The Febrile Infant: Incorporating the 2021 American Academy of Pediatr

The Febrile Infant: Incorporating the 2021 American Academy of Pediatrics guidelines

By Corey Ziemba, MD March 29, 2023 0 comments

Can you trust a febrile infant?

“No” has been, and continues to be, the resounding answer over the last 40 years as researchers and clinicians work to determine the optimal evaluation and management of the well-appearing young febrile infant [1].

The goal remains to identify infants with bacterial infections in this at-risk cohort of patients while also considering the balance of cost-effectiveness on a population scale and the potential for iatrogenic harm with evaluation such as unnecessary lumbar punctures, unnecessary antibiotics, and unnecessary hospitalization. Fortunately, bacteremia and bacterial meningitis in this age group are uncommon [2]. Unfortunately, delayed or missed diagnosis can be devastating [1-3].

In the most recent 2021 Clinical Practice Guideline, the American Academy of Pediatrics (AAP) aims to provide guidance with 3 separate age-based algorithms for the evaluation and management of the well-appearing febrile infant [4]. These guidelines were made possible by the recent PECARN, Step by Step, and other studies and the invaluable information they have provided [5-7].

Who’s included?

Well-appearing febrile infants
- The AAP acknowledges that clinician experience is likely the best determinate of what is “well-appearing”, further admitting that there is no measure or definition of either “experience” or “well-appearing”
Febrile
- Rectal temperatures of 38.0C or 100.4F at home in the past 24 hours or determined in a clinical setting
- Subjective fevers at home are excluded
Gestation
- Between 37-42 weeks
- Premature infants excluded
Age
- Days 8 to 60 and have been discharged home following birth

Who is not included?

Preterm or infants with congenital/chromosomal abnormalities
Infants with focal bacterial infections
Cellulitis, omphalitis, septic arthritis, osteomyelitis
Bronchiolitis
- With or without a positive RSV test
Immunocompromised
- Either suspected or known deficiency
Immunizations in the previous 48 hours

It should also be noted that the AAP has named the following as high-risk inflammatory markers that will be referenced in the soon-to-be-discussed guidelines [4,5].

Temperature >101.3F (38.5C)
C-reactive protein (CRP) > 20 mg/L
Procalcitonin >0.5 ng/mL
Absolute neutrophil count (ANC) >4000 mm³ (or 5200 mm³ if your facility does not have procalcitonin available)

The Groups

Group 1: 8-21 Days

While the AAP makes the distinction of an age 0-7 days group from the age 8-21 days, they provide no specific recommendations about emergency department (ED) management in the youngest group [4]. Despite this, these infant groups are likely best evaluated and managed similarly in the ED:

Urinalysis (UA) +/- urine culture if indicated by UA
Blood culture
Lumbar puncture (LP)
- Cell count, Gram stain, glucose, protein, bacterial culture, and enterovirus PCR (if available)
Admission

Inflammatory markers are not required to determine ED management in this age group but may guide inpatient clinicians.

Treatment

Ampicillin IV or IM
Ceftazidime IV or IM or gentamicin IV or IM

The addition of acyclovir to IV antibiotics depends on the following risk factors which increase the likelihood of HSV:

Maternal genital HSV lesions or fever 48 hours before or after delivery
Infants with vesicles, seizures, hypothermia, mucous membrane ulcers
CSF pleocytosis with a negative Gram stain result
Leukopenia, thrombocytopenia, or elevated AST/ALT levels

Group 2: 22-28 Days

Although many febrile infants in this group will still require a full evaluation for sepsis, there are some new alternatives in patients meeting certain criteria. At the minimum, all 22-28 day old infants will need:

UA +/- culture
Blood culture
Inflammatory markers (ANC, CRP, procalcitonin)

Further management of a well-appearing infant in this group can be based on the following pathways:

1. If UA positive with negative inflammatory markers
  - LP may be performed but is not required
  - IV antibiotics and admission are required regardless
2. If UA negative with negative inflammatory markers, then there are 2 options
  - Perform LP
    - If LP negative, then the patient can be given a dose of parenteral antibiotics and discharged home with close follow-up in 24 hours.
    - If LP is traumatic or pleocytosis is present, administer antibiotics and admit.
  - Defer LP
    - Antibiotics may be administered, but the patient should be admitted.
3. If UA negative and ANY positive inflammatory marker (procalcitonin > 0.5 mg/mL, CRP >20 mg/L, ANC >4000, or temperature >101.3F), LP is required
  1. If LP positive
    - Admit with IV antibiotics
  2. If LP negative
    - Admit +/- antibiotics, OR
    - Discharge home after one dose of parenteral antibiotic with 24-hour follow-up

Treatment

Same antibiotic options as the day 0-21 infants

Group 3: 29-60 days

The nuances of this group’s decision tree revolve around the inflammatory markers.

Each infant in this group should have the following completed:

Urinalysis
Blood Cultures
Inflammatory markers (CRP, ANC, and procalcitonin)

If everything is negative (UA & inflammatory markers):

Infants may be discharged home without antibiotics and with close follow-up within 36 hours.

If inflammatory markers are negative:

Infants with a positive urinalysis and negative inflammatory markers may be treated with oral antibiotics.
- They may be either admitted to the hospital for observation or discharged with 24-hour follow-up.
- No LP needed.

If inflammatory markers are positive:

A LP may be performed if the clinician feels it necessary but is not required.
- If performed and CSF is negative the infant may be discharged with close follow-up.
- Given high risk of bacteremia with elevated inflammatory markers in this age group, a dose of parenteral antibiotics prior to discharge is appropriate.

If LP deferred:
- Administer parenteral antibiotics, and likely admit to hospital.
- The caveat to this is if they have viral testing completed that is positive and are well appearing.
  - Example: A 48-day-old infant presents with a fever of 100.6F, CRP of 22 mg/L, and otherwise normal procalcitonin, ANC, and UA. The mother reports that an older brother has had a runny nose. Viral PCR testing is positive for rhinovirus. Seeing as the UA is negative, the infant appears well with a positive viral test, they may go home with shared decision-making and close outpatient follow-up, despite a positive inflammatory marker (CRP 22 mg/L) [3].

Treatment

Urinary Tract Infection:

Ceftriaxone (IV/IM) or cephalexin/cefixime as oral options.

Concern for Bacteremia/Meningitis:

Ceftriaxone + vancomycin
May add acyclovir for the above-mentioned antiviral treatment indications.

What should be done if the viral panel is positive?

Children 29 days or older with fever from a documented viral source can be managed according to their clinical presentation and can go outside the algorithm.
This requires a documented positive viral swab and not just a presentation consistent with a viral syndrome.
UTI is common in this age group, and a UA should be obtained [8].

Conclusion

Over the course of nearly the last half century there has been a lack of clear evidence-based guidelines in evaluating the young febrile infant [1]. Although serious bacterial infections in these young, febrile infants are uncommon, studies show that in the first month of life, bacteremia can be present in nearly 3% of febrile infants, with bacterial meningitis occurring in about 1% [2]. The absence of consensus regarding management has led to significant costs due to hospitalizations and their associated iatrogenic complications [9]. In the movement to create new recommendations, shifting epidemiology pushed changes in previous guidelines with a new focus on the use of the now widely available inflammatory markers [10]. With the advent of multiple large-scale studies and the recent improvements in lab testing, the newly updated AAP guidelines provide recommendations on how to manage this challenging population [4-7].

Take Home Points

These management strategies can only be used in WELL-APPEARING infants – if they’re ill-appearing, do a complete workup.
Evaluation of febrile infants 0-21 days remains the same – do everything (blood culture, UA +/- culture, LP with CSF studies), give antibiotics, and admit.
For those infants 22-28 days, get the UA, blood culture, and inflammatory markers to guide management.
- Not all febrile infants in the 22-28 day subset need an LP, though it should still be obtained in certain clinical circumstances, and discussed between provider and parents in other situations
In infants ≤28 days, a complete workup is still needed even if a viral source is present.
Febrile infants 29-60 days old may be sent home after a negative workup with close follow-up.

References:

1. Roberts KB. Young, febrile infants: a 30-year odyssey ends where it started. JAMA. 2004 Mar 10;291(10):1261-2. PMID: 15010450.
2. Biondi EA, Lee B, Ralston SL, et al. Prevalence of Bacteremia and Bacterial Meningitis in Febrile Neonates and Infants in the Second Month of Life: A Systematic Review and Meta-analysis.JAMA Network Open. 2019 Mar; 2(3). PMID: 30901044.
3. Baker MD, Avner JR, Bell LM. Failure of infant observation scales in detecting serious illness in febrile, 4- to 8-week old infants. Pediatrics. 1990;85(6):1040–1043. PMID: 2339027
4. Pantell RH, Roberts KB, Adams WG, et al. Clinical Practice Guideline: Evaluation and Management of Well Appearing Febrile Infants 8 to 60 Days Old. Pediatrics. 2021;148(2):e2021052228. PMID: 34281996
5. Kuppermann N, Dayan PS, Levine DA, et al. A Clinical Prediction Rule to Identify Febrile Infants 60 Days and Younger at Low Risk for Serious Bacterial Infections. JAMA Pediatr. 2019;173(4):342-351. PMID: 30776077
6. Gomez B, Mintegi S, Bressan S, et al. Validation of the “Step-by-Step” approach in the management of young febrile infants. The Journal of Pediatrics. 2016 Aug; 138(2):e20154381. PMID: 27382134
7. Nguyen THP, Young BR, Poggel LE, et al. Roseville Protocol for the Management of Febrile Infants 7-60 Days. Hosp Pediatr. 2020 Dec 17:hpeds.2020-0187. PMID: 33334815
8. Shaikh N, Morone NE, Bost JE, Farrell MH. Prevalence of urinary tract infection in childhood: a meta-analysis. Pediatr Infect Dis J. 2008;27(4):302-308. PMID: 18316994
9. Coyle C, Brock G, Wallihan R, Leonard JC. Cost Analysis of Emergency Department Criteria for Evaluation of Febrile Infants Ages 29 to 90 Days. J Pediatr. 2021 Apr;231:94-101.e2. doi: 10.1016/j.jpeds.2020.10.033. Epub 2020 Oct 31. PMID:33130155.
Milcent K, Faesch S, Gras-Le Guen C, et al. Use of Procalcitonin Assays to Predict Serious Bacterial Infection in Young Febrile Infants [published correction appears in JAMA Pediatr. 2016 Jun 1;170(6):624].JAMA Pediatr. 2016;170(1):62-69. doi:10.1001/jamapediatrics.2015.3210 PMID: 26595253