Febrile Infants (Younger Than 90 Days of Age): Outpatient Evaluation

Febrile infants (younger than 90 days of age): Outpatient evaluation

Authors:

Hannah F Smitherman, MD

Charles G Macias, MD, MPH

Section Editors:

Stephen J Teach, MD, MPH

Sheldon L Kaplan, MD

Deputy Editor:

James F Wiley, II, MD, MPH

Contributor Disclosures

All topics are updated as new evidence becomes available and ourpeer review processis complete.

Literature review current through:Sep 2016.|This topic last updated:Sep 06, 2016.

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 young infants (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 less 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 young infants (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 young infants (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 influenzaetype b vaccine,varicella vaccine, androtavirus 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"Clinical manifestations and diagnosis of enterovirus and parechovirus infections")

●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-acquiredStaphylococcus aureushas 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 againstHaemophilus 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 Hibvaccine)– 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, ortotal parenteral nutrition)

●Received antibiotics within the prior 3 to7 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 ofdiseases/educationalbarriers

•Limited access to a medical home for questionsand/orfollow-up

•Lack of transportation

•Language limitations

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

Listeria monocytogenesis 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 includeS. aureus,Streptococcus pneumoniae, Salmonella species,Enterococcus faecalis,Enterobacter cloacae,Moraxella catarrhalis, Klebsiella species, and Citrobacter species [18-20]. Of these,S. aureusis 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, bacteremiaand/ormeningitis) 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 [26]. 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)andabnormal white blood cell (WBC) count, absolute band count (ABC), inflammatory markers (procalcitonin [PCT]and/orC-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 donothave a focal bacterial infection, clinical findings of HSV infection,andother risk factors for IBI and who have a rectal temperature <38.6°C (101.5°F) undergo the following evaluation:

●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

•PCT >0.3ng/mL

•CRP >20mg/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 young infants (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/oradministration of antibiotic prophylaxis at delivery (see"Management of the infant whose mother has received group B streptococcal chemoprophylaxis", section on 'Overview of management')