')

MATERNAL RISK FACTORS — Maternal factors that are associated with an increased risk of early-onset sepsis in the neonate, particularly group B Streptococcus (GBS) infection, include chorioamnionitis (intraamniotic infection), intrapartum maternal fever, maternal GBS colonization, preterm delivery, and prolonged rupture of the membranes [5,6,29]. The approach to identifying pregnancies at risk for neonatal early-onset sepsis and indications for maternal intrapartum antibiotic prophylaxis (IAP) are discussed separately. (See "Prevention of early-onset group B streptococcal disease in neonates", section on 'Identification of pregnancies at increased risk for early-onset neonatal GBS' and "Prevention of early-onset group B streptococcal disease in neonates", section on 'Intrapartum antibiotic prophylaxis'.)

Maternal GBS screening and IAP reduces the risk of GBS infection but does not eliminate it. In a prospective national surveillance study that included 117 term neonates with early-onset GBS infection, 66 percent were born to mothers who did not receive IAP, because maternal GBS screening culture was either not performed (29 percent of mothers) or was negative (51 percent of mothers), and there were no other indications for IAP [11].

CLINICAL MANIFESTATIONS — Clinical manifestations range from subtle symptoms to profound septic shock. Signs and symptoms of sepsis are nonspecific and include temperature instability (primarily fever), irritability, lethargy, respiratory symptoms (eg, tachypnea, grunting, hypoxia), poor feeding, tachycardia, poor perfusion, and hypotension (table 2) [8].

Because the signs and symptoms of sepsis can be subtle and nonspecific, it is important to identify neonates with risk factors for sepsis and to have a high index of suspicion for sepsis when an infant deviates from his or her usual pattern of activity or feeding [8].

Signs and symptoms of neonatal sepsis include:

Fetal and delivery room distress – The following signs of fetal and neonatal distress during labor and delivery may be early indicators of neonatal sepsis:

Intrapartum fetal tachycardia, which may be due to intraamniotic infection (see "Fetal arrhythmias", section on 'Tachyarrhythmias')

Meconium-stained amniotic fluid, which is associated with a twofold increased risk of sepsis [6] (see "Meconium aspiration syndrome: Pathophysiology, clinical manifestations, and diagnosis", section on 'Meconium composition and passage')

Apgar score ≤6, which is associated with a 36-fold increased risk of sepsis [30] (see "Overview of the routine management of the healthy newborn infant", section on 'Apgar score')

Temperature instability – The temperature of an infected infant can be elevated, depressed, or normal. Term infants with sepsis are more likely to be febrile than preterm infants who are more likely to be hypothermic [8]. Temperature elevation in full-term infants is concerning and, if persistent, is highly indicative of infection [31,32].

Cardiorespiratory symptoms – Respiratory and cardiocirculatory symptoms are common in infected neonates. Approximately 85 percent of newborns with early-onset sepsis present with respiratory distress (eg, tachypnea, grunting, flaring, use of accessory muscles) [11]. Apnea is less common, occurring in 38 percent of cases, and is more likely in preterm than term infants. Apnea is a classic presenting symptom in late-onset group B streptococcal (GBS) sepsis. Early-onset disease can be associated with persistent pulmonary hypertension of the newborn. (See "Persistent pulmonary hypertension of the newborn".)

Tachycardia is a common finding in neonatal sepsis but is nonspecific. Bradycardia may also occur. Poor perfusion and hypotension are more sensitive indicators of sepsis, but these tend to be late findings. In a prospective national surveillance study, 40 percent of neonates with sepsis required volume expansion and 29 percent required vasopressor support [11].

Neurologic symptoms – Neurologic manifestations of sepsis in the neonate include lethargy, poor tone, poor feeding, irritability, and seizures [8]. Seizures are an uncommon presentation of neonatal sepsis but are associated with a high likelihood of infection. In a prospective study in a single neonatal unit, 38 percent of neonates with seizures had sepsis as the etiology [33]. Seizures are a presenting feature in 20 to 50 percent of infants with neonatal meningitis [34]. (See "Bacterial meningitis in the neonate: Clinical features and diagnosis" and "Etiology and prognosis of neonatal seizures".)

Other findings – Other findings associated with neonatal sepsis and their approximate frequencies are listed below (table 2) [8,11]:

Jaundice – 35 percent

Hepatomegaly – 33 percent

Poor feeding – 28 percent

Vomiting – 25 percent

Abdominal distension – 17 percent

Diarrhea – 11 percent

EVALUATION AND INITIAL MANAGEMENT — Neonates with signs and symptoms of sepsis (table 2) require prompt evaluation and initiation of antibiotic therapy [5,8]. Because the signs and symptoms of sepsis are subtle and nonspecific, laboratory testing is performed in any infant with identifiable risk factors and/or signs and symptoms concerning for sepsis. Our approach is generally consistent with guidelines published by the American Academy of Pediatrics [5,35].

Early-onset sepsis — The evaluation of a neonate with suspected early-onset sepsis includes all of the following:

Review of the pregnancy, labor, and delivery, including risk factors for sepsis and the use and duration of maternal intrapartum antibiotic prophylaxis (IAP) (see 'Maternal risk factors' above)

Comprehensive physical examination (see "Assessment of the newborn infant")

Laboratory testing (see 'Laboratory tests' below)

The extent of the diagnostic evaluation for sepsis is directed by the infant's symptoms and maternal risk factors.

Early-onset sepsis calculator — Multivariate predictive models for risk of early-onset sepsis have been developed and validated in clinical use, including the early-onset sepsis calculator [29,36-38]. The early-onset sepsis calculator is a web-based tool that can be used to estimate the risk of early-onset sepsis in individual patients based on risk factors (eg, newborn clinical condition, highest intrapartum maternal temperature, maternal group B Streptococcus [GBS] status, administration of maternal IAP, gestational age, duration of rupture of membranes). The calculator requires the user to input the local incidence of early-onset sepsis. If the local incidence of early-onset sepsis is unknown, the users should enter "0.5 per 1000." The calculator provides guidance on the diagnostic evaluation and empiric antibiotic treatment. The threshold used to trigger evaluation and empiric treatment varies depending on the clinical circumstances. The early-onset sepsis calculator is not valid for preterm infants (<34 weeks gestation) and does not apply to late-onset sepsis.

Symptomatic neonates — Infants with signs and symptoms of sepsis (table 2) should undergo a full diagnostic evaluation and should receive empiric antibiotic treatment. (See 'Clinical manifestations' above and 'Empiric antibiotic therapy' below.)

A full diagnostic evaluation includes (see 'Laboratory tests' below):

Blood culture

Lumbar puncture (if the infant is clinically stable enough to tolerate the procedure and it will not delay initiation of antibiotic therapy) (see 'Lumbar puncture' below)

Complete blood count (CBC) with differential and platelet count

Chest radiograph (if respiratory symptoms are present)

Cultures from tracheal aspirates if intubated

C-reactive protein (CRP) and/or procalcitonin (PCT) levels – These tests are not routinely required but may be helpful in determining length of therapy if followed serially (see 'Other inflammatory markers' below)

Well-appearing neonates — Well-appearing infants with identified risk factors for neonatal sepsis, particularly GBS, should be observed for 36 to 48 hours. Based on the nature of the risk factor(s) and the use and duration of maternal IAP, they may require a limited diagnostic evaluation (ie, blood culture). Accepted approaches to determining the need for laboratory evaluation and empiric antibiotics include categorical risk assessment (algorithm 1), clinical observation (algorithm 2), and the early-onset sepsis calculator. The early-onset sepsis calculator is discussed above (see 'Early-onset sepsis calculator' above). The other two approaches are discussed in detail separately. (See "Management of neonates at risk for early-onset group B streptococcal infection", section on 'Approaches to risk assessment'.)

Late-onset sepsis — Infants presenting with signs and symptoms at ≥7 days of age should undergo prompt evaluation and empiric antibiotic treatment. (See "Management and outcome of sepsis in term and late preterm infants", section on 'Late-onset sepsis'.)

A full diagnostic evaluation should be performed. In addition to the tests described above for early-onset sepsis (see 'Symptomatic neonates' above), the following should also be obtained:

Urine culture

Cultures from any other potential foci of infection (eg, tracheal aspirates if intubated, purulent eye drainage, or pustules)

Infants with late-onset sepsis generally present to the outpatient or emergency department setting unless comorbid conditions have prolonged the birth hospitalization. (See "Approach to the ill-appearing infant (younger than 90 days of age)" and "The febrile infant (29 to 90 days of age): Management".)

Empiric antibiotic therapy — Indications for empiric antibiotic therapy (after obtaining cultures) include:

Ill appearance (see "Approach to the ill-appearing infant (younger than 90 days of age)")

Concerning symptoms, including temperature instability or respiratory, cardiocirculatory, or neurologic symptoms (see 'Clinical manifestations' above)

Cerebrospinal fluid pleocytosis (white blood cell [WBC] count of >20 to 30 cells/microL) (table 3) (see "Bacterial meningitis in the neonate: Clinical features and diagnosis", section on 'Interpretation of cerebrospinal fluid')

Confirmed or suspected maternal chorioamnionitis (intraamniotic infection) (see 'Maternal risk factors' above)

High estimated sepsis risk based on a validated risk calculator (see 'Early-onset sepsis calculator' above)

The empiric antibiotic regimen should include agents active against GBS and other organisms that most commonly cause neonatal sepsis (eg, E. coli and other gram-negative pathogens) (table 1). The combination of ampicillin and gentamicin or ampicillin and an expanded-spectrum cephalosporin (eg, cefotaxime [where available], ceftazidime, or cefepime) are appropriate regimens that provide empiric coverage for these organisms until culture results are available. Ampicillin and gentamicin is generally the preferred regimen; however, local antibiotic resistance patterns must be considered. Our suggested empiric regimens in special circumstances are summarized in the table (table 4) and discussed in greater detail separately. (See "Management and outcome of sepsis in term and late preterm infants", section on 'Initial empiric therapy'.)

LABORATORY TESTS — The goals of the diagnostic evaluation are to identify and treat all infants with bacterial sepsis and minimize the treatment of patients who are not infected. Laboratory assessment includes cultures of body fluids that confirm the presence or absence of a bacterial pathogen and other studies that are used to evaluate the likelihood of infection.

Blood culture — A definitive diagnosis of neonatal sepsis is established by a positive blood culture. The sensitivity of a single blood culture to detect neonatal bacteremia is approximately 90 percent.

Blood sampling – The following considerations are important when obtaining a blood culture:

Sampling site – Blood cultures can be obtained by venipuncture or arterial puncture or by sampling from a newly inserted umbilical artery or vascular access catheter. Positive culture results of blood drawn from indwelling umbilical or central venous catheters can be difficult to interpret since they can indicate contamination or catheter colonization rather than a true systemic infection. In such circumstances, obtaining a peripheral blood culture may help determine if there is a true bloodstream infection [8].

Number of cultures – We obtain at least one culture prior to initiating empiric antibiotic therapy in neonates with a high clinical suspicion for sepsis, although other institutions may routinely obtain two blood cultures.

Volume of blood – The optimal volume of blood is based on the weight of the infant. A minimum blood volume of 1 mL is desirable for optimal detection of bacteremia when a single blood culture bottle is used [5]. At the author's institution, the suggested optimal volume is 2 mL for infants weighing ≤3 kg and 3 mL for those who weigh >3 to 5 kg. Dividing this volume into two aliquots to inoculate an anaerobic as well as the aerobic culture bottle may optimize recovery of rare strict anaerobic species, and most neonatal pathogens grow under anaerobic conditions.

Time to positivity – Automated systems for continuous monitoring of blood cultures are routinely used in the United States and have shortened the time to identify positive blood cultures. In most cases of neonatal sepsis, blood cultures become positive within 24 to 36 hours [39].

Distinguishing infection from contamination – A positive blood culture is diagnostic of sepsis when a known bacterial pathogen is isolated (table 1). Isolation of skin flora (eg, diphtheroids) suggests contamination rather than infection. Contamination is also suggested when multiple species grow in culture. Coagulase-negative staphylococci may be pathogenic in patients with indwelling vascular catheters or other invasive devices, whereas a single blood culture positive for coagulase-negative staphylococci is likely to represent a contaminant in full-term infants without these risk factors [8].

Lumbar puncture — The clinical presentation of neonatal meningitis is indistinguishable from that of neonatal sepsis without meningitis. Specific clinical signs of meningitis (eg, bulging fontanelle, nuchal rigidity) are often lacking in neonates. For this reason, we suggest performing a lumbar puncture as part of the diagnostic evaluation in symptomatic neonates. Lumbar puncture should ideally be performed before the initiation of antibiotics for infants in whom the clinical suspicion for sepsis is high, particularly those with critical illness. However, lumbar puncture should be deferred if the procedure would compromise the infant's clinical condition or if the procedure would delay initiation of antibiotics [5].

Lumbar puncture is indicated in neonates with:

Clinical findings concerning for sepsis (table 2)

Positive blood culture

Worsening clinical status while on antibiotic therapy

Cerebrospinal fluid should be sent for Gram stain, routine culture, cell count with differential, and protein and glucose concentrations. The interpretation of cerebrospinal fluid needs to account for variations due to gestational age, chronologic age, and birth weight (table 3).

The clinical features and diagnosis of neonatal bacterial meningitis are discussed separately. (See "Bacterial meningitis in the neonate: Clinical features and diagnosis".)

Urine culture — Urine culture obtained by catheter or bladder tap should be included in the sepsis evaluation for infants one week of age or older. A urine culture need not be routinely performed in the evaluation of an infant ≤6 days of age, because a positive urine culture in this setting is a reflection of high-grade bacteremia rather than an isolated urinary tract infection [5]. (See "Urinary tract infections in neonates".)

Other cultures — In patients with late-onset infection, cultures should be obtained from any other potential foci of infection (eg, purulent eye drainage or pustules).

Tracheal aspirates can be of value if obtained immediately after intubation. However, they may reflect lower respiratory tract colonization rather than indicating a causative pathogen in an infant who has been intubated for several days.

Gram stain or culture of other sites (eg, gastric aspirate, body surface sites [eg, axilla, groin, and external ear canal]) add little to the evaluation and should not be performed [5].

Complete blood count — A complete blood count (CBC) is used to evaluate the likelihood of sepsis in a neonate with risk factors or signs of infection. Abnormal findings on a CBC cannot be used to establish the diagnosis of sepsis.

Early-onset sepsis — For most neonates with suspected early-onset sepsis, we suggest obtaining a CBC as part of the diagnostic evaluation. In neonates who are undergoing evaluation because they have identified risk factors for group B Streptococcus (GBS) and who are otherwise well appearing, it is reasonable to omit the CBC (ie, obtain only a blood culture) [35]. (See "Management of neonates at risk for early-onset group B streptococcal infection", section on 'Diagnostic evaluation'.)

The CBC does not perform well in predicting risk of infection in neonates and should not be used as the sole determinant of whether to treat empirically with antibiotics [40-44]. However, when used in conjunction with other assessments, it may be useful in the evaluation of infants with suspected early- or late-onset sepsis. The CBC is more useful in identifying neonates who are unlikely to have sepsis than in identifying infants with sepsis [5,8]. When used in the evaluation of early-onset sepsis, the predictive value of the CBC improves if obtained after four to six hours of age [41,45].

Two large multicenter studies have evaluated the diagnostic value of CBCs in early-onset neonatal sepsis [40,41]. These studies found that low white blood cell (WBC) count (<5000/microL), absolute neutropenia (absolute neutrophil count [ANC] <1000 neutrophils/microL), relative neutropenia (ANC <5000 neutrophils/microL), and elevated ratio of immature to total neutrophil counts (I/T ratio) were associated with culture-proven sepsis. However, none of the tests was sufficiently sensitive to reliably predict neonatal sepsis.

CBCs obtained 6 to 12 hours after delivery are more predictive of sepsis than those obtained immediately after birth because the WBC and ANC normally increase during the first six hours of life [40,46].

The following neutrophil indices are used to determine the likelihood of infection:

I/T ratio – An elevated I/T ratio (≥0.2) has the best sensitivity of the neutrophil indices for predicting neonatal sepsis and can be helpful as an initial screen when used in combination with risk factors, clinical assessment, and/or other tests [6,47]. A normal I/T ratio can help rule out sepsis; however, an elevated value is not highly predictive of sepsis and may be observed in 25 to 50 percent of uninfected infants [6,47,48].

The I/T ratio is limited by the wide range of normal values, which reduces its positive predictive value, especially in asymptomatic patients [49]. Inter-reader differences in band neutrophil identification with manual differential counts is another limitation. In addition, exhaustion of the bone marrow reserves, which may occur during critical illness, will result in low band counts and lead to falsely low ratios. (See "Evaluating diagnostic tests", section on 'How well does the test perform in specific populations?'.)

ANC – Although both elevated and low neutrophil counts can be associated with neonatal sepsis, neutropenia has greater specificity since few conditions other than sepsis and preeclampsia depress the neutrophil count in neonates.

Neutrophil counts vary with gestational age (counts decrease with decreasing gestational age), type of delivery (counts are lower in infants born by cesarean delivery), site of sampling (counts are lower in arterial than in venous samples), altitude (counts are higher at elevated altitudes), and timing after delivery (counts increase during the first six hours of life) [40].

The lower limit of a normal neutrophil count for infants >36 weeks of gestation is 3500/microL at birth and 7500/microL six to eight hours after delivery (figure 1) [50]. For infants born at 28 through 36 weeks of gestation, the lower limits of normal neutrophil counts at birth and at six to eight hours after birth are 1000/microL and 1500/microL, respectively (figure 2).

Late-onset sepsis — CBCs are frequently used to support the diagnosis of late-onset sepsis. In this setting, CBCs are less variable than in the first days of life. However, WBC indices still perform poorly in identifying neonates with late-onset sepsis.

In a study of 37,826 neonates (mostly infants continuously hospitalized from birth) who underwent evaluation for late-onset (defined as 4 to 120 days) sepsis with blood culture and CBC, abnormal WBC (<1000 or >50,000/microL), high ANC (>17,670/microL), elevated I/T ratio (≥0.2), and low platelet count (<50,000/microL) were associated with culture positivity [51]. However, sensitivity was inadequate to reliably predict late-onset sepsis.

Screening protocols used to identify serious bacterial infections in febrile infants two to three months of age are inadequate in neonates as they fail to accurately identify neonates with serious bacterial infections [52]. (See "The febrile infant (29 to 90 days of age): Outpatient evaluation".)

Other inflammatory markers — A number of acute phase reactants have been used to identify infected newborns. Many of these tests have a high sensitivity; however, they lack specificity, resulting in a poor predictive value [53]. No single biomarker or panel of screening tests is sufficiently sensitive to reliably detect neonatal sepsis [54].

C-reactive protein (CRP) – CRP is increased in inflammatory conditions, including sepsis. A variety of noninfectious inflammatory conditions can also cause elevated CRP, including maternal fever, fetal distress, stressful delivery, perinatal asphyxia, meconium aspiration, and intraventricular hemorrhage [55].

A single measurement of CRP is not a useful aid in the diagnosis of neonatal sepsis, because it lacks sufficient sensitivity and specificity [56]. However, sequential assessment of CRP values may help support a diagnosis of sepsis. If the CRP level remains persistently normal (<1 mg/dL [10 mg/L]), neonatal bacterial sepsis is unlikely [5].

CRP levels can be helpful in guiding the duration of antibiotic therapy in suspected neonatal bacterial infection. Infants with elevated CRP levels that decrease to <1 mg/dL (10 mg/L) 24 to 48 hours after initiation of antibiotic therapy typically are not infected and generally do not require further antibiotic treatment if cultures are negative. However, routine use of serial CRP measurements can be associated with longer length of hospital stay [57].

An elevated CRP level alone does not justify continuation of empiric antibiotics for more than 36 to 48 hours in well-appearing infants with negative culture results [58]. Additional evaluation may be warranted to investigate alternative explanations for persistently elevated CRP values.

Procalcitonin (PCT) – PCT is the peptide precursor of calcitonin. It is released by parenchymal cells in response to bacterial toxins, leading to elevated serum levels in patients with bacterial infections. Several observational studies have suggested that PCT may be a useful marker to identify neonates who are infected [59-61]. In a 2015 systematic review of 18 studies, the sensitivity of PCT for detection of neonatal sepsis ranged from 72 to 79 percent and the specificity ranged from 72 to 90 percent [61]. Thus, although PCT is a promising marker, it does not appear to be reliable as the sole or main diagnostic indicator for neonatal sepsis.

PCT may have utility in guiding the duration of antibiotic therapy in neonates with suspected sepsis. In a multicenter randomized trial involving 1710 neonates with suspected early-onset sepsis, infants assigned to a treatment protocol in which duration of antibiotic therapy was guided by serial PCT measurements in addition to standard criteria (ie, clinical examination, blood culture results, WBC, and CRP) had shorter duration of antibiotic therapy compared with infants managed according to standard criteria without PCT measurements (55.1 versus 65.0 hours, respectively) [62]. The rate of reinfection was low in both groups (0.7 percent for the PCT group, and 0.6 percent for the control group). However, the study protocol's suggested duration of antibiotic therapy was overruled by the treating clinician in 45 percent of infants in the PCT group and 41 percent of those in the control group. The findings reinforce the concept that when serial PCT levels are obtained, they should be used in conjunction with other clinical indicators of sepsis and should not be the sole basis of decision-making.

Cytokines, chemokines, and other biomarkers – Both proinflammatory cytokines, such as interleukin-6 and tumor necrosis factor-alpha, and antiinflammatory cytokines (interleukin-4 and interleukin-10) are increased in infected infants compared with those without infections [63-66]. Elevations of serum amyloid A and the cell surface antigen CD64 also have high sensitivity for identifying infants with sepsis [61,67]. However, these biomarkers are generally not used in clinical practice.

Further research aimed at better understanding the neonatal inflammatory response to sepsis may result in the identification of sensitive and specific markers of inflammation or the development of pathogen-specific rapid diagnostic tests for early detection of neonatal sepsis. With a sensitive and specific marker for systemic bacterial infection, the management of neonatal sepsis would be significantly altered so that antimicrobial therapy could be safely withheld in infants for whom sepsis is unlikely.

DIAGNOSIS

Culture-proven sepsis — The isolation of pathogenic bacteria from a blood culture is the gold standard to confirm the diagnosis of neonatal sepsis. A positive blood culture is diagnostic of sepsis when a bacterial pathogen is isolated (table 1). Isolation of skin flora (eg, diphtheroids and coagulase-negative staphylococci) in culture suggests contamination rather than infection, although coagulase-negative staphylococci can be pathogenic in patients with indwelling vascular catheters or other devices [8]. (See 'Blood culture' above and "Management and outcome of sepsis in term and late preterm infants", section on 'Culture-proven sepsis'.)

Probable sepsis — In some cases, a pathogen may not be isolated in culture, yet the neonate has a clinical course that is concerning for sepsis (eg, ongoing temperature instability; ongoing respiratory, cardiocirculatory, or neurologic symptoms not explained by other conditions; or ongoing laboratory abnormalities suggestive of sepsis [ie, cerebrospinal fluid pleocytosis, elevated ratio of immature to total neutrophil counts, or elevated C-reactive protein (CRP)]).

A composite of observational assessment and serial laboratory testing is typically used to make a diagnosis of probable sepsis [68]. The criteria used are usually broad, in an attempt to ensure that all infected infants are identified, but at the cost of testing and treating a number of uninfected infants. There is no consensus definition for the diagnosis of probable sepsis in neonates [1].

Alternative diagnoses (table 5) should also be entertained when an infant with suspected sepsis has negative cultures. (See "Management and outcome of sepsis in term and late preterm infants", section on 'Probable but unproven sepsis' and 'Differential diagnosis' below.)

Infection unlikely — Infants with mild and/or transient symptoms (ie, fever alone or other symptoms that quickly resolve) who remain well-appearing with normal laboratory values and negative cultures at 36 to 48 hours are unlikely to have sepsis. Empiric antibiotic therapy should be discontinued after 36 to 48 hours in these neonates [5,69].

In a retrospective study of 2785 newborns who underwent evaluation for sepsis based on clinical symptoms (54 percent) or risk factors (46 percent), 22 infants (0.8 percent) were found to have culture-proven sepsis and 40 (1.4 percent) had probable sepsis (ie, culture-negative clinical sepsis) [6].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of neonatal sepsis includes systemic viral, fungal, and parasitic infections and noninfectious causes of temperature instability and respiratory, cardiocirculatory, and neurologic symptoms (table 5). Appropriate microbiologic testing distinguishes neonatal bacterial sepsis from nonbacterial systemic infections. The clinical history, disease course, chest radiograph, electrocardiogram (ECG), hyperoxia testing, drug screening, neuroimaging, blood glucose, serum electrolytes, and newborn screening may assist in distinguishing noninfectious disorders from neonatal sepsis.

It is often difficult to differentiate neonatal sepsis from other conditions. However, given the morbidity and mortality of neonatal sepsis, empiric antibiotic therapy should be provided (after cultures are obtained) to infants with suspected sepsis pending definitive culture-based diagnosis.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sepsis in neonates" and "Society guideline links: Group B streptococcal infection in pregnant women and neonates".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Sepsis in newborn babies (The Basics)")

SUMMARY AND RECOMMENDATIONS

Epidemiology and microbiology – Sepsis is an important cause of morbidity and mortality in newborn infants.

Incidence – Although the incidence of sepsis in term and late preterm infants is low (approximately 1 to 6 cases per 1000 births), the potential for serious adverse outcomes, including death, is of such great consequence that caregivers should have a low threshold for evaluation and treatment for possible sepsis. (See 'Epidemiology' above.)

Common pathogens – Group B Streptococcus (GBS) and Escherichia coli are the most common bacteria causing neonatal sepsis (table 1). (See 'Etiologic agents' above.)

Maternal risk factors – Maternal risk factors for neonatal sepsis include chorioamnionitis (intraamniotic infection), intrapartum fever, preterm delivery, maternal GBS colonization, and prolonged rupture of membranes. (See "Prevention of early-onset group B streptococcal disease in neonates", section on 'Identification of pregnancies at increased risk for early-onset neonatal GBS'.)

Clinical manifestations – Clinical manifestations are nonspecific and include fetal distress, low Apgar score, temperature instability (usually fever), respiratory and cardiocirculatory symptoms (most commonly, respiratory distress and tachycardia), neurologic symptoms (irritability, lethargy, poor tone, and seizures), and gastrointestinal abnormalities (poor feeding, vomiting, and abdominal distension) (table 2). (See 'Clinical manifestations' above.)

Evaluation – Evaluation and initial management of neonates with suspected sepsis should include a review of the pregnancy, labor, and delivery; complete physical examination; laboratory evaluation; and prompt initiation of empiric antibiotics (after obtaining cultures). Our suggested empiric antibiotic regimens are summarized in the table (table 4) and are discussed in detail separately. (See 'Evaluation and initial management' above and "Management and outcome of sepsis in term and late preterm infants", section on 'Initial empiric therapy'.)

Early-onset – In neonates <7 days old, the approach to the evaluation depends upon whether the neonate is symptomatic or well appearing.

Symptomatic neonates should undergo a full diagnostic evaluation including (see 'Symptomatic neonates' above and 'Laboratory tests' above):

-Blood culture

-Complete blood count (CBC) with differential

-Lumbar puncture (if the infant is clinically stable enough to tolerate the procedure and it will not delay initiation of antibiotic therapy)

-Chest radiograph (if respiratory symptoms are present) and cultures from tracheal aspirates (if intubated)

-C-reactive protein (CRP) and/or procalcitonin (PCT) levels are not routinely required but may be helpful in determining length of therapy if followed serially

Empiric antibiotics should be provided to these neonates pending culture results (table 4). (See 'Symptomatic neonates' above and "Management and outcome of sepsis in term and late preterm infants", section on 'Early-onset sepsis'.)

For well-appearing newborns who have risk factors for early-onset sepsis, decisions regarding evaluation and use of empiric antibiotics are based upon the nature of the risk factor(s) and whether or not the mother received adequate intrapartum antibiotic prophylaxis (IAP). Accepted approaches include categorical risk assessment (algorithm 1), clinical observation (algorithm 2), and the early-onset sepsis calculator. This is discussed in detail separately. (See "Management of neonates at risk for early-onset group B streptococcal infection", section on 'Approaches to risk assessment'.)

Late-onset – Neonates presenting with signs and symptoms of late-onset sepsis (onset of symptoms from 7 to 28 days of life) should undergo a full diagnostic evaluation similar to that described above for early-onset sepsis but also including a urine culture and cultures from potential foci of infection. Empiric antibiotic treatment should be initiated in these infants pending culture results (table 4). (See 'Late-onset sepsis' above and "Management and outcome of sepsis in term and late preterm infants", section on 'Late-onset sepsis' and "The febrile infant (29 to 90 days of age): Management".)

Diagnosis – Isolation of a pathogen from a blood culture confirms the diagnosis of neonatal sepsis. (See 'Diagnosis' above.)

The differential diagnosis of neonatal sepsis includes other systemic infections and noninfectious conditions including respiratory diseases (eg, transient tachypnea of the newborn and respiratory distress syndrome), cardiac diseases (eg, congenital heart disease and supraventricular tachycardia), neurologic injury (eg, from anoxia or hemorrhage), inborn errors of metabolism, and neonatal abstinence syndrome (table 5). (See 'Differential diagnosis' above.)

REFERENCES

  1. Wynn JL, Wong HR, Shanley TP, et al. Time for a neonatal-specific consensus definition for sepsis. Pediatr Crit Care Med 2014; 15:523.
  2. Raju TN, Higgins RD, Stark AR, Leveno KJ. Optimizing care and outcome for late-preterm (near-term) infants: a summary of the workshop sponsored by the National Institute of Child Health and Human Development. Pediatrics 2006; 118:1207.
  3. American Academy of Pediatrics. Group B streptococcal infections. In: Red Book: 2018 Report of the Committee on Infectious Diseases, 31st ed, Kimberlin DW, Brady MT, Jackson MA, Long SS (Eds), American Academy of Pediatrics, Itasca, IL 2018. p.762.
  4. Rao SC, Srinivasjois R, Moon K. One dose per day compared to multiple doses per day of gentamicin for treatment of suspected or proven sepsis in neonates. Cochrane Database Syst Rev 2016; 12:CD005091.
  5. Puopolo KM, Benitz WE, Zaoutis TE, et al. Management of Neonates Born at ≥35 0/7 Weeks' Gestation With Suspected or Proven Early-Onset Bacterial Sepsis. Pediatrics 2018; 142.
  6. Escobar GJ, Li DK, Armstrong MA, et al. Neonatal sepsis workups in infants >/=2000 grams at birth: A population-based study. Pediatrics 2000; 106:256.
  7. Alexander JM, McIntire DM, Leveno KJ. Chorioamnionitis and the prognosis for term infants. Obstet Gynecol 1999; 94:274.
  8. Nizet V, Klein JO. Bacterial sepsis and meningitis. In: Infectious diseases of the Fetus and Newborn Infant, 8th ed, Remington JS, et al (Eds), Elsevier Saunders, Philadelphia 2016. p.217.
  9. Bailit JL, Gregory KD, Reddy UM, et al. Maternal and neonatal outcomes by labor onset type and gestational age. Am J Obstet Gynecol 2010; 202:245.e1.
  10. Weston EJ, Pondo T, Lewis MM, et al. The burden of invasive early-onset neonatal sepsis in the United States, 2005-2008. Pediatr Infect Dis J 2011; 30:937.
  11. Stoll BJ, Hansen NI, Sánchez PJ, et al. Early onset neonatal sepsis: the burden of group B Streptococcal and E. coli disease continues. Pediatrics 2011; 127:817.
  12. Fleischmann-Struzek C, Goldfarb DM, Schlattmann P, et al. The global burden of paediatric and neonatal sepsis: a systematic review. Lancet Respir Med 2018; 6:223.
  13. Oza S, Lawn JE, Hogan DR, et al. Neonatal cause-of-death estimates for the early and late neonatal periods for 194 countries: 2000-2013. Bull World Health Organ 2015; 93:19.
  14. Cohen-Wolkowiez M, Moran C, Benjamin DK, et al. Early and late onset sepsis in late preterm infants. Pediatr Infect Dis J 2009; 28:1052.
  15. Phares CR, Lynfield R, Farley MM, et al. Epidemiology of invasive group B streptococcal disease in the United States, 1999-2005. JAMA 2008; 299:2056.
  16. Bizzarro MJ, Raskind C, Baltimore RS, Gallagher PG. Seventy-five years of neonatal sepsis at Yale: 1928-2003. Pediatrics 2005; 116:595.
  17. van den Hoogen A, Gerards LJ, Verboon-Maciolek MA, et al. Long-term trends in the epidemiology of neonatal sepsis and antibiotic susceptibility of causative agents. Neonatology 2010; 97:22.
  18. Puopolo KM, Eichenwald EC. No change in the incidence of ampicillin-resistant, neonatal, early-onset sepsis over 18 years. Pediatrics 2010; 125:e1031.
  19. Bauserman MS, Laughon MM, Hornik CP, et al. Group B Streptococcus and Escherichia coli infections in the intensive care nursery in the era of intrapartum antibiotic prophylaxis. Pediatr Infect Dis J 2013; 32:208.
  20. Centers for Disease Control and Prevention. Active Bacterial Core Surveillance Report, Emerging Infections Program Network, Group B Streptococcus 2000. http://www.cdc.gov/abcs/reports-findings/survreports/gbs00.pdf (Accessed on March 29, 2013).
  21. Centers for Disease Control and Prevention. Active Bacterial Core Surveillance (ABCs) Report, Emerging Infections Program Network, group B Streptococcus, 2018 . Available at: https://www.cdc.gov/abcs/reports-findings/survreports/gbs18.pdf (Accessed on April 27, 2021).
  22. Kuhn P, Dheu C, Bolender C, et al. Incidence and distribution of pathogens in early-onset neonatal sepsis in the era of antenatal antibiotics. Paediatr Perinat Epidemiol 2010; 24:479.
  23. Schrag SJ, Farley MM, Petit S, et al. Epidemiology of Invasive Early-Onset Neonatal Sepsis, 2005 to 2014. Pediatrics 2016; 138.
  24. Stoll BJ, Puopolo KM, Hansen NI, et al. Early-Onset Neonatal Sepsis 2015 to 2017, the Rise of Escherichia coli, and the Need for Novel Prevention Strategies. JAMA Pediatr 2020; 174:e200593.
  25. Gottlieb SL, Newbern EC, Griffin PM, et al. Multistate outbreak of Listeriosis linked to turkey deli meat and subsequent changes in US regulatory policy. Clin Infect Dis 2006; 42:29.
  26. Okike I, Lamont R, Heath P. Do We Really Need to Worry About Listeria in Newborn Infants? Pediatr Infect Dis J 2013; 32:405.
  27. Fortunov RM, Hulten KG, Hammerman WA, et al. Community-acquired Staphylococcus aureus infections in term and near-term previously healthy neonates. Pediatrics 2006; 118:874.
  28. Gordon A, Isaacs D. Late onset neonatal Gram-negative bacillary infection in Australia and New Zealand: 1992-2002. Pediatr Infect Dis J 2006; 25:25.
  29. Puopolo KM, Draper D, Wi S, et al. Estimating the probability of neonatal early-onset infection on the basis of maternal risk factors. Pediatrics 2011; 128:e1155.
  30. Soman M, Green B, Daling J. Risk factors for early neonatal sepsis. Am J Epidemiol 1985; 121:712.
  31. Osborn LM, Bolus R. Temperature and fever in the full-term newborn. J Fam Pract 1985; 20:261.
  32. Voora S, Srinivasan G, Lilien LD, et al. Fever in full-term newborns in the first four days of life. Pediatrics 1982; 69:40.
  33. Anand V, Nair PM. Neonatal seizures: Predictors of adverse outcome. J Pediatr Neurosci 2014; 9:97.
  34. Pong A, Bradley JS. Bacterial meningitis and the newborn infant. Infect Dis Clin North Am 1999; 13:711.
  35. Puopolo KM, Lynfield R, Cummings JJ, et al. Management of Infants at Risk for Group B Streptococcal Disease. Pediatrics 2019; 144.
  36. Escobar GJ, Puopolo KM, Wi S, et al. Stratification of risk of early-onset sepsis in newborns ≥ 34 weeks' gestation. Pediatrics 2014; 133:30.
  37. Kuzniewicz MW, Puopolo KM, Fischer A, et al. A Quantitative, Risk-Based Approach to the Management of Neonatal Early-Onset Sepsis. JAMA Pediatr 2017; 171:365.
  38. Kaiser Permanente neonatal early-onset sepsis calculator. Available at: https://neonatalsepsiscalculator.kaiserpermanente.org.
  39. Garcia-Prats JA, Cooper TR, Schneider VF, et al. Rapid detection of microorganisms in blood cultures of newborn infants utilizing an automated blood culture system. Pediatrics 2000; 105:523.
  40. Newman TB, Puopolo KM, Wi S, et al. Interpreting complete blood counts soon after birth in newborns at risk for sepsis. Pediatrics 2010; 126:903.
  41. Hornik CP, Benjamin DK, Becker KC, et al. Use of the complete blood cell count in early-onset neonatal sepsis. Pediatr Infect Dis J 2012; 31:799.
  42. Hashavya S, Benenson S, Ergaz-Shaltiel Z, et al. The use of blood counts and blood cultures to screen neonates born to partially treated group B Streptococcus-carrier mothers for early-onset sepsis: is it justified? Pediatr Infect Dis J 2011; 30:840.
  43. Greenberg DN, Yoder BA. Changes in the differential white blood cell count in screening for group B streptococcal sepsis. Pediatr Infect Dis J 1990; 9:886.
  44. Ottolini MC, Lundgren K, Mirkinson LJ, et al. Utility of complete blood count and blood culture screening to diagnose neonatal sepsis in the asymptomatic at risk newborn. Pediatr Infect Dis J 2003; 22:430.
  45. Newman TB, Puopolo KM, Wi S, et al. Interpreting complete blood counts soon after birth in newborns at risk for sepsis. Pediatrics 2010; 126:903.
  46. Rozycki HJ, Stahl GE, Baumgart S. Impaired sensitivity of a single early leukocyte count in screening for neonatal sepsis. Pediatr Infect Dis J 1987; 6:440.
  47. Russell GA, Smyth A, Cooke RW. Receiver operating characteristic curves for comparison of serial neutrophil band forms and C reactive protein in neonates at risk of infection. Arch Dis Child 1992; 67:808.
  48. Murphy K, Weiner J. Use of leukocyte counts in evaluation of early-onset neonatal sepsis. Pediatr Infect Dis J 2012; 31:16.
  49. Jackson GL, Engle WD, Sendelbach DM, et al. Are complete blood cell counts useful in the evaluation of asymptomatic neonates exposed to suspected chorioamnionitis? Pediatrics 2004; 113:1173.
  50. Schmutz N, Henry E, Jopling J, Christensen RD. Expected ranges for blood neutrophil concentrations of neonates: the Manroe and Mouzinho charts revisited. J Perinatol 2008; 28:275.
  51. Hornik CP, Benjamin DK, Becker KC, et al. Use of the complete blood cell count in late-onset neonatal sepsis. Pediatr Infect Dis J 2012; 31:803.
  52. Baker MD, Bell LM. Unpredictability of serious bacterial illness in febrile infants from birth to 1 month of age. Arch Pediatr Adolesc Med 1999; 153:508.
  53. Malik A, Hui CP, Pennie RA, Kirpalani H. Beyond the complete blood cell count and C-reactive protein: a systematic review of modern diagnostic tests for neonatal sepsis. Arch Pediatr Adolesc Med 2003; 157:511.
  54. Iroh Tam PY, Bendel CM. Diagnostics for neonatal sepsis: current approaches and future directions. Pediatr Res 2017; 82:574.
  55. Pourcyrous M, Bada HS, Korones SB, et al. Significance of serial C-reactive protein responses in neonatal infection and other disorders. Pediatrics 1993; 92:431.
  56. Brown JVE, Meader N, Cleminson J, McGuire W. C-reactive protein for diagnosing late-onset infection in newborn infants. Cochrane Database Syst Rev 2019; 1:CD012126.
  57. Mukherjee A, Davidson L, Anguvaa L, et al. NICE neonatal early onset sepsis guidance: greater consistency, but more investigations, and greater length of stay. Arch Dis Child Fetal Neonatal Ed 2015; 100:F248.
  58. Benitz WE, Wynn JL, Polin RA. Reappraisal of guidelines for management of neonates with suspected early-onset sepsis. J Pediatr 2015; 166:1070.
  59. Maniaci V, Dauber A, Weiss S, et al. Procalcitonin in young febrile infants for the detection of serious bacterial infections. Pediatrics 2008; 122:701.
  60. Vouloumanou EK, Plessa E, Karageorgopoulos DE, et al. Serum procalcitonin as a diagnostic marker for neonatal sepsis: a systematic review and meta-analysis. Intensive Care Med 2011; 37:747.
  61. Hedegaard SS, Wisborg K, Hvas AM. Diagnostic utility of biomarkers for neonatal sepsis--a systematic review. Infect Dis (Lond) 2015; 47:117.
  62. Stocker M, van Herk W, El Helou S, et al. Procalcitonin-guided decision making for duration of antibiotic therapy in neonates with suspected early-onset sepsis: a multicentre, randomised controlled trial (NeoPIns). Lancet 2017; 390:871.
  63. Arnon S, Litmanovitz I. Diagnostic tests in neonatal sepsis. Curr Opin Infect Dis 2008; 21:223.
  64. Panero A, Pacifico L, Rossi N, et al. Interleukin 6 in neonates with early and late onset infection. Pediatr Infect Dis J 1997; 16:370.
  65. Sherwin C, Broadbent R, Young S, et al. Utility of interleukin-12 and interleukin-10 in comparison with other cytokines and acute-phase reactants in the diagnosis of neonatal sepsis. Am J Perinatol 2008; 25:629.
  66. Zhou M, Cheng S, Yu J, Lu Q. Interleukin-8 for diagnosis of neonatal sepsis: a meta-analysis. PLoS One 2015; 10:e0127170.
  67. Lynema S, Marmer D, Hall ES, et al. Neutrophil CD64 as a diagnostic marker of sepsis: impact on neonatal care. Am J Perinatol 2015; 32:331.
  68. Gerdes JS. Diagnosis and management of bacterial infections in the neonate. Pediatr Clin North Am 2004; 51:939.
  69. Polin RA, Watterberg K, Benitz W, Eichenwald E. The conundrum of early-onset sepsis. Pediatrics 2014; 133:1122.
Topic 5043 Version 54.0

References