Fever in infants ≤ 60 days of age

Fever in infants ≤ 60 days of age is a concerning clinical feature as it may be a sign of invasive bacterial infection. The immune system of neonates and young infants is immature and they face additional infection risks compared to older infants, such as vertical transmission of pathogens at birth and vaccine-preventable illnesses. While the etiology may be benign, infant ≤ 60 days old should be fully assessed even if they appear well. The extent of the diagnostic studies required depends on the age of the infant and their clinical status. Management usually consists of empiric antibiotic therapy. Younger neonates require admission; in infants > 21 days old home observation can be considered if select criteria are met.

Traditionally this guidance was extended to all infants ≤ 90 days of age with fever. In 2021, guidance from the AAP suggested that in well-appearing infants > 60 days of age, this strategy risks iatrogenic harm from over-investigation and treatment. For management of fever in children and infants > 60 days of age, see “Pediatric fever.”

• Every year approximately 100,000 infants ≤ 60 days of age are assessed for fever in the emergency department. ^[1]
• Fever occurs in 1.4% of full-term infants 8–60 days old. ^[2][3]

Epidemiological data refers to the US, unless otherwise specified.

• Similar to older children (see “Etiology of pediatric fever”); however, severe infections are more common. ^[4][5]
• Invasive bacterial infections can occur secondary to: ^[6][7]
  • E. coli
  • S. agalactiae (Group B streptococcus)
  • L. monocytogenes
  • S. aureus
  • Enterococcus species
• Viral infections that are typically mild can be life-threatening for young infants, e.g.: ^[2][7]
  • Neonatal HSV infection
  • Severe VZV infection
• Fever in neonates can also result from dehydration. ^[8]

Infants < 28 days old are at a higher risk for life-threatening infections because of an immature immune system. ^[9]

• Febrile infants with serious infections may be well-appearing or only show non-specific symptoms, e.g.: ^[10][11][12]
  • Abnormal vital signs
  • Poor feeding
  • Irritability or excessive sleepiness ^[13]
  • Abnormal appearance
  • Full fontanelle
• See also “Clinical features of pediatric fever.”

Appearance is unreliable in neonates and infants ≤ 60 days of age who may initially look well despite having a life-threatening infection. ^[11]

• Obtain a full history (including birth history), examine the child, and obtain vital signs.
• Look for specific sources of infection, e.g., cellulitis; if present, follow established treatment for that condition. ^[2]
• If there is no clear source of infection:
  • Assess whether the infant is ill-appearing or looks well. ^[10]
  • Determine exact age; management of well-appearing infants depends on age.

• Admit to hospital.
• Obtain full sepsis workup including CSF analysis.
• Start empiric parenteral antibiotic therapy.

Overview ^[2]

• The advice below is based on AAP guidance and applies to well-appearing infants without:
  • A recognizable serious source of infection ^[2]
  • Significant past medical history
  • A history of immunization within the preceding 48 hours (if ≥ 8 days of age) ^[2]
• Thoroughly evaluate all infants including those with nonspecific symptoms and/or minor infections, to exclude bacteria coinfection. ^[2]
• Diagnostic and treatment recommendations differ by age (i.e., 8–21 days, 22–28 days, and 29–60 days).

Diagnostic studies for febrile infants ≤ 60 days of age

All infants

• Inflammatory markers; abnormal inflammatory markers in infants ≤ 60 days of age include: ^[2]
  • Procalcitonin > 0.5 ng/mL
  • CRP > 20 mg/L
  • ANC > 4000–5200
  • Temperature 38.5 °C (> 101.3 °F)
• Blood culture
• Urinalysis with reflex urine culture ^[14]

Inflammatory markers are not required in 8–21-day-old infants since empiric IV antibiotics are always started in this age group. However, inflammatory markers can guide management. ^[2]

Select infants (depending on age and clinical status)

• CSF analysis ^[2]
  • ≤ 7 days: recommended for high-risk infants ^[14]
  • 8–21 days: required for all infants
  • 22–28 days: Perform if inflammatory markers are abnormal, consider for all.
  • 29–60 days: Consider if inflammatory markers are abnormal.
• HSV testing in infants: if red flag features for HSV in infants are present

Initial disposition and treatment

• Provide supportive care for pediatric fever.
• Further management is based on age and laboratory studies.

• Etiologies of fever in this age group depend on:
  • If the infant is term or premature ^[15]
  • Onset of symptoms after birth
  • If the infection is community-acquired or hospital-acquired ^[16]
  • Whether the mother had suspected or confirmed infections prior to delivery
• Manage in consultation with a specialist (neonatology, infectious disease). ^[14]
  • Diagnostic studies may include blood cultures, inflammatory markers, CSF, and urine cultures.
  • Empiric parenteral antibiotics are usually recommended.

The following guidance pertains to well-appearing infants; for all other infants, see “Management of the ill-appearing febrile infant ≤ 60 days of age.”

Approach ^[2]

• Perform diagnostic studies for febrile infants ≤ 60 days; inflammatory markers are optional in this age group.
• Admit to hospital.
• Administer empiric parenteral antibiotics.

Empiric antibiotics for infants 8–21 days of age ^[2]

• Suspected meningitis: See “Treatment of meningitis in children.”
• No signs of meningitis
  • Ampicillin
  • PLUS ceftazidime
  • OR gentamicin ^[2]

In febrile neonates 8–21 days of age, always obtain a full workup for infection (i.e, urinalysis, blood culture, and lumbar puncture), administer empiric antibiotics, and admit to the hospital. ^[2]

The following guidance pertains to well-appearing infants; for all other infants, see “Management of the ill-appearing febrile infant ≤ 60 days of age.”

Approach ^[2]

• Perform diagnostic studies for febrile infants ≤ 60 days.
• Determine if CSF analysis is required.
  • Abnormal inflammatory markers in infants ≤ 60 days: Obtain CSF analysis.
  • Normal inflammatory markers: Consider CSF analysis.
• Determine treatment and disposition based on:
  • Results of diagnostic studies
  • Home observation criteria for infants 22–28 days of age

Initial treatment

Treatment is determined by inflammatory markers, urinalysis, and CSF analysis (if performed).

• Abnormal urinalysis or abnormal or uninterpretable CSF: Admit and start empiric antibiotics.
• Urinanalysis and CSF analysis normal
  • Hospital observation planned: Consider empiric parenteral antibiotics.
  • Home observation planned : Give empiric parenteral antibiotic prior to discharge.
• CSF not performed
  • Abnormal inflammatory markers: Admit and start empiric IV antibiotics.
  • Normal inflammatory markers: hospital observation with or without empiric parenteral antibiotics

Empiric antibiotics for neonates 22–28 days of age

• Suspected meningitis: See “Treatment of meningitis in children.”
• No signs of meningitis: ceftriaxone ^[2]

Home observation criteria for infants 22–28 days of age

• Consider home observation after a single dose of parenteral empiric antibiotics if all of the following are present:
  • Inflammatory markers normal
  • Urinalysis normal
  • CSF analysis normal
• No barriers to treatment and follow-up are present, i.e. all parents and caregivers:
  • Express understanding of care instructions
  • Can obtain all prescribed medications
  • Are able to attend follow-up in 24 hours
  • Have reliable transportation for immediate follow-up if the infant worsens

Neonates 22–28 days of age cannot be observed at home unless a full work-up (i.e., inflammatory markers, blood cultures, urinalysis, and CSF analysis) is normal and a single dose of parenteral antibiotics (typically ceftriaxone) has been administered. ^[2]

The following guidance pertains to well-appearing infants; for all other infants, see “Management of the ill-appearing febrile infant ≤ 60 days of age.”

Approach ^[2]

• Perform diagnostic studies for febrile infants ≤ 60 days of age.
• Any abnormal inflammatory markers in infants ≤ 60 days of age: Consider CSF analysis.
• Determine treatment and disposition based on:
  • Results of diagnostic studies
  • Home observation criteria for infants 29–60 days of age

Initial treatment ^[2]

CSF analysis is only considered for infants with abnormal inflammatory markers; therefore, management differs between infants with normal inflammatory markers and those with abnormal ones.

Abnormal inflammatory markers

• Abnormal CSF analysis
  • Suggestive of meningitis: Admit and start empiric parenteral antibiotics.
  • Uninterpretable: Consider observation and either repeat CSF analysis and/or inflammatory markers or give empiric antibiotics and reassess.
• Abnormal urinalysis
  • Administer empiric parenteral or oral antibiotics.
  • Observe patients in hospital or at home.
• Normal urinalysis and CSF analysis
  • Consider IV or oral antibiotics.
  • Observe in hospital or at home.
• CSF analysis not performed
  • Administer parenteral antibiotics.
  • Observe in hospital or at home.

Normal inflammatory markers

• Abnormal urinalysis
  • Administer oral antibiotics.
  • Observe either in hospital or at home with follow-up in 12–24 hours.
• Normal urinalysis: Observe at home.

Febrile infants 29–60 days of age with normal urinalysis and normal inflammatory markers do not need a lumbar puncture or antibiotics and can be observed at home. ^[2]

Empiric antibiotics for infants 29–60 days of age

Parenteral antibiotics ^[2]

• Suspected meningitis: See “Treatment of meningitis in children.”
• No signs of meningitis: ceftriaxone ^[2]

Oral antibiotics ^[2]

• Cephalexin ^[2]
• Cefixime ^[2]

Home observation criteria for infants 29–60 days of age

• Home observation without empiric antibiotics if all of the following are present:
  • Inflammatory markers normal
  • Urinalysis normal
  • CSF not indicated
• Consider home observation with empiric antibiotics if CSF analysis is normal (or not performed) and one of the following is present:
  • Urinalysis is abnormal
  • Inflammatory markers are abnormal
• No barriers to treatment and follow-up are present, i.e. all parents and caregivers:
  • Express understanding of care instructions
  • Can obtain all prescribed medications
  • Are able to attend follow-up in 24 hours
  • Have reliable transportation for immediate follow-up if the infant worsens

Tailor antimicrobial therapies if a pathogen is isolated.

Infant improving ^[2]

• Identified pathogen: Continue treatment per guidance.
• All other patients
  • Stop empiric antibiotics if blood and CSF cultures are negative at 24–36 hours.
  • Discharge home if:
    • Clinical appearance is good
    • HSV PCR studies, if sent, are negative

Infant not improving ^[2]

If the patient is not improving and/or worsening:

• Start antibiotics, if not already started, or broaden antimicrobial coverage.
• Consider nonbacterial infections (e.g., HSV, fungal infections) and alternative causes of fever (see “Etiology”).

In febrile infants < 60 days of age with persistent fever and/or no clinical improvement despite antibiotics and/or negative blood cultures, consider testing for neonatal HSV and initiating acyclovir even if red flag features for neonatal HSV are not present. ^[17]

• Encourage pregnant patients to have recommended immunizations in pregnancy. ^[18]
• Prevent vertical transmission of infections to newborns.
  • For early onset group B Streptococcal infections, ensure appropriate:
    • Maternal GBS screening
    • Intrapartum prophylactic antibiotics for GBS
    • Monitoring of newborns at risk for GBS infection
  • Congenital and neonatal HSV infections: See “Prevention of neonatal HSV infection.”
• Prevent transmission to or from infants.
  • Practice rigorous hand hygiene and respiratory hygiene, especially around at-risk populations.
  • Follow guidance on when it is safe to return to daycare following an infection