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Febrile infant (younger than 90 days of age): Outpatient evaluation
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Febrile infant (younger than 90 days of age): Outpatient evaluation
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Literature review current through: Aug 2017. | This topic last updated: Jul 27, 2017.

INTRODUCTION — The outpatient evaluation of febrile infants younger than 90 days of age is discussed in this topic.

For a discussion of the management of febrile infants younger than 90 days of age; definition of fever in the young infant; the diagnosis, evaluation, and initial management of early-onset sepsis in neonates; and the approach to the ill-appearing infant without fever, refer to the following topics:

(See "Febrile infant (younger than 90 days of age): Management".)

(See "Febrile infant (younger than 90 days of age): Definition of fever".)

(See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants", section on 'Evaluation and initial management'.)

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

DEFINITION OF FEVER — Rectal temperatures are the standard for detecting fever in infants younger than 3 months of age; the majority of studies establishing the risk of serious infections in febrile young infants have relied upon rectal temperatures. We regard a rectal temperature of 38°C (100.4°F) or greater as fever in infants 90 days of age and younger. (See "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 are discussed in detail separately. (See "Febrile infant (younger than 90 days of age): Definition of fever", section on 'Definition of fever'.)

ETIOLOGY — The ability to generalize data from prior studies of the infectious etiology of fever in young infants is limited because many studies were conducted in an era when numerous vaccines that are now included in routine childhood immunizations were unavailable (eg, pneumococcal conjugate vaccine, Haemophilus influenzae type b vaccine, varicella vaccine, and rotavirus vaccine) and perinatal prophylaxis for group B Streptococcus was less common. Additionally, the Advisory Committee on Immunization Practices recommends influenza vaccine administration for all children ≥6 months [1]. While vaccination for influenza does not directly impact the youngest infants, older children serve as the most effective vectors of disease transmission in the community. Consequently, the epidemiology of influenza in the youngest infants is likely affected by the vaccination of older children and adult family members.

Viral infection — Viral infection is the most common cause of fever in young infants. In a study of infants 28 days or younger, including a subgroup of 960 neonates with fever, 17 percent had identifiable viral infections and 14 percent had an invasive bacterial infection [2]. By contrast, a prospective study of 1779 febrile infants 1 to 90 days of life identified viral pathogens in 35 percent of the cohort versus bacterial pathogens in 10 percent [3].

The neonate acquires infection through vertical transmission from the mother during delivery and postnatally from sources such as family members and hospital personnel. Neonates and young infants 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 "Immunity of the newborn".)

Viruses that can cause serious illness in febrile young infants include:

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

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

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 "Epidemiology and clinical manifestations of adenovirus infection")

Respiratory syncytial virus (see "Respiratory syncytial virus infection: Clinical features and diagnosis")

Invasive bacterial infection (IBI)

Definition — Many of the studies of fever in the young infant defined outcomes by the occurrence of serious bacterial infection (SBI) defined as invasive infections such as bacteremia, bacterial meningitis, bacterial pneumonia, skin and soft tissue infections, osteomyelitis, bacterial gastroenteritis, septic arthritis, or urinary tract infection (UTI) [4]. Although not classically described in the literature of the early 1990s, the attention to community-acquired Staphylococcus aureus has made pustulosis a relevant disease entity to be considered in skin and soft tissue infections in neonates [5].

More recently, the focus on the specific type infection (eg, UTI, bacteremia, or meningitis) has replaced the general concept of SBI in terms of evaluation and management secondary to the overall decreased prevalence of bacterial infections in the febrile infant and the unique nature of risk attributed to the specific type of infection. IBI, which refers to bacteremia and meningitis, has become the more common term. (See "Febrile infant (younger than 90 days of age): Management", section on 'Management'.)

Risk factors — Risk factors for IBI in young infants include the following [4,6-10]:

Age, especially younger than 28 days – Observational studies performed after the introduction of vaccination against Haemophilus influenzae type b and evaluating febrile neonates 28 days of age and younger who presented to an emergency department have reported a higher prevalence of IBI (9 to 19 percent) [4,6,11-13] compared with approximately 7 to 11 percent in infants 29 to 90 days of age [6,13]. Similarly, febrile neonates evaluated in primary care physician offices have a higher rate of bacteremia and meningitis than older febrile young infants as follows [7]:

3 and 1.1 percent, respectively, in infants 0 to 1 month of age

1.4 and 0.4 percent, respectively, in infants from 0 to 2 months of age

0.7 and 0 percent, respectively, in infants from 2 to 3 months of age

Ill-appearance – Ill-appearance has consistently been associated with a higher risk of IBI based upon clinical experience and multiple observational studies [7,8,14]. However, a substantial number of previously healthy, well-appearing infants without a focus of infection on physical examination can also have an IBI.

Rectal temperature ≥40°C (104°F) – Hyperpyrexia is rare among febrile infants younger than 3 months but is highly associated with IBI when it occurs. As an example, in an observational study of 98 infants younger than 90 days of age, patients with a temperature ≥40°C had a 29 percent absolute increase in the frequency of SBI (38 versus 9 percent) [10].

Rectal temperature ≥38.6°C (101.5°F) – The risk for bacterial etiology appears to increase with increasing fever (historically defined in the literature for infants of >38.0°C or >38.5°C) despite a decrease in the incidence of invasive disease across all ages following the introduction of conjugate vaccines. (See 'Etiology' above.)

Although increasing temperatures may increase risk, thresholds merely represent cutoffs described in the literature for the purposes of research; true risk is a continuum. Nevertheless, many experts use fever ≥38.6°C (101.5°F) as an additional risk factor that requires a full sepsis evaluation.

Unimmunized (have not received the first dose of pneumococcal and Hib vaccine) – Immunization with conjugate pneumococcal vaccines has significantly decreased the rates of bacteremia in young infants and children and, in young infants, it appears to both confer direct and herd immunity benefits [9]. As an example, in an observational cohort study that identified children 3 years of age or younger and included 50 immunized and 67 unimmunized infants 0 to 90 days of age, the rates of bacterial infection were significantly higher among unimmunized febrile young infants 0 to 90 days of age (7 percent unimmunized versus 0 percent, respectively). In addition, there were no cases of pneumococcal bacteremia in any of the infants who had received at least one dose of heptavalent pneumococcal vaccine or the 22 unimmunized infants younger than 28 days.

Prematurity (gestational age younger than 37 weeks) – Because of their immature immune protective mechanisms, 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. Thus, febrile young infants who are premature should be regarded as being at an increased risk for invasive bacterial infection. (See "Clinical features and diagnosis of bacterial sepsis in the preterm infant (<34 weeks gestation)", section on 'Incidence' and "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants", section on 'Epidemiology'.)

However, excluding any comorbidities, former premature infants, once corrected for post-conceptual age, have similar incidence of bacterial infection when compared with their term matched controls [15]. As an example, an infant who is 8 weeks of age but was born at 34 weeks gestation (or 6 weeks early) is regarded as having a similar risk for SBI as a 2-week old term infant.

Comorbidities or chronic illness – Historically, studies of IBI in young infants have excluded the patients with the following comorbidities who are considered at higher risk for IBI [4]:

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

Medically fragile patients who are dependent upon technology or specific therapies (eg, home ventilator, home oxygen, or total parenteral nutrition)

Received antibiotics within the prior 3 to 7 days Because of the long half-lives of antibiotics in young infants, administration up to 7 days prior to evaluation may mask signs and symptoms of IBI.

Risk of maternally transmitted infection – Potential findings that increase the risk for neonatal infection include maternal fever, prolonged rupture of membranes, maternal culture positive for group B Streptococcus (GBS), and maternal history of genital herpes. GBS screening and maternal intrapartum antibiotic prophylaxis reduces the risk of early-onset GBS infection but does not eliminate it. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants", section on 'Maternal risk factors' and "Neonatal group B streptococcal disease: Prevention".)

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 reevaluate a young febrile infant on an outpatient basis pose a risk for safe management:

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 limitations

Bacterial pathogens — Escherichia coli and group B Streptococcus are the pathogens most likely to cause bacteremia and bacterial meningitis in febrile infants younger than 3 months of age [16]. E. coli is the most common pathogen and also causes the majority of UTIs in this age group.

Listeria monocytogenes is still an important cause of bacterial meningitis, but its overall prevalence as a pathogen in febrile infants is becoming rare [17]. It is primarily isolated in neonates younger than 28 days of age and premature infants.

Other potential etiologies of SBI in febrile young infants include S. aureus, Streptococcus pneumoniae, Salmonella species, Enterococcus faecalis, Enterobacter cloacae, Moraxella catarrhalis, Klebsiella species, and Citrobacter species [18-20]. Of these, S. aureus is the most frequent isolate from skin and soft tissue infections and osteomyelitis.

Types of infections — UTI accounts for most bacterial infections in infants under 90 days of age; occurring in approximately 80 percent of 440 febrile infants with IBIs in one series [21]. Bacteremia, cellulitis, meningitis, and pneumonia constitute other important sources of infection [3,22]. Additional studies indicate the importance of UTI as a source of infection in febrile young infants as follows:

In a multicenter study of SBI among 3066 febrile infants ages 3 months and younger, who were evaluated in the primary care office setting rather than the emergency department, UTI occurred much more frequently than bacteremia and meningitis (5.4 versus 0.4 percent, respectively) [7]. These numbers are likely underestimates, as only slightly more than 50 percent of infants had a urine test performed.

In a prospective, multicenter observational study of 1025 febrile young infants 60 days of age or younger who were evaluated for fever ≥38°C, UTI was diagnosed in 9 percent of patients [23]. UTI was diagnosed in 21 percent of uncircumcised males and was significantly associated with fever ≥39°C.

The risk of UTI in uncircumcised male infants is discussed in detail separately. (See "Urinary tract infections in children: Epidemiology and risk factors", section on 'Lack of circumcision'.)

Salmonella is a consideration in young infants with fever, particularly in those who also have diarrhea or blood in the stool. A relatively small percent of these infants will have associated bacteremia [24,25]. Salmonella meningitis should be excluded in young infants with Salmonella bacteremia. (See "Nontyphoidal Salmonella bacteremia", section on 'Incidence' and "Nontyphoidal Salmonella bacteremia", section on 'Risk factors'.)

EVALUATION — When evaluating the febrile young infant, the goal is to identify infants who are at high risk for invasive bacterial infection (IBI; ie, bacteremia and/or meningitis) or serious viral infection (eg, herpes simplex virus [HSV] infection) and who therefore require empiric antimicrobial therapy and hospitalization. The young febrile infant may demonstrate few, if any, interpretable clues to the underlying illness on physical examination despite evaluation by experienced physicians or the use of an observation scale score [26,27]. However, careful assessment and judicious use of ancillary studies can identify patients at both high and low risk of IBI.

Our approach — We recommend a full sepsis evaluation for the following febrile young infants:

All ill-appearing infants regardless of age (see 'Ill-appearing infants' below)

Neonates younger than 28 days of age including neonates with a recognizable or testable viral infection (eg, bronchiolitis, croup, influenza, or enterovirus) or a focal bacterial infection (see 'Neonates (28 days of age and younger)' below and 'Focal infection' below)

Any infant with findings suggesting HSV infection upon examination (eg, mucocutaneous vesicles, seizures, or focal neurologic findings), especially those with maternal risk factors for vertical transmission (see "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Clinical suspicion')

Infants 29 to 60 days of age (corrected for prematurity as indicated) with any one of the following risk factors for IBI (see 'Infants 29 to 60 days of age' below):

Rectal temperature ≥38.6°C

Congenital or chromosomal defects, particularly those known to be associated with an increased risk of infection

Technology dependent (eg, home oxygen, home ventilator, indwelling central line)

Antibiotic therapy in past 3 to 7 days

Infants 29 to 90 days of age with a focal infection (eg, cellulitis, abscess, osteomyelitis, bacterial arthritis, or bacterial pneumonia) and abnormal white blood cell (WBC) count, absolute band count (ABC), inflammatory markers (procalcitonin [PCT] and/or C-reactive protein [CRP] but only if rapidly available), or urinalysis. Traditionally, a full sepsis evaluation has been suggested for all well-appearing febrile young infants with focal infections. However, evidence regarding the risk of IBI in febrile patients with focal infections who are older than 28 days of age is limited. The authors of this topic prefer to evaluate the extent of the focal infection, results of preliminary blood and urine studies, and determine the need for a full sepsis evaluation on a case-by-case basis (see 'Focal infection' below)

We suggest that well-appearing febrile infants 29 to 60 days of age (corrected for prematurity) who do not have a focal bacterial infection, clinical findings of HSV infection, and other risk factors for IBI and who have a rectal temperature <38.6°C (101.5°F) undergo the following evaluation (algorithm 1):

Complete blood count (CBC) with differential

PCT (only if results are rapidly available [eg, within 60 minutes])

CRP (only if results are rapidly available [eg, within 60 minutes])

Blood culture

Urinalysis

Urine culture (by transurethral bladder catheterization or suprapubic aspiration)

Chest radiograph in patients with signs of respiratory illness (eg, cough, tachypnea, or abnormal breath sounds)

These patients should also undergo a lumbar puncture with collection of cerebrospinal fluid (CSF) studies if they have any one of the following results and are thus candidates for empiric antibiotic therapy (see "Febrile infant (younger than 90 days of age): Management", section on 'Infants 29 to 60 days of age'):

WBC count ≤5000/microL, ≥15,000/microL)

ABC >1500/microL

Immature to mature neutrophil (band to poly) ratio >0.2

PCT >0.3 ng/mL

CRP >20 mg/L

If obtained, findings of pneumonia on chest radiograph

We also suggest a similar evaluation, but without blood studies or a lumbar puncture in every case, for well-appearing febrile infants 29 to 90 days of age with a recognizable or testable viral infection (eg, bronchiolitis, croup, influenza, or enterovirus). (See 'Patients with recognizable viral infections' below.)

We suggest that well-appearing febrile infants 61 to 90 days of age (corrected for prematurity) with temperature ≤38.6°C undergo urinalysis and urine culture only, although some experts would recommend a CBC and blood culture, particular for infants who have not received the first immunization with conjugated vaccines. (See 'Infants 61 to 90 days of age' below.)

The expert contributors to this topic vary on their approach to infants 42 to 90 days of age who have a fever within 48 hours of an immunization. Options for evaluation of these patients are discussed separately. (See 'Recently immunized' below.)

History — A thorough history is an essential component of the assessment of young febrile infants. The physician should first determine if the report of fever represents a true and reliably measured elevation in body temperature. Rectal temperatures are the standard for detecting fever in infants, 90 days of age. (See "Febrile infant (younger than 90 days of age): Definition of fever", section on 'Definition of fever'.)

The physician should also identify findings that may indicate a higher risk for IBI (see 'Risk factors' above):

A significant change in behavior (eg, decreased feeding, irritability, lethargy, or increased sleeping) that may represent subtle symptoms of bacterial meningitis or HSV encephalitis

Documented rectal temperature ≥38.6°C (101.5°F)

Antibiotic administration in the past 7 days

History of prematurity (gestational age younger than 37 weeks)

Increased risk of vertically transmitted infection (applicable to neonates younger than 28 days of age):

Maternal fever

Maternal colonization with group B streptococcus (GBS) and/or administration of antibiotic prophylaxis at delivery (see "Management of the infant whose mother has received group B streptococcal chemoprophylaxis", section on 'Overview of management')

Maternal history of sexually transmitted infections such as HSV, gonorrhea, and chlamydia (see "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Epidemiology and transmission')

Prolonged rupture of membranes

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

Unimmunized (infants who have not received the first dose of pneumococcal and Haemophilus influenzae type b [Hib] vaccine)

In addition, the history should assess:

Associated symptoms (eg, rhinorrhea, cough, wheezing, vomiting, diarrhea, blood or mucus in the stool, or rash [eg, vesicular rash suggesting HSV infection])

Exposures to sick contacts (caregivers, siblings, babysitters, or other children at day care)

Social barriers to outpatient management (limited caregiver skills or confidence to assess severity or progression of disease, limited access to a medical home, lack of transportation, and language limitations)

Physical examination — Infants who have respiratory or circulatory compromise (eg, apnea, respiratory distress, or signs of shock [eg, tachycardia with poor perfusion]) must be quickly identified and their conditions stabilized. These ill-appearing patients are at high risk for IBI and warrant a complete evaluation for sepsis and prompt administration of empiric antibiotics. (See "Febrile infant (younger than 90 days of age): Management", section on 'Ill-appearing' and "Septic shock in children: Rapid recognition and initial resuscitation (first hour)", section on 'Resuscitation'.)

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 that, in addition to a sepsis evaluation, warrant further studies. (See "Approach to the ill-appearing infant (younger than 90 days of age)", section on 'Evaluation'.)

Although the majority of young febrile infants have no obvious focus of infection on examination, they should undergo a complete assessment to look for the following sources:

Bacterial infection:

Acute suppurative otitis media – Bulging and inflammation of the tympanic membrane (picture 1) (see "Acute otitis media in children: Diagnosis", section on 'Otoscopy')

Pneumonia – Tachypnea, respiratory distress (including grunting, flaring, and retractions), decreased oxygen saturation, cough, and 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) (see "Care of the umbilicus and management of umbilical disorders", section on 'Omphalitis')

Bacterial arthritis – 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 use of a limb with localized swelling or erythema (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

Meningitis – Irritability or lethargy on examination; bulging fontanelle (late finding) and nuchal rigidity (rare finding in young infants) (see "Bacterial meningitis in children older than one month: Clinical features and diagnosis", section on 'Meningeal signs')

Serious viral infection:

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

-Conjunctivitis, excessive tearing, or painful eye symptoms

-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')

Suggested ancillary studies by risk group — In febrile young infants, ancillary studies provide a way to stratify patients by risk of IBI based upon age and clinical findings. The suggested studies for each risk group is provided here. The evidence supporting the ability of specific tests to identify febrile young infants at lower or higher risk of IBI is discussed separately. (See 'Utility of ancillary studies' below.)

Ill-appearing infants — Regardless of age, febrile and afebrile young infants who are ill-appearing are at high risk for IBI and warrant a full evaluation for sepsis as follows [13,26,28]:

CBC with differential

Blood or serum glucose (to permit comparison with CSF glucose)

Inflammatory markers (eg, PCT and CRP, if rapidly available [eg, within 60 minutes])

Blood culture

Urinalysis

Urine culture (by bladder catheterization or suprapubic aspiration) (see "Urine collection techniques in infants and children with suspected urinary tract infection")

Chest radiograph

Stool culture in infants with diarrhea or stool containing blood or mucus

CSF cell count with differential

CSF glucose and protein

CSF for bacterial culture and Gram stain

CSF polymerase chain reaction (PCR) as indicated based upon clinical risk:

Enterovirus studies during time of high prevalence or in patients with CSF pleocytosis

HSV in infants with clinical findings or increased risk of maternal HSV transmission

CSF for viral culture if there is pleocytosis; if there is a limited CSF sample, we prioritize PCR over viral culture.

Additional studies are often obtained for patients with signs of septic shock (see "Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis", section on 'Laboratory studies'):

Prothrombin time (PT), partial thromboplastin time (aPTT), international normalized ratio (INR)

Fibrinogen and D-dimer

Serum lactate

Serum total bilirubin and alanine aminotransferase

Ionized calcium

Ill-appearing infants with clinical findings of bronchiolitis or, during a time of high regional prevalence, influenza, warrant rapid testing for respiratory viruses (eg, respiratory syncytial virus [RSV]) and influenza. However, these test results should not be used to determine the need for antibiotics or anti-influenzal drugs in an ill-appearing infant (see 'Patients with recognizable viral infections' below)

In addition, infants with findings of HSV infection (eg, mucocutaneous vesicles, seizures, or focal neurologic findings) warrant the following studies (see "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Neonatal HSV'):

Surface viral cultures from the conjunctivae, mouth, nasopharynx, and rectum

Swab or scraping from skin vesicles or mucous membrane lesions for direct immunofluorescence assay and viral culture

Blood PCR for HSV

Serum alanine transaminase and aspartate transaminase to identify elevation in association with HSV-associated hepatitis; although these studies can also be elevated in patients with disseminated enteroviral infection or in septic shock

Other causes of ill appearance in addition to sepsis include congenital heart disease, congenital adrenal hyperplasia, inborn errors of metabolism, malrotation with volvulus, and a variety of other conditions discussed separately. (See "Approach to the ill-appearing infant (younger than 90 days of age)", section on 'Causes'.)

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'.)

Focal infection — In patients with fever and focal infections (eg, cellulitis, abscess, pneumonia, osteomyelitis, bacterial arthritis, or omphalitis), a full sepsis workup is recommended in all ill-appearing infants and neonates younger than 28 days of age. (See 'Ill-appearing infants' above and 'Neonates (28 days of age and younger)' below.)

We suggest that well-appearing febrile infants 29 to 90 days of age with a focal infection undergo the following evaluation:

CBC with differential

PCT (only if results are rapidly available)

CRP (only if results are rapidly available)

Blood culture

Chest radiograph in patients with signs of respiratory illness (eg, cough, tachypnea, or abnormal breath sounds)

In patients, other than those with cellulitis or abscess:

Urinalysis

Urine culture (by bladder catheterization or suprapubic aspiration) (see "Urine collection techniques in infants and children with suspected urinary tract infection")

We suggest a lumbar puncture with collection of CSF studies for patients that have any one of the following results (see "Febrile infant (younger than 90 days of age): Management", section on 'Infants 29 to 60 days of age'):

WBC count ≤5000/microL or ≥15,000/microL

ABC >1500/microL

PCT >0.3 ng/mL (if rapidly available [eg, within 60 minutes])

CRP >20 mg/L (if rapidly available [eg, within 60 minutes])

Unspun urine WBC count >10 WBCs/high-power field (hpf), spun urine WBC count >5 WBCs/hpf, or urine Gram stain positive

If obtained, findings of pneumonia on chest radiograph

Because these patients will undergo empiric treatment with antibiotics, some experts advocate for a lumbar puncture in all febrile infants 29 to 90 days of age with a focal infection to minimize the risk of missing bacterial meningitis, especially patients with focal infections likely to be caused by GBS, such as septic arthritis or osteomyelitis.

Evidence is lacking regarding the risk of bacteremia and meningitis in well-appearing febrile infants with focal infections. In one retrospective study of 197 non-toxic infants younger than 2 months of age with a focal infection (39 with a fever), a concomitant systemic infection was diagnosed in four patients; three with a urinary tract infection (UTI) caused by E. coli and one with bacteremia caused by S. pneumoniae [29]. Of the febrile infants with focal infections, 30 had a lumbar puncture and none had meningitis. The most common focal infections included cellulitis, abscess, impetigo, and acute otitis media.

Otitis media — We suggest that febrile infants with acute otitis media who are 60 days of age and younger should be evaluated and managed similarly to febrile infants without acute otitis media (AOM). (See 'Neonates (28 days of age and younger)' below and 'Infants 29 to 60 days of age' below.)

The expert contributors to this topic do not agree regarding the approach to well-appearing healthy febrile infants older than 60 days of age with AOM and evidence is lacking. Some experts would do no further studies while others would obtain urinalysis and urine culture alone or with a blood culture prior to treatment. (See "Febrile infant (younger than 90 days of age): Management", section on 'Otitis media'.)

AOM is diagnosed infrequently in neonates and young infants. Nevertheless, the infant who presents with otitis media, with or without fever, can present a diagnostic and management challenge. (See "Acute otitis media in children: Diagnosis", section on 'Diagnosis' and "Acute otitis media in children: Epidemiology, microbiology, clinical manifestations, and complications", section on 'Clinical manifestations'.)

Limited evidence suggests that the risk of IBI in infants younger than 60 days of age is not increased by the presence of AOM [30-33]. As an example, in a report of 130 patients 60 days and younger with AOM confirmed by tympanocentesis, the presence of AOM did not predict a higher risk for serious bacterial infection (SBI) in either febrile or afebrile patients [32]. None of the afebrile infants with AOM or the febrile infants who were otherwise determined to be at low risk developed a SBI. On the other hand, 14 percent of high-risk infants with AOM also had a SBI.

The decision to forego evaluation in afebrile infants younger than 60 days of age with AOM who are going to receive oral antibiotics should be made with caution. The definition of AOM indicates the presence of erythema and serous fluid (as can be common in the neonate) or the presence of purulent fluid behind a nonmobile tympanic membrane (picture 7). The physician should be confident that the physical findings meet this definition before empiric treatment is prescribed. Furthermore, it is important to weigh the risk of masking an IBI and the difficult situation that will arise if the infant becomes febrile or ill-appearing.

Well-appearing infants — Age and risk factors for infection are the primary determinants for the evaluation of well-appearing febrile young infants.

Neonates (28 days of age and younger) — We recommend that all febrile neonates younger than 28 days of age undergo a full evaluation for sepsis, as described above for ill-appearing infants, including studies to detect herpes simplex virus for neonates with risk factors or physical examination findings for this infection. (See 'Ill-appearing infants' above and "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Clinical suspicion'.)

As noted separately in this topic, neonates who are ill-appearing, have a focal infection, or a recognizable viral illness (eg, bronchiolitis or influenza) have a substantial risk for IBI. (See 'Ill-appearing infants' above and 'Focal infection' above and 'Patients with recognizable viral infections' below.)

Well-appearing neonates also have considerable risk for IBI [4,34,35]. Based upon observational studies performed since the introduction of conjugate vaccines, the estimated risk for bacterial infection in neonates 28 days of age and younger is as follows [34,35]:

Meningitis 0.3 to 3 percent

Bacteremia or sepsis 1 to 5 percent

UTI 16 to 28 percent

However, only about 60 percent of febrile neonates underwent full sepsis evaluations in these studies; patients who did not undergo testing were assumed to have negative cultures based upon follow-up. Thus, these estimates may not be precise or generalizable.

Furthermore, strategies for identifying the risk of IBI in well-appearing febrile young infants, developed prior to the widespread availability of conjugate vaccines, can miss neonates with invasive bacterial infection (table 1). (See 'Traditional approaches' below.)

In addition, more recent strategies that utilize appearance, CRP, and PCT, CBC, and urinalysis to stratify risk of bacterial infection without the routine performance of a lumbar puncture still identify some neonates with IBI as low risk [14,36]. (See 'Risk factors' above and 'Traditional approaches' below and 'Step-by-step approach' below.)

The approach to well-appearing febrile neonates (younger than 28 days of age) whose preliminary urine studies suggest a UTI (eg, positive nitrites on dipstick, uncentrifuged sample with a positive Gram stain or >10 WBCs/mm3, or centrifuged sample with >5 WBCs/hpf) is evolving. Evidence from small observational studies, suggests that the risk of bacterial meningitis in all neonates with positive urine studies is approximately 1 to 2 percent and is probably lower in well-appearing neonates [37,38]. However, given the difficulty in discerning well appearance in this age group and the lack of sensitive predictors of meningitis in neonates with urinary tract infections, we and most experts still recommend a full evaluation including collection of CSF studies in these patients.

However, one multicenter, prospective study of 766 febrile infants younger than 90 days of age with an abnormal urinalysis demonstrated a negative predictive value for IBI of 100 percent (95% CI: 97.5 to 100 percent) when all of the following results were present [39]:

Normal CBC with differential

PCT <0.5 ng/mL

CRP <20 mg/L

The prevalence of IBI in these patients was 6.5 percent.

Infants 29 to 60 days of age — Premature febrile infants 29 to 60 days of age should undergo evaluation based upon adjusted age (Chronologic age in weeks – [40 – gestational age in weeks]) which may classify them as neonates. (See 'Neonates (28 days of age and younger)' above.)

Our approach to the evaluation of well-appearing febrile infants 29 to 60 days of age who do not have a bacterial focus for infection is described in the algorithm (algorithm 1).

We recommend that febrile infants 29 to 60 days of age undergo a full sepsis evaluation, as described for ill-appearing infants above, if they have risk factors for invasive bacterial illness (IBI) or a rectal temperature ≥38.6°C (101.5°F). (See 'Ill-appearing infants' above.)

Patients with risk factors for IBI and those with rectal temperature ≥38.6°C (101.5°F) are considered at higher risk for bacteremia and meningitis and have been excluded from most studies designed to identify low risk criteria in well-appearing febrile infants [4]. (See 'Risk factors' above.)

The evaluation of infants 29 to 60 days of age with a focal bacterial infection is discussed separately. (See 'Focal infection' above.)

We suggest that well-appearing infants with rectal temperature <38.6°C, no risk factors for IBI, no infectious focus on examination, and who have not received an immunization within the previous 48 hours undergo the following evaluation:

CBC with differential

PCT (only if results are rapidly available [eg, within 60 minutes])

CRP (only if results are rapidly available [eg, within 60 minutes])

Blood culture

Urinalysis

Urine culture (by bladder catheterization or suprapubic aspiration) (see "Urine collection techniques in infants and children with suspected urinary tract infection")

Chest radiograph in patients with signs of respiratory illness (eg, cough, tachypnea, or abnormal breath sounds)

These patients should also undergo a lumbar puncture with collection of CSF studies if they have any one of the following results and are thus candidates for empiric antibiotic therapy (see "Febrile infant (younger than 90 days of age): Management", section on 'Infants 29 to 60 days of age'):

WBC count ≤5000/microL, ≥15,000/microL)

ABC >1500/microL

PCT >0.3 ng/mL

CRP >20 mg/L

If obtained, findings of pneumonia on chest radiograph

Preliminary urine studies that suggest a UTI such as a positive dipstick for nitrites and leukocytes, uncentrifuged sample with a positive Gram stain or >10 WBCs/mm3, or centrifuged sample with >5 WBCs/hpf (table 2) do not necessarily indicate a higher risk for meningitis in well-appearing infants if all other studies are within normal limits. Some experts do not recommend obtaining CSF studies in these patients [39].

Our approach to these patients varies among the expert contributors to this topic, options include:

Obtain CSF. This option is especially appropriate for infants with a temperature >38.6°C or with abnormal blood studies (WBC count, ABC, and, if rapidly available [eg, within 60 minutes] elevated PCT or CRP).

Do not obtain CSF. This option is especially appropriate for infants with no abnormalities of blood studies and a temperature ≤38.6°C.

If a lumbar puncture is planned in a well-appearing infant with signs of a UTI, normal blood studies and a temperature ≤38.6°C, then the physician should inform the family of the risks and benefits involved with this approach (eg, the benefit of identifying a rare case of meningitis versus the risks of lumbar puncture, including a significant risk for a dry or traumatic tap), and include the family's values and preferences before making the decision to proceed.

Treatment of febrile young infants with preliminary testing that suggests a UTI is discussed separately. (See "Febrile infant (younger than 90 days of age): Management", section on 'Infants 29 to 60 days of age'.)

The evaluation of patients with clinical findings of bronchiolitis or influenza is discussed separately. (See 'Patients with recognizable viral infections' below.)

Infants 61 to 90 days of age — Premature febrile infants 61 to 90 days of age should undergo evaluation based upon adjusted age (Chronologic age in weeks – [40 – gestational age in weeks]) which may classify them as neonates or infants 29 to 60 days of age. (See 'Neonates (28 days of age and younger)' above and 'Infants 29 to 60 days of age' above.)

We suggest that well-appearing infants 61 to 90 days of age with no bacterial focus for infection on examination or a recognizable viral infection such as bronchiolitis or influenza have urine obtained for culture and either urine dipstick or microscopic urinalysis (algorithm 2). This is especially recommended for females and uncircumcised males based upon the elevated probability of a UTI (table 3). Transurethral bladder catheterization is the preferred method for obtaining urine cultures. Some experts recommend CBC and blood culture for infants in this age range, particularly if they have not received conjugate vaccines. (See "Urine collection techniques in infants and children with suspected urinary tract infection", section on 'Transurethral bladder catheterization'.)

Patients with recognizable viral infections — Despite the concern for invasive bacterial illness, most young infants with fever have a viral infection. Based upon observational studies, infants with a "recognizable viral syndrome" or identified viral infection by testing such as RSV bronchiolitis, influenza, or enterovirus have a lower risk for bacteremia or meningitis, although UTI remains a concern in patients with bronchiolitis and influenza [4]. As an example, in a prospective observational study of 1385 febrile young infants who had some form of viral testing, the frequency of SBI (eg, UTI, pneumonia, bacteremia, or meningitis) among those infants who had a viral infection was significantly lower than for infants without a viral infection (4 versus 12 percent, respectively) [3]. Of those infants who had a viral infection and were also low risk by the Rochester criteria (table 1), the prevalence of SBI was 2 percent.

Thus, evidence supports limiting diagnostic testing for bacterial illness in febrile infants for whom highly accurate rapid viral testing is positive. The greatest experience involves evaluation of febrile infants with bronchiolitis and influenza.

Bronchiolitis — The approach to febrile infants younger than 90 days of age with bronchiolitis, considered a clinically recognizable viral syndrome, depends upon the age of the patient:

Neonates (28 days of age and younger) – Febrile neonates younger than 28 days of age with bronchiolitis remain at substantial risk for an IBI and should have a full evaluation [40-42].

Infants older than 28 days of age – We recommend measurement of urinalysis and urine culture by transurethral bladder catheterization or suprapubic aspiration (algorithm 1 and algorithm 2). UTI is the most common concomitant bacterial infection in these patients. While additional testing is not routinely recommended, some experts would obtain a CBC and blood culture is infants who were not well-appearing and/or had not received conjugate vaccines.

These patients should also receive further care based upon the degree of respiratory compromise. (See "Bronchiolitis in infants and children: Treatment, outcome, and prevention".)

Multiple retrospective and prospective observational studies demonstrate that the incidence of bacterial infection (including UTI, bacteremia, and meningitis) is 0 to 7 percent among febrile infants with bronchiolitis as opposed to 10 to 17 percent in high-risk febrile infants without bronchiolitis [3,4,40,41,43-52]. However, the risk of bacterial infection among neonates (0 to 28 days of age) is substantial and does not appear to be altered by the presence of RSV infection [40-42].

UTI is the most common bacterial infection seen in febrile infants with bronchiolitis who are older than 28 days and its prevalence in these patients often exceeds the threshold of 4 percent at which urine culture and testing is recommended [52]. (See "Urinary tract infections in infants and children older than one month: Clinical features and diagnosis", section on 'Decision to obtain'.)

By contrast, a systematic review of occult bacterial infection in young infants older than 28 days with clinical or RSV-positive bronchiolitis indicates that bacteremia is uncommon, occurring in only 5 out of 1749 patients [52]. In addition, this systematic review identified no cases of meningitis.

Taken together, this evidence indicates that limiting laboratory testing in well-appearing febrile infants older than 28 days of age with bronchiolitis is appropriate and has a low risk for missing bacteremia or meningitis.

Influenza — We recommend a full sepsis evaluation in febrile neonates ≤28 days of age regardless of the findings of rapid influenza testing. Similar to neonates with RSV infection, evidence is insufficient to suggest that the risk of invasive bacterial illness is lower in infants with influenza [4].

Ill-appearing febrile infants 29 to 90 days of age also warrant a full sepsis evaluation. (See 'Ill-appearing infants' above.)

We suggest that well-appearing febrile infants 29 to 90 days of age with influenza diagnosed by highly accurate influenza testing (eg, polymerase chain reaction [PCR] or influenza viral RNA or nucleic acid detection (table 4)) have urine obtained by transurethral bladder catheterization or suprapubic aspiration for urinalysis and urine culture. Additional testing is determined by the patient's age and urine findings (algorithm 1 and algorithm 2). (See 'Infants 29 to 60 days of age' above and 'Infants 61 to 90 days of age' above.)

Rapid diagnostic tests for the detection of viral neuraminidase or viral antigen are commercially available for influenza A and B viruses and can be used for rapid point of care testing. However, test performance is variable and less accurate than PCR or other molecular assays (table 4). False positive results occur and are of particular concern if rapid influenza testing is used to limit further laboratory evaluation in young febrile infants. As a result, the authors of this topic only rely on these tests for guiding evaluation and management of febrile young infants during the time of regional high prevalence for influenza infection, because high prevalence will raise the positive predictive value. However, some experts do not feel that rapid tests using viral neuraminidase or viral antigen detection has sufficient accuracy to guide the evaluation of febrile young infants. (See "Seasonal influenza in children: Clinical features and diagnosis", section on 'Whom to test'.)

Evidence suggests that the risk of bacteremia and meningitis is also lower in infants with positive rapid influenza testing that has less accuracy than PCR or other molecular assays [4,53]. For example, in a multicenter trial of 844 febrile infants ≤60 days of age who were tested for influenza, a significantly lower rate of SBI was noted in the 123 infants who were influenza-positive compared with the 721 infants who were influenza-negative (2.5 versus 11.7 percent, relative risk 0.19 [95% CI 0.06-0.59]) [54]. The three infants with SBI in the influenza-positive group all had a UTI; none had bacteremia or meningitis. By contrast, SBI in influenza-negative patients included 77 with UTIs, 16 with bacteremia, and 6 with meningitis. In another study of 218 infants younger than 3 months of age with laboratory confirmed influenza, SBI occurred in 5 infants (4 with UTIs [one also with E. coli bacteremia] and 1 with Salmonella enteritidis bacteremia) [53]. If PCR is used, the rate of concomitant bacterial infection would likely be even lower than described in these studies.

Recently immunized — Evidence is lacking regarding the best approach to well-appearing febrile infants 42 to 90 days of age who have received immunizations within the previous 48 hours. The expert contributors to this topic vary in their practice. The following options are suggested and assume that the caregiver has the ability to identify worsening of condition and the capability to adhere to close follow-up:

No testing with close follow-up to ensure that the fever resolves within 48 hours of vaccine administration – This approach is most applicable to infants older than 60 days of age who are seen <24 hours after immunization and who have a rectal temperature <38.6°C (101.5°F).

Urine testing with empiric oral treatment for patients in whom preliminary studies suggest a UTI as described above – This approach may be preferred in febrile infants older than 60 days of age who are seen 24 to 48 hours after immunizations.

Urine and blood testing as described for well-appearing infants 29 to 60 days of age with CSF studies obtained if inflammatory markers are abnormal – This approach is favored by some experts for all immunized infants younger than 60 days who have a rectal temperature <38.6°C and no other risk factors for IBI. (See 'Infants 29 to 60 days of age' above.)

Full evaluation for sepsis. This approach is favored by some experts for all immunized infants younger than 60 days with a rectal temperature >38.6°C or other risk factor for IBI. (See 'Infants 29 to 60 days of age' above and 'Risk factors' above.)

The caregiver's values and preferences should be sought as well, given the lack of evidence to identify the optimal approach.

Based upon one retrospective observational study of 213 recently immunized febrile infants 6 to 12 weeks of age, the frequency of SBIs (UTI, bacteremia, or meningitis) within 48 hours of immunization is approximately 3 percent (95% CI 1 to 5 percent) and within 24 hours of immunization is 0.6 percent (95% CI 0 to 2 percent) [55]. UTI was the only SBI reported in this study. Thus, restricting evaluation initially to consideration of urine testing appears appropriate for well-appearing febrile infants younger than 60 days of age who are seen within 48 hours of receiving immunizations.

The evaluation of infants 61 to 90 days of age with ill appearance or focal infections is discussed separately. (See 'Ill-appearing infants' above and 'Focal infection' above.)

Traditional approaches — Prior to the introduction of pneumococcal conjugate vaccines and Haemophilus influenzae type b (Hib) vaccines, the "Boston," "Milwaukee," "Rochester," and "Philadelphia" criteria were developed to identify febrile young infants who were at low risk of SBI such as UTI, pneumonia, bacteremia, or meningitis, and who could be safely managed as outpatients with or without empiric antibiotic treatment (table 1) [22,30,56,57]. In observational studies that evaluated the frequency of SBI among well-appearing infants who were considered low risk by one of the four criteria, SBI was reported in 2.2 percent (range 0 to 6.3 percent) [58]. When analysis was limited to studies that prospectively identified infants at low risk of SBI and performed outpatient observation with no antibiotics (Philadelphia or Rochester criteria), the frequency of SBI varied from 0.5 to 1.1 percent in studies that either did or did not include lumbar puncture as part of the initial evaluation, respectively [59]. However, among febrile neonates (≤28 days of age) identified as low risk by these criteria, the risk of SBI was higher (approximately 3 to 6 percent) [11,12,60-62].

Overall, these four criteria have had high negative predictive values for SBI in febrile infants (94 to 100 percent when prevalence of SBI was approximately 15 percent) [4]. The range of sensitivity and specificity for SBI utilizing the different criteria varies from 84 to 100 percent and 27 to 69 percent, respectively.

Although successful in identifying a low risk cohort when close outpatient follow-up was assured, these criteria have had several limitations [4]:

The specificity of these strategies for identifying patients with SBI is poor. Therefore, with the Boston, Rochester, and Milwaukee strategies large numbers of infants who do not have a bacterial infection are considered high risk, receive broad-spectrum antibiotics, and may be hospitalized [22,30]. With the Boston approach, fewer children are hospitalized, but all those who are discharged receive ceftriaxone.

All of these approaches require extensive laboratory testing, increasing both patient discomfort and expense.

Studies performed after the wide availability of rapid viral testing (eg, influenza, RSV, enterovirus, or respiratory virus panels) suggest that modification of these strategies may be performed in selected infants with identified viral infections. (See 'Patients with recognizable viral infections' above.)

Because these criteria fail to adequately identify neonates (≤28 days) at low risk for SBI, the traditional approach is to perform a complete sepsis evaluation, administer empiric antibiotics, and hospitalize all neonates [11,12,60-62].

The strategies were developed and tested in urban emergency departments and may not apply in community primary care settings.

Guidelines that were developed based upon these low risk criteria for SBI in febrile infants have been inconsistently followed [7,63-66]. As an example, in a prospective observational study of 3066 febrile infants 3 months and younger who had no other major comorbidities and were evaluated in a pediatric office, practitioners followed the recommended guidelines in only 42 percent of patients; physicians hospitalized 36 percent of infants, performed laboratory testing in 75 percent, and initially treated 57 percent with antibiotics [7]. Despite a less aggressive approach to testing, 61 of 63 infants (97 percent) with bacteremia/bacterial meningitis were treated with antibiotics at the initial visit. UTI was diagnosed in 5 percent of patients. Only 4 of 1056 infants (0.4 percent) who were well-appearing, aged 25 days or older, and who had a fever of less than 38.6°C, had bacteremia and/or bacterial meningitis.

On the other hand, 96 percent of infants had more than one contact with their physician during the illness (either by phone or office visit) indicating the importance of reliable follow-up when a practitioner decides to forego invasive studies in a well-appearing young infant.

Several factors suggest that a less aggressive approach to testing is reasonable in selected well-appearing infants at low risk of IBI who have assured follow-up within 12 to 24 hours (see 'Utility of ancillary studies' below and 'Our approach' above):

Since development of the low risk criteria and publication of related guidelines in 1993 [8], evidence suggests that the assessment of a combination of WBC count, absolute band count, PCT, and CRP can identify well-appearing febrile infants 29 to 90 days of age at low risk for invasive bacterial infection without the need to obtain CSF studies. (See 'Markers of inflammation' below.)

The prevalence of bacterial meningitis appears to be declining with reported rates of 0 to 0.5 percent in studies performed since the widespread utilization of conjugate vaccines [67-69].

The availability of continuous monitoring of blood cultures permits more rapid identification of bacteremia with an increased ability to intervene before the patient develops clinical deterioration. (See 'Blood culture' below.)

Step-by-step approach — The recommended approach to evaluation presented in this topic differs in important ways from the "step-by-step" approach: in some settings where the results of CRP and PCT are readily available (eg, within 60 minutes), well-appearing infants 22 to 90 days of age do not routinely undergo lumbar puncture if the initial evaluation consisting of a CBC, CRP, PCT, and urinalysis is normal [14,67]. These patients are observed for 24 hours without receiving antibiotics and, are discharged if they remain well-appearing [70]. The “step-by-step” approach is based upon prospective observational studies in febrile infants 90 days of age and younger that indicate a low risk for meningitis (<0.2 percent) and bacteremia (<2 percent) when these criteria are met [14,34,36,39,67,70]. In a large multicenter prospective observational study, the sensitivity and specificity of this approach for detecting bacteremia or meningitis was 92 percent and 46 percent with a negative predictive value of 99.3 percent (prevalence of bacteremia or meningitis: 4 percent) [14]. However, among low risk patients, the prevalence of IBI was still approximately 1 percent and four infants 22 to 28 days of age classified as low risk by the step-by-step approach had an IBI. Furthermore, hospitalization rates for 24-hour observation is high among practitioners of this approach. As an example, in the above study almost 60 percent of febrile infants were hospitalized. Based on these findings, we urge practitioners to utilize the approach with caution in infants 21 to 28 days of age. Furthermore, the step-by-step approach may be more resource intensive than our approach which permits more outpatient management of febrile infants.

Thus, the step-by-step approach appears to identify febrile young infants older than 28 days of age who are at low risk for IBI but often requires hospital observation for 24 hours in a large proportion of patients in order to avoid lumbar puncture or empiric antibiotic administration.

MANAGEMENT — The management of febrile young infants (younger than 90 days of age) is discussed separately. (See "Febrile infant (younger than 90 days of age): Management".)

UTILITY OF ANCILLARY STUDIES

Markers of inflammation — Studies that have included cohorts of infants younger than 3 months without an obvious source of fever on physical examination have used a variety of inflammatory markers to identify infants at low risk of serious bacterial infection (SBI; typically including urinary tract infection [UTI], bacteremia, meningitis, and pneumonia) and invasive bacterial infection (IBI; specifically, bacteremia and meningitis) [6,22,30,31,56,57,71-77].

Individual and combined measurements of C-reactive protein (CRP) and procalcitonin (PCT) appear to complement and enhance the ability to detect SBI and IBI in young febrile infants when used along with urine dipstick, white blood cell (WBC) count, or absolute band count (ABC) [4,78]. However, no single inflammatory marker has adequate test characteristics to be used in isolation for this purpose (table 5).

PCT has the best ability to discriminate for low risk of IBI in well-appearing febrile infants [4,6,76,77,79]. In a multicenter observational study of 1112 well-appearing febrile infants (26 percent with a SBI [UTI, bacterial gastroenteritis, bacteremia, or bacterial meningitis] and 2 percent with an IBI [bacteremia or bacterial meningitis]), a PCT ≥0.5 ng/mL was the only marker independently associated with IBI (adjusted odds ratio [OR] 22) [76]. A PCT <0.5 ng/mL was better than WBC count, ABC, and CRP for ruling out an IBI and reduced the posttest probability of IBI to 0.4 percent among infants with fever and normal urine dipstick results. In a separate prospective multicenter study of over 2000 well-appearing febrile infants 7 to 91 days of age, a PCT ≥0.3 ng/mL was optimal for detection of IBI with good discrimination in all ages (area under the curve for receiver operator characteristic: 0.91) [79].

However, in many clinical settings, PCT has limited availability or a turnaround time that is too long to influence initial evaluation and treatment. Any evaluation of risk in febrile infants that utilizes PCT must take this availability into account.

Host RNA biosignatures — Preliminary results suggest that molecular assays using host ribonucleic acid (RNA) biosignatures may outperform traditional blood markers of inflammation (table 5) when used to identify febrile infants with bacterial infections. In a prospective, multicenter study of 279 infants (89 with bacterial infections), 66 classifier genes identified the presence of bacterial infection with a sensitivity of 87 percent (95% CI: 73 to 95 percent) and specificity of 89 percent (95% CI: 81 to 93 percent); 10 classifier genes distinguished the presence of bacteremia in 111 febrile patients (16 with bacteremia) with a sensitivity of 94 percent (95% CI: 70 to 100 percent) and specificity of 95 percent (95% CI: 88 to 98 percent) [80]. The post-test negative probability for the 279 infants was 0.2 to 0.4 percent for bacteremia (prevalence 2.1 percent) and 0 percent for meningitis (prevalence 0.4 percent). Application of a two-gene signature previously used in children to the data set of infants with definitive bacterial diagnoses and proven viral infections from the above study yielded similar results (sensitivity 89 percent, specificity 94 percent, area under the receiver-operator curve 96 percent) [81].

Although early results are promising, molecular assays based upon host RNA biosignatures need further validation and studies addressing their integration into emergency department to delineate best practices before they can be clinically implemented.

Urine examination — We recommend that a urinalysis and urine culture be obtained because the prevalence of UTI is high (>4 percent) among febrile young infants [7,23,30]. (See "Urinary tract infections in children: Epidemiology and risk factors", section on 'Prevalence'.)

The test characteristics for dipstick and microscopic urinalysis in children are provided in the table (table 2). In febrile young infants, the sensitivity and specificity for positive leukocytes or nitrites on dipstick and white blood cell (WBC) counts per high-power field (hpf) for spun urine (>5 WBCs/hpf) and unspun urine (>10 WBCs/mm3) are comparable with negative predictive values that range from 90 to 98 percent when the prevalence of UTI is 7 to 10 percent [4]. Diagnostic accuracy is improved when testing is performed on catheterized urine rather than urines collected using a bag.

A urine specimen for culture should be obtained by urethral catheterization or suprapubic aspiration; bag urine collections frequently are contaminated [82]. (See "Urine collection techniques in infants and children with suspected urinary tract infection" and "Urinary tract infections in neonates", section on 'Urine culture'.)

A negative urine dipstick or urinalysis alone does not exclude UTI [83]; pyuria is absent on initial urinalysis in up to 20 percent of febrile infants with pyelonephritis [84]. Thus, urine culture should be performed on all specimens.

Stool examination — Not all studies of febrile neonates and young infants included evaluation of the stool for WBCs in patients with diarrhea. One study found the presence of ≥5 WBCs/hpf to be a predictor of occult Salmonella infection, including bacteremia [30]. However, a Wright stain of the stool for WBCs may not be readily available (eg, within 1 to 2 hours). A stool culture is suggested when there is blood and/or mucus in the stool or for the infant with diarrhea when a Wright stain is not available.

Blood culture — Blood culture does not help with the immediate assessment of fever but should be obtained depending upon patient characteristics, including age, risk factors for invasive bacterial infection, and physical findings as described above. (See 'Our approach' above.)

Rapid detection of bacterial pathogens is possible with automated blood culture techniques, permitting the identification of positive culture results often within 24 to 36 hours when the volume of the blood sample is >1 mL and when the patient has not been exposed to antibiotics [85,86]. This is particularly helpful in infants managed as outpatients [59].  

Cerebrospinal fluid studies — We recommend that lumbar puncture always be performed in febrile infants with any one of the following indications:

Age 28 days or younger (see 'Neonates (28 days of age and younger)' above)

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

Diagnostic evaluation identifies a high risk for invasive bacterial infection (see 'Focal infection' above and 'Infants 29 to 60 days of age' above)

Seizures

Cerebrospinal fluid (CSF) should be sent for cell count, glucose, protein, bacterial culture, and Gram stain. In addition, viral studies (eg, PCR for herpes simplex virus [HSV] and enterovirus and viral culture) should be sent if the clinical picture suggests viral meningitis or CSF pleocytosis is present. (See "Viral meningitis: Clinical features and diagnosis in children", section on 'CSF studies'.)

Several observational studies suggest that infants at low risk for meningitis can be identified without performing a lumbar puncture [30,56,71,73,74,87]. In a retrospective study performed during the post-conjugate vaccine era, bacterial meningitis was rare (1 of 1188 patients) and did not occur in patients who met low risk criteria determined by past medical history, physical examination, white blood cell count, band to neutrophil ratio, blood glucose, urinalysis, and, if obtained, chest radiograph [87]. Based upon these reports, some experts feel that lumbar puncture can be omitted in well-appearing infants older than 28 days of age who meet low risk criteria for bacterial illness, particularly if the infant has a rectal temperature ≤38.6°C [7]. (See 'Infants 29 to 60 days of age' above.)

Seizures may be a sign of meningitis, and we recommend that a lumbar puncture be performed in all neonates and young infants who have had a seizure. Appropriate CSF studies to identify possible viral etiologies may be useful diagnostically (table 6). (See "Viral meningitis: Clinical features and diagnosis in children", section on 'Virology'.)

Chest radiograph — Not all studies of febrile neonates and young infants have included a chest radiograph as part of the initial evaluation [4]. A chest radiograph is helpful in identifying a source of infection in infants with at least one clinical sign of pulmonary disease [82]. This was illustrated in a meta-analysis of 617 febrile infants younger than 3 months of age [88]. All 361 infants who had no clinical evidence of pulmonary disease (defined as respiratory rate >50 breaths/minute, rales, rhonchi, retractions, wheezing, coryza, grunting, stridor, nasal flaring, or cough) had normal chest radiographs. By contrast, 85 of 256 infants (33 percent) with at least one of these signs had an abnormal chest radiograph.

Even when the chest radiograph reveals pneumonia, a viral etiology is most likely, given that nonbacterial pneumonias comprise the majority of cases of pneumonia in children [89]. A bacterial process is more likely if alveolar disease (consolidation and air bronchograms) or bronchopneumonia (diffuse bilateral pattern with increased peribronchial markings and small fluffy infiltrates) is present. (See "Community-acquired pneumonia in children: Clinical features and diagnosis", section on 'Etiologic clues'.)

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 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 topic (see "Patient education: Fever in children (The Basics)")

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

SUMMARY AND RECOMMENDATIONS

We regard a rectal temperature of 38°C (100.4°F) or greater as fever in infants 90 days of age and younger. (See 'Definition of fever' above.)

Viral infection is the most common cause of fever in young infants. However, invasive bacterial infection (IBI) occurs in a significant proportion of febrile infants younger than 90 days of age. Common bacterial sources in febrile young infants include urinary tract infection (UTI), bacteremia, soft tissue infection, meningitis, and pneumonia. (See 'Etiology' above.)

The goal of the evaluation is to identify those infants who are at high risk for invasive bacterial illness and/or herpes simplex virus (HSV) and who therefore require empiric antimicrobial therapy and hospitalization. The young febrile infant may demonstrate few, if any, interpretable clues to the underlying illness on physical examination. However, careful assessment and judicious use of ancillary studies can identify patients at both high and low risk of serious illness. (See 'Evaluation' above.)

We recommend a full sepsis evaluation for the following febrile young infants (see 'Our approach' above):

All ill-appearing infants (eg, respiratory or circulatory compromise, irritability, poor tone, or lethargy) (see 'Ill-appearing infants' above)

Neonates younger than 28 days of age (see 'Neonates (28 days of age and younger)' above)

Any infant with findings suggesting HSV infection upon examination (eg, mucocutaneous vesicles, seizures, or focal neurologic findings), especially those with maternal risk factors for vertical transmission (see "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Clinical suspicion')

Infants younger than 60 days of age (corrected for prematurity as indicated) with any one of the following risk factors for IBI (see 'Infants 29 to 60 days of age' above):

-Rectal temperature ≥38.6°C

-Congenital or chromosomal defects known or suspected to increase the risk of infection

-Technology dependent (eg, home oxygen, home ventilator, indwelling central line)

-Antibiotic therapy in past 3 to 7 days

-In neonates younger than 28 days of age, maternal factors (eg, peripartum fever, prolonged rupture of membranes, or positive vaginal culture for group B Streptococcus [GBS])

Infants 29 to 90 days of age (corrected for prematurity as indicated) with a focal infection (eg, cellulitis, abscess, osteomyelitis, bacterial arthritis, or bacterial pneumonia) and ill appearance or abnormal white blood cell count, absolute band count (ABC), or inflammatory markers (procalcitonin [PCT] and/or C-reactive protein [CRP]).

Because these patients will undergo empiric treatment with antibiotics, some experts advocate for a lumbar puncture in all febrile infants 29 to 90 days of age with a focal infection to minimize the risk of missing bacterial meningitis, especially patients with focal infections likely to be caused by GBS, such as septic arthritis or osteomyelitis. (See 'Focal infection' above.)

We suggest that well-appearing febrile infants 29 to 60 days of age who do not have a focal bacterial infection, risk factors or findings of HSV infection, and other risk factors for invasive bacterial infection and who have a rectal temperature <38.6°C (101.5°F) undergo the following evaluation (algorithm 1):

Complete blood count (CBC) with differential

PCT (only if results are rapidly available [eg, within 60 minutes])

CRP (only if results are rapidly available [eg, within 60 minutes])

Blood culture

Urinalysis

Urine culture (by transurethral bladder catheterization or suprapubic aspiration)

Chest radiograph in patients with signs of respiratory illness (eg, cough, tachypnea, or abnormal breath sounds)

These patients should also undergo a lumbar puncture with collection of cerebrospinal fluid (CSF) studies if they have any one of the following results and are thus candidates for empiric antibiotic therapy (see "Febrile infant (younger than 90 days of age): Management", section on 'Infants 29 to 60 days of age'):

-White blood cell count ≤5000/microL, ≥15,000/microL

-ABC >1500/microL

-PCT >0.3 ng/mL (if obtained)

-CRP >20 mg/L (if obtained)

-If obtained, findings of pneumonia on chest radiograph

We also suggest a less extensive evaluation for the following patients as described above:

Well-appearing febrile infants 28 to 90 days of age who have a recognizable viral infection (eg, bronchiolitis, croup, influenza, or enterovirus) (algorithm 1 and algorithm 2) (see 'Patients with recognizable viral infections' above)

Well-appearing febrile infants 61 to 90 days of age without a focal bacterial infection on examination (algorithm 2) (see 'Infants 61 to 90 days of age' above)

Evidence is lacking regarding the best approach to well-appearing febrile infants 42 to 90 days of age who have received immunizations within the previous 48 hours and febrile infants over 60 days of age with acute otitis media. The expert contributors to this topic vary in their practice. Options for testing are provided above. (See 'Recently immunized' above and 'Otitis media' above.)

Other causes of ill appearance in addition to sepsis include congenital heart disease, congenital adrenal hyperplasia, inborn errors of metabolism, malrotation with volvulus, and a variety of other conditions. 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 'Causes' and "Approach to the ill-appearing infant (younger than 90 days of age)", section on 'Evaluation'.)

The management of febrile young infants 90 days of age and younger is discussed separately. (See "Febrile infant (younger than 90 days of age): Management".)

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