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

INTRODUCTION — 

The outpatient evaluation of febrile infants 29 to 90 days old is discussed in this topic. For a discussion of the management of febrile infants 29 to 90 days old, the definition of fever in the young infant, the outpatient evaluation and initial management of febrile neonates, 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 (younger than 90 days of age): Definition of fever".)

●(See "The febrile neonate (28 days of age or younger): Outpatient evaluation".)

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

FEVER DEFINITION — 

We regard a rectal temperature of ≥38°C (100.4°F) as fever in infants 29 to 90 days old. Most studies establishing the risk of serious infections in febrile young infants have relied upon rectal temperatures. Thus, they are the standard for detecting fever in infants ≤90 days old. (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'.)

ETIOLOGY

Viral infection — Viral infection is the most common cause of fever in young infants. Depending upon the specific pathogen and type of diagnostic testing, viral infections have been documented in up to 58 percent of young febrile infants, while bacterial infections account for 10 to 15 percent of pathogens (although molecular testing may reflect prior asymptomatic disease rather than the causative pathogen for some viruses) [1-3]. The types of viruses vary by season and type of testing, with respiratory viruses being very commonly detected [3].

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

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

●Varicella-zoster virus (see "Varicella-zoster virus (VZV) 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 infections")

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

●Coronavirus disease 2019 (COVID-19) (see "COVID-19: Clinical manifestations and diagnosis in children", section on 'In infants <12 months of age')

Febrile infants, 29 to 90 days, with either clinically recognizable and/or laboratory documented viral infections have been shown to have a lower risk of certain invasive bacterial infections. More recent studies have focused more on the 29-to-60-day-old age group compared with the 61 to 90 days old age group because the risk of invasive bacterial infection (ie, bacteremia and meningitis) is lower in the older age cohort, the clinical examination is more discriminatory, and some older infants have had their first set of conjugate vaccinations further mitigating their risk for bacterial infection. (See 'Patients with documented viral infections' below.)

Invasive bacterial infection

Definition and risk factors — For this topic, invasive bacterial infection (IBI) refers to bacteremia or bacterial meningitis. Many prior studies of fever in the young infant defined outcomes by the occurrence of "serious bacterial infection" (SBI), which included bacteremia, bacterial meningitis, bacterial pneumonia, skin and soft tissue infections, osteomyelitis, bacterial gastroenteritis, septic arthritis, and UTI [4]. More recent studies focus on the specific type of infection such as UTI, bacteremia, or meningitis. This approach 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. (See "The febrile infant (29 to 90 days of age): Management", section on 'Management' and "The febrile neonate (28 days of age or younger): Initial management", section on 'Approach'.)

Risk factors for IBI in young infants include the following (table 1) [4-10]:

●Age – For well-appearing, low-risk, febrile infants 29 to 90 days of age, the risk of IBI decreases with age:

•29 to 60 days old – Estimates based upon observational studies of young infants 29 to 60 days old who present to primary care offices and pediatric emergency departments suggest the upper limit of risk for bacteremia is just over 2 percent, and the risk of bacterial meningitis is approximately 0.25 percent [11].

•61 to 90 days old – For well-appearing, low-risk infants 60 to 90 days of age, the likelihood of IBI (mostly bacteremia) is <1 percent [6,12]. However, the risk of IBI exceeds 1 percent in the subgroup of infants 60 to 90 days old who have a temperature ≥39^o C (102.2^o F) without an obvious source [12].

The risk of IBI in neonates (≤28 days) is substantially higher than for infants 29 to 90 days of age as discussed separately. (See "The febrile neonate (28 days of age or younger): Outpatient evaluation", section on 'Risk factors for IBI'.)

●Ill appearance – Ill appearance has consistently been associated with a higher risk of IBI based upon clinical experience and multiple observational studies [6,7,13].

●Rectal temperature ≥38.6°C (101.5°F) – The risk for serious bacterial infections increases with increasing fever (rectal temperature ≥38°C [100.4°F]) [14,15]. (See 'Etiology' above.)

Although increasing temperatures may increase risk, thresholds merely represent cutoffs used for the purposes of research; the true risk is a continuum. Approximately one-third of IBI occurs in infants with temperatures of 38 to 38.5°C, in part because temperatures at this range are more common than higher fevers [11,15]. Hyperpyrexia (rectal temperature ≥40°C [104°F]) is rare among febrile infants younger than three months but is highly associated with IBI when it occurs [16,17]. 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); the frequency of IBI (bacteremia or meningitis) was 8 percent [9].

The height of fever alone is not an independent predictor of IBI in well-appearing febrile infants 29 to 60 days of age undergoing a laboratory evaluation if other biomarkers of infection such as procalcitonin and urinalysis are normal. In such patients, it is not an indicator for more aggressive evaluation and treatment (eg, lumbar puncture, empiric antibiotics, and/or hospitalization) [13,18,19].

However, when procalcitonin is not available, fever ≥38.6°C (101.5°F) is considered a marker of higher risk of IBI for infants 29 to 60 days old in conjunction with an abnormal urinalysis, CRP >20 mg/L, and an absolute neutrophil count >5200/mm³ [11,18].

●Prematurity (gestational age younger than 37 weeks) – Because of their immature immune protective mechanisms, former premature infants 29 to 90 days old are at higher risk for IBI [20]. For example, premature infants have rates of sepsis, including late-onset sepsis, that are approximately 10 to 12 times that of term infants. (See "Neonatal bacterial sepsis: Clinical features and diagnosis in neonates born at less than 35 weeks gestation", section on 'Incidence' and "Neonatal bacterial sepsis: Clinical features and diagnosis in neonates born at or after 35 weeks gestation", 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 [21]. As an example, an infant who is 12 weeks (84 days) of age but was born at 34 weeks gestation (or six weeks early) is regarded as having a similar risk for IBI as a six-week-old term infant.

●Comorbidities or chronic illnesses – Historically, studies of IBI in young infants have excluded patients with the following comorbidities who are considered at higher risk for IBI [4,11]:

•Infants with a perinatal course that is complicated by surgery, infection, or 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 three days – Because of the longer half-lives of antibiotics in young infants 29 to 90 days of age, administration up to three days prior to evaluation may mask signs and symptoms of bacterial infection including IBI and UTIs.

●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 an indirect risk for safe outpatient 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 and other communication limitations

Pathogens and type of infections — Escherichia coli is the most common pathogen causing UTI, bacteremia and bacterial meningitis in febrile infants younger than 90 days of age followed by group B Streptococcus (GBS) [10,22-24].

Although Listeria monocytogenes remains a consideration as a cause of bacterial meningitis, its overall prevalence as a pathogen in febrile infants is becoming rare [25]. It is primarily isolated in neonates younger than 28 days of age and premature infants. (See "Epidemiology and pathogenesis of Listeria monocytogenes infection".)

Other potential pathogens in febrile young infants include Staphylococcus aureus, Streptococcus pneumoniae, Salmonella species, Enterococcus faecalis, Enterobacter cloacae, Moraxella catarrhalis, Klebsiella species, and Citrobacter species [26-28]. Of these, S. aureus is the most frequent isolate from skin and soft tissue infections and osteomyelitis.

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 [29,30]. Salmonella meningitis should be excluded in young infants with Salmonella bacteremia. (See "Nontyphoidal Salmonella bacteremia and extraintestinal infection", section on 'Epidemiology'.)

UTI accounts for most bacterial infections in infants under 90 days of age, accounting for approximately 80 percent of 440 febrile infants with bacterial infections in one series [31]. Bacteremia, cellulitis, meningitis, and pneumonia constitute other important sources of infection [2,32]. 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 three months of age 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) [6]. 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 [33]. 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 elevated compared with circumcised males as discussed in detail separately. (See "Urinary tract infections in children: Epidemiology and risk factors", section on 'Lack of circumcision'.)

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), UTI, or serious viral infection (eg, herpes simplex virus [HSV] infection) and who therefore require comprehensive evaluation (table 2), 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 [11,34,35]. However, careful assessment and judicious use of ancillary studies can identify patients at both high and low risk of IBI.

Stabilization — 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 treated (table 3 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 IBI and warrant a complete evaluation for sepsis (table 2) with prompt administration of empiric antimicrobial agents. (See "Children with sepsis in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Resuscitation' and "The febrile infant (29 to 90 days of age): Management", section on 'Ill-appearing' and "The febrile neonate (28 days of age or younger): Initial management", section on 'Ill-appearing'.)

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

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 "The 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 (table 1) (see 'Definition and 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 three days

●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)

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 — All febrile young infants require a complete physical examination and a complete set of vital signs (rectal temperature, respiratory rate, heart rate, and blood pressure) with particular attention to general appearance, degree of fever, tachycardia, tachypnea, perfusion, and signs of focal infection.

Appearance — Clinical appearance is an essential yet subjective assessment during evaluation of febrile infants 29 to 90 days old. Identifying a young infant as well appearing relies heavily upon the clinician's pediatric knowledge and experience. Prior to the development of a reliable social smile at approximately six weeks of age, this task is especially challenging [11].

In addition to a careful physical examination, observation of febrile young infants over time (eg, one feeding cycle) to ensure that the infant feeds well, remains vigorous, has normal vital signs, and does not develop new findings suggestive of bacterial illness on physical examination (eg, pulmonary rales, focal bone or joint tenderness, abdominal tenderness, petechiae, or purpura) provides additional reassurance.

Height of fever — For ill-appearing infants and those at increased risk for IBI, the height of the fever does not change further evaluation or management.

However, for well-appearing infants with rectal temperatures ≥38°C (100.4°F) and no obvious source of infection on physical examination, the likelihood of IBI (bacteremia or meningitis) or urinary tract infection (UTI) increases with higher fevers unless urinalysis and procalcitonin results are normal [19]. When procalcitonin is not available, a rectal temperature >38.5°C (101.3°F) is our recommended threshold for performing more comprehensive evaluation for IBI and UTI in these patients [11].

Signs of focal infection — During physical examination and review of the vital signs, including oxygen saturation, the clinician should look for these manifestations of focal infection in febrile young infants:

●Focal bacterial infections

•Acute suppurative otitis media – Bulging and inflammation of the tympanic membrane (picture 1) (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, 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), and/or foul odor (see "Care of the umbilicus and management of umbilical disorders in children", section on 'Omphalitis')

•Bacterial arthritis – Swollen, painful, warm, and/or red joint with decreased range of motion (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 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

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

•Meningitis – Irritability, lethargy, decreased or increased tone 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 'Clinical findings')

●Serious viral infections

•HSV infection – Clinical findings concerning for HSV infection are most common in neonates but can occur beyond 28 days of age and include (see "Neonatal herpes simplex virus (HSV) 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')

Ancillary studies — In febrile young infants, performance of ancillary studies is based upon the risk of IBI as determined by age and clinical findings. The suggested studies for each risk group are provided below. 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 specific 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 (table 2) [34,36,37].

In addition to diagnostic testing to identify IBI and UTI, diagnostic testing for viral etiologies is warranted in selected patients:

●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'.)

●Influenza – During high seasonal prevalence, testing for influenza using highly accurate testing (table 4) is helpful for determining the need for continued contact precautions and antiviral treatment in addition to empiric antibiotics. 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'.)

●HSV – Infants with findings of HSV infection (eg, mucocutaneous vesicles, seizures, or focal neurologic findings) warrant additional blood studies, surface viral cultures, and scraping from skin vesicles or mucous membranes for additional testing as described separately. (See "Neonatal herpes simplex virus (HSV) infection: Clinical features and diagnosis", section on 'Neonatal HSV'.)

●Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – Although SARS-CoV-2 is an uncommon cause of ill appearance in febrile young infants, 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 in all hospitalized patients. (See "COVID-19: Clinical manifestations and diagnosis in children", section on 'In infants <12 months of age'.)

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. 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 infants with IBI risk factors — Our suggested approach to well-appearing infants with risk factors for IBI (table 1) depends upon age:

●29-60 days – For these infants who are otherwise healthy and well-appearing but who have IBI risk factors, we advise blood, urine, cerebrospinal fluid studies, and, as indicated by clinical findings and regional prevalence, viral testing (table 2). Further management is based upon risk factors and laboratory results and should involve shared decision-making with the family. (See "The febrile infant (29 to 90 days of age): Management".)

●61 to 90 days – Modified evaluation as described below for well-appearing, low-risk infants 29 to 60 days old (table 5) (see '29 to 60 days old' below)

Patients with risk factors for IBI have been excluded from most studies designed to identify low-risk criteria in well-appearing febrile infants [4]. (See 'Definition and risk factors' above.)

Low-risk, well-appearing infants — Age and risk factors for IBI are the primary determinants for the evaluation of well-appearing febrile young infants 29 to 90 days old.

29 to 60 days old — For low-risk, well-appearing infants 29 to 60 days old with fever, we advise a stepwise evaluation for IBI based upon the Pediatric Emergency Care Applied Research Network (PECARN) low-risk prediction rule (algorithm 2 and table 5) [11,38]. (See 'Clinical prediction rules' below.)

Our approach is consistent with the 2021 American Academy of Pediatrics Clinical Practice Guideline (AAP CPG) for the evaluation and management of low-risk, well-appearing, 29- to 60-day-old febrile infants (algorithm 3) except that a lumbar puncture need not be performed for infants with abnormal urine testing and elevated inflammatory markers (IM) (table 6) [11]:

●Normal UA and IM – CSF studies are not needed in patients with a normal UA and IM because the risk of meningitis is very low (≤0.025 percent) (see 'Clinical prediction rules' below). Due to the low risk of UTI in patients with normal urine results, the AAP CPG also recommends not sending a urine culture [11]. However, it is reasonable for clinicians to send a urine culture obtained by catheterization or SPA in all febrile infants 29 to 60 days old in settings with documented low rates of specimen contamination and with timely specimen processing as false positives are less likely in such settings.

●Normal UA but elevated IM – We obtain cerebrospinal fluid (CSF) studies in individuals with elevated IM (table 6) because the risk of meningitis is increased when any one of these inflammatory markers is elevated [11]. Although evidence that compares the prevalence of meningitis between young infants with elevated versus normal IM is lacking, a combination of IM, including procalcitonin (PCT) whenever rapidly available (eg, within one to two hours), C-reactive protein (CRP), and/or ANC (>4,000/mm³) provides superior diagnostic accuracy for IBI.

As indicated in the table, when procalcitonin is not available, we consider fever ≥38.6°C (101.5°F) to be another marker of high risk and use an ANC threshold ≥5,200/mm³ rather than >4,000/mm³ [4,11,23]. (See 'Inflammatory markers' below.)

The white blood cell (WBC) count alone has very poor sensitivity for identifying well-appearing infants at low risk for IBI.

●Positive UA and either normal or elevated IM – If the UA is positive (ie, leukocyte esterase or nitrite present on dipstick, >5 WBCs/high-power field [centrifuged urine], or >10 WBCs/mm³ [uncentrifuged urine]), the infant is well-appearing, and IM results are normal, then CSF studies are not necessary [11,38,39].

For patients with a positive UA and elevated IM, the risk of meningitis remains low enough that it is reasonable and appropriate not to obtain CSF studies (algorithm 2) [11,38,39]. This approach differs from the 2021 AAP CPG management. However, it reflects more recent evidence. The decisions to obtain or forego CSF and to hospitalize or discharge these infants should be made with clinician-parent shared decision-making, an approach supported by the AAP [11]. Shared decision-making not only highlights the risks involved but also the ability and willingness of the caregiver to observe closely at home, return for a reevaluation, and follow up if needed [40]. Specifically, they should be aware that the benefit of identifying a rare case of meningitis may be offset by the risks of lumbar puncture, including a significant risk for a dry or traumatic tap which will make the CSF results uninterpretable.

In low-risk well-appearing infants >28 days old, a positive UA does not indicate a higher risk for bacterial meningitis [38,41,42]. For example, in a secondary analysis of a prospective, observational study of nearly 700 febrile young infants 29 to 60 days old with positive UA, none had bacterial meningitis, including over 200 individuals with elevated procalcitonin results (PCT) or absolute neutrophil counts (ANC) [38]. Furthermore, of 111 infants 29 to 60 days old with a positive UA but normal PCT and ANC, none had IBI. Although C-reactive protein was not measured in this study, it has lower diagnostic accuracy for IBI than PCT. Therefore, this study provides support for not obtaining CSF studies in these infants, regardless of IM results. (See 'Inflammatory markers' below.)

Bacterial meningitis is also rare in febrile infants with a documented UTI. For example, in a systematic review and meta-analysis of nearly 3900 infants 29 to 90 days of age (20 observational studies), the pooled prevalence of bacterial meningitis in individuals with a UTI was 0.25 percent (95% CI 0.09-0.70 percent) [42]. Finally, sterile CSF pleocytosis occurs in up to 29 percent of infants with a UTI, which may complicate hospital management and lead to unnecessary and prolonged antibiotic therapy for patients who undergo a lumbar puncture for this indication [42-44].

Clinical prediction rules — Based on several regional and national studies, the prevalence of bacteremia seen in febrile infants 29 to 60 days old is approximately 1.5 to 2 percent, and the prevalence of bacterial meningitis is approximately 0.25 percent [6,10,11,45,46]. Prediction rules that use combinations of blood inflammatory markers such as procalcitonin, C-reactive protein, and absolute neutrophil count demonstrate the ability to identify febrile young infants at low risk for IBI:

●Pediatric Emergency Care Applied Research Network (PECARN) rule – The PECARN rule identifies well-appearing infants 29 to 60 days of age at low risk of IBI for patients if they have a normal urinalysis, a procalcitonin <0.5 ng/mL, and an absolute neutrophil count (ANC) <4000/mm³ (table 6). C-reactive protein is not included in this prediction rule.

The PECARN clinical prediction rule was derived and validated in a prospective, multicenter cohort of 1820 well-appearing febrile young infants ≤60 days old [18]. Patients with a normal urinalysis, procalcitonin ≤1.7 ng/mL, and absolute neutrophil count ≤4090/mm³ had a very low risk for IBI (99.6 percent [95% CI 98.4-99.9], negative likelihood ratio 0.04 [95% CI 0.01-0.15, prevalence of IBI 1.7 percent]). The PECARN's rule sensitivity for IBI was 97.7 percent (95% CI 91.3-99.6), and its specificity was 60 percent (95% CI 56.6-63.3). Reducing the procalcitonin threshold to <0.5 ng/mL and the ANC threshold to <4000/mm³ did not significantly impact negative predictive value or sensitivity of the rule. We suggest that clinicians use the rounded cut-offs of the PECARN rule as they are easier to remember and apply.

●Step-by-step rule – The "step-by-step" approach is based upon prospective observational studies in febrile infants 90 days of age and younger presenting for evaluation to pediatric emergency departments that indicate a low risk for meningitis (<0.2 percent) and bacteremia (<2 percent) when initial evaluation demonstrated a C-reactive protein <20 mg/L, procalcitonin <0.5 ng/mL, ANC ≤10,000/mm³, and a normal urinalysis [13,39,47-50]. In a large, multicenter prospective observational study, the sensitivity and specificity of this approach for detecting bacteremia or meningitis were 92 percent (95% CI 84-96 percent) and 46 percent (95% CI 45-49 percent), respectively, with a negative predictive value of 99.3 percent (95% CI 98.5-99.7 percent, prevalence of bacteremia or meningitis 4 percent) [13].

●Febrile young infant collaborative – In a multicenter, case-control study of 543 febrile infants ≤60 days old presenting to pediatric emergency departments (181 cases and 362 controls), age <21 days (1 point), ANC ≥5185/mm³ (2 points), abnormal urinalysis (3 points), and height of fever in the emergency department (38.0-38.4C; 2 points, ≥38.5C; 4 points) were the four features of a risk predictor score and a score of ≥2 had a sensitivity of 98.8 percent (CI 95.7-99.9 percent) and specificity of 31.3 percent (26.3-36.6 percent) [51].

In a secondary analysis of a single-center data registry of 2411 well-appearing febrile infants ≤90 days old, the algorithms proposed by the PECARN and step-by-step prediction rules as well as the AAP guidelines had variable testing characteristics by duration of fever prior to presentation using three cutoffs (<2 hours, 2 to <12 hours, and ≥12 hours) with poorer performance in the 633 infants with fever duration <2 hours [52]. Biomarker performance as measured by the area under the curve declined for ANC and CRP at <2 hours; PCT had similar performance regardless of fever duration. These findings suggest that these algorithms may be less able to identify well-appearing febrile young infants at low risk for IBI if the duration of fever is short. However, duration of fever was not a significant contributor to the PECARN prediction rule during derivation and validation [18]. Thus, further studies are needed before altering the evaluation of febrile infants based upon the duration of fever.

61 to 90 days old — For low-risk, well-appearing infants 61 to 90 days old, dipstick or microscopic urinalysis and urine culture is indicated. Transurethral bladder catheterization or SPA is the preferred method for obtaining urine cultures. This is especially recommended for females and uncircumcised males based upon the elevated probability of a UTI (table 7). (See "Urine collection techniques in infants and children with suspected urinary tract infection", section on 'Transurethral bladder catheterization'.)

For infants who have a high fever ≥39^o C (102.2^oF), we advise complete blood count with differential, inflammatory markers such as C-reactive protein or procalcitonin, and blood culture because the risk of IBI (primarily bacteremia) is approximately 2 to 4 percent including in patients who have received initial conjugate vaccine immunizations [12]. Some experts also perform these blood test for all infants in this age range, especially in unimmunized infants who have the least protection against S. pneumococcus and H. influenzae type b [53]. We do not routinely obtain these tests in these patients, but we will sometimes perform them when close follow-up is not possible or when there is concern about caregiver ability to identify progression of illness.

Patients with documented viral infections — Highly accurate rapid tests for many different viruses are available to supplement the evaluation of febrile young infants 29 to 90 days old. Rapid tests for RSV, influenza, and COVID-19 are most commonly used. For febrile young infants with a documented viral infection, our approach depends upon the patient's appearance and age:

●Ill-appearing or well-appearing with IBI risk factors – These patients should undergo evaluation and treatment as for ill-appearing patients or well-appearing patients at elevated risk for IBI who do not have a documented viral infection. (See 'Ill-appearing infants' above and 'Well-appearing infants with IBI risk factors' above.)

●Well-appearing and at low-risk for IBI – Our approach for these patients varies by age:

•29 to 60 days old – For well-appearing febrile infants 29 to 60 days old at low risk for IBI and with a documented viral infection, we perform the same step-by-step testing as for those patients with negative viral testing; the results of inflammatory markers and urine testing, as well as shared decision-making with the family, then guides our approach to obtaining cerebrospinal fluid and further management as discussed separately. (See '29 to 60 days old' above.)

For patients with normal inflammatory markers and urine testing, the disposition is determined by the severity of the viral illness. Antiviral therapy is suggested for febrile infants with influenza. (See "Seasonal influenza in children: Management", section on 'Antiviral therapy'.)

These patients remain at risk for bacterial co-infection until their viral illness resolves; they require close follow-up to ensure complete recovery.

In many centers, well-appearing infants 29 to 60 days old do not undergo routine testing of blood inflammatory markers because previous observational studies have found low rates of bacteremia and meningitis, especially in patients with documented RSV bronchiolitis or influenza [2,54-64]. Several of these studies described cohorts of febrile young infants with documented viral infections with no cases of meningitis or bacteremia. However, the sample size in these studies was low and not all patients had a full sepsis evaluation. More recent evidence suggests that the risk of IBI in well-appearing infants 29 to 60 days old is non-negligible as discussed below [65].

•61 to 90 days old – For well-appearing febrile infants 61 to 90 days old with a documented viral infection, we make decisions about also obtaining urine studies based upon patients characteristics using UTICalc. However, patients with a prior history of UTI or congenital genitourinary abnormalities should undergo urine testing and have a urine culture obtained by transurethral bladder catheterization. (See "Urinary tract infections in infants older than one month and children younger than two years: Clinical features and diagnosis", section on 'Laboratory evaluation and diagnosis'.)

There is no standardized approach to febrile infants 29 to 90 days with documented viral infections and wide practice variation regarding testing and management. Although evidence suggests a lower prevalence of IBI or UTI in well-appearing febrile infants 29 to 90 days of age with documented viral infections compared with those who have negative viral testing, the risk of co-infection remains non-negligible. For example, in a prospective study of 4778 well-appearing, febrile infants ≤60 days old, rates of specific bacterial infections in infants 29 to 60 days old with positive testing for viral infections were [65]:

●UTI – 2.8 percent (95% CI 1.8-4.2 percent)

●Bacteremia – 0.6 percent (95% CI 0.2-1.4 percent)

●Bacterial meningitis – 0.2 percent (95% CI 0.0-0.9 percent)

●UTI, bacteremia, and/or bacterial meningitis – 3.4 percent (95% CI 2.3-4.9 percent)

In this study, the rates of UTI and bacteremia in infants with positive viral testing was significantly lower than those with negative viral testing. However, the difference was not significant for bacterial meningitis. Furthermore, UTI, bacteremia, or bacterial meningitis was documented in infants with a wide variety of viruses including enterovirus, influenza, RSV, rhinovirus, and human metapneumovirus.

Multiple testing panels for other viral respiratory pathogens such as human rhinovirus, adenovirus, non-SARS-CoV-2 coronavirus, parainfluenza, and/or human metapneumovirus have expanded the capability of documenting viral infections in febrile young infants. Evidence also indicates that IBI is less common in febrile young infants with positive PCR testing for these respiratory viruses but remains non-negligible [2-4,11,65-67]. For example, in a retrospective study of almost 3000 febrile young infants 29 to 90 days of age who underwent respiratory PCR panel testing that did not include influenza or RSV testing, the risk of IBI was 4 percent for infants who tested negative for respiratory viruses but was still 1 to 1.4 percent for those who tested positive [3]. Non-negligible rates of IBI (approximately 1 percent) have also been reported for well-appearing febrile infants with SARS-CoV-2 infection. For example, in an international cohort study of 563 febrile infants ≤60 days old (41 neonates), IBI was identified in 1 percent of infants with COVID-19 and 6.1 percent of infants without COVID-19 [68].

In a secondary analysis of a single-center registry that included over 700 febrile infants ≤90 days old with blood PCR testing for enterovirus, none of the 174 infants with a positive test had an IBI (0 percent, 95% CI 0-2.1 percent) compared with 2.6 percent (95% CI 1.5-4.4 percent) of infants with a negative test [67]. More evidence is needed to determine the value of blood PCR for risk stratification in febrile young infants.

Focal infection — Ill-appearing young infants with fever and focal infections require a full sepsis workup and additional testing depending upon the type of focal infection (table 2). (See 'Ill-appearing infants' above.)

For well-appearing febrile infants 29 to 90 days of age with a focal infection, evaluation varies according to the specific focus. CSF studies are an important consideration in selected well-appearing infants with elevated inflammatory markers (table 6) in consultation with appropriate specialists and based upon shared decision-making with parents/primary caregivers.

The evaluation and diagnosis of mastitis, osteomyelitis, and bacterial arthritis are discussed in greater detail separately:

●(See "Mastitis and breast abscess in infants younger than two months".)

●(See "Hematogenous osteomyelitis in children: Evaluation and diagnosis".)

●(See "Bacterial arthritis: Clinical features and diagnosis in infants and children".)

Evidence is limited regarding the risk of bacteremia and meningitis in well-appearing febrile infants with focal infections. In one retrospective study of 197 nontoxic infants <2 months of age with a focal infection (39 febrile), a concomitant systemic infection was diagnosed in four patients (three with a UTI caused by E. coli and one with bacteremia caused by S. pneumoniae) [69]. 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.

Acute otitis media — Acute suppurative otitis media is an important cause of fever in young infants. Visualization of the tympanic membrane can be difficult in this age group. Whenever possible, a provider experienced in the evaluation of infants, such as an experienced pediatrician, otolaryngologist, or pediatric otolaryngologist, should confirm the diagnosis. The two most specific findings are (see "Acute otitis media in children: Clinical manifestations and diagnosis", section on 'Clinical diagnosis'):

●Bulging, erythematous tympanic membrane, especially when purulent fluid is seen behind the tympanic membrane (picture 7)

●Perforation of the tympanic membrane with acute purulent otorrhea (rare in young infants)

By contrast, middle ear effusion, unlike acute otitis media, is common in young infants but does not reflect a focal infection. Physical examination demonstrates a dull tympanic membrane that may have unclear landmarks, abnormal color (blue or gray is common in infants), and, if performed, decreased mobility to pneumatic otoscopy.

Our approach to young infants with confirmed acute otitis media varies according to age:

●≤60 days – For low-risk, well-appearing, febrile infants with acute otitis media who are 29 to 60 days of age, we advise an initial evaluation tailored to the baseline risk for IBI with further studies as needed for patients with abnormal results (table 5 and algorithm 3). (See '29 to 60 days old' above.)

●61 to 90 days – The expert contributors to this topic differ in their evaluation of well-appearing, healthy, febrile infants 61 to 90 days of age with acute otitis media prior to antimicrobial treatment, and evidence is lacking regarding the best management.

Options include:

•No testing – This approach may be most appropriate for infants approaching 90 days of age with rectal temperatures <38.6°C (101.5°F).

•Urinalysis and urine culture – This approach may be most appropriate for infants closer to 60 days of age with rectal temperatures ≥38.6°C (101.5°F). Some contributors to this topic also support obtaining a blood culture prior to treatment in these patients to avoid missing bacteremia although the prevalence of IBI is likely similar to the contamination rate in many settings.

The contributors do not obtain CSF studies in these patients if they are otherwise well appearing.

Limited evidence suggests that the risk of IBI in infants younger than 90 days of age is not increased by the presence of acute otitis media [70-74]. For example, in a multicenter, retrospective study of 1637 afebrile young infants with acute otitis media (most 57 to 90 days of age), none of the 278 patients with blood cultures had bacteremia (0 percent, 95% CI 0-1.4 percent), and none of the 102 infants with CSF cultures had meningitis (0 percent, 95% CI 0-3.6 percent) [70]. The diagnosis of acute otitis media was not routinely verified by subspecialist consultation or tympanocentesis. Two of 645 infants with 30-day follow-up had an adverse event requiring hospitalization. Compared with infants 0 to 28 days of age, infants 29 to 90 days of age were much less likely to undergo diagnostic testing or hospitalization. In another retrospective observational study of 130 patients 60 days of age and younger with acute otitis media confirmed by tympanocentesis, the presence of acute otitis media did not predict a higher risk for serious bacterial infection (SBI) in either febrile or afebrile patients [73]. None of the afebrile infants with acute otitis media or the febrile infants who were otherwise determined to be at low risk developed an SBI. On the other hand, 14 percent of high-risk infants with acute otitis media also had an SBI.

Nevertheless, the presence of acute otitis media does not exclude the possibility of a UTI, and the true prevalence of bacteremia in these infants is uncertain. (See "Urinary tract infections in infants older than one month and children younger than two years: Clinical features and diagnosis", section on 'Younger children'.)

Recently immunized — Before attributing fever to recent immunizations (ie, within 24 to 48 hours) in a febrile infant, the clinician should perform a complete history and physical examination. Characteristics of systemic inflammation and fever from immunizations in young infants include (see "Pneumococcal vaccination in children", section on 'Adverse effects' and "Diphtheria, tetanus, and pertussis immunization in children 6 weeks through 6 years of age", section on 'Adverse reactions'):

●Fever height – Fever <39°C (102.2^oF) occurs in up to 50 percent of recently immunized patients and usually lasts no more than 24 to 48 hours; those infants who present with a fever ≥39°C should undergo evaluation according to age as described above. (See 'Ancillary studies' above.)

●Fever duration – If fever occurs, it resolves within 24 to 48 hours

●Appearance – Immunized infants are frequently fussy but consolable due to local pain and inflammation but are not ill-appearing; ill-appearing patients require a full evaluation for sepsis regardless of recent immunization. (See 'Ill-appearing infants' above.)

Recently immunized young infants 6 to 12 weeks old (42 to 84 days) with findings consistent with systemic inflammation from immunization appear to have low rates of IBI, but UTI has been described [75,76]. For these patients, decisions about testing should be individualized and involve shared decision-making with the parents/primary caregivers. All patients require close follow-up until fever resolves.

Options include:

●Age ≤60 days: Urine testing; urine culture by bladder catheterization if urine tests are abnormal or evaluation according to the PECARN rule (see '29 to 60 days old' above)

●Age 61 to 90 days:

•<24 hours post-immunization – No testing

•24 to 48 hours post-immunization – Urine testing; urine culture by bladder catheterization if urine tests are abnormal

In two small retrospective studies, there were no cases of IBI (>300 infants 6 to 12 weeks of age with fever <48 hours after immunizations, estimated 95% CI 0-1 percent) [75,76].) UTI was found in 1 to 2 percent of recently immunized infants with fever <24 hours and 3 to 4 percent of infants with fever 24 to 48 hours.

UTILITY OF SPECIFIC ANCILLARY STUDIES

Urine examination — Due to the lower risk of urinary tract infection (UTI) in febrile infants with normal urine studies, the 2021 American Academy of Pediatrics Clinical Practice Guideline (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 WBCs/high-power field [centrifuged urine], or >10 WBCs/mm³ [uncentrifuged urine]) [11]. Given a reported sensitivity of 94 percent (95% CI 91-97 percent) for a normal urinalysis in febrile young infants, sending the urine culture in this situation may risk inappropriately treating asymptomatic bacteriuria or a contaminated specimen.

However, 6 to 10 percent of confirmed UTIs in young infants occur in individuals with a normal urinalysis (approximately 3 percent of UTIs associated with bacteremia) [77,78]. Not detecting these UTIs prevents recognition of an associated genitourinary abnormality and potential for renal scarring. Thus, it is reasonable for clinicians to send a urine culture obtained by catheterization or SPA (invasive procedures) in all febrile young infants ≤90 days old in settings with documented low rates of specimen contamination and timely specimen processing. (See "Urinary tract infections in infants older than one month and children younger than two years: Clinical features and diagnosis", section on 'Laboratory evaluation and diagnosis'.)

Urine specimens should be obtained by urethral catheterization or, less commonly, SPA. Diagnostic accuracy is improved when urine testing is performed on catheterized urine rather than urine collected using a bag. Urine cultures from bag urine collections are frequently contaminated and should be avoided [79]. (See "Urine collection techniques in infants and children with suspected urinary tract infection" and "Urinary tract infections in neonates", section on 'Urine culture'.)

When UTI is defined as >50,000 colony-forming units/mL on urine culture, the urinalysis, consisting of a dipstick for leukocyte esterase and nitrites and microscopy for WBCs, has high diagnostic accuracy for UTIs in young febrile infants. In a secondary analysis of a prospective observational study of over 4000 febrile infants 60 days of age or younger who were evaluated for UTI (prevalence of UTI 7 percent), a positive urinalysis consisting of any positive leukocyte esterase or nitrites on dipstick or >5 WBC/high-power field on microscopy had a sensitivity of 94 percent and a specificity of 91 percent for UTI (table 8) [77]. The positive and negative predictive values were 43 and 100 percent, respectively.

The urinalysis was more likely to be positive in febrile young infants with a UTI and bacteremia. When the threshold for a positive urine culture was lowered to >10,000 colony-forming units/mL, the sensitivity decreased to 87 percent (95% CI 83-90 percent), but the specificity was unchanged. Test performance for urinalysis did not differ significantly between neonates and infants 29 to 60 days of age. (See "Urinary tract infections in neonates", section on 'Urinalysis'.)

When UTI is defined as >10,000 colony-forming units/mL, other studies have reported lower sensitivity ranging from 48 to 81 percent [36,79] and somewhat lower negative predictive values (90 to 98 percent with a prevalence of UTI of 7 to 10 percent) [4].

Inflammatory markers — Individual and combined measurements of procalcitonin and C-reactive protein have the best test characteristics to identify young febrile infants at low risk for invasive bacterial infection (IBI) [4,11,80,81]. However, they should not be used in isolation for this purpose. In large cohort studies of febrile infants evaluated in pediatric emergency departments, the highest-performing prediction rules incorporate procalcitonin, C-reactive protein, or both along with urinalysis and absolute neutrophil count to guide decisions regarding testing for meningitis and hospitalization. (See '29 to 60 days old' above.)

Among the commonly used inflammatory markers, procalcitonin has the best ability to identify IBI in well-appearing febrile infants [4,5,11,82-84]. For example, in two large, multicenter cohort studies, procalcitonin had the best ability to discriminate febrile young infants with IBI based upon receiver-operator area under the curve [82,84]:

●Procalcitonin – 0.83 to 0.91

●C-reactive protein – 0.72 to 0.75

●Absolute neutrophil count – 0.61 to 0.63

●White blood cell (WBC) count – 0.48 to 0.58

In nearly 2300 febrile young infants undergoing evaluation in pediatric emergency departments in Spain and Italy, a threshold of procalcitonin ≥0.5 ng/mL had a sensitivity of 85 percent, specificity of 85 percent, positive likelihood ratio of 5.6, and negative likelihood ratio of 0.2 for IBI [82]. Among all patients, a procalcitonin <0.5 ng/mL reduced the post-test probability of IBI to 0.5 percent (0.4 percent among febrile infants with normal urine dipstick results).

C-reactive protein is more accurate than WBC or absolute neutrophil count for detecting IBI but is inferior to procalcitonin. However, in settings in which procalcitonin is not available, C-reactive protein can help to identify febrile young infants at more than low risk for IBI [82,85]. In a prospective observational study of nearly 1000 well-appearing, febrile young infants in Canada from a single center, at the threshold of 20 mg/L, C-reactive protein had a sensitivity of 100 percent (95% CI 87-100 percent) and a negative predictive value of 100 percent (95% CI 99-100 percent, prevalence of IBI 2.8 percent) [85].

In some clinical settings, procalcitonin or C-reactive protein 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 procalcitonin must take this availability into account.

Although a mainstay in years past, studies continue to show that the WBC count, absolute neutrophil count, absolute band count, band to neutrophil ratio, and platelet count lack diagnostic accuracy for IBI in healthy, well-appearing, febrile infants [4,11,23].

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 IBI, and physical findings as described above. (See 'Ancillary studies' above and "The febrile neonate (28 days of age or younger): Outpatient evaluation", section on 'Ancillary studies'.)

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 [86,87]. This is particularly helpful in infants managed as outpatients [88].

Cerebrospinal fluid studies — We recommend that a lumbar puncture be performed in febrile infants 29 to 90 days old with any one of the following indications:

●Ill appearance (see 'Ill-appearing infants' above and "The febrile neonate (28 days of age or younger): Outpatient evaluation")

●Diagnostic evaluation identifies an elevated risk for IBI

●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 for enterovirus and viral culture) should be sent if the clinical picture suggests viral meningitis or CSF pleocytosis is present. (See "Viral meningitis in children: Clinical features and diagnosis", section on 'Cerebrospinal fluid studies'.)

Several observational studies suggest that infants at low risk for meningitis can be identified without performing a lumbar puncture [71,89-93]. 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, WBC count, band to neutrophil ratio, blood glucose, urinalysis, and (if obtained) chest radiograph [93]. Based upon these reports, some experts feel that lumbar puncture can be omitted in well-appearing infants older than 22 days of age who meet low-risk criteria for bacterial illness, particularly if the infant has a rectal temperature <38.6°C [6]. (See '29 to 60 days old' 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. (See "Viral meningitis in children: Clinical features and diagnosis", section on 'Detection of virus'.)

Stool examination — Not all studies of febrile young infants included evaluation of the stool for WBCs in patients with diarrhea. One study found the presence of ≥5 WBCs/high-power field to be a predictor of occult Salmonella infection, including bacteremia [71]. However, a Wright stain of the stool for WBCs may not be readily available (eg, within one to two 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.

Chest radiograph — Not all studies of febrile 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 [79]. This was illustrated in a meta-analysis of 617 febrile infants younger than three months of age [94]. 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 [95]. A bacterial process is more likely if alveolar disease (consolidation and air bronchograms), large pleural effusion, 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'.)

Host RNA biosignatures (investigational) — Preliminary results suggest that molecular assays using host messenger ribonucleic acid (mRNA) biosignatures may outperform traditional blood markers of inflammation 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 73-95 percent) and specificity of 89 percent (95% CI 81-93 percent); 10 classifier genes distinguished the presence of bacteremia in 111 febrile patients (16 with bacteremia) with a sensitivity of 94 percent (95% CI 70-100 percent) and specificity of 95 percent (95% CI 88-98 percent) [96]. 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) [97].

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

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) is the standard for fever in infants ≤90 days old. When procalcitonin measurements are not available, a temperature >38.5°C (101.3°F) is the recommended threshold for performing more comprehensive evaluation for invasive bacterial infection (IBI) in well-appearing febrile infants 22 to 60 days of age. (See 'Fever definition' above and 'Height of fever' above.)

●Evaluation – Evaluation of the febrile young infant focuses on findings that indicate a high risk for IBI (invasive bacterial infection; bacteremia and/or meningitis) or herpes simplex virus (HSV) infection.

•Stabilization – The clinician must rapidly identify and treat unstable infants (table 3 and algorithm 1). (See "Approach to the ill-appearing infant (younger than 90 days of age)", section on 'Initial stabilization'.)

•History – Key history includes risk factors for IBI (table 1) and subtle signs of illness (eg, poor feeding, lethargy, and decreased activity). (See 'History' above.)

•Physical examination – Physical examination should focus on appearance and signs of (see 'Physical examination' above):

-Focal bacterial infection

-Bronchiolitis

-HSV infection

Identifying a young infant as well appearing is difficult, especially before the development of a reliable social smile at six weeks of age. Furthermore, well appearance does not exclude the possibility of IBI. (See 'Appearance' above.)

●Ancillary studies – The performance of ancillary studies is based upon the risk of IBI:

•Increased IBI risk – A full sepsis evaluation (table 2) is indicated for the following febrile young infants:

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

-Well-appearing infants 29 to 60 days of age with risk factors for IBI (table 1) (see 'Well-appearing infants with IBI risk factors' above)

-Any infant with findings suggesting herpes simplex virus (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 (HSV) infection: Clinical features and diagnosis", section on 'Clinical suspicion')

•Low IBI risk – Initial testing of low-risk, well-appearing infants varies by age:

-29 to 60 days old – For low-risk, well-appearing infants 29 to 60 days old, we advise a stepwise evaluation for IBI based upon the Pediatric Emergency Care Applied Research Network (PECARN) low-risk clinical prediction rule (algorithm 2 and table 5). (See '29 to 60 days old' above and 'Clinical prediction rules' above.)

-61 to 90 days old – For low-risk, well-appearing infants 61 to 90 days old, we typically obtain a urine dipstick or microscopic urinalysis and urine culture by bladder catheterization and no additional studies. (See '61 to 90 days old' above.)

•Documented viral infection – For febrile young infants with a documented viral infection, our approach depends upon the patient's appearance and age. Because the risk of IBI is not negligible, we do not modify the evaluation for febrile infants who are:

-Ill-appearing (full evaluation for sepsis)

-Well-appearing but at elevated risk for IBI (full evaluation for sepsis)

-29 to 60 days old, well-appearing, and at low risk for IBI (obtain urine testing and blood inflammatory markers)

For low-risk, well-appearing infants 61 to 90 days old we make decisions about also obtaining urine studies based upon patients characteristics using UTICalc. We perform urine testing in all infants with a prior history of UTI (urinary tract infection) or congenital genitourinary abnormalities. (See 'Patients with documented viral infections' above.)

•Focal infection – Initial evaluation of febrile young infants with focal infection and high risk of bacteremia depends upon appearance and the specific type of infection. (See 'Focal infection' above.)

•Immunized patients – Options for testing recently immunized febrile infants 42 to 90 days of age are provided. (See 'Recently immunized' above.)