Fever, Absolute Neutrophil Count, Procalcitonin,
and the AAP Febrile Infant Guidelines
Nathan Kuppermann, MD, MPH,a Prashant Mahajan, MD, MPH, MBA,b Peter S. Dayan, MD, MScc
In 2021, the American Academy of Pediatrics (AAP) published clinical
practice guidelines for the evaluation and management of well-
appearing febrile infants 8 to 60 days old (of which one of us [N.K.] is
an author).1 These guidelines were much needed for 2 fundamental
reasons: (1) hundreds of thousands of febrile infants are evaluated in
US emergency departments and other outpatient settings annually and
(2) substantial variation in the management of this vulnerable patient
population suggests inefficient and suboptimal care.
THE AAP GUIDELINES AND INFLAMMATORY MARKERS
The AAP guidelines reviewed a considerable body of research
performed over the past several decades on this topic to summarize
the evidence and present simplified algorithms for clinicians to apply at
the bedside. These guidelines represent a substantial step forward not
only in synthesizing the evidence but also in providing the evidence in
a form geared toward translating into practice. Nonetheless, trying to
simplify such a comprehensive body of research (a task of more than a
decade for the committee) inevitably has led to some challenges in
applying the guidelines at the bedside. Comments and inquiries about
the guidelines since publication have reflected several issues pertaining
to inflammatory markers. One of the main goals of the AAP guidelines
was to identify which inflammatory markers best stratify the risk of
“important bacterial infections” (here defined as urinary tract
infections, bacteremia, and bacterial meningitis) in young febrile
infants. In addition, the guidelines attempted to define the threshold
values at which clinicians should act on these inflammatory markers
with more invasive testing (lumbar punctures [LPs]), empirical
antibiotics, and hospital admission.
In the algorithms in the AAP guidelines, 4 different inflammatory
markers with “high risk” thresholds are provided (T >38.5 C,
procalcitonin (PCT) >0.5 ng/mL, C-reactive protein (CRP) >20 mg/L,
and absolute neutrophil count (ANC) either >4000 or >5200/mm3).
These appear in the footnotes of the figures of the algorithms in the
PEDIATRICS Volume 151, number 2, February 2023:e2022059862
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a
Departments of Emergency Medicine and Pediatrics, University of
California, Davis School of Medicine, Sacramento, California;
b
Departments of Emergency Medicine and Pediatrics, University of
Michigan School of Medicine, Ann Arbor, Michigan; and cDivision of
Pediatric Emergency Medicine, Department of Emergency Medicine,
Columbia University Vagelos College of Physicians & Surgeons, New
York City, New York
Dr Kuppermann drafted the manuscript, Drs Mahajan and
Dayan reviewed and made critical revisions to the
manuscript, and all authors approved the final manuscript
as submitted and agree to be accountable for all aspects
of the work.
The guidelines/recommendations in this article are not
American Academy of Pediatrics policy, and publication
herein does not imply endorsement.
DOI: https://doi.org/10.1542/peds.2022-059862
Accepted for publication Oct 28, 2022
Address correspondence to Nathan Kuppermann, MD, MPH,
Departments of Emergency Medicine and Pediatrics,
University of California, Davis School of Medicine, 2315
Stockton Blvd, PSSB Suite 2100, Sacramento CA 95817. E-mail:
nkuppermann@ucdavis.edu
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2023 by the American Academy of Pediatrics
CONFLICT OF INTEREST DISCLOSURES: The authors have
indicated they have no potential conflicts of interest
relevant to this article to disclose.
To cite: Kuppermann N, Mahajan P, Dayan PS. Fever, Absolute
Neutrophil Count, Procalcitonin, and the AAP Febrile Infant
Guidelines. Pediatrics. 2023;151(2):e2022059862
PEDIATRICS PERSPECTIVES
 AAP guidelines for the management importance of height of invasive bacterial infections2,5,7
of febrile infants 8 to 21 days old temperature. The above-referenced and enhances the test accuracy
(Fig 1), 22 to 28 days old (Fig 2), articles citing higher temperatures beyond serum PCT.6,7 As a
and 29 to 60 days old (Fig 3).1 How as a risk factor for important result, the AAP guidelines
to use those inflammatory markers bacterial infections did not include appropriately include the ANC
in combination, however, and at and therefore adjust for serum PCT, as an inflammatory marker that,
which thresholds, needs further a biomarker that has the best test if elevated, should trigger a
clarification. In addition, the characteristics (compared with the more comprehensive evaluation
algorithm footnotes state that “If ANC and CRP) for identifying febrile of the infant. Given the existing
procalcitonin is unavailable, both infants with bacteremia and/or literature, the AAP guidelines
ANC and CRP should be obtained, bacterial meningitis in this age reference 3 different ANC
and a temperature >38.5 C is group.5 In fact, the authors of 2 cutoffs from 3 different studies
considered abnormal.”1 In this large prospective multicenter that attempt to identify febrile
commentary, we discuss the use of studies who aimed to generate infants at high and low risk of
3 of these inflammatory markers: prediction rules to identify young, important bacterial infections.
fever, the ANC, and PCT. We will not febrile infants with these important The Step-by-Step study6 uses
address CRP because there is bacterial infections did not find that the ANC at a predetermined
insufficient evidence on how best to height of temperature was a cutoff of 10 000 cells/mm3, as
use CRP and at what thresholds, as significant predictor after adjusting well as serum PCT and CRP as
a component of prediction rules. for other variables, including serum blood biomarkers. The febrile
Robust multicenter data are needed PCT.6,7 Therefore, for clinicians who infant prediction rule derived
to understand the exact role CRP have access to routine laboratory and validated by our group in
could play in circumstances when testing that includes PCT, height of the Pediatric Emergency Care
PCT is unavailable. temperature should not be the Applied Research Network
driver of more aggressive identified an ANC threshold of
Temperature and ANC Thresholds management, including LPs, 4100 cells/mm3 using recursive
With and Without PCT partitioning (although an ANC
empirical antibiotics, or
hospitalization in the face of normal threshold of 4000 cells/mm3
1. Fever is the hallmark clinical biomarker values, including PCT.6,7 was nearly identical in
finding for identifying infants at Although adding height of accuracy, is easier to use, and
risk for important bacterial temperature to prediction is, therefore, appropriately
infections. Earlier guidelines2 algorithms that include PCT may recommended in the AAP
identified temperatures slightly increase the sensitivity of guidelines).7 Finally, a
$38.0 C or 38.2 C as indicating the prediction rules for identifying prediction rule derived in a
risk of important bacterial infants with important bacterial multicenter retrospective study
infections and suggesting the infections, this will decrease to identify young febrile infants
need for a comprehensive specificity and likely lead to at risk for invasive bacterial
laboratory evaluation, usually unnecessary LPs, empirical infections, which did not
including LPs. Other studies antibiotics, and hospitalizations. include either PCT or CRP in
identified higher temperatures3 the model, identified an ANC
or a temperature >38.5 C4 as In contrast, in settings in which threshold of 5200 cells/mm3
markers of higher risk. As a clinicians do not have access to for determining high risk. In the
consequence, the AAP PCT testing, height of temperature algorithms provided by the AAP
guidelines suggest that a should be considered an guidelines, both the 4000/mm3
temperature >38.5 C should be inflammatory marker2,3,4 and and 5200/mm3 ANC thresholds
considered an inflammatory should be incorporated as a are mentioned in the footnotes.
marker and that this should risk factor for bacterial However, to be clear, the
trigger a more comprehensive infections. 4000/mm3 threshold should be
evaluation.1 used in conjunction with serum
An important issue that needs 2. Of the routine measures PCT and the urinalysis, and
clarification, however, is the included in the complete blood the 5200/mm3 threshold
consideration of whether other count, the ANC is the most should be used with height
clinical and laboratory factors are accurate for identifying febrile of temperature and the
available and how they affect the infants at high and low risk for urinalysis when PCT is

2 KUPPERMANN et al
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 unavailable. This distinction is
essential for consideration of
the importance of fever and
the appropriate application
of the ANC in the prediction
rules.
In summary, the AAP guidelines on
the management of well-appearing
young febrile infants 8 to 60 days of
age at risk for important bacterial
infections have synthesized years of
research and provided actionable
data that can be translated into
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ABBREVIATIONS
AAP: American Academy of
Pediatrics
ANC: absolute neutrophil count
CRP: C-reactive protein
LP: lumbar puncture
PCT: procalcitonin
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