The febrile neonate (28 days of age or younger): Outpatient evaluation

INTRODUCTION — The outpatient evaluation of febrile neonates (≤28 days old) is discussed in this topic.

For a discussion of the management of the febrile neonate; the evaluation and management of febrile infants 29 to 90 days old; the definition of fever in the young infant; the diagnosis, evaluation, and initial management of neonatal sepsis, and the approach to the ill-appearing infant without fever, refer to the following topics:

●(See "The febrile infant (29 to 90 days of age): Management".)

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

●(See "The febrile infant (younger than 90 days of age): Definition of fever".)

●(See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates" and "Management and outcome of sepsis in term and late preterm neonates".)

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

TERMINOLOGY

●Fever – We define fever in neonates as a rectal temperature of ≥38°C (100.4°F). This is the standard for detecting fever in neonates because most studies establishing the risk of serious infections in neonates have relied upon rectal temperatures. (See "The febrile infant (younger than 90 days of age): Definition of fever", section on 'Definition of fever'.)

Interpretation of other means of temperature measurement and caregiver reports of fever in young infants is discussed in detail separately. (See "The febrile infant (younger than 90 days of age): Definition of fever", section on 'Definition of fever'.)

●Invasive bacterial infection (IBI) – For this topic, IBI refers to bacteremia or bacterial meningitis. IBI replaces the previously used term "serious bacterial infection" (SBI), which includes urinary tract infection (UTI), the most common bacterial infection in febrile neonates. However, urinalysis and urine cultures remain an integral part of a comprehensive evaluation for IBIs because some patients with UTIs also have bacteremia.

ETIOLOGY

Viral infection — Viral infection is a common cause of fever in neonates undergoing outpatient evaluation [1-4]. However, neonates with viral infection remain at a lower but non-negligible risk for concomitant invasive bacterial infection (IBI). Viruses that can cause serious illness in febrile neonates include but are not limited to:

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

●Varicella-zoster virus (see "Varicella-zoster infection in the newborn")

●Some enteroviruses (see "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention")

●Influenza virus (see "Seasonal influenza in children: Clinical features and diagnosis", section on 'Clinical features')

●Some adenoviruses (see "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection")

●Respiratory syncytial virus (RSV) (see "Respiratory syncytial virus infection: Clinical features and diagnosis in infants and children")

●Rhinovirus (see "Epidemiology, clinical manifestations, and pathogenesis of rhinovirus infections")

●Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (see "COVID-19: Clinical manifestations and diagnosis in children", section on 'In infants <12 months of age')

The neonate may acquire a viral infection through vertical transmission from the mother during delivery or postnatally from sources such as hospital personnel, family members, and daycare staff or attendees. Neonates are more likely than older infants to experience morbidity from a viral infection, in part because of a decreased responsiveness of T cell-mediated immunity. (See "Normal B and T lymphocyte development".)

Invasive bacterial infection

Risk factors for IBI — Risk factors for IBI in neonates undergoing outpatient evaluation include (table 1):

●Age – Age has long been used to determine risk levels for infection in young infants. Traditionally, 28 days of age has been set as the threshold for a full sepsis evaluation in neonates with fever [5-9]. More recent evidence from large observational studies indicate that the highest risk for IBI occurs in febrile neonates ≤21 days old (bacteremia 3 to 5 percent, meningitis 1.1 to 2.7 percent) [10-13]. Although the incidence of IBI in febrile neonates 22 to 28 days old is still substantial, clinical prediction rules based upon inflammatory markers and urine testing can identify neonates in this age range who are at lower risk for IBI [11,14,15].

●Ill appearance – Ill appearance, as indicated by lethargy, irritability, respiratory distress, or poor perfusion, significantly increases the risk of IBI in febrile neonates [13,14,16]. However, signs of IBI may be subtle and difficult to identify; appearance by itself has low predictive ability for presence of IBI [17].

●Prematurity (gestational age younger than 37 weeks) – Because of their relatively immature immune system, premature infants are at a much higher risk for IBI. For example, premature infants have rates of sepsis that are approximately 10 to 12 times that of term infants, including late-onset sepsis. (See "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Incidence' and "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Epidemiology'.)

●Maternal group B Streptococcus (GBS) infection – Potential findings that increase the risk for GBS infection and both early-onset and some late-onset sepsis in neonates include:

•Maternal fever

•Chorioamnionitis typically caused by prolonged rupture of membranes

•Maternal colonization with GBS

GBS screening and maternal intrapartum antibiotic prophylaxis reduce the risk of early-onset GBS infection but do not eliminate it. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Maternal risk factors' and "Prevention of early-onset group B streptococcal disease in neonates".)

●Comorbidities or chronic illness – Neonates with the following comorbidities who are considered at higher risk for IBI [5,11]:

•Infants with congenital or chromosomal abnormalities or a perinatal course that is complicated by surgery or infection

•Patients who are dependent upon technology or specific therapies (eg, home ventilator, home oxygen, or total parenteral nutrition)

●Received antibiotics within the prior three to seven days – Because of the long half-lives of antibiotics in neonates, administration from three up to seven days prior to evaluation may mask signs and symptoms of IBI.

●Social barriers to follow-up – Although it has not been shown to be a direct risk factor for IBI, factors that negatively impact the ability to re-evaluate a young febrile infant on an outpatient basis pose a risk for safe management including any one of the following:

•Limited skills by the caregiver to assess severity of diseases/educational barriers

•Limited access to a medical home for questions and/or follow-up

•Lack of transportation

•Language and other communication limitations

Infection source and common pathogens — Urinary tract infection (UTI) accounts for most bacterial infections in neonates undergoing outpatient evaluation for fever [6,9,14]. Bacteremia, bacterial meningitis, cellulitis, pneumonia, septic arthritis, and osteomyelitis constitute other important but less common infection sources.

Escherichia coli is the most common pathogen causing bacteremia, neonatal sepsis, and bacterial meningitis in febrile neonates presenting for outpatient evaluation, followed by Group B Streptococcus [11,12,18-20]. E. coli also causes the majority of UTIs in this age group. Other bacterial pathogens include [21-23]:

●Staphylococcus aureus, including community-acquired methicillin-resistant S. aureus (MRSA), usually association with skin, bone, or joint sites of involvement

●Streptococcus pneumoniae

●Haemophilus influenzae (nontypeable)

●Neisseria meningitidis

●Streptococcus pyogenes

●Enterococcus faecalis

●Gram-negative bacteria such as Enterobacter cloacae, Moraxella catarrhalis, Klebsiella species, and Citrobacter species

●Salmonella species may also cause bacteremia in neonates with diarrhea [24,25]

●Listeria monocytogenes (sporadic cause of late-onset sepsis and meningitis) (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Epidemiology')

STABILIZATION — Neonates who have respiratory or circulatory compromise (eg, apnea, respiratory distress, or signs of shock [eg, tachycardia with poor perfusion]) must be quickly identified and treated (table 2 and algorithm 1). (See "Approach to the ill-appearing infant (younger than 90 days of age)", section on 'Initial stabilization'.)

These ill-appearing patients are at high risk for invasive bacterial infection (IBI) and warrant a complete evaluation for sepsis and meningitis (table 3) and prompt empiric administration of broad-spectrum antibiotics. (See "Management and outcome of sepsis in term and late preterm neonates".)

In addition to respiratory or circulatory compromise, ill-appearing infants may display irritability, poor tone, or lethargy. A careful physical examination may identify a pattern of clinical features that suggests the etiology of an infant's symptoms (table 4) and warrants further studies in addition to an evaluation for sepsis and meningitis. (See "Approach to the ill-appearing infant (younger than 90 days of age)", section on 'Evaluation'.)

HISTORY — For the febrile neonate, history should focus on identifying risk factors for invasive bacterial infection (IBI) and on subtle signs and symptoms of illness, including:

●Poor feeding (eg, decreased frequency, amount, or length of feeding; and, for breastfeeding infants, weak suck)

●Lethargy (eg, increased sleep or difficulty waking the infant)

●Increased fussiness, difficult to console

●Weak cry

●Difficulty breathing

For neonates in whom fever is the only presenting symptom reported by caregivers, the clinician should determine how the temperature was taken and the exact reading. Rectal temperatures are the standard for detecting fever in neonates. Afebrile neonates who present to the emergency department with history of fever are still at risk for IBIs. Thus, absence of documented fever should not change clinician decision regarding evaluation and management. (See "The febrile infant (younger than 90 days of age): Definition of fever", section on 'Definition of fever'.)

Perinatal history should identify maternal risk factors that indicate a higher risk for late-onset neonatal sepsis or herpes simplex virus (HSV) infection:

●Late-onset (8-28 days) sepsis (most applicable to neonates <14 days old) (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Maternal risk factors'):

•Maternal fever

•Maternal colonization with group B Streptococcus (GBS) and/or administration of antibiotic prophylaxis at delivery

•Chorioamnionitis, typically caused by prolonged rupture of membranes

●HSV infection (applicable to all neonates) (see "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Epidemiology and transmission'):

•Active genital lesions at the time of delivery

•Maternal history of sexually transmitted infections (STIs) such as HSV, gonorrhea, and chlamydia

Neonates with the following risk factors also remain at significant risk of sepsis and other IBI:

●History of prematurity (gestational age younger than 37 weeks)

●Comorbidities or chronic illness, including infants whose perinatal course was complicated by surgery, infection, or congenital or chromosomal anomalies; or those who are medically fragile (eg, receiving home ventilator therapy, home oxygen, or total parenteral nutrition)

●Antibiotic administration within the past three to seven days due to potential masking of a partially treated IBI

PHYSICAL EXAMINATION — The febrile neonate demonstrates few, if any, interpretable clues to the underlying cause of fever on physical examination despite evaluation by experienced clinicians or the use of an observation scale score [11,26,27]. The risk of sepsis and other invasive bacterial infection (IBI) remains elevated for all neonates, especially those ≤21 days old [11]. Furthermore, fever may be the only manifestation of either early- or late-onset sepsis. Of note, approximately 50 percent of infants presenting with neonatal sepsis are normothermic or hypothermic. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates".)

Appearance — Ill-appearing neonates require emergency stabilization (table 2 and algorithm 1), comprehensive sepsis evaluation (table 3), and treatment.

For most neonates, comprehensive sepsis evaluation is required despite well appearance. However, selected neonates 22 to 28 days old may undergo a modified, potentially less comprehensive evaluation by incorporating parental preferences (ie, shared decision making) to decide about the performance of a lumbar puncture and/or hospitalization [11]. (See '22 to 28 days old' below.)

Identifying a young infant as well-appearing relies heavily upon the clinician's pediatric knowledge and experience. Prior to the development of a social smile at approximately six weeks of age, this task is especially challenging, and research has revealed that use of clinician intuition and/or standardized scores such as the Yale Observation Scale score is unreliable [27].

Degree of fever — For neonates ≤ 21 days of age, the height of the fever does not change further evaluation or management. This is because the risk of IBIs and herpes simplex virus infection remains high.

However, for well-appearing neonates 22 to 28 days old with rectal temperatures ≥38°C (100.4°F) and no obvious source of infection on physical examination, the likelihood of IBI (bacteremia or meningitis) and urinary tract infection (UTI) increases with higher fevers as shown in cohort studies for deriving and validating prediction rules that include fever thresholds [11].

Signs of focal infection — During physical examination, the clinician should look for focal infection as indicated by the following signs:

●Focal bacterial infections

•Meningitis – Irritability, lethargy, decreased or increased tone on examination, bulging fontanelle (late finding), and nuchal rigidity (rare finding in neonates) (see "Bacterial meningitis in children older than one month: Clinical features and diagnosis", section on 'Clinical findings')

•Acute suppurative otitis media – Bulging and inflammation of the tympanic membrane (picture 1) or perforation of the tympanic membrane with acute purulent otorrhea (rare in neonates) (see "Acute otitis media in children: Clinical manifestations and diagnosis", section on 'Otoscopic evaluation')

•Pneumonia – Tachypnea, respiratory distress (including grunting, flaring, and retractions), decreased oxygen saturation, cough, crackles, or decreased breath sounds on auscultation (see "Community-acquired pneumonia in children: Clinical features and diagnosis", section on 'Clinical evaluation')

•Omphalitis – Purulent drainage from the umbilical stump, circumferential erythema with tenderness and/or induration around the umbilicus (picture 2 and picture 3), and/or foul odor (see "Care of the umbilicus and management of umbilical disorders", section on 'Omphalitis')

•Bacterial arthritis – Decreased range of motion of an extremity and/or a swollen, painful, warm, and/or red joint (picture 4A-B) (see "Bacterial arthritis: Clinical features and diagnosis in infants and children", section on 'Neonates and infants')

•Osteomyelitis – Decreased movement of a limb with and/or localized swelling or erythema overlying a bony structure (see "Hematogenous osteomyelitis in children: Clinical features and complications", section on 'Birth to three months')

•Cutaneous cellulitis or abscess – Redness, induration, warmth, and drainage from a skin lesion, which is often located in the scalp at the site of monitoring probe insertion

•Mastitis – Unilateral redness, tenderness, and/or induration of a breast, which also may have fluctuance or purulent nipple discharge (see "Mastitis and breast abscess in infants younger than two months")

●Serious viral infections

•HSV infection – Clinical findings concerning for HSV infection include (see "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Clinical suspicion'):

-Mucocutaneous vesicles (picture 5 and picture 6)

-Seizures, which typically consist of facial automatisms (eg, lip smacking or pursing), eye deviation, or unresponsiveness rather than tonic-clonic motor activity

-Focal neurologic signs

-Respiratory distress, apnea, or progressive pneumonitis symptoms

-Conjunctivitis, excessive tearing, or eyelid swelling

-Sepsis-like illness (fever or hypothermia, irritability, lethargy, respiratory distress, apnea, abdominal distension, hepatomegaly, or ascites)

•Bronchiolitis – Tachypnea, copious nasal discharge, cough, auscultation demonstrating rales and/or wheezing, or apnea (see "Bronchiolitis in infants and children: Clinical features and diagnosis", section on 'Clinical features')

ANCILLARY STUDIES

Ill-appearing — Regardless of age, all febrile neonates who are ill appearing are at high risk for invasive bacterial infection (IBI) and warrant a comprehensive evaluation for sepsis (table 3) [9,26,28].

In addition to diagnostic testing to identify IBI and urinary tract infection (UTI), diagnostic testing for viral etiologies may be warranted in selected patients:

●Herpes simplex virus (HSV) – Infants with clinical suspicion for HSV infection (table 5) warrant additional blood and cerebrospinal fluid (CSF) studies, surface viral cultures, and scraping from skin vesicles and mucous membranes for additional testing as described separately. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Neonatal HSV'.)

●Respiratory syncytial virus (RSV) – Ill-appearing infants with clinical findings of bronchiolitis warrant rapid testing for respiratory viruses (eg, RSV) to permit proper infection control measures during hospitalization. However, empiric antibiotics are still indicated. (See "Bronchiolitis in infants and children: Clinical features and diagnosis", section on 'Approach to testing' and "The febrile neonate (28 days of age or younger): Initial management", section on 'Other viral infections'.)

●Influenza – During high seasonal prevalence, testing for influenza using highly accurate methods (table 6) is helpful for determining the need for continued contact precautions and antiviral treatment in neonates. However, laboratory confirmation is not necessary before initiation of these measures and should not delay their initiation in patients in whom they are indicated. (See "Seasonal influenza in children: Clinical features and diagnosis", section on 'Whom to test'.)

●Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – Coronavirus disease 2019 (COVID-19) can cause fever with or without ill appearance in young infants. Therefore, SARS-CoV-2 viral testing (nasal or nasopharyngeal swab for nucleic acid amplification testing [NAAT], which includes polymerase chain reaction [PCR] testing) is indicated for infection control and COVID-19-specific treatment in all hospitalized patients. (See "COVID-19: Clinical manifestations and diagnosis in children", section on 'In infants <12 months of age' and "COVID-19: Management in children".)

Other causes of ill appearance in addition to sepsis include child abuse, congenital heart disease, congenital adrenal hyperplasia, inborn errors of metabolism, malrotation with volvulus, and a variety of other conditions discussed separately. Infants with clinical manifestations suggesting a diagnosis other than or in addition to serious infection warrant additional studies based upon specific findings as discussed separately. (See "Approach to the ill-appearing infant (younger than 90 days of age)", section on 'Evaluation' and "Approach to the ill-appearing infant (younger than 90 days of age)", section on 'Targeted Evaluation'.)

Well-appearing — Age and risk factors for bacterial or HSV infection are the primary determinants for the evaluation of well-appearing febrile young neonates. The risk of IBI for otherwise low-risk, febrile neonates is highest in the first three weeks of life and then decreases in the fourth week [11].

<7 days old — The evaluation of neonates ≤7 days old with possible early-onset sepsis, which includes individuals with fever, is discussed separately. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates".)

7 to 21 days old — Febrile neonates 7 to 21 days of age should have a full evaluation for sepsis, including studies to detect HSV in neonates with risk factors or physical examination findings that raise risk for HSV (table 3). (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Clinical suspicion'.)

These patients also warrant empiric antimicrobial therapy (table 7) and hospital admission to a unit with nurses and ancillary staff experienced in caring for neonates. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Symptomatic neonates' and "The febrile neonate (28 days of age or younger): Initial management", section on 'Neonates 7 to 21 days old'.)

The 2021 American Academy of Pediatrics Clinical Practice Guideline (AAP CPG) provides an algorithm for the evaluation and management of well-appearing, 8- to 21-day-old febrile neonates (algorithm 2) [11]. Due to the low risk of UTI in patients with normal urine results, the AAP CPG recommends sending a urine culture (obtained by bladder catheterization or suprapubic aspiration [SPA]) only when the urinalysis is positive (leukocyte esterase present on dipstick, >5 white blood cells (WBCs)/high-power field [centrifuged urine], or >10 WBCs/mm³ [uncentrifuged urine]) [11]. However, it is reasonable for clinicians to send a urine culture obtained by catheterization or SPA in all febrile neonates younger than 21 days old in settings that have documented low rates of specimen contamination and timely specimen processing; false positive cultures due to contamination are less likely in such settings. (See "The febrile infant (29 to 90 days of age): Outpatient evaluation".)

Based upon observational studies performed in febrile neonates presenting to the emergency department or pediatric provider office, the estimated risk for bacterial infection in febrile, well-appearing neonates 0 to 21 days of age is high (bacteremia 3 to 5 percent (figure 1), meningitis 1.1 to 2.7 percent) [10-12]. The risk for UTI is higher (16 to 28 percent) [10,29]. However, a full sepsis evaluation was not performed in all febrile neonates in these studies; patients who did not undergo testing were assumed to have negative cultures based upon follow-up. Thus, these estimates may be low and may not be precise or generalizable. Nevertheless, the benefit of early detection and treatment of bacterial meningitis or HSV meningoencephalitis outweighs the risks of lumbar puncture. In addition, the ability to rapidly test for enterovirus as the cause of pleocytosis permits earlier discontinuation of antibiotics and hospital discharge.

22 to 28 days old — For well-appearing febrile neonates 22 to 28 days old in settings where procalcitonin (PCT) results are rapidly available, we use the Pediatric Emergency Care Applied Research Network (PECARN) clinical prediction rule to guide the need for cerebrospinal fluid studies [15]. Our approach is also consistent with the AAP CPG regarding the choice of inflammatory markers, options for urine testing, and when cerebrospinal fluid studies may be obtained [11].

The evaluation of well-appearing febrile neonates 22 to 28 days old varies according to the presence of risk factors for IBI (table 1):

●IBI risk factor present – For well-appearing febrile neonates 22 to 28 days old with any one of the risk factors for invasive bacterial infection (IBI), we recommend a full sepsis evaluation (table 3).

●No IBI risk factor – Based upon declines in sepsis and bacterial meningitis due to peri-partum GBS prophylaxis and the availability of more rapid blood culture results (typically within 24 to 36 hours), the 2021 AAP CPG offers the opportunity to do less evaluation in well-appearing, febrile neonates 22 to 28 days old (algorithm 3). For these patients, we obtain a blood culture, blood inflammatory markers (table 8), and urinalysis [11]:

•Blood inflammatory markers (IMs) – The IMs used depend upon the availability of PCT:

-If PCT results are rapidly available (ie, within 1 to 2 hours), then measure PCT and absolute neutrophil count (ANC), C-reactive protein (CRP) is optional.

-If PCT is not rapidly available, then measure CRP and ANC; rectal temperature >38.5°C (101.3°F) also counts as evidence of abnormal inflammation in this situation [11].

•Urinalysis (UA) – The clinician may use urine dipstick, microscopic urinalysis, or both for urine testing; bladder catheterization is recommended for urine collection in neonates. (See "Urinary tract infections in neonates", section on 'Urinalysis'.)

The results of IM and UA guide further evaluation (table 9) [11,30]:

•Any IM abnormal – If any IM is abnormal (table 8), then we recommend CSF studies and related testing to evaluate for meningitis. For patients with an abnormal UA, the clinician should also send a urine culture obtained by bladder catheterization or suprapubic aspiration. If the urinalysis is normal, a urine culture is not necessary, but CSF studies are still recommended. For these patients, we also recommend empiric parenteral antimicrobial therapy and hospitalization. Of note, if PCT testing is not rapidly available, a temperature greater than >38.5°C (101.3°F) is considered an abnormal inflammatory marker along with ANC and/or CRP. (See "The febrile neonate (28 days of age or younger): Initial management", section on 'Neonates 22 to 28 days old'.)

Due to the lower risk of UTI in these patients, the 2021 AAP CPG recommends sending a urine culture obtained by bladder catheterization or, less commonly, SPA only when the urinalysis is positive (leukocyte esterase on dipstick, >5 WBCs/high-power field [centrifuged urine], or >10 WBCs/mm³ [uncentrifuged urine]) [11]. This recommendation is based upon the low likelihood that a febrile young infant with a negative urine dipstick for leukocyte esterase and/or pyuria will have a UTI (table 10). If a urine culture is sent in these patients, the chance that a positive culture reflects specimen contamination exceeds the chance that it identifies a true UTI, thus exposing neonates to excess treatment that may be harmful.

However, it is reasonable for clinicians to send a urine culture in all febrile neonates younger than 22 to 28 days old in settings that have documented low rates of specimen contamination and timely specimen processing; false positives due to bacterial contaminants are less likely in such settings. (See "The febrile infant (29 to 90 days of age): Outpatient evaluation".)

•Normal IM – For 22- to 28-day old neonates with normal IM, clinicians and parents/primary caregivers through shared decision-making may elect not to obtain CSF studies.

If the UA is also negative for leukocyte esterase and/or pyuria, a urine culture is not recommended by the AAP CPG, but it is reasonable to send a urine culture in settings with documented low specimen contamination rates and timely specimen processing. The authors of this topic routinely send urine cultures in this situation.

If the UA is abnormal, the clinician should send a urine culture. Clinicians and parents/primary caregivers through shared decision-making may decide whether or not to obtain CSF studies, especially in patients with normal IMs [11].

Evidence suggests that the risk of IBI (primarily bacteremia) in febrile young infants with normal IMs is 0.2 to 0.7 percent. Thus, 140 to 500 patients would have to have interpretable CSF studies obtained to diagnose one case of meningitis [14,31,32].

In febrile neonates with a positive UA, the risk of IBI is 1 to 3 percent. However, a majority of IBIs are bacteremia, and the risk of bacterial meningitis is <1 percent. (See "Urinary tract infections in neonates", section on 'Sepsis evaluation'.)

During derivation and validation in a prospective cohort of nearly 1700 infants, including over 500 neonates, the PECARN rule has demonstrated a high negative predictive value for IBI (99.8 percent [95% CI 98.9 to 100 percent; prevalence of IBI 1.8 percent]) and no missed cases of meningitis [15]. The PECARN rule and other clinical prediction rules in febrile young infants are discussed in greater detail separately. (See "The febrile infant (29 to 90 days of age): Outpatient evaluation", section on 'Clinical prediction rules'.)

Additional considerations

Focal infection — All febrile neonates with focal infections (eg, acute otitis media, cellulitis, cutaneous abscess, mastitis, pneumonia, osteomyelitis, bacterial arthritis, or omphalitis) require a complete sepsis evaluation (table 3).

Diagnosed with viral infections — For febrile neonates <21 days old diagnosed with a viral infection, including RSV bronchiolitis, influenza, COVID-19, or other respiratory viral infections (eg, human rhinovirus, adenovirus, non-SARS-CoV-2 coronavirus, parainfluenza, and/or human metapneumovirus), should undergo a full sepsis evaluation (table 3). For neonates 22 to 28 days old, a positive viral test can be incorporated into shared decision-making. Neonates with a viral infection remain at substantial risk for an IBI that does not appear to differ from neonates with negative testing for viral infection [4,5,33-36]. For example, in a retrospective study of over 287 neonates who tested positive for respiratory viruses, up to 2.1 percent also had an IBI [4]. The risk of concomitant bacterial infection decreases with advancing age in neonates.

Testing panels for viral pathogens such as human rhinovirus, adenovirus, non-SARS-CoV-2 coronavirus, parainfluenza, and/or human metapneumovirus are not always readily available and may be cost prohibitive depending upon the setting.

Evidence regarding the risk of IBI in neonates with SARS-CoV-2 infection is limited [37]. All febrile young infants warrant testing for SARS-CoV-2 regardless of their exposure history as part of the initial evaluation. Furthermore, chest radiographs are strongly encouraged for patients who are positive for SARS-CoV-2, regardless of respiratory symptoms. For those who are well appearing but have positive radiographic findings, hospital admission is advised, especially if oxygen saturation is consistently <95 percent on room air, work of breathing is increased, or feeding is poor. (See "COVID-19: Clinical manifestations and diagnosis in children", section on 'In infants <12 months of age' and "COVID-19: Clinical manifestations and diagnosis in children", section on 'Laboratory tests for SARS-CoV-2'.)

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: Febrile young infants (younger than 90 days of age)".)

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 5^th to 6^th 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 10^th to 12^th 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 topic (see "Patient education: Fever in babies younger than 3 months (The Basics)")

●Beyond the Basics topic (see "Patient education: Fever in children (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Fever definition – A rectal temperature ≥38°C (100.4°F) defines a fever in neonates. (See 'Terminology' above.)

●Evaluation – The febrile neonate has an elevated risk for invasive bacterial infection (IBI; bacteremia and/or meningitis) or herpes simplex virus [HSV] infection. (See 'Risk factors for IBI' above.)

•Stabilization – Unstable febrile neonates require rapid identification and treatment for septic shock (algorithm 1). (See 'Stabilization' above.)

The evaluation should also identify and treat other causes of ill appearance in young infants (table 4) as discussed separately. (See "Approach to the ill-appearing infant (younger than 90 days of age)".)

•History – History should focus on risk factors for IBI (table 1) and subtle findings of illness (eg, poor feeding, lethargy, or decreased activity). (See 'History' above.)

•Physical examination – Physical examination focuses on general appearance and signs of (see 'Physical examination' above):

-Focal bacterial infection

-HSV infection (table 5)

-Bronchiolitis

Well appearance does not exclude the possibility of IBI. (See 'Appearance' above.)

●Ancillary studies – The risk of IBI guides further evaluation:

•Higher IBI risk – All febrile neonates 8 to 21 days old, should have a full sepsis evaluation (table 3 and algorithm 2) (see 'Ancillary studies' above):

Febrile neonates 22 to 28 days old with any one of the following should also undergo a full sepsis evaluation (see '22 to 28 days old' above):

-Ill appearance (see 'Ill-appearing' above)

-Focal bacterial infection

-Risk factors for IBI

The evaluation of inpatient neonates <8 days of age is discussed separately. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates".)

•Lower IBI risk – For low-risk, well-appearing febrile neonates 22 to 28 days old, the evaluation includes a blood culture, blood inflammatory markers (IMs) (table 8), and urinalysis. The choice of IM testing depends upon the availability of procalcitonin (PCT) (see '22 to 28 days old' above):

-If PCT results are rapidly available (ie, within 1 to 2 hours), then measure PCT and absolute neutrophil count (ANC), C-reactive protein (CRP) is optional.

-If PCT is not rapidly available, then measure CRP and ANC; rectal temperature >38.5°C (101.3°F) also counts as evidence of abnormal inflammation in this situation.

Results of IM and urinalysis determine decisions regarding cerebrospinal fluid (CSF) testing:

-Abnormal IM – If any IM is abnormal, then CSF studies and related testing are indicated to evaluate for meningitis. For patients with an abnormal urinalysis (UA), the clinician should also send a urine culture obtained by bladder catheterization or suprapubic aspiration.

-Normal IM – For 22- to 28-day old neonates with normal IMs, clinicians and parents/primary caregivers through shared decision-making may elect not to obtain CSF studies.

If urine testing is also negative for leukocyte esterase and/or pyuria, a urine culture is not recommended by the American Academy of Pediatrics Clinical Practice Guideline (AAP CPG), but it is reasonable to send a urine culture in settings with documented low specimen contamination rates and timely specimen processing. We routinely send urine cultures in this situation.

If the UA is abnormal, the clinician should send a urine culture. Clinicians and parents/primary caregivers through shared decision-making may decide whether or not to obtain CSF studies, especially in patients with normal IMs.

•Viral infection – Febrile neonates ≤21 days old diagnosed with a viral infection still require a full sepsis evaluation (table 3). For neonates 22 to 28 days old with a positive viral test, evaluation as for patients with lower IBI risk that is described above is indicated.

All neonates with clinical features of HSV infection also require testing for HSV, including CSF studies (table 5). (See 'Diagnosed with viral infections' above.)