Sixteen years in the making, the American Academy of Pediatrics just released a new clinical practice guideline (CPG), “Evaluation and Management of Well-Appearing Febrile Infants 8-60 Days Old.” The recommendations were derived from interpretations of sequential studies in young, febrile but well-appearing infants that covered invasive bacterial infection (IBI) incidence, diagnostic modalities, and treatment during the first 2 months of life, further refining approaches to evaluation and empirical treatment.
Pediatricians have long had solid information to help assess the risk for IBI among febrile infants 0-3 months of age, but there has been an ongoing desire to further refine the suggested evaluation of these very young infants. A study of febrile infants from the Pediatric Research in Office Settings network along with subsequent evidence has identified the first 3 weeks of life as the period of highest risk for IBI, with risk declining in a graded fashion between 22 and 56 days of age.
Critical Caveats
First, some caveats. Infants 0-7 days are not addressed in the CPG, and all should be treated as high risk and receive full IBI evaluation according to newborn protocols. Second, the recommendations apply only to “well-appearing” infants. Any ill-appearing infant should be treated as high risk and receive full IBI evaluation and begun on empirical antimicrobials. Third, even though the CPG deals with infants as young as 8-21 days old, the recommendations are to treat all infants in this age group as high risk, even if well-appearing, and complete full IBI evaluation and empirical therapy while awaiting results. Fourth, these guidelines apply only to infants born at at least 37 weeks of gestation. Finally, the new CPG action statements are meant to be recommendations rather than a standard of medical care, leaving some leeway for clinician interpretation of individual patient scenarios. Where appropriate, parents’ values and preferences should be incorporated as part of shared decision-making.
The CPG divides young, febrile infants into three cohorts based on age:
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8-21 days old
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22-28 days old
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29-60 days old
Age 8-21 Days
For well-appearing febrile infants 8-21 days old, the CPG recommends a complete IBI evaluation that includes urine, blood, and cerebral spinal fluid (CSF) for culture, approaching all infants in this cohort as high risk. Inflammatory markers may be obtained, but the evidence is not comprehensive enough to evaluate their role in decision-making for this age group. A two-step urine evaluation method (urine analysis followed by culture if the urine analysis looks concerning) is not recommended for infants 8-21 days old. Urine samples for culture from these young infants should be obtained by catheterization or suprapubic aspiration.
The CPG recommends drawing blood cultures and CSF by lumbar puncture from this cohort. These infants should be admitted to the hospital, treated empirically with antimicrobials, and actively monitored. However, if the cultures are negative at 24-36 hours, the clinician should discontinue antimicrobials and discharge the infant if there is no other reason for continued hospitalization.
Age 22-28 Days
Well-appearing, febrile infants 22-28 days old are in an intermediate-risk zone. The recommendation for infants in this cohort is to obtain a urine specimen by catheterization or suprapubic aspiration for both urine analysis and culture. Clinicians may consider obtaining urine samples for analysis noninvasively (eg, urine bag) in this cohort, but this is not the preferred method.
Blood culture should be obtained from all infants in this group. Inflammatory markers can help clinicians identify infants at greater risk for IBI, including meningitis. Previous data suggested that inflammatory markers such as serum white blood cell counts > 11,000/µL, a serum absolute neutrophil count of > 4000/µL, and elevated C-reactive protein and procalcitonin levels could help providers identify febrile infants with true IBI. A 2008 study demonstrated that procalcitonin had the best receiver operating characteristic curve in regard to predicting IBI in young febrile infants. Other research backed up that finding and identified cutoff values for procalcitonin levels > 1.0 ng/mL The CPG recommends considering a procalcitonin value of 0.5 ng/mL or higher as positive, indicating that the infant is at greater risk for IBI and potentially should undergo an expanded IBI workup. Therefore, in infants 22-28 days old, inflammatory markers can play a role in deciding whether to perform a lumbar puncture.
Many more nuanced recommendations for whether to and how to empirically treat with antimicrobials in this cohort can be found in the CPG, including whether to manage in the hospital or at home. Treatment recommendations vary greatly for this cohort on the basis of the tests obtained and whether tests were positive or negative at the initial evaluation.
Age 29-60 Days
The CPG will be most helpful when clinicians are faced with well-appearing, febrile infants in the 29- to 60-day age group. As with the other groups, a urine evaluation is recommended; however, the CPG suggests that the two-step approach — obtaining a urine analysis by a noninvasive method and only obtaining culture if the urine analysis is positive — is reasonable. This means that a bag or free-flowing urine specimen would be appropriate for urinalysis, followed by catheterization/suprapubic aspiration if a culture is necessary. This would save approximately 90% of infants from invasive urine collection. Regardless, only catheter or suprapubic specimens are appropriate for urine culture.
The CPG also recommends that clinicians obtain blood culture on all of these infants. Inflammatory markers should be assessed in this cohort because avoiding lumbar puncture for CSF culture would be appropriate in this cohort if the inflammatory markers are negative. If CSF is obtained in this age cohort, enterovirus testing should be added to the testing regimen. Again, for any infant considered at higher risk for IBI on the basis of screening tests, the CPG recommends a 24- to 36-hour rule-out period with empirical antimicrobial treatment and active monitoring in the hospital.
Summary
The recommended approach for febrile infants 8-21 days old is relatively aggressive, with urine, blood, and CSF evaluation for IBI. Clinicians gain some leeway for infants age 22-28 days, but the guidelines recommend a more flexible approach to evaluating well-appearing, febrile infants age 29-60 days, when a two-step urine evaluation and inflammatory marker assessment can help clinicians and parents have a better discussion about the risk-benefit tradeoffs of more aggressive testing and empirical treatment.
The author would like to thank Dr Ken Roberts for his review and helpful comments on this summary of the CPG highlights. Summary points of the CPG were presented by the writing group at the 2021 Pediatric Academic Societies (PAS) meeting (virtual).
William T. Basco, Jr, MD, MS, is a professor of pediatrics at the Medical University of South Carolina and director of the Division of General Pediatrics. He is an active health services researcher and has published more than 60 manuscripts in the peer-reviewed literature.
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