Febrile Infants: The New Guideline

What’s the big deal with fever?

Febrile infants have higher rates of invasive bacterial infections (bacteremia and meningitis) than older children, and this risk appears highest in infants <30 days of age.

• Febrile neonates may have roughly twice the rate of bacteremia and meningitis as febrile infants in their second month of life, although overall rates in both groups are low.
  • Febrile neonates <30 days old: 2.9% had bacteremia and 1.2% had meningitis
  • Febrile infants 30-60 days old: 1.6% had bacteremia and 0.4% had meningitis

Ongoing research has challenged whether we should classify all infants <30 days of age as high risk, leading to the algorithms discussed below.

SBI or IBI?

Serious bacterial illness (SBI) is a non-specific term that originated in the 1980s, incorporating a variety of infections affecting children but most consistently UTI, bacteremia, and meningitis. However, UTIs in children are MUCH more common than bacteremia or meningitis, so much so that they distort the accuracy of a prediction model to detect bacteremia or meningitis. As such, there has been a shift in favor of the term invasive bacterial infection (IBI), referring to bacteremia and meningitis.

The New Guideline

Check it out here: Clinical Practice Guideline: Evaluation and Management of Well-Appearing Febrile Infants 8 to 60 Days Old.

One of the most important things about the guideline is understanding who it applies to!

Applies to:

• Full term infants
• Age criteria: 8 to 60 days old
• Temp ≥38.0ºC in the past 24 hours
• Well-appearing infants

Excludes:

• 0-7 day-old neonates
• Premature infants (<37 weeks gestation)
• Infants <14 days old with perinatal complications (e.g., maternal fever, infection, and/or antimicrobial use)
• Infants whose neonatal course was complicated by surgery or infection
• Ill-appearing infants
• Infants with a diagnosis of bronchiolitis or focal infection (e.g., cellulitis, omphalitis, septic arthritis, osteomyelitis)
• Infants with a chronic medical condition, congenital or chromosomal abnormalities, or immunocompromised
• Immunization within past 48 hours
• Infants with high suspicion of HSV (e.g., vesicles)

What is well-appearing?

Clinical appearance is a subjective assessment, and likely related to experience.

The accuracy of clinician assessment is likely related to experience. Unfortunately, there is no measure or adequate definition for what constitutes “experienced,” or of “well appearing.” Researchers in large studies have often treated clinical appearance as binary: well appearing or not, or ill appearing or not.

Pantell et al, Pediatrics 2021

Ill-appearing infants are at higher risk for IBI, and are thus not included in the guideline. The guideline notes that “when clinicians are uncertain as to whether an infant is well appearing, this guideline should not be applied.”

But Wait! What if the kid has…

Febrile infants show up with myriad issues. Some look perfectly happy and asymptomatic, while others have a combination of symptoms. The guideline specifically notes that infants with the following issues may be included:

1. Respiratory symptoms: the presence of upper respiratory tract infection symptoms or other respiratory symptoms not diagnostic of bronchiolitis should not exclude infants from inclusion in the pathway.
2. Diarrhea: infants suspected of having diarrhea caused by treatable bacterial pathogens should have stool specimens tested. If studies for bacteria are negative, infants may then enter the decision tree pathway. Loose stools do not exclude infants from the pathway.
3. Otitis media: diagnosing infants with presumed otitis media does not preclude their entry into the pathway.
4. Current or recent use of antimicrobial agents in infants older than 2 weeks of age requires individualized interpretation for febrile infants who enter the pathway.
5. Positive viral test results: the availability of rapid respiratory molecular testing for a variety of viruses is increasing, outpacing the availability of evidence for how such testing should be used.

In evaluating the implications of a positive viral respiratory test result, numerous studies have documented lowering of IBI risk in subsets of patients. However, no prospective study has yet provided convincing data on whether a positive viral test result sufficiently reduces the IBI risk to change decision-making, after considering other historical, clinical, and available markers of inflammation.

Pantell et al, Pediatrics 2021

What about all these inflammatory markers?

Inflammatory markers are a frequent discussion point in the guideline, and include (high) fever, procalcitonin, CRP, and ANC. Procalcitonin is the most accurate inflammatory marker available for risk stratification in this population, but its availability varies across the US.

Abnormal cutoffs for purposes of this guideline:

• Fever ≥38.5ºC, particularly in settings in which procalcitonin is not available
• Procalcitonin >0.5 ng/mL
• CRP >20 mg/L
• ANC >4000 per mm³ (when used in conjunction with procalcitonin) or >5200 per mm³ (when procalcitonin is not available)

Case 1:

Liz Terria is a 2 week ex-FT infant who comes to the Med-Peds Clinic for a weight check. On check-in, her mom mentions Lizzy felt a little warm this morning and they took a rectal temperature before coming into clinic and it was 100.5. Her vitals are normal on check-in and she is afebrile.

Evaluation and Management of Well-Appearing Febrile Infants: 8 to 21 Days of Age

Notes on the above algorithm for infants 8 to 21 days of age:

• Urine specimen should be obtained via catheterization or suprapubic aspiration. Obtain urine culture if urinalysis is positive.
  • The guideline defines a positive urinalysis result as the presence of any leukocyte esterase on dipstick, >5 WBCs/hpf in centrifuged urine, or >10 WBCs/mm³ in uncentrifuged urine on microscopic urinalysis using a hemocytometer.
• Send CSF for cell count, Gram stain, glucose, protein, bacterial culture, and enterovirus PCR (if available)
  • In general, if CSF is positive for enterovirus, antimicrobial agents should be discontinued (or withheld), because concomitant enteroviral and bacterial meningitis is rare.
• Inflammatory markers (IMs) include CRP, ANC, and procalcitonin. In this algorithm, they are not needed for diagnosis as they will not change management, but can be considered if they will guide ongoing clinical decisions (e.g., whether to discontinue antimicrobial agents at 24 or 36 hours while awaiting final results of bacterial cultures)
• HSV should be considered when there is a maternal history of genital HSV lesions or fevers from 48 hours before to 48 hours after delivery and in infants with vesicles, seizures, hypothermia, mucous membrane ulcers, CSF pleocytosis in the absence of a positive Gram stain result, leukopenia, thrombocytopenia, or elevated ALT

Treatment:

Overall, for studies since the year 2000 in infants <90 days of age, Gram-negative organisms have been responsible for the majority of infections (60% to 80%). E coli has been the most common pathogen detected, with a prevalence of 70% to 90% of UTIs, 30% to 60% of bacteremia infections, and 15% to 30% of bacterial meningitis.

Pantell et al, Pediatrics 2021

Notes on the above table for infants 8 to 21 days of age:

• GBS remains the most common organism for bacterial meningitis, followed by E Coli.
• If not concerned about meningitis, start [ampicillin + gentamicin] OR [ampicillin + ceftazidime].
• If concerned about meningitis, start [ampicillin + ceftazidime].
  • Why not gentamicin? –> Gentamicin doesn’t cross the blood brain barrier as well.
• In communities with circulation of ESBL-producing E coli strains, gentamicin should be used instead of ceftazidime for treatment of suspected bacteremia or sepsis, and meropenem should be used instead of ceftazidime when bacterial meningitis is suspected.

Case 2:

Hugh T Eye is an ex-FT 26 day old who comes to the ER for fever. He seemed “not himself” today so on the recommendation of his pediatrician, his parents took a rectal temperature which was 100.4.

Evaluation and Management of Well-Appearing Febrile Infants: 22 to 28 Days of Age

Notes on the above algorithm for infants 22 to 28 days of age:

• The risk of bacteremia and bacterial meningitis is lower in infants 22 to 28 days of age than in infants 8 to 21 days of age. However, they continue to be at higher risk than older infants.
• The use of IMs is based on data from the PECARN and Step-By-Step studies.
• If no LP is performed, then the infant should be admitted for monitoring.
• If LP is unremarkable, then the infant can be discharged home after a single dose of ceftriaxone with repeat clinical evaluation within the next 24 hours.

Notes on the above table for infants 22 to 28 days of age:

• Meningitis concern?
  • Yes: ampicillin + ceftazidime
  • No: ceftriaxone alone
    • The risk of bilirubin displacement from ceftriaxone is extremely low in this age group

Case 3:

Zora Throte is an ex-FT 45 day old who presents to the ED for fever. Her 2 y.o. sister came home from daycare 3 days ago with a viral URI. Parents are concerned because now Zora has been noted to have rhinorrhea, decreased PO intake, and a fever.

Evaluation and Management of Well-Appearing Febrile Infants: 29 to 60 Days of Age

Notes on the above algorithm for infants 29 to 60 days of age:

• Circumcised boys in this age group have a likelihood of UTI <1% and may be exempted from urinalysis.
• If inflammatory markers are normal and urinalysis is negative, then it’s reasonable to discharge patient home from the ED with close follow-up within 24 hours.
  • The risk for well-appearing infants with these negative findings having bacteremia is 0.1% for infants 29 to 60 days of age.
• If inflammatory markers are abnormal, shared decision-making should occur regarding admission and antibiotics.

Notes on the above table for infants 29 to 60 days of age:

• Meningitis concern?
  • Yes: ceftriaxone/ceftazidime + vancomycin to cover resistant Gram-positives
  • No: ceftriaxone alone
• Caveat is if there is a presumed UTI (positive UA and normal inflammatory markers), then start oral antibiotics

Discharge Criteria

Clinicians should discontinue parenteral antimicrobial agents and discharge hospitalized patients when all of the following criteria are met:

1. Culture results are negative for 24 to 36 hours or only positive for contaminants;
2. The infant continues to appear clinically well or is improving (eg, fever, feeding); and
3. There are no other reasons for hospitalization

Time to positivity of blood culture is dependent on the type and concentration of bacterial organism. Between 4% and 17.6% of pathogens take >24 hours to grow; between 0% and 9% take >36 hours. Compared with ill-appearing infants, infants not appearing ill are less likely to have pathogens identified in <24 hours (85.0% vs 92.9%). Pathogens vary in median times to positivity: GBS takes 9.3–14.3 hours; E coli takes 11.3–13.6 hours; and S aureus takes 18.5–19.9 hours. For E coli, the most common organism identified, 24% take longer than 24 hours to grow, whereas only 5.9% of GBS grow after 24 hours.

Pantell et al, Pediatrics 2021

Take-Home Points!

• IBI is a more precise term than SBI.
• For febrile infants 8 to 60 days of age, the risk of IBI is highest among infants 8 to 21 days of age, followed by infants 22 to 28 days of age, and lowest in infants 29 to 60 days of age.
• The above guideline applies to febrile infants who are 8 to 60 days of age, full term, and well-appearing.
• There are many nuances in each algorithm, from the use of inflammatory markers to antibiotic initiation.
• Check out the Cribsiders episode on this topic! This episode was co-produced by Sam Masur, MP Class of 2022, and co-hosted by Justin Berk, MP Core Faculty!

Blog post based on Med-Peds Forum talk by Rebecca Raymond-Kolker, PGY2