Evaluation and Management of July 2019

Volume 16, Number 7

the Febrile Young Infant in the Authors

Lauren Palladino, MD

Emergency Department Chief Resident, Department of Pediatrics, Yale School of Medicine,

New Haven, CT
Christopher Woll, MD
Fellow, Section of Pediatric Emergency Medicine, Department of
Abstract Pediatrics, Yale School of Medicine, New Haven, CT
Paul L. Aronson, MD, MHS
Associate Professor of Pediatrics and Emergency Medicine, Section
Among young infants presenting with fever, untreated serious of Pediatric Emergency Medicine, Yale School of Medicine,
bacterial infections can have severe outcomes, so a full sepsis New Haven, CT
workup is often recommended but may not be necessary. This
issue reviews the use of novel diagnostic tools such as procalci- Peer Reviewers

tonin, C-reactive protein, and RNA biosignatures as well as new Jeffrey R. Avner, MD, FAAP
risk stratification tools such as the Step-by-Step approach and the Chairman, Department of Pediatrics, Professor of Clinical Pediatrics,
Maimonides Children’s Hospital of Brooklyn, Brooklyn, NY
Pediatric Emergency Care Applied Research Network prediction Jessica S. Williams, MD
rule to determine which febrile young infants require a full sepsis Pediatric Emergency Medicine Faculty, Assistant Professor, UT
Southwestern, Children’s Health Plano, Plano, TX
workup and to guide the management of these patients in the
emergency department. The most recent literature assessing the Prior to beginning this activity, see “CME Information”
on the back page.
risk of concomitant bacterial meningitis with urinary tract infec-
tions and the role for viral testing, specifically herpes simplex This issue is eligible for 4 Infectious Disease CME credits.
virus and enterovirus, are also reviewed.

Editors-in-Chief
Ilene Claudius, MD
Associate Professor; Director,
Process & Quality Improvement
Program, Harbor-UCLA Medical
Center, Torrance, CA
Tim Horeczko, MD, MSCR, FACEP,
FAAP
Associate Professor of Clinical
Emergency Medicine, David Geffen
School of Medicine, UCLA; Core
Faculty and Senior Physician, Los
Angeles County-Harbor-UCLA
Medical Center, Torrance, CA
Editorial Board
Jeffrey R. Avner, MD, FAAP Medicine, Los Angeles, CA
Chairman, Department of
Pediatrics, Professor of Clinical
Pediatrics, Maimonides Children's
Hospital of Brooklyn, Brooklyn, NY
Steven Bin, MD
Associate Clinical Professor, UCSF
School of Medicine; Medical Director,
Pediatric Emergency Medicine, UCSF
Benioff Children's Hospital, San
Francisco, CA
Richard M. Cantor, MD, FAAP, FACEP
Professor of Emergency Medicine
and Pediatrics; Section Chief,
Pediatric Emergency Medicine;
Medical Director, Upstate Poison
Control Center, Golisano Children's
Hospital, Syracuse, NY
Steven Choi, MD, FAAP
Chief Quality Officer and Associate
Dean for Clinical Quality, Yale
Medicine/Yale School of Medicine;
Vice President, Chief Quality Officer, Assistant Professor of Emergency
Yale New Haven Health System,
New Haven, CT
Ari Cohen, MD, FAAP
Chief of Pediatric Emergency
Medicine, Massachusetts General
Hospital; Instructor in Pediatrics,
Harvard Medical School, Boston, MA
Jay D. Fisher, MD, FAAP, FACEP
Clinical Professor of Emergency
Medicine and Pediatrics, University
of Nevada, Las Vegas School of
Medicine, Las Vegas, NV
Marianne Gausche-Hill, MD, FACEP,
FAAP, FAEMS
Medical Director, Los Angeles
County EMS Agency; Professor of
Clinical Emergency Medicine and
Pediatrics, David Geffen School
of Medicine at UCLA; Clinical
Faculty, Harbor-UCLA Medical
Center, Department of Emergency
Michael J. Gerardi, MD, FAAP,
FACEP, President
Associate Professor of Emergency
Medicine, Icahn School of Medicine
at Mount Sinai; Director, Pediatric
Emergency Medicine, Goryeb
Children's Hospital, Morristown
Medical Center, Morristown, NJ
Sandip Godambe, MD, PhD
Chief Quality and Patient Safety Officer,
Professor of Pediatrics, Attending
Physician of Emergency Medicine,
Children's Hospital of The King's
Daughters Health System, Norfolk, VA
Ran D. Goldman, MD
Professor, Department of Pediatrics,
University of British Columbia;
Research Director, Pediatric
Emergency Medicine, BC Children's
Hospital, Vancouver, BC, Canada
Joseph Habboushe, MD, MBA
Medicine, NYU/Langone and
Bellevue Medical Centers, New
York, NY; CEO, MD Aware LLC
Alson S. Inaba, MD, FAAP
Pediatric Emergency Medicine
Specialist, Kapiolani Medical Center
for Women & Children; Associate
Professor of Pediatrics, University
of Hawaii John A. Burns School of
Joshua Nagler, MD, MHPEd
Medicine, Honolulu, HI
Madeline Matar Joseph, MD, FACEP,
FAAP Medical School; Associate Division
Professor of Emergency Medicine
and Pediatrics, Assistant Chair,
Pediatric Emergency Medicine
Quality Improvement, Pediatric
James Naprawa, MD
Emergency Medicine Division,
University of Florida College of
Medicine-Jacksonville,
Jacksonville, FL
Joshua Rocker, MD
Stephanie Kennebeck, MD
Associate Pr ofessor, University of
Cincinnati Department of Pediatrics,
Cincinnati, OH
Anupam Kharbanda, MD, MS
Chief, Critical Care Services
Steven Rogers, MD
Children's Hospitals and Clinics of
Minnesota, Minneapolis, MN
Tommy Y. Kim, MD, FAAP, FACEP
Associate Professor of Pediatric
Emergency Medicine, University of
California Riverside School of Medicine,
Riverside Community Hospital,
Department of Emergency Medicine,
Riverside, CA
Melissa Langhan, MD, MHS
Associate Professor of Pediatrics and
Emergency Medicine; Fellowship
Director, Director of Education,
Pediatric Emergency Medicine, Yale
University School of Medicine, New
Haven, CT
Robert Luten, MD
Professor, Pediatrics and
Emergency Medicine, University of
Florida, Jacksonville, FL
Garth Meckler, MD, MSHS
Associate Professor of Pediatrics,
University of British Columbia;
Division Head, Pediatric Emergency
Medicine, BC Children's Hospital,
Vancouver, BC, Canada
Assistant Professor of Pediatrics
and Emergency Medicine, Harvard
Chief and Fellowship Director, Division
of Emergency Medicine, Boston
Children’s Hospital, Boston, MA
Attending Physician, Emergency
Department USCF Benioff
Children's Hospital, Oakland, CA
Associate Chief and Medical
Director, Assistant Professor of
Pediatrics and Emergency Medicine,
Cohen Children's Medical Center of
New York, New Hyde Park, NY
Associate Professor, University of
Connecticut School of Medicine,
Attending Emergency Medicine
Physician, Connecticut Children's
Medical Center, Hartford, CT
Christopher Strother, MD
Associate Professor, Emergency
Medicine, Pediatrics, and Medical
Education; Director, Pediatric
Emergency Medicine; Director,
Simulation; Icahn School of Medicine
at Mount Sinai, New York, NY
Adam E. Vella, MD, FAAP
Director of Quality Assurance,
Pediatric Emergency Medicine,
New York-Presbyterian,
Weill Cornell, New York, NY
David M. Walker, MD, FACEP, FAAP
Chief, Pediatric Emergency
Medicine, Department of Pediatrics,
Joseph M. Sanzari Children's
Hospital, Hackensack University
Medical Center, Hackensack, NJ
Vincent J. Wang, MD, MHA
Professor of Pediatrics and
Emergency Medicine; Division
Chief, Pediatric Emergency
Medicine, UT Southwestern
Medical Center; Director of
Emergency Services, Children's
Health, Dallas, TX
International Editor
Lara Zibners, MD, FAAP, FACEP,
MMed
Honorary Consultant, Paediatric
Emergency Medicine, St. Mary's
Hospital Imperial College Trust,
London, UK; Nonclinical Instructor
of Emergency Medicine, Icahn
School of Medicine at Mount Sinai,
New York, NY
Pharmacology Editor
Aimee Mishler, PharmD, BCPS
Emergency Medicine Pharmacist,
Program Director – PGY2
Emergency Medicine Pharmacy
Residency, Maricopa Medical
Center, Phoenix, AZ
CME Editor
Brian S. Skrainka, MD, FACEP, FAAP
Clinical Assistant Professor of
Emergency Medicine, Oklahoma
State University Center for Health
Sciences, The Children’s Hospital at
Saint Francis, Tulsa, OK
APP Liaison
Brittany M. Newberry, PhD, MSN,
MPH, APRN, ENP-BC, FNP-BC
Faculty, Emory University School
of Nursing, Emergency Nurse
Practitioner Program, Atlanta, GA;
Nurse Practitioner, Fannin Regional
Hospital Emergency Department,
Blue Ridge, GA
Case Presentations
A 20-day-old boy presents to the ED in August for evalu-
ation of a rectal temperature of 38˚C (100.4˚F). The baby
was born by spontaneous vaginal delivery at 39 weeks’
gestational age. The mother’s prenatal labs were normal,
including negative screening for group B Streptococ-
cus. The patient felt warm to the parents today but has
otherwise been asymptomatic. The baby has been eating 3
ounces every 4 hours and making an appropriate amount
of wet diapers. The physical examination is normal,
including a flat anterior fontanel and good hydration.
When you explain to the mother that the baby will need
to undergo the full sepsis workup, including lumbar
puncture, she starts asking you questions: Is all of that
testing necessary? Since her baby appears well other than
the fever, what is the probability that he has a serious
infection? Can other infections besides bacterial infections
cause a fever, and does the baby need testing to identify
those infections? After the testing is completed, will the
baby need to be admitted to the hospital?
A 40-day-old girl presents to the ED in January for
evaluation of a rectal temperature of 38˚C (100.4˚F). The
history and physical examination are similar to the infant
you saw in August, except that she has nasal discharge and
a cough. Which risk stratification algorithm should you use
for this infant? Would your workup change if a respiratory
swab was positive for respiratory syncytial virus?
Your next patient is a 50-day-old girl who also
presents to the ED with a rectal temperature of 38˚C
(100.4˚F). The history and physical examination are simi-
lar to the patient you just saw, except this patient does not
have nasal discharge or a cough. You send routine blood
and urine tests, and the urinalysis results are positive
for leukocyte esterase, > 20 white blood cells/high-power
field, and many bacteria. Does this baby require a lumbar
puncture? What is the likelihood of concomitant bacterial
meningitis with a urinary tract infection?
Introduction
Due to an immature immune system and pathogens
often specific to the age group, the young infant (gen-
erally aged < 60-90 days, depending on the specific
study or review) is at high risk for serious bacterial
infections (SBIs); in particular, urinary tract infection
(UTI), bacteremia, and bacterial meningitis. Conse-
quently, the febrile young infant with a rectal tem-
perature ≥ 38°C (100.4°F) is commonly encountered
in the emergency department (ED).1 The incidence of
SBI in febrile infants aged < 90 days is 8% to 12.5%,2
and it is nearly 20% in neonates (aged ≤ 28 days).3 The
incidence of potentially life-threatening bacteremia
and/or bacterial meningitis (ie, invasive bacterial
infection [IBI]) is approximately 2%.4
Due to their lack of social responsiveness (eg,
social smile) and verbal cues, even well-appearing
febrile young infants may harbor an SBI, in contrast
Copyright © 2019 EB Medicine. All rights reserved. 2
to well-appearing febrile older infants and children
who are at lower risk for IBI.5 Multiple studies have
demonstrated that both observation scales and
clinician suspicion for SBI are poorly predictive of
bacterial infection in febrile infants.6,7 Additionally,
bacterial meningitis is the most common diagnosis
involved in pediatric medical malpractice claims in
the emergency department (ED).8
Over 2 decades ago, several risk stratification
criteria were created to identify febrile young infants
at low risk for SBI, and the criteria have been utilized
to potentially avoid hospitalization of certain low-risk
patients.9-11 More recently, newer risk stratification al-
gorithms that incorporate biomarkers such as procal-
citonin (PCT) and C-reactive protein (CRP) have been
developed and validated in febrile infants.12,13
In addition to bacterial disease, the febrile infant
aged ≤ 28 days is also at risk for neonatal herpes sim-
plex virus (HSV) infection, a rare but life-threatening
disease that is controversial in its workup and man-
agement.14 Other current controversies include the
utility of the full sepsis workup in febrile young infants
with identifiable sources of fever such as respiratory
syncytial virus (RSV)15 and bronchiolitis, and the need
for cerebrospinal fluid (CSF) testing in infants with
presumptive UTI but who are otherwise at low risk
for bacteremia and/or bacterial meningitis. Parents
understandably question why invasive testing is rec-
ommended for their febrile baby, and the emergency
clinician needs to clearly communicate the rationale
behind the management of patients in this high-risk
age group.
This issue of Pediatric Emergency Medicine Practice
reviews the most up-to-date evidence for evaluation
and management of febrile young infants, including
the newer risk stratification algorithms, the need for
routine versus selective CSF testing, the role of viral
testing, and diagnostic and therapeutic challenges.
Critical Appraisal of the Literature
A literature search was performed in the PubMed
database using multiple combinations of the search
terms: febrile young infant, febrile infant, fever, low risk
criteria, neonate, serious bacterial infection, invasive bacte-
rial infection, neonatal herpes simplex virus, and infant
less than 90 days old. In addition to reviewing articles
included in the original version of this review pub-
lished in 2013, all relevant articles published in or after
2013 were reviewed. Over 140 articles were reviewed,
109 of which were selected for inclusion. Emphasis
was placed on reviewing the most important historical
evidence, as well as recent studies with evidence that
has been incorporated into clinical practice.
The body of research on the evaluation and
management of febrile young infants is extensive
and growing, but there is a paucity of randomized
controlled trials, and there is no universally accepted
Reprints: www.ebmedicine.net/pempissues
clinical practice guideline. Additionally, IBIs (partic-
ularly bacterial meningitis) are rare in febrile young
infants, so there are limited data on the precision of
algorithms (eg, Rochester, Boston, and Philadelphia
criteria) for the risk stratification of infants with an
IBI. There are also limited data on the risk of adverse
outcomes among infants who experience a delay
in diagnosis of IBI. The Step-by-Step approach is a
recently validated risk stratification algorithm, but
this approach needs to be evaluated in certain popu-
lations of febrile young infants, such as infants with
bronchiolitis. Additionally, the statistically derived
and newly published Pediatric Emergency Care Ap-
plied Research Network (PECARN) prediction rule
should, ideally, be further validated.
Etiology and Pathophysiology
The young infant has an immature immune sys-
tem,16 and the incidence of SBI in this age group is
approximately 10%.2 SBIs in this age group include:
UTI/pyelonephritis, bacteremia/sepsis, bacterial
meningitis, pneumonia, cellulitis, and bone and joint
infections. (See Table 1.) While investigations for
pneumonia, cellulitis, and bone and joint infections
are performed on the basis of signs and symptoms,
UTI, bacteremia, and bacterial meningitis are often
occult at onset, with fever as the only symptom.
UTI is the most common SBI identified in this age
group,3,17,18 with an incidence of up to 13.6% in
febrile infants.18 The incidence of bacteremia and
bacterial meningitis in febrile infants are approxi-
mately 2% and 0.4%, respectively, and the incidence
is higher in neonates (3% and 1%, respectively).4,19
Since the implementation of peripartum screen-
ing and prophylaxis for Group B Streptococcus (GBS)
and widespread childhood vaccinations that pro-
Table 1. Definitions Associated With Febrile
Young Infants
• Neonate: aged ≤ 28 days
• Young infant: aged < 60-90 days (depending on the study or review)
• Fever: rectal temperature ≥ 38°C (100.4°F)
• Serious bacterial infection:
l
Bacterial meningitis (invasive bacterial infection)
l
Bacteremia/sepsis (invasive bacterial infection)
Urinary tract infection/pyelonephritis
l
l
Pneumonia (focal consolidation consistent with a bacterial
process)
l
Bacterial enteritis
l
Cellulitis
l
Abscess
l
Osteomyelitis
l
Septic arthritis
Adapted from: Paul L. Aronson. Evaluation of the Febrile Young Infant:
An Update. Pediatric Emergency Medicine Practice. 2013;10(2):1-20.
© 2019 EB Medicine.
July 2019 • www.ebmedicine.net
vide herd immunity, the epidemiology of SBIs and
IBIs has changed in recent years.20,21 Most notably,
the incidence of IBI is now as low as 1% to 2% of
febrile infants aged ≤ 90 days.4,19,21,22 The young
infant is susceptible to both perinatally acquired
and community-acquired infections including GBS,
Escherichia coli and other gram-negative infections,
Enterococcus spp, and Staphylococcus aureus.3,4,23-25 E
coli is the most common infection identified in febrile
young infants.3,4,24 The neonate is also susceptible
to infection with Listeria monocytogenes, though this
infection is rare.4,24,25 Neonatal HSV is also a rare but
life-threatening infection in this age group.14
Differential Diagnosis
The well-appearing febrile young infant should
be evaluated for UTI/pyelonephritis, bacteremia/
sepsis, and bacterial meningitis. Viral infections are
the most common cause of fever in this age group,
though they are usually benign. Enterovirus is a
common viral cause of fever in the young infant,26
especially in the summer and early fall months. RSV
and other upper respiratory tract viral pathogens are
common in the winter. While uncommon, perinatal-
ly acquired HSV is a cause of fever in neonates, es-
pecially those aged ≤ 21 days.27,28 In addition to SBI
and neonatal HSV, consider noninfectious etiologies
in infants who are ill-appearing or cardiovascularly
compromised. (See Table 2, page 4.)
Prehospital Care
While emergency medical services (EMS) providers
may be contacted to transport well-appearing febrile
young infants to the ED, they should be prepared to
provide basic and advanced life support to the sick
infant with sepsis. In addition to obtaining intrave-
nous (IV) access and providing hemodynamic sup-
port with isotonic fluids in boluses of 10 to 20 mL/
kg (10 mL/kg if a cardiac pathology is suspected),29
early identification and treatment of hypoglycemia
should also be undertaken.29 EMS providers should
also recognize other potential etiologies of shock in
the young infant and be prepared to provide respira-
tory and cardiovascular support.
Emergency Department Evaluation
History
In the well-appearing febrile young infant, ask the
parent for the exact temperature that was obtained
and the method by which the temperature was
measured (eg, rectal, axillary, ear), as tympanic, axil-
lary, and forehead temperatures may be inaccurate
in infants.30 Inquire about associated viral symptoms
such as coryza, feeding (poor or slow), urine and
stool output history, and fussiness or lethargy. The
3 Copyright © 2019 EB Medicine. All rights reserved.
patient’s detailed birth history should be obtained,
including gestational age at birth, as premature
infants are at higher risk for bacterial infection,
especially E coli.31 The mother’s prenatal laboratory
studies, particularly the results of screening for GBS
and HSV, should be included in the birth history.
If the mother is GBS-positive, inquire whether she
received appropriate antenatal antibiotic therapy to
reduce GBS transmission to the newborn.32 While
a mother with recurrent HSV may transmit the
infection to her newborn, the risk is much lower due
to passage of protective IgG antibodies across the
placenta. The highest risk for perinatally acquired
HSV occurs when babies are born to mothers with
a first-episode primary HSV infection at the time of
delivery.33 The method of delivery and history of
maternal fever at delivery should also be obtained,
as cesarean delivery reduces the rate of neonatal
HSV,33 and maternal chorioamnionitis is associ-
Table 2. Differential Diagnosis of the Febrile
Young Infant
Well-Appearing Febrile Young Infants
• Serious bacterial infections
l
Urinary tract infection
l
Bacteremia
l
Bacterial meningitis
l
Pneumonia
l
Soft-tissue infections
l
Bacterial enteritis
l
Bone and joint infections
• Viral infections
Enterovirus infection
l
ated with neonatal bacterial infection.34 The infant’s
postnatal history should include receipt of antibiot-
ics while hospitalized in the newborn nursery or a
prolonged stay in the nursery or neonatal intensive
care unit.
For the ill-appearing infant, a similar history
should be obtained, with the addition of any family
history of early, unexplained deaths or metabolic
disease that might indicate cardiac disease or inborn
errors of metabolism.
Physical Examination
Although physical examination findings are often
used to differentiate well- and ill-appearing infants,
these findings are unreliable in infants aged < 60
days. Important physical examination findings in
the febrile young infant include whether the baby
is difficult to arouse or console, as these may be
signs of sepsis or bacterial meningitis. The anterior
fontanel should be palpated for fullness or elevation
that can be seen with meningitis. The skin should be
evaluated for vesicles (though up to 40% of neo-
nates with severe types of HSV will not have skin
vesicles).35 Jaundice may also be noted in infants
with HSV or bacterial sepsis. Examine the ears for
signs of acute otitis media. Tachypnea, accessory
muscle use, crackles, or wheezing may be observed
in patients with bronchiolitis or bacterial pneumo-
nia. In the ill-appearing infant, signs of right- or
left-sided obstructive congenital heart disease may
include respiratory distress, murmur, and weak or
absent pulses (or weak femoral compared to brachial
pulses). Nonetheless, there are no symptoms that
can easily differentiate infants with sepsis versus
congenital heart disease.36

l
Upper respiratory tract infection

Bronchiolitis
Diagnostic Studies
l

l
Viral gastroenteritis

l
Neonatal herpes simplex virus infection

The critical principles in approaching the diagnos-

Ill-Appearing Febrile Young Infants tic workup of the febrile young infant are that the
• Infectious causes incidence of SBI is high2,3 and that a well appearance
l
Serious bacterial infections
does not lower the pretest probability of an SBI sub-
l
Neonatal herpes simplex virus infection
stantially enough to defer testing.6 These principles
l
Enterovirus infection
provide the rationale for performance of the full sep-
l
Respiratory syncytial virus infection
sis evaluation (see Table 3, page 5) in this age group.
• Cardiac causes* The specific evaluation of the febrile young infant
l
Ductal-dependent left-sided obstructive lesions
is dependent on the age and stability of the patient
l
Ductal-dependent right-sided obstructive lesions
and which low-risk criteria are utilized. Histori-
• Metabolic causes* cally, the risk stratification criteria (eg, Rochester,
l
Inborn errors of metabolism

Philadelphia, Boston) have included urinalysis,
l
Congenital adrenal hyperplasia

peripheral white blood cell (WBC) count with dif-
• Gastrointestinal causes* ferential, and CSF WBC counts for risk stratification
l
Malrotation with volvulus

(except for the Rochester criteria, which does not
include CSF testing).37 However, more recent al-
*Patients with these conditions are ill-appearing but often not febrile. gorithms have replaced peripheral WBC and band
count with other biomarkers to increase sensitivity
Adapted from: Paul L. Aronson. Evaluation of the Febrile Young Infant:
and/or specificity.12,13
An Update. Pediatric Emergency Medicine Practice. 2013;10(2):1-20.
© 2019 EB Medicine.

Copyright © 2019 EB Medicine. All rights reserved. 4 Reprints: www.ebmedicine.net/pempissues

Risk Stratification
Ill-Appearing Febrile Infants
All ill-appearing infants should receive a full evalua-
tion for sepsis, including CSF testing. If the infant is
too unstable for lumbar puncture, fluid resuscitation
and broad-spectrum IV antibiotics should be admin-
istered and CSF testing deferred until the infant is
stable. The rationale is that the prevalence of IBI is
higher among ill-appearing infants.6
Well-Appearing Febrile Infants
Among well-appearing febrile infants, neonates
have the highest prevalence of SBI and IBI and the
least reliable clinical examination. These infants
should undergo a full sepsis evaluation, including
CSF testing.37,38 While the Rochester criteria and the
recently published PECARN prediction rule13 do not
include routine CSF testing in this age group (see
Table 4, page 6), infants classified as low-risk by any
criteria may still have bacterial meningitis,39-41 so
CSF testing is generally recommended for all infants
aged ≤ 28 days. Consideration should be given to
testing for HSV in the neonate aged ≤ 21 days,28 even
in the absence of vesicles or maternal history of HSV
infection.35 See the “Neonatal Herpes Simplex Virus
Infection” section on page 14 for testing and treat-
ment strategies for neonatal HSV.
The well-appearing febrile infant aged 29 to 56
days requires a more thoughtful approach to the
diagnostic workup. The historical low-risk crite-
ria (ie, Rochester, Philadelphia, and Boston) use a
combination of past medical history, clinical appear-
ance, physical examination, urinalysis, and complete
blood cell count (CBC) with differential, with or
without CSF testing for risk stratification.37 More
recently, the “Step-by-Step” approach, a CRP- and
PCT-based algorithm that does not include CSF
testing for risk stratification, has been validated
in febrile infants.12 The PECARN prediction rule,
another PCT-based algorithm that does not include
CSF testing, was also recently derived and validated
Table 3. Components of a Full Sepsis Workup
Full Sepsis Workup
• Complete blood cell count +/- C-reactive protein and procalcitonin
(if available)
• Blood culture
• Urinalysis
• Urine culture
• Serum glucose
• Liver enzymes
• Cerebrospinal fluid cell count, glucose, protein
• Cerebrospinal fluid culture
• Stool culture, as indicated
Adapted from: Paul L. Aronson. Evaluation of the Febrile Young Infant:
An Update. Pediatric Emergency Medicine Practice. 2013;10(2):1-20.
© 2019 EB Medicine.
July 2019 • www.ebmedicine.net
in a multicenter prospective cohort.13 All of these
algorithms have a sensitivity for identification of
infants with SBI and IBI of > 90%.12,13,37
A reasonable initial approach would be to
acquire a CBC with differential, urinalysis, CRP and
PCT (if available), and urine and blood cultures.
Further testing (eg, chest x-ray, stool studies) can be
considered if clinically indicated.
Cerebrospinal Fluid Testing
Historically, many infants aged 29 to 56 days would
have undergone a full evaluation for sepsis, includ-
ing CSF testing.9-11 However, given the low preva-
lence of bacterial meningitis in febrile infants aged
> 28 days39,41,42 and the potential risks of routine
lumbar puncture in this age group (eg, traumatic
lumbar puncture resulting in unnecessary hospital-
ization, and parents’ stress) without clear benefit,43-45
many clinicians have adopted a more selective ap-
proach to CSF testing.46 Recent retrospective studies
found that, without application of CSF testing, no
bacterial meningitis cases would have been missed
among febrile young infants classified as low-risk by
the Philadelphia criteria.41,42 The level of comfort the
emergency clinician has in determining well-appear-
ance in a young infant is of paramount importance
in choosing not to perform CSF testing. If the emer-
gency clinician has had limited exposure to febrile
infants or is unsure whether the infant is well-ap-
pearing, CSF testing should be strongly considered
regardless of the results of other laboratory tests.
Of note, the low-risk criteria have historically used
a definition of < 10 WBC/HPF (high-power field)
or < 10 WBC/mcL on enhanced urinalysis to define
an abnormal urinalysis.18,37 However, more recently,
using the presence of either leukocyte esterase or ni-
trites, and/or > 5 WBC/HPF to define an abnormal
urinalysis should be used, as it has > 90% sensitivity
and specificity for UTI in febrile infants.47
Febrile Infants Aged 57 to 89 Days
Febrile infants aged 57 to 89 days may be managed
similar to older infants because the prevalence of
IBI is lower in this age group.48 Additionally, many
patients in this age group will have received their
2-month vaccinations. Nevertheless, many experts
recommend that these infants undergo, at a mini-
mum, testing with a urinalysis and urine culture
when no source for infection is present on exami-
nation.48 However, there are fewer data to guide
blood and CSF testing. One management strategy
is to apply the Step-by-Step approach, which was
developed and validated in infants aged < 90 days
(see the “Newer Biomarkers” section on page 7 for
more information).12 In this age group, CSF testing
is generally limited to ill-appearing infants, or those
with significantly abnormal laboratory parameters
from the blood.
5 Copyright © 2019 EB Medicine. All rights reserved.
Table 4. Most Common Risk Stratification Criteria for Management of Febrile Young Infants
Prediction Rule Patient History and Physical Laboratory Parameters Management for Management for Low-
Age Examination Findings (Defines Low Risk) Intermediate-Risk or Risk Patients
High-Risk Patients

Boston Criteria9 28-90 days • Well-appearing
1992 • No antibiotics in
preceding 48 hours
• No immunizations in
preceding 48 hours
• No focal infection
Philadelphia 29-56 days • Well-appearing
Criteria10,52 • No focal infection
1993
Rochester 0-60 days • Well-appearing
Criteria11 • Full-term
1994 • Normal prenatal and
postnatal historiesa
• No postnatal antibiotics
• No focal infection
Step-by-Step12 0-90 days • Well-appearing
2016 • Aged > 21 days
• Normal pediatric
assessment triangle
• No clear source of
fever
• WBC: < 20,000 cells/mcL Hospitalize and • Discharge home, if
• UA: < 10 WBC/HPF administer empiric caregiver available by
• CSF: < 10 WBC/mcL antibiotics telephone
• Chest radiograph: no • Administer empiric IM
infiltrateb ceftriaxone 50 mg/kg
• Return for 24-hour
follow-up for second
dose IM ceftriaxone
• WBC: 5000-15,000 cells/ Hospitalize and • Discharge home, if
mcLc administer empiric patient lives within 30
• Band:total neutrophil (I:T) antibiotics minutes of the hospital
ratio: < 0.2 • 24-hour follow-up
• UA: < 10 WBC/HPF required
• Urine Gram stain: negative • No empiric antibiotics
• CSF: < 8 WBC/mcL
(modified Philadelphia
criteria does not include
routine CSF testing)
• CSF Gram stain: negativec
• Chest x-ray: no infiltrateb
• Stool: no blood, few or no
WBC on smearb
• WBC: 5000-15,000 cells/ Hospitalize, perform • Discharge home
mcL LP, and administer • 24-hour follow-up
• Absolute band count: empiric antibiotics required
≤ 1500/mcL • No empiric antibiotics
• UA: ≤ 10 WBC/HPF
• Stool: ≤ 5 WBC/HPF on
smearb
*No CSF required for risk
stratification
• No leukocyturia Hospitalize, perform • Discharge home
• PCT: < 0.5 ng/mL LP, and administer • 24-hour follow-up
• CRP: ≤ 20 mg/L empiric antibiotics required
• ANC: ≤ 10,000 cells/mcL • No empiric antibiotics
*No CSF required for risk
stratification

PECARN13 0-60 days • Gestational age > 36 • UA: negative leukocyte Hospitalize, perform • Not defined as rule
2019 weeks esterase, negative nitrites, LP, and administer recently published, but
• No pre-existing and ≤ 5 WBC/HPF empiric antibiotics consider the following:
medical conditions or • ANC: ≤ 4090 cells/mcLd l
Discharge home

indwelling catheters • PCT: ≤ 1.71 ng/mLd l

24-hour follow-up

• No antibiotics within *No CSF required for risk required

48 hours stratification l
No empiric

• No soft-tissue infection antibiotics

• Not critically ill

a
Normal prenatal and postnatal histories include being full-term, having received no antibiotics, having no unexplained hyperbilirubinemia, no prior
hospitalizations (including no prolonged stay in the newborn nursery), and no underlying chronic medical condition.
b
Obtained based on symptoms.
c
Original Philadelphia criteria used WBC < 15,000/mcL to define low-risk but this has been modified to WBC 5000-15,000/mcL.
d
Results similar when using ANC ≤ 4000/mcL and/or PCT ≤ 0.5 ng/mL.

Abbreviations: ANC, absolute neutrophil count; CRP, C-reactive protein; CSF, cerebrospinal fluid; HPF, high-power field; IM, intramuscular; IV,
intravenous; LP, lumbar puncture; PCT, procalcitonin; PECARN, Pediatric Emergency Care Applied Research Network; UA, urinalysis; WBC, white
blood cell.
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Copyright © 2019 EB Medicine. All rights reserved. 6 Reprints: www.ebmedicine.net/pempissues

Newer Biomarkers
Because peripheral WBC count is poorly predictive of
IBI in febrile infants,49 emerging studies have focused
on the utility of other biomarkers (eg, CRP, PCT, and
RNA biosignatures) to provide newer tools to assist
in the risk stratification of febrile infants. However,
multiple studies have demonstrated that neither CRP
nor PCT should be used alone to risk-stratify febrile
infants.50 While a 2016 prospective study reported
that a PCT level of 0.3 ng/mL had a sensitivity of
90% for IBI, there were only 21 infants with IBI in the
study, and the precision of this estimate was poor.51
Newer Risk-Stratification Algorithms
The Step-by-Step approach is a newer risk stratifica-
tion algorithm that does not include routine CSF
testing but uses patient age, clinical appearance,
urine dipstick, PCT, CRP, and absolute neutrophil
count (ANC) in a stepwise fashion to determine
which infants are at high, intermediate, and low risk
for SBI and IBI. (See Table 4, page 6.) The Step-by-
Step approach was prospectively validated in a
multicenter cohort of febrile infants that included 87
infants with IBI, and it had a sensitivity of 92% for
the identification of IBI.12
The PECARN prediction rule, which includes
urinalysis, ANC, and PCT without a lower age
cut-off, was derived using recursive partitioning
analysis and was validated prospectively. For the
identification of IBI, the PECARN prediction rule
had a sensitivity of 96.7% and a specificity of 61.5%
(which is higher than the specificity of previously
published algorithms), though the study included
fewer infants with IBI (n = 30) compared with the
validation study of the Step-by-Step approach.13
An MDCalc online tool for the
Rochester criteria is available at:
www.mdcalc.com/rochester-criteria-
febrile-infants
An MDCalc online tool for the Step-
by-Step approach is available at:
www.mdcalc.com/step-step-ap-
proach-febrile-infants
An MDCalc online tool for the PECARN
prediction rule is available at:
www.mdcalc.com/pecarn-rule-low-
risk-febrile-infants
Situation-Specific Testing
Testing for Enterovirus and Parechovirus
CSF enterovirus testing should be considered in
febrile infants aged ≤ 60 days who have undergone
CSF testing and are being admitted to the hospital.
July 2019 • www.ebmedicine.net
In particular, infants who have CSF pleocytosis
should undergo enterovirus testing, especially dur-
ing the summer and early fall months, which is peak
enterovirus season. A positive test is associated with
a shorter length of stay and duration of antibiotic
use in hospitalized febrile infants.26,53-55 The reason
for the shorter length of stay and duration of antibi-
otic use is that enterovirus polymerase chain reac-
tion (PCR) returns results within 24 hours in most
laboratories, which is before final bacterial culture
results can be considered definitively negative (at 36-
48 hours). In the absence of concomitant multiorgan
disease, enterovirus meningitis typically portends
a good prognosis, so those infants are usually able
to be safely discharged home if they are clinically
well.56 An enterovirus CSF PCR test may be positive
in the absence of CSF pleocytosis, so testing should
be considered for all febrile infants who are hospital-
ized during peak enterovirus season.55,57
At some hospitals, parechovirus PCR can be run
simultaneously with enterovirus PCR,58 and while
data are more limited, parechovirus testing can also
be considered for febrile infants during the summer
and fall.59
Testing for Respiratory Viruses
Rapid antigen testing and/or PCR for respiratory
viruses should be sent for all febrile infants with
rhinorrhea, nasal congestion, or bronchiolitis, as
infants who are positive for certain viruses may have
a lower prevalence of IBI. Levine et al prospectively
enrolled 1248 febrile infants aged ≤ 60 days, 22% of
which were positive for RSV. RSV-negative patients
had an SBI rate of 12.5%; RSV-positive patients had
an SBI rate of 7.0%. In the 29- to 60-day-old age
group, RSV-positive patients had a lower rate of SBI
(5.5% vs 11.7%), and all infections were UTIs. Rates
of bacteremia and meningitis could not be compared
by RSV status in this age group, due to small num-
bers. Neonates who had RSV infection, however,
had a 10.1% rate of SBI, including 3 patients with
bacteremia (but no meningitis), and the rate of SBI
was not significantly different from RSV-negative
neonates.60 A 2016 meta-analysis evaluated the
prevalence of SBI in 789 febrile neonates who under-
went full blood, urine, and CSF evaluation and who
had nasopharyngeal aspirate antigen testing for RSV.
Notably, the rate of SBI was 11.5% among infants
with RSV and 15.3% in patients who tested negative
for RSV, which was not significantly different.61
Using the same cohort as Levine et al, Krief et
al found that febrile infants aged ≤ 60 days who
were infected with influenza virus had a lower rate
of SBI (2.5%), and that all of the infections were
UTI. However, for both age groups (≤ 28 days and
29-60 days), the numbers of infants with bacteremia
and/or bacterial meningitis were too small to allow
the incidence to be compared.62
7 Copyright © 2019 EB Medicine. All rights reserved.
 Febrile infants aged < 90 days who are rhino-
virus-positive have a higher rate of SBI compared
with infants who are positive for other respiratory
viruses, and the prevalence of UTI is similar to
infants with negative viral testing. Furthermore, the
prevalence of IBI is not significantly different among
rhinovirus-positive and viral-negative neonates,
though rhinovirus-positive infants aged > 28 days
have a modestly lower rate of IBI.63 A recent pro-
spective study similarly reported a lower, but not
negligible, prevalence of SBI and IBI among febrile
infants aged ≤ 60 days who had documented viral
infections.64 A systematic review of 11 studies that
reported the rate of SBI in febrile infants aged < 90
days with clinical bronchiolitis or RSV found a 3.3%
incidence of UTI (95% confidence interval [CI], 1.9%-
5.7%).65 Notably, 7 of the 11 studies included infants
aged up to 90 days; therefore, the risk of UTI should
be applied to the 61- to 89-day-old age group with
bronchiolitis as well. There were no cases of menin-
gitis in any of the studies.64 A more recent meta-anal-
ysis using both positive urine culture and urinalysis
for diagnosis of UTI demonstrated a 0.8% rate of UTI
in infants with bronchiolitis, with similar results in a
sensitivity analysis of infants aged < 90 days.66
There is no standard of care for febrile infants
aged 29 to 60 days who have bronchiolitis. Given the
high incidence of UTI even in children with bronchi-
olitis, a urinalysis and urine culture should be per-
formed, and strong consideration should be given to
obtaining a blood culture as well as a CBC, or CRP,
ANC, and PCT, given the low but not negligible
prevalence of contaminant bacteremia.64
One approach, published in 2012, is to perform
urine and blood testing in RSV-positive infants
aged > 28 days who have a temperature > 38.5°C
(101.3°F), but to forgo blood testing for otherwise
well RSV-positive infants with a temperature
≤ 38.5°C.67 Although the prevalence of bacterial
meningitis in infants with bronchiolitis and/or
documented viral infection is very low,60,62,64,65 if the
infant is ill-appearing or has abnormal laboratory
parameters on blood testing, or is otherwise at high
risk (eg, a history of prematurity or a chronic medi-
cal condition), performance of a lumbar puncture
should be strongly considered. Febrile infants who
are rhinovirus-positive, without other documented
viral infection, should be evaluated and managed
similarly to febrile infants without a viral source.63
Summarizing the literature, all febrile infants
aged < 90 days should have a urinalysis and urine
culture considered, even those with clinical bronchi-
olitis or laboratory-proven RSV or influenza. Given
the high incidence of SBI in infants aged ≤ 28 days
(regardless of viral positivity, including an apprecia-
ble incidence of IBI), the full sepsis workup, including
CSF testing, should be performed in this age group
unless the infant’s respiratory distress prohibits the
Copyright © 2019 EB Medicine. All rights reserved. 8
performance of a lumbar puncture. The PECARN
network has opened the discussion of more selec-
tive CSF testing for infants aged ≤ 28 days, but many
emergency clinicians will await further data before
accepting this paradigm change.
Other Diagnostic Testing
Imaging studies should be performed based on
symptoms. In one study, none of the 361 febrile
infants aged < 12 weeks without respiratory signs
or symptoms had an abnormal chest x-ray.68 Ad-
ditionally, another study found that only 2 of 148
asymptomatic infants had an abnormal chest x-ray.69
Therefore, routine chest radiography in the febrile
young infant is not recommended unless signs or
symptoms of pneumonia are present. Stool studies
such as culture and fecal leukocytes for bacterial gas-
troenteritis should also be obtained based on symp-
toms (ie, blood or mucus in the stool).10,11
There is less evidence for the diagnostic workup
when other sources of infection are present. The guid-
ing principle should be that the febrile young infant is
a high-risk patient. Focal infections such as cellulitis,
abscess, and osteomyelitis often require a full sepsis
workup in a febrile infant, including evaluation for
bacteremia and meningitis. However, in some cases,
lumbar puncture may be deferred, depending on the
infant’s age, clinical appearance, and specific focal
infection.23,70 Two studies evaluated the risk of SBI in
young infants with acute otitis media, and reported
SBI rates of 6.2% and 8.8%, including 1 patient with
bacteremia.71,72 While there were no cases of meningi-
tis, the numbers were small in these studies71,72 and,
given this limited data, performing the full sepsis
workup is a reasonable approach for managing a
febrile infant aged ≤ 56 days with acute otitis media.
Application of Risk Stratification Criteria
and Treatment
Application of Risk Stratification Criteria
Prior to the 1980s, most febrile infants aged < 60 to 90
days who were being treated in academic medical cen-
ters would routinely undergo the full sepsis workup,
including CSF testing, and would be hospitalized for
48 hours pending bacterial culture results. Beginning in
the mid-1980s with the Rochester criteria,73 risk stratifi-
cation criteria were developed to identify febrile infants
who were at low risk for SBI who may be discharged
from the ED prior to availability of bacterial culture
results, thereby avoiding unnecessary hospitalization
and antibiotic exposure. The risk stratification criteria
algorithms all use varying combinations of patient age,
past medical history, clinical appearance, urine, and
blood, with or without CSF testing to classify infants as
being at low risk versus high risk for SBI. (See Table 4,
page 6.) Historically, the most commonly used criteria
are the Rochester, Philadelphia, and Boston criteria,
Reprints: www.ebmedicine.net/pempissues
though more recently, the Step-by-Step approach has
been validated and was shown to have a sensitivity of
92% and a negative predictive value of 99.3% for the
identification of IBI in febrile infants, similar to that of
the modified Philadelphia criteria, but higher than that
of the Rochester criteria.12,37 Additionally, the newly
published PECARN prediction rule also has high sensi-
tivity for identification of SBI (97.7%) and IBI (96.7%).13
Febrile Infants Aged ≤ 28 Days
Although the risk stratification algorithms vary in
their age cutoffs, most recommend that neonates
should have the full sepsis workup and be hospital-
ized and treated with empiric antibiotic therapy.74
The rationale for this practice is that the prevalence
of IBI is higher in this age group4 and multiple stud-
ies have demonstrated a diminished performance of
the low-risk criteria in neonates, including “missed”
cases of bacteremia and bacterial meningitis.3,39-41 In
the validation study of the Step-by-Step approach, 4
infants aged between 22 and 28 days with IBI were
classified as low risk.12
Febrile Infants Aged > 28 Days
If the infant aged > 28 days is ill-appearing, has a
high-risk past medical history (eg, prematurity), has
a focal infection, or the laboratory studies are abnor-
mal, the patient should be hospitalized and receive
empiric antibiotic therapy pending bacterial culture
results. If the low-risk criteria are met, the infant can
be discharged home without empiric antibiotics,
provided that the infant lives within a reasonable
distance of the hospital and 24-hour follow-up can
be arranged. If follow-up cannot be established,
consideration should be given to hospitalization
with or without empiric antibiotic therapy. Low-risk
febrile infants can be discharged home without CSF
testing and without empiric antibiotics, according to
the Rochester criteria, modified Philadelphia crite-
ria, and Step-by-Step approach, as well as the new
PECARN prediction rule. In the study from which
the Boston criteria were derived, patients were dis-
charged with a dose of intramuscular (IM) ceftriax-
one 50 mg/kg; however, all infants in this study un-
derwent lumbar puncture. In general, patients with
an unclear source of infection and no CSF obtained
should not receive empiric antibiotics, to prevent dif-
ficulty in diagnosing meningitis later on.
All of the criteria were prospectively developed
and validated, and each has high sensitivity and
negative predictive value for identification of SBI.9-13,75
Given its recent prospective validation12 and concerns
regarding the reliability of band counts,76 we recom-
mend the Step-by-Step approach for infants aged > 28
days if PCT testing is available. The PECARN predic-
tion rule is also an option in this age group.13 Nonethe-
less, in previous risk stratification criteria studies, a few
infants with UTI and bacteremia had been classified as
July 2019 • www.ebmedicine.net
low-risk, so 24-hour follow-up and detailed discharged
instructions are necessary, especially for infants dis-
charged from the ED without CSF testing, and with
particular caution for patients with a brief duration of
fever who may be considered low-risk by the Step-by-
Step approach.12,37 While febrile infants discharged
from the ED and subsequently diagnosed with IBI
have been reported to do well, the small numbers of
these infants in the literature limit the availability of
robust outcome data for low-risk infants who experi-
ence a delayed diagnosis and treatment of IBI.37,77-79
Empiric Antibiotic Therapy
Empiric antibiotic therapy for neonates and high-risk
febrile infants aged > 28 days should be tailored to
the most likely pathogens. The febrile young infant is
susceptible to perinatally acquired and community-
acquired infections, including GBS, E coli and other
gram-negative bacteria, Enterococcus spp, and S aureus.80
In the well-appearing febrile neonate, empiric antibiotic
therapy is routinely IV ampicillin (50 mg/kg/dose)
and cefotaxime (50 mg/kg/dose) or gentamicin (4-5
mg/kg/dose). Gentamicin does not penetrate the CSF
as readily as cefotaxime, so cefotaxime should be used
when there is concern for bacterial meningitis (ie, ill ap-
pearance, CSF pleocytosis, positive CSF Gram stain).81
Ceftriaxone (50 mg/kg/dose IV) is more commonly
used, due to the discontinuation of cefotaxime produc-
tion; however, a number of cautions/contraindications
exist for ceftriaxone use in the neonate (typically related
to calcium administration and hyperbilirubinemia), so
consultation with the pharmacy is recommended if us-
ing ceftriaxone in neonates.
In the well-appearing febrile infant aged > 28
days, L monocytogenes is not a significant pathogen.
Monotherapy with a broad-spectrum third-gener-
ation cephalosporin (eg, cefotaxime or ceftriaxone)
may be sufficient. However, a recent multicenter
cross-sectional study of 442 infants aged ≤ 60 days
with IBI reported that 10% of IBI in infants aged 29
to 60 days (mostly Enterococcus spp) are resistant to
third-generation cephalosporins.80 Therefore, combi-
nation therapy with ampicillin plus either a third-
generation cephalosporin (if suspected meningitis)
or gentamicin may be more appropriate. In both age
groups, ampicillin therapy alone is not adequate due
to a high percentage of ampicillin-resistant patho-
gens causing SBI in the febrile young infant.80,82
In the ill-appearing febrile infant, or in the
infant with CSF pleocytosis, purulence, or positive
Gram stain (indicating potential bacterial meningi-
tis), coverage should be broadened to treat highly
resistant S pneumoniae as well as the less common
S aureus.80 Coverage should include the addition of
vancomycin, 15 mg/kg/dose IV, to ampicillin and a
third-generation cephalosporin. Neonatal dosing of
IV vancomycin is unclear, and should be discussed
with the institution’s pharmacy.83
9 Copyright © 2019 EB Medicine. All rights reserved.
 Clinical Pathway for Evaluation and Management of
Febrile Neonates in the Emergency Department

Febrile infant aged ≤ 28 days presents to the ED

Ill-appearing Well-appearing

• Evaluate ABCs
• Perform full sepsis workup including CSF testing (Class I)
• Perform glucose, full sepsis workup including CSF testing, LFTs,
• Consider HSV testing if the patient is aged ≤ 21 days (perform if
HSV testing
hypothermia, seizures, hepatitis, vesicles) (Class II)
• Admit
• Admit (Class II)
• Administer IV ampicillin plus cefotaxime or gentamicin
• Administer IV ampicillin plus cefotaxime or gentamicin
• Add vancomycin if CSF pleocytosis or gram-positive organisms
• Add vancomycin if CSF pleocytosis or gram-positive organisms
on CSF Gram stain
on CSF Gram stain
• Obtain infectious disease consult if gram-negative organisms on
• Obtain infectious disease consult if gram-negative organisms on
CSF Gram stain
CSF Gram stain
• Administer IV acyclovir if the infant is at high risk for HSV
• Administer IV acyclovir if HSV testing is performed and the infant
• Consider other causes of the ill neonate
is at high risk for HSV (Class II)

Suggested Dosage Information for Medications*

Medication Dose Route of
Administration
Ampicillin 50-100 mg/kg/dose IV
Cefotaxime 50 mg/kg/dose IV
Gentamicin 4-5 mg/kg/dose IV
Vancomycin 15 mg/kg/dose IV
Acyclovir 20 mg/kg/dose IV

*The pharmacy should be consulted for exact dosing.

Abbreviations: ABCs, airway, breathing, circulation; CSF, cerebrospinal fluid; ED, emergency department; HSV, herpes simplex virus; IV, intravenous;
LFTs, liver function tests.

Class of Evidence Definitions

Each action in the clinical pathways section of Pediatric Emergency Medicine Practice receives a score based on the following definitions.
Class I Class II Class III Indeterminate
• Always acceptable, safe • Safe, acceptable • May be acceptable • Continuing area of research
• Definitely useful • Probably useful • Possibly useful • No recommendations until further
• Proven in both efficacy and effectiveness • Considered optional or alternative treat- research
Level of Evidence: ments
Level of Evidence: • Generally higher levels of evidence Level of Evidence:
• One or more large prospective studies • Nonrandomized or retrospective studies: Level of Evidence: • Evidence not available
are present (with rare exceptions) historic, cohort, or case control studies • Generally lower or intermediate levels of • Higher studies in progress
• High-quality meta-analyses • Less robust randomized controlled trials evidence • Results inconsistent, contradictory
• Study results consistently positive and • Results consistently positive • Case series, animal studies, • Results not compelling
compelling consensus panels
• Occasionally positive results

This clinical pathway is intended to supplement, rather than substitute for, professional judgment and may be changed depending upon a patient’s individual
needs. Failure to comply with this pathway does not represent a breach of the standard of care.
Copyright © 2019 EB Medicine. 1-800-249-5770. No part of this publication may be reproduced in any format without written consent of EB Medicine.

Copyright © 2019 EB Medicine. All rights reserved. 10 Reprints: www.ebmedicine.net/pempissues

 Clinical Pathway for Evaluation and Management of Febrile Young Infants
Aged 29 to 56 Days in the Emergency Department

Febrile infant aged 29-56 days

presents to the ED

Ill-appearing or high-risk
past medical history
Well-appearing

• Perform full sepsis workup including

CSF testing (Class I)
• Admit
• Administer IV ampicillin plus
No bronchiolitis Bronchiolitis
cefotaxime, ceftriaxone, or
gentamicin
• Add vancomycin if CSF pleocytosis
or gram-positive organisms on CSF
Gram stain
• Obtain infectious disease consult if
gram-negative organisms on CSF • Order urinalysis and urine culture
Gram stain (Class I)
• Consider HSV testing and IV • Consider CBC or CRP+PCT, and
acyclovir blood culture (Class II)
• Order urinalysis, CBC or CRP+PCT
• Consider CSF testing if high WBC,
(if available); urine and blood cultures
CRP, PCT, or ANC (Class III)
(Class I)

If high-risk criteria present: If low-risk criteria present: If high-risk criteria present or the patient
• Admit (Class I) • Discharge home if 24-hour follow up is in distress, admit (Class II)
• Obtain CSF testing; can defer CSF arranged
testing if only urinalysis is positive • No empiric antibiotics
(Class II) (Class I)
• Administer IV ampicillin plus
cefotaxime, ceftriaxone, or
gentamicin Suggested Dosage Information for Medications*
• Add vancomycin if CSF pleocytosis Medication Dose Route of
or gram-positive organisms on CSF Administration
Gram stain
Ampicillin 50-100 mg/kg/dose IV
• Obtain infectious disease consult if
gram-negative organisms on CSF Cefotaxime 50 mg/kg/dose IV
Gram stain Ceftriaxone 50-100 mg/kg/dose IV
Gentamicin 4-5 mg/kg/dose IV
Vancomycin 15 mg/kg/dose IV
Acyclovir 20 mg/kg/dose IV

*The pharmacy should be consulted for exact dosing.

Abbreviations: ANC, absolute neutrophil count; CBC, complete blood cell count; CRP, C-reactive protein; CSF, cerebrospinal fluid; ED, emergency
department; HSV, herpes simplex virus; IV, intravenous; PCT, procalcitonin; WBC, white blood cell.
For Class of Evidence definitions, see page 10.

July 2019 • www.ebmedicine.net 11 Copyright © 2019 EB Medicine. All rights reserved.

 Clinical Pathway for Evaluation and Management of Febrile Young Infants
Aged 57 to 89 Days in the Emergency Department

Febrile infant aged 57-89 days

presents to the ED

Ill-appearing Well-appearing

• Perform full sepsis workup including

No bronchiolitis Bronchiolitis
CSF testing (Class I)
• Admit
• Administer IV ceftriaxone
• Add vancomycin if CSF pleocytosis
or gram-positive organisms on CSF
Gram stain
• Obtain infectious disease consult if • Consider urinalysis and urine culturea
Urinalysis and urine culture
gram-negative organisms on CSF (Class I)
(Class II)
Gram stain • Consider CBC, CRP, PCT, blood
culture

If high-risk criteria present: If low-risk criteria present:

• Obtain CSF testing, unless meningitis • Discharge home with 24-hour follow-up
is clinically unlikely • No empiric antibiotics
• Admit (Class II)
• Administer IV ceftriaxone
• Add vancomycin if CSF pleocytosis
or gram-positive organisms on CSF
Gram stain Suggested Dosage Information for Medications*
• Obtain infectious disease consult if Medication Dosage Route(s) of
gram-negative organisms on CSF Administration
Gram stain Ceftriaxone 50-100 mg/kg/dose IV
Vancomycin 15 mg/kg/dose IV

*The pharmacy should be consulted for exact dosing.

Abbreviations: CBC, complete blood cell count; CRP, C-reactive protein; CSF, cerebrospinal fluid; ED, emergency department; IV, intravenous; PCT,
procalcitonin.
a
In otherwise stable and well-appearing infants aged > 2 months with a low suspicion for bacteremia or meningitis, outpatient management of a febrile
urinary tract infection without performance of a lumbar puncture is an option.
For Class of Evidence definitions, see page 10.

Copyright © 2019 EB Medicine. All rights reserved. 12 Reprints: www.ebmedicine.net/pempissues

 Two issues that arise in treatment decisions
for bacterial meningitis are: (1) the definition of
CSF pleocytosis in the febrile young infant and
(2) whether to adjust the CSF WBC count for CSF
red blood cell (RBC) count. A 2018 cross-sectional
study used the largest sample, to date, to determine
CSF norms in infants aged ≤ 60 days. Based on this
study of 7766 infants, CSF pleocytosis is defined as
≥ 16 cells/mcL in infants aged ≤ 28 days and as
≥ 10 cells/mcL in infants aged 29 to 60 days.84
A 2017 retrospective cohort study found a 1000:1
CSF RBC:CSF WBC correction factor could be used
in infants aged 29 to 60 days with traumatic lum-
bar punctures (≥ 10,000 CSF RBC/mcL) to reduce
the number of infants misclassified as having CSF
pleocytosis without misclassifying infants with
bacterial meningitis. However, the correction factor
should be used with caution in neonates, given a
higher number of neonates with bacterial meningi-
tis who were misclassified.85
In the rare—but potentially devastating—sce-
nario of a positive CSF Gram stain of gram-negative
rods (indicating gram-negative meningitis), the local
infectious disease specialist should be consulted
immediately, and coverage with broad-spectrum
antibiotics such as imipenem and amikacin should
be considered.86
Special Circumstances
Fever at Home Reported but Afebrile in the
Emergency Department
A commonly encountered situation is an infant with
a reported rectal temperature of > 38˚C at home who
did not receive antipyretics but is afebrile in the
ED. Similarly, an infant may present with a history
of fever taken by an axillary measurement or other
method, or who “felt warm.” Do these infants war-
rant the same workup as an infant with a document-
ed fever in the ED? While data are somewhat limited
to guide management in these situations, febrile
infants are at higher risk for SBI, so it is prudent to
maintain a low threshold to evaluate for these infec-
tions. A retrospective study reported that 92% of
infants whose caretakers had documented a rectally
obtained temperature at home were febrile in the
subsequent 48 hours, while only 46% of infants with
tactile fever at home had documented fever during
their ED or hospital stay. Additionally, only 1 of the
26 infants with tactile fever at home who were also
afebrile in the ED had an SBI (UTI), and none of the
26 had an IBI.87 Two studies reported recently that
the incidence of SBI and IBI was similar for infants
who were febrile in the ED and for infants with a
reported fever at home but who were afebrile in the
ED.88,89 Additionally, Woll et al found that 17% of
infants with bacteremia and/or bacterial meningitis
had a history of fever at home but not in the ED.80
July 2019 • www.ebmedicine.net
Therefore, evaluation of infants with documented
fever at home requires the same evaluation as in-
fants who are febrile in the ED. Of note, a 2019 study
that derived and internally validated a prediction
model to identify febrile infants at low risk for IBI
found that infants with a history of fever at home
but who were afebrile in ED had a low probability
of IBI if their urinalysis was normal and their ANC
was < 5185 cells/mcL.90 For well-appearing infants
with tactile fever only at home, there is less evidence
to guide management. A 2017 meta-analysis found
the sensitivity and specificity of caregivers’ tactile
assessment of fever to be 87.5% and 54.6%, respec-
tively.91 While one option is to observe the infant
in the ED with measurement of a rectal tempera-
ture, consideration should also be given to a sepsis
workup, particularly in neonates.
Controversies and Cutting Edge
Need for CSF Testing For Infants with
Abnormal Urinalysis
Because a febrile infant with an abnormal urinalysis
is considered high-risk according to any of the risk
stratification criteria, even in the absence of other
abnormal laboratory parameters, the question arises
as to the risk of bacterial meningitis in the well-ap-
pearing, otherwise low-risk infant with an abnormal
urinalysis. Should CSF studies be obtained in these
infants? The available literature indicates that the
prevalence of bacterial meningitis in febrile infants
with an abnormal urinalysis is similar to the preva-
lence in infants with a normal urinalysis. A 2011
review of the available literature concluded that,
although the existing literature has limitations, the
incidence of bacterial meningitis was < 1% in febrile
infants aged < 3 months with a UTI.92 A 2011 cross-
sectional study reported the incidence of meningi-
tis to be 1.2% among neonates with a UTI and 0%
(95% CI, 0%-1.25%) in infants aged 1 to 2 months.93
A 2017 23-center cross-sectional study reported
the incidence of bacterial meningitis to be 0.9% in
neonates with a UTI and 0.2% in infants aged 29 to
60 days with a UTI.94 Similarly, a 2018 retrospective
cohort study reported that the incidence of bacterial
meningitis was similar among febrile infants aged 29
to 60 days with a positive urinalysis compared with
those with a negative urinalysis (0.9% and 1.0%,
respectively). Additionally, of 345 infants with a UTI
who received antibiotic therapy without CSF testing,
none were subsequently diagnosed with meningitis
or experienced an adverse outcome.95
Taken together, the studies demonstrate that an
abnormal urinalysis alone should not be used in the
decision to perform CSF testing in febrile infants
aged > 28 days. If the infant is well-appearing and
is otherwise at low risk for SBI according to the risk
stratification criteria, it is reasonable to hospitalize
13 Copyright © 2019 EB Medicine. All rights reserved.
the infant and start empiric antibiotic therapy, with-
out CSF testing, though we recommend a discussion
with both the family and the inpatient team. For
neonates, CSF testing should be performed as rec-
ommended for all patients in this age group, since
UTI in this age group does not significantly decrease
the prevalence of concomitant bacterial meningi-
tis, and a diagnosis of bacterial meningitis would
greatly prolong the treatment duration compared to
the treatment duration for uncomplicated UTI.
American Academy of Pediatrics REVISE Project
The American Academy of Pediatrics (AAP) REVISE
(Reducing Excessive Variability in Infant Sepsis
Evaluation) is a national quality improvement col-
laborative that aims to standardize and optimize
evidence-based care for young infants presenting
with a fever without a source. There is significant
variation in clinicians’ approaches to evaluation
and management of febrile infants.46,74 Beginning in
2016, data on more than 20,000 febrile infants at 133
community hospitals and academic medical centers
were retrospectively analyzed, with particular atten-
tion paid to obtaining a urinalysis within 24 hours,
deferral of a chest x-ray in patients without respira-
tory symptoms, appropriate hospitalization with
initiation of recommended empiric antibiotics, and
timely discharge according to evidence-based guide-
lines. Utilizing educational tools such as standard-
ized order sets, flow charts, webinars, and the cell
phone app “PedsGuide,” the REVISE investigators
successfully demonstrated improvements in length
of stay and appropriate hospitalization.96 These
findings highlight the impact of innovative educa-
tional technologies in improving and standardizing
evidence-based care.
Neonatal Herpes Simplex Virus Infection
While the evidence for identifying febrile young
infants at low risk for SBI is expansive, controversy
exists as to which infants should be tested and em-
pirically treated for HSV infection. Neonatal HSV is
rare, with an incidence of 9.6 cases per 100,000 births27
or approximately 1500 cases per year in the United
States.14 Among > 26,000 infants aged ≤ 60 days who
underwent CSF testing at 23 hospitals, the incidence
of HSV was 0.42% overall and 0.17% among infants
aged 29 to 60 days,97 which is similar to or even lower
than that of bacterial meningitis.8 The vast major-
ity of HSV infections are acquired in the peripartum
period.14 The landmark 2003 study of more than
58,000 patients identified the highest risk for HSV
transmission to the neonate is a primary, first-episode
maternal infection at the time of delivery, as there is
no time for development of protective IgG antibodies.
The rate of neonatal HSV was 30.8% in babies born to
these mothers.33 Other risk factors for transmission
of neonatal HSV included premature delivery and
vaginal versus cesarean delivery.33 These risk factors
are important, as the highest-risk babies are likely
those who have been born to a mother who has no
prior history of HSV and may not know she had HSV
infection during delivery (due to subclinical disease).
There are 3 types of neonatal HSV. (See Table
5.) The most benign type is skin, eyes, and mouth
(SEM) disease. SEM HSV is limited to the skin and
mucous membranes and accounts for approxi-
mately 45% of cases. The second type is central
nervous system (CNS) HSV disease, in which HSV
is in the CNS (and possibly the skin and mucous
membranes) and accounts for 30% of cases. The
third type is disseminated HSV disease, which is
essentially HSV sepsis, with diffuse organ injury in-

Table 5. Clinical Presentation of Neonatal Herpes Simplex Virus Infection14,35

HSV Type Mean Age at Areas Involved Signs and Laboratory Method of Therapy106
Presentation Symptoms and Imaging Diagnosis14
Abnormalities
Skin, eyes, 12 days Skin; possibly Vesicles, None HSV PCR from High-dose acyclovir
and mouth mucous conjunctivitis vesicles, (20 mg/kg/dose
membranes conjunctivae, TID) x 14 days
oropharynx, and
rectum
Central 19.7 days CNS; possibly Seizures, lethargy, CSF pleocytosis HSV PCR from High-dose acyclovir
nervous skin and mucous coma, possibly SEM CSF (20 mg/kg/dose
system membranes symptoms TID) x 21 days
Disseminated 11.4 days Liver, pulmonary, Respiratory distress, Transaminitis, HSV PCR from High-dose acyclovir
coagulopathy; hypotension, DIC, pulmonary serum and CSF (20 mg/kg/dose
possibly CNS, hypothermia, infiltrates, TID) x 21 days
possibly skin bleeding, possibly acidosis, possibly
and mucous SEM and CNS CSF pleocytosis
membranes symptoms

Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; DIC, disseminated intravascular coagulation; HSV, herpes simplex virus; PCR,
polymerase chain reaction; SEM, skin, eyes, and mouth; TID, 3 times a day.

Copyright © 2019 EB Medicine. All rights reserved. 14 Reprints: www.ebmedicine.net/pempissues

cluding liver dysfunction, pulmonary involvement,
disseminated intravascular coagulopathy, and CNS
involvement (in about 60%-75% of patients). Dis-
seminated HSV disease accounts for approximately
25% of cases and is associated with a high mortal-
ity rate.98 The median age of neonates with HSV
infection is 14 days, and 80% to 90% of infections
occur in infants aged ≤ 28 days, with the highest
incidence in infants aged ≤ 21 days.28,97,99
While the presence of vesicles (the hallmark
of HSV) is helpful in making the diagnosis, the
vesicles will not always be present. In the landmark
2011 study, only 63% of patients with CNS disease
and 58% with disseminated disease had vesicles at
presentation.35 No other single symptom identifies
the majority of patients, and signs and symptoms
include lethargy, fever, seizure, and coagulopathy.35
(See Table 5, page 14.) While the majority of infants
with HSV infection will have vesicles, seizures, or
will be clinically ill, some studies have reported that
16% to 50% of neonates will have nonspecific symp-
toms, including up to 33% who are well-appearing,
with fever as the only sign.28,99 In contrast, another
study reported that of 10 neonates with HSV, 6 had
vesicles, 2 had hypothermia, 1 had lethargy and
CSF pleocytosis of 836 WBC/mcL, and 1 had fever
with severe transaminitis.100 Infants who are ill at
presentation with altered mental status, pneumonia,
or disseminated intravascular coagulopathy have
higher mortality rates, as do premature babies with
neonatal HSV.35,101 Therefore, early identification
of neonates with HSV prior to the development of
severe illness may improve mortality and neurologic
morbidity. Indeed, in a retrospective multicenter co-
hort study, delayed initiation of acyclovir initiation
was associated with increased mortality,102 likely
due to progression of disease.
Which neonates should be tested and treated
empirically for neonatal HSV? Certainly, if the febrile
infant aged ≤ 60 days has skin lesions suspicious for
HSV, elevated alanine transaminase (ALT), seizures,
cardiovascular instability, a history of birth to a wom-
an with active HSV lesions, or is exposed to someone
with cold sores, HSV testing and empiric acyclovir
therapy should be undertaken. Additionally, for neo-
nates, the presence of ill appearance, hypothermia,
lethargy, or CSF pleocytosis, particularly outside of
peak enteroviral season, should prompt consideration
of HSV testing and initiation of acyclovir therapy. But
what about the well-appearing neonate presenting to
the ED for fever or other nonspecific symptoms? It is
important to recognize that neonatal HSV is uncom-
mon after 21 days of age.28,103 The emergency clini-
cian must balance the thoroughness of early detection
and treatment with the risk of potential side effects
from acyclovir therapy. With the development of
rapid HSV PCR assays at many institutions that result
within 24 hours, empiric acyclovir therapy may be
July 2019 • www.ebmedicine.net
administered for only a mean time of 17.1 hours until
the PCR results are available.104
Currently, there is a wide variation across hospi-
tals regarding HSV testing and initiation of empiric
acyclovir therapy,46,97 likely due to the challenge
of the high morbidity but low prevalence of HSV
among febrile infants. In response to this dilemma,
Brower et al proposed a diagnostic and therapeutic
algorithm in which all infants aged ≤ 21 days who
are being evaluated for SBI also had PCR testing for
CSF HSV performed.105 According to the algorithm,
infants who were well-appearing with a normal
physical examination and normal CSF parameters
can have IV acyclovir deferred until HSV PCR
results are available. In contrast, infants with high-
risk clinical or laboratory findings (eg, vesicles, ill
appearance, and CSF pleocytosis with a lymphocytic
predominance) should receive empiric acyclovir
therapy while awaiting CSF PCR results. Testing in
these high-risk infants should include both serum
and CSF HSV PCR as well as HSV PCR or cultures
from the skin and mucous membranes.105 Empiric
therapy is high-dose acyclovir at 20 mg/kg/dose
IV, which has been shown to significantly reduce
24-month mortality with few side effects.106 (See
Table 5, page 14.)
RNA Biosignatures
Although not yet studied in the clinical setting, in an
exploratory study conducted by PECARN, RNA biosig-
natures have demonstrated higher combined sensitivity
(87%, [95% CI, 73%-95%]) and specificity (89%, [95% CI,
81%-93%]) than other diagnostic tests (ie, WBC, absolute
band count, ANC, CRP, PCT) in distinguishing bacterial
from viral infections in febrile infants.107 While further
studies of RNA biosignatures are warranted, the initial
results highlight potential molecular advances in risk
stratification tools for febrile infants.
Disposition
The febrile neonate should be hospitalized on empiric
antibiotic therapy, and consideration should be given
to empiric acyclovir therapy. The ill-appearing febrile
infant aged 29 to 56 days, or an infant who is at high
risk for SBI according to the risk stratification criteria
used, should likewise be hospitalized, with initiation
of empiric antibiotic therapy. The well-appearing,
low-risk febrile infant aged 29 to 56 days can be dis-
charged home if the family lives within a reasonable
distance of the hospital, there is a reliable caretaker
with good observation skills, there is reliable tele-
phone access, and 24-hour outpatient follow-up can
be arranged prior to disposition from the ED. Similar-
ly, the well-appearing febrile infant aged 57 to 89 days
with normal laboratory studies can be discharged
home with 24-hour primary care follow-up.
15 Copyright © 2019 EB Medicine. All rights reserved.
 A common question is whether otherwise well-
appearing, low-risk febrile infants aged > 28 days
with only a positive urinalysis can be discharged
home with oral antibiotic treatment, as UTI is the
most benign of the SBIs. A multicenter retrospective
study of 1895 febrile infants aged 29 to 60 days with
a UTI derived a prediction model to identify patients
at low risk for adverse events. Febrile young infants
with UTI were at low risk for an adverse event if
they were clinically well in the ED and did not have
a high-risk past medical history; however, the study
was retrospective, and the vast majority of the study
Risk Management Pitfalls in the Management of Febrile Infants
(Continued on page 17)
1. “The neonate had a fever, but he appeared to
be well. I couldn’t justify doing the full sepsis
workup, since there was little chance he had a
serious infection.”
The prevalence of infection is too high for testing
to be deferred. The febrile young infant is at
high risk for an SBI, especially if he is aged ≤ 28
days, as nearly 1 in 5 febrile neonates will have
an SBI.3 Additionally, the well-appearing febrile
infant aged ≤ 60 days is also at risk, as 9.6% of
these infants have an SBI and 1.8% have an IBI.6
2. “The baby was bundled, so I thought the rectal
temperature of 38°C (100.4°F) was environmen-
tal and that I didn’t need to perform the sepsis
workup.”
While temperatures can be falsely elevated
from excessive external heat, the febrile young
infant is a high-risk population. A rectal
temperature of 38°C should be assumed to
be true, and the sepsis workup should be
performed. It is unclear how to manage babies
with fever by axillary or ear thermometers,
which are less accurate than rectal
thermometers. The guiding principle is that,
due to the high prevalence of SBI in this age
group, strong consideration should be given to
performance of the sepsis workup.
3. “The CBC was normal for the ill-appearing
febrile young infant, so the risk of meningitis
was very low, and I didn’t need to perform a
lumbar puncture.”
The CBC alone is not an adequate screen for
bacterial meningitis. In a retrospective study of
5353 febrile infants aged 3 to 89 days, 22 of whom
had bacterial meningitis, the WBC count was
normal (between 5000 and 15,000 WBC/mcL) in
41% of patients with meningitis.109
Copyright © 2019 EB Medicine. All rights reserved. 16
sample received parenteral antibiotics.108 Therefore,
while that multicenter retrospective study is a good
first step to identify febrile young infants with a
UTI who are at low risk for adverse events and may
therefore be discharged home on oral antibiotics, at
the current time, these infants should still be hospi-
talized on IV antibiotics pending further prospective
study. Typically, stable, well-appearing infants aged
> 2 months with a UTI can be discharged home on
oral antibiotics with appropriate follow-up.
4. “The febrile baby was 61 days old, which was
beyond the upper age limit of both the Phila-
delphia and Rochester criteria. We didn’t have
to do any testing.”
The Boston criteria use an upper age limit
of 89 days for performance of the full sepsis
workup and the Step-by-Step approach uses
90 days. While the Philadelphia and Rochester
criteria have upper age limits of 56 and 60 days,
respectively, the febrile young infant does not
become low-risk for SBI when the baby becomes
61 days old. Among febrile infants in the third
month of life, the incidence of UTI is still high,48
so a urinalysis and urine culture should be
obtained. Further testing should certainly be
performed in an ill-appearing infant. In a young
infant who looks well, substantial diagnostic
variability exists.
5. “The mother denied any history of HSV, so I
thought the 12-day-old neonate who looked
ill likely had a bacterial infection and did not
have neonatal HSV.”
The highest risk for transmission of neonatal
HSV is babies born to mothers who have a
primary infection at the time of delivery.31 The
infection may be subclinical, so the mother
may not know she has HSV when the baby
presents to the ED. While the incidence of
neonatal HSV is low,14 comprehensive HSV
testing should be performed and empiric
acyclovir therapy initiated in the ill-appearing,
hypothermic, or seizing neonate, or when
vesicles or a CSF pleocytosis with lymphocyte
predominance are present.105
Reprints: www.ebmedicine.net/pempissues
Summary
Febrile young infants, even those who are well-
appearing, are at high risk for SBI, including occult
infections such as UTI, bacteremia, and bacterial
meningitis. All febrile neonates should undergo the
full sepsis workup with urine, serum, and CSF test-
ing. Even with normal laboratory testing, the febrile
neonate is still at risk for SBI and should be hospital-
ized on empiric antibiotic therapy, and consideration
should be given to testing and treatment for HSV. If
the febrile infant aged 29 to 56 days is considered to
Risk Management Pitfalls in the Management of Febrile Infants
(Continued from page 16)
6. “Acyclovir is a toxic drug, so we waited for
HSV testing to result before starting acyclovir
therapy in this high-risk neonate.”
In the landmark neonatal HSV therapy study,
the only adverse effect directly attributed to
acyclovir was transient neutropenia. Elevated
creatinine and low hemoglobin occurred in the
sickest babies with disseminated HSV infection,
so the abnormalities were possibly related to the
HSV and not to the acyclovir.106 Additionally,
a retrospective study showed that each day's
delay in acyclovir initiation was associated with
increased mortality in neonates with HSV.102
Therefore, empiric acyclovir therapy should
accompany HSV testing in the neonate with
high-risk findings concerning for HSV.
7. “Although the labs and physical examination
of this 50-day-old febrile infant were reassur-
ing, I started antibiotics and admitted her just
to be safe.”
When utilizing the Step-by-Step approach,
if an infant aged > 21 days is well-appearing
and has a normal urinalysis, PCT < 0.5 ng/
mL, CRP ≤ 20 mg/L, and ANC ≤ 10,000 cells/
mcL, she may be discharged home safely as
long as pediatrician follow-up is definitively
established for the following day to evaluate
the infant and follow the urine and blood
cultures.12,78 Similarly, in a prospective study,
infants considered low-risk by the Philadelphia
criteria were safely discharged home without
antibiotics if the infant lived within 30 minutes
of the hospital and 24-hour outpatient follow-up
was arranged.10 Administration of antibiotics
without a lumbar puncture may also cloud the
diagnosis of meningitis and impact subsequent
care if a lumbar puncture is performed later and
the infant has CSF pleocytosis.
July 2019 • www.ebmedicine.net
be at low risk according to the risk stratification cri-
teria, the baby can be discharged home without CSF
testing if the emergency clinician feels comfortable
assessing well-appearance in a young infant and if
a 24-hour outpatient follow-up plan is established.
The febrile infant aged 57 to 89 days is still at risk for
UTI and should undergo, at minimum, testing for
UTI, with strong consideration given to blood test-
ing as well.
8. “The urinalysis, CBC, and CSF cell count were
all normal in my febrile 10-day-old patient, so
he met the low-risk criteria. I felt comfortable
sending him home for his pediatrician to fol-
low up on the cultures.”
The low-risk criteria do not perform as well in
neonates, as demonstrated by 2 retrospective
studies that showed a lower negative predictive
value of the criteria in neonates, with potential
to falsely classify up to 1 in 10 febrile neonates
as low risk.3,40 Therefore, neonates should be
admitted on empiric antibiotic therapy pending
bacterial culture results.
9. “The 40-day-old febrile baby was very fussy
on my exam, but the labs were normal, so he
met the low-risk criteria, and I discharged him
home.”
All of the low-risk criteria require the infant to
be well-appearing on physical examination. (See
Table 4, page 6.) Even with normal laboratory
studies, if the infant is ill-appearing or has a
focal infection, the baby should be hospitalized
with initiation of empiric antibiotic therapy.
10. “The neonate was in shock. I administered anti-
biotics, which should have treated the sepsis.”
While bacterial sepsis is a likely diagnosis
in the neonate in shock, other etiologies
include neonatal HSV, ductal-dependent
congenital heart disease, and inborn errors of
metabolism. (See Table 2, page 4.) In addition to
antibiotic therapy and hemodynamic support,
consideration should be given to other potential
etiologies, as initiation of acyclovir therapy,
prostaglandin infusion, and treatment of
metabolic disturbances can be life-saving, and
infections can occur in conjunction with other
neonatal disasters.
17 Copyright © 2019 EB Medicine. All rights reserved.
Case Conclusions
For the 20-day-old boy, you performed a full sepsis
workup with urine, serum, and CSF studies, including
testing for enterovirus and HSV. The baby’s enhanced
urinalysis had 0 WBC, the CBC had a WBC count of
12,000/mcL with no bandemia, and the CSF had 2 WBC.
Since the risk stratification criteria do not perform as well
in neonates, you admitted the patient to the hospital with
initiation of empiric ampicillin and cefotaxime therapy.
Since the infant had no high-risk findings concerning for
HSV, you did not start acyclovir therapy.
Although the 40-day-old infant’s signs and symptoms
were suggestive of a benign URI, you remembered that
several studies demonstrated that infants in this age group
(29-56 days) with documented RSV or influenza are still at
risk for SBI, especially UTI, though the risk of IBI is lower
in this age group compared with infants who have negative
RSV or influenza testing. You ordered urine studies, blood
culture, CBC, CRP, and PCT, given the nonnegligible prev-
alence of IBI. The urinalysis was normal, the CBC showed
a WBC of 10,000/mcL, the CRP was < 20 mg/L, the PCT
was < 0.5 ng/mL, and the ANC was < 10,000 cells/mcL.
Since the girl's labs were reassuring and she was well-
appearing and feeding appropriately with reliable follow-
up, you discharged her home without CSF testing and with
close primary care follow-up the next day.
For the 50-day-old girl whose urinalysis suggested a
UTI, you ordered CBC, CRP, PCT, and blood culture, and
the urine was also sent for culture. The CBC demonstrat-
ed a WBC count of 9500/mcL with 0 bands, the CRP was
< 20 mg/L, the PCT was < 0.5 ng/mL, and the ANC was
< 10,000 cells/mcL. Since the labs and appearance of the
infant were otherwise well-appearing, and the prevalence
of concomitant bacterial meningitis has been demon-
strated to be low in otherwise low-risk febrile infants aged
> 28 days, you decided to treat her for a UTI and observe
without performing a lumbar puncture. You administered
a dose of ceftriaxone to treat the presumptive UTI, and
admitted the girl to the hospital for treatment of the UTI
and monitoring of the blood culture.
Time- and Cost-Effective Strategies
• Application of the low-risk criteria would allow
approximately 30% of febrile young infants to
be observed without the need for hospitalization
or empiric antibiotic therapy, thereby reducing
cost, in addition to lowering the risk of nosoco-
mial infection and adverse medication effects.2
Risk Management Caveat: The low-risk criteria
apply only to the well-appearing febrile young
infant. At this point, most emergency clinicians
would not apply these criteria to infants aged
< 29 days. For outpatient management, there
should be a reliable caregiver with good obser-
vation skills and reliable access to a telephone.
In addition, 12- to 24-hour follow up with the
Copyright © 2019 EB Medicine. All rights reserved. 18
infant’s primary care physician should be ar-
ranged prior to ED discharge to ensure that bac-
terial culture results are followed and a repeat
physical examination is performed to identify
any changes in clinical status.
• Development of evidence-based institutional clini-
cal practice guidelines and pathways can stan-
dardize the workup of the febrile young infant and
lead to more efficient and cost-effective care.67
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Evidence-based medicine requires a critical ap-
praisal of the literature based upon study methodol-
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equally robust. The findings of a large, prospective,
randomized, and blinded trial should carry more
weight than a case report.
To help the reader judge the strength of each
reference, pertinent information about the study is
included in bold type following the reference, where
available. In addition, the most informative referenc-
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20. Biondi E, Evans R, Mischler M, et al. Epidemiology of
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22. Watt K, Waddle E, Jhaveri R. Changing epidemiology of
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CME Questions
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1. A diagnosis to consider in the febrile neonate
is:
a. Sepsis
b. Ductal-dependent congenital heart disease
c. Inborn errors of metabolism
d. All of the above
2. A 48-day-old febrile infant has undergone a
sepsis workup. Which of the following should
be present for the infant to be discharged
home?
a. White blood cell count (WBC) < 5000 cells/
mcL
b. Established follow-up within 24 hours
c. Procalcitonin (PCT) < 2 ng/mL
d. Cerebrospinal fluid (CSF) < 20 WBC/mcL
3. According to the Step-by-Step approach, which
of the following criteria classifies a patient as
high-risk?
a. Age < 30 days
b. Absolute neutrophil count < 1500/mcL
c. Procalcitonin ≥ 0.5 ng/mL
d. WBC > 15,000 cells/mcL
4. In a febrile young infant with CSF pleocytosis,
other testing to consider, regardless of symp-
toms, includes:
a. A chest x-ray
b. Stool cultures
c. A brain CT scan
d. Enterovirus polymerase chain reaction
(PCR)
Copyright © 2019 EB Medicine. All rights reserved. 22
5. The incidence of serious bacterial infection
(SBI) in febrile infants aged ≤ 60 days with
respiratory syncytial virus (RSV) infection is
approximately:
a. < 1%
b. 7%
c. 20%
d. 30%
6. Which of the following antibiotic(s) would be
the most appropriate empiric coverage for a
7-day-old febrile infant?
a. Ampicillin and cefotaxime
b. Ampicillin alone
c. Gentamicin alone
d. Ceftriaxone alone
7. A 20-day-old infant presents to the ED with a
reported rectal temperature of 38.3°C (101°F)
when measured by the mother at home. The
infant did not receive an antipyretic. In the ED,
the infant is fussy, and the rectal temperature is
37.3°C (99.2°F). What is the appropriate man-
agement of this infant?
a. Discharge home with routine outpatient care
b. Order blood culture only
c. Order urine, blood, and CSF testing (full
sepsis workup)
d. Order a complete blood cell count (CBC) for
risk stratification
8. A 52-day-old febrile infant has positive nitrites
and 20 WBC on urinalysis. A lumbar puncture
is indicated if which of the following is pres-
ent?
a. WBC 10,000 cells/mcL
b. Ill appearance
c. Absolute neutrophil count of 5000 cells/mcL
d. The infant should undergo a lumbar
puncture based on the urinalysis results
9. The median age at which infants present with
herpes simplex virus (HSV) infection is ap-
proximately:
a. 1 day
b. 3 days
c. 14 days
d. 27 days
10. What approximate percentage of neonates
with disseminated and central nervous system
(CNS) types of neonatal HSV will have skin
vesicles at presentation?
a. 5%
b. 20%
c. 60%
d. 95%
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Pediatric Pa gnition Are Critical
nal
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Garth Meckl
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of Pediatrics,
AAP Accreditation: This continuing medical education activity has been reviewed by the
American Academy of Pediatrics and is acceptable for a maximum of 48 AAP credits per
n's
Professor Sanzari Childre sity
MD, FAAP Associate bia; Joseph M.
Alson S. Inaba, ency Medicine of British Colum ency nsack Univer
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, MD, FAAP Pediatric Emerg ani Medical Cente Division Head,Children's Hospital, l Center
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year. These credits can be applied toward the AAP CME/CPD Award available to Fellows and
Chief of Pediatr chusetts General BC, Canad
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of Pediatrics, School of Vancouver, Vincent J. of Pediatrics and
Editors-in Medicine, Massator in Pediatrics, Professor A. Burns r, MD, MHPE ics
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FACEP, Pediatric Emerg
ency Medic nal Editor

AOA Accreditation: Pediatric Emergency Medicine Practice is eligible for up to 48 American

FAAP
Professor
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wa, MD
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Associate David Geffen Marianne Gausc Quality Improv Physician, VISIT US AT ACEP s, MD, FAAP,
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Osteopathic Association Category 2-A or 2-B credit hours per year.

Faculty and County EMS ency Medicine and Medicine-Ja ency Medic
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Angeles Countr, Torrance, CA Clinical Emerg Geffen School Jacksonville, Joshua Rocke Medical
MD Chief and Hospital Imperi
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of Associate ant Profes
sor BOOTH 1921 Nonclinical Instruc
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Editorial Boar FAAP Faculty, Harbotment of Emergency
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Needs Assessment: The need for this educational activity was determined by a survey of
Jeffrey R. of Center, Depar Angeles, CA Cincinnati,
OH Medicine, York, New
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New York,
NY
Depar tment Los MS Center of New
Chairman,
Professor
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Pharmacolog
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Maimonides Michael J. Chief, Critica Clinics of BCPS
Pediatrics, yn, NY ent
FACEP, Presid sor of Emergency Hospitals and MN s, MD of r, PharmD,
Brooklyn, Brookl Children's Steven Roger University Aimee Mishle Medicine Pharmacist,

medical staff, including the editorial board of this publication; review of morbidity and mortality
Hospital of Profes Minneapolis, Professor,
Associate l of Medicine Minnesota, Associate
School of
Medicine, Emergency
Icahn Schoo Pediatric or – PGY2 acy

Tick-Borne Illnesses:
Steven Bin,
MD UCSF Medicine, Director, FAAP, FACEP Connecticut Medicine Program Direct
l Professor, Tommy Y.
Kim, MD, ic Emergency Children's Medicine
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data from the CDC, AHA, NCHS, and ACEP; and evaluation of prior activities for emergency
town Physic ency,
September 2018
Morris Medici r, Hartfo rd, Resid
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Identification and Manageme

r, Morristown, California Riversi unity Hospital, er, MD
Benioff Childre Medical Cente Stroth r
Riverside Comm Medicine, Volume 15, Number 9
opher ency
CME Edito
nt
CA be, MD, PhD Christ Emerg
Francisco, of Emergency Professor, l , FAAP
FAAP, Sandip Godamand Patient Safety Officer, Department Associate and Medica ka, MD, FACEP

physicians.
Cantor, MD, Pediatrics,
Richard M. Chief Quality ng
Riverside, CA
Authors Medicine, ric Brian S. Skrain ant Professor,

in the Emergency Department

Pediatrics, Attendi ne, Director, Pediat r, Clinical Assist Emergency
FACEP Medicine Professor of Medici an, MD, MHS rics and Education; ne; Directo
of EmergencyChief, Emergency Melissa Langh ency Medici Medicine Depar tment
of
Professor n Physician of l of The King's sor of PediatBellis, MD, Emerg
Jennifer MPH tion; Icahn School of Oklahoma
State
rics; Sectio Children's Hospita System, Norfolk, VA Associate Profes Instructor, ship Medicine,
and Pediat ency Medic
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of Pediatrics, York, NY
sity Cente
r for Health
Pediatric Emergr, Upstate Poison Daughters
Health Emergency of Education, Yale
r University at Mount Section of EmergencyUniver Medicine, Tulsa, OK
Director, Directo ency Medicine, of Colorado, Aurora, COMD, FAAP

Target Audience: This enduring material is designed for emergency medicine physicians,
Medical Directo Children's an, MD Sciences,
Abstract Contro l Cente r, Golisano
se, NY
Ran D. Goldm
Professor,
Depar tment of Pediatrics,
bia;
Pediat ric Emerg Ee Tay,
University
Schoo l of Medici MD ne, New Adam E. Vella,
Associate
Profes sor of Emerg al
rics, and Medic
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Hospital, Syracu of British Columric Clinical Assistant Professor, ine, Pediat ric
University Haven, CT MedicRonald O. Perelman
r of Pediat Department
MD, FAAP Director, Pediat Children's Emergency Medicine, Clinical Education,
Directo l of
Steven Choi, y Officer and Assoc
iate Research Site Chief,ine, Icahn Schoo

physician assistants, nurse practitioners, and residents.

BC , MD
Tick-borne illnesses are increasing Emergency
Medicine, a Robert LutenPediat Bellevue
rics andHospitalofCenter, ency Medic Pediatric New Emergency Medicine,
Chief Qualit l Quality, Yale ine; uver, BC, Canad Emerg
New York,atNY Mount Sinai,
Dean for Clinica in prevalence and geographi Hospital, Vanco Professor,
Medicine,
University of Medicine
reach. Because the presentati le School of
Medic
, c MD, MBA Emergency Peer Reviewers
nville, FL York, NY
Medicine/Ya on of these illnesses is sometime
ent, Chief
Quality Officer Joseph Habboushe, of Emergency
Florida, Jackso
nonspecific, they can often
Vice Presid Health System
, s sor
Assistant Profes angone and Michael Gottlieb, MD, RDMS
be misdiagnosed, especially
Yale New Haven NYU/L

Goals: Upon completion of this activity, you should be able to: (1) demonstrate medical decision-
early stages of illness. A detailed
, CT in the Medicine, al Cente rs, New Director of Emergency
New Haven Bellevue Medic MD Aware LLC Ultrasound, Department of
history with questions involv- Rush University Medical Emergency Medicine,
ing recent activities and travel York, NY; CEO, Center, Chicago, IL
and a
tion will help narrow the diagnosis. thorough physical examina-
Lise Nigrovic, MD, MPH

making based on the strongest clinical evidence; (2) cost-effectively diagnose and treat the
Associate Professor of Pediatrics
While some illnesses can be and Emergency Medicine,
diagnosed on clinical findings Medical School, Boston Children’s
Hospital, Boston, MA
Harvard
alone, others require confirma-
tory testing, which may take Prior to beginning this activity,

most critical ED presentations; and (3) describe the most common medicolegal pitfalls for
days to weeks to result. This see “Physician CME Information”
reviews the emergency departme issue on the back page.
nt presentation of 9 common
tick-borne illnesses and evidence-
based recommendations for
identification, testing, and
treatment. each topic covered.
Editors-in-Chief Ari Cohen, MD, FAAP
CME Objectives: Upon completion of this activity, you should be able to: (1) describe the most
up-to-date epidemiology of invasive bacterial infections in febrile young infants; (2) discuss the
Ilene Claudius, MD Chief of Pediatric Emergency Joseph Habboushe, MD,
MBA Robert Luten, MD
Associate Professor; Director, Medicine, Massachusetts General Assistant Professor of Emergency Adam E. Vella, MD, FAAP
Medicine, NYU/Langone and Professor, Pediatrics and
Process & Quality Improvement Hospital; Instructor in Pediatrics, Emergency Medicine, University Associate Professor of Emergency
Program, Harbor-UCLA Medical Harvard Medical School, Boston, Bellevue Medical Centers, of Medicine, Pediatrics, and Medical
New Florida, Jacksonville, FL

use of novel biomarkers and the new risk stratification tools that incorporate these biomarkers
MA York, NY; CEO, MD Aware
Center, Torrance, CA LLC Education, Director of Pediatric
Jay D. Fisher, MD, FAAP Garth Meckler, MD, MSHS
Tim Horeczko, MD, MSCR, Clinical Professor of Pediatric Alson S. Inaba, MD, FAAP Emergency Medicine, Icahn
FACEP, Associate Professor of Pediatrics, School
and Pediatric Emergency Medicine of Medicine at Mount Sinai,
FAAP Emergency Medicine, University University of British Columbia; New
Specialist, Kapiolani Medical York, NY

Associate Professor of Clinical
Emergency Medicine, David
Geffen
School of Medicine, UCLA;
Core
Faculty and Senior Physician,
Los
for the evaluation of invasive bacterial infections in febrile young infants; and (3) determine
of Nevada, Las Vegas School Center Division Head, Pediatric Emergency
of for Women & Children; Associate
Medicine, Las Vegas, NV Medicine, David M. Walker, MD, FACEP,
Professor of Pediatrics, University BC Children's Hospital, FAAP
Director, Pediatric Emergency
Marianne Gausche-Hill, MD, of Hawaii John A. Burns School Vancouver, BC, Canada
FACEP, of Medicine; Associate Director,
FAAP, FAEMS Medicine, Honolulu, HI Joshua Nagler, MD, MHPEd

Angeles County-Harbor-UCLA
Medical Director, Los Angeles
Medical Center, Torrance,
CA County EMS Agency; Professor
of
Editorial Board Clinical Emergency Medicine
and
Pediatrics, David Geffen School
appropriate treatment and disposition of febrile young infants based on screening laboratory
Department of Emergency
Assistant Professor of Pediatrics Medicine,
Madeline Matar Joseph, and New York-Presbyterian/Queens,
MD, FACEP, Emergency Medicine, Harvard
FAAP Medical Flushing, NY
Professor of Emergency Medicine School; Fellowship Director,
Division Vincent J. Wang, MD, MHA

Jeffrey R. Avner, MD, FAAP
Chairman, Department of
Pediatrics, Professor of Clinical
Pediatrics, Maimonides Children's
Hospital of Brooklyn, Brooklyn,
NY
of
Medicine at UCLA; EMS Fellowship
Director, Harbor-UCLA Medical
Center, Department of Emergency
Medicine, Los Angeles, CA
Michael J. Gerardi, MD, FAAP,
and Pediatrics, Chief and Medical
Director, Pediatric Emergency
Medicine Division, University
of Florida College of Medicine-
Jacksonville, Jacksonville,
FL
of Emergency Medicine, Boston
Children’s Hospital, Boston,
MA
James Naprawa, MD
Attending Physician, Emergency
Department USCF Benioff
tests.
Professor of Pediatrics and
Emergency Medicine; Division
Chief, Pediatric Emergency
Medicine, UT Southwestern
Medical Center; Director
of

Discussion of Investigational Information: As part of the journal, faculty may be presenting

Steven Bin, MD Stephanie Kennebeck, MD Children's Hospital, Oakland, Emergency Services, Children's
FACEP, President CA
Associate Clinical Professor, Associate Professor of Emergency Associate Professor, University Joshua Rocker, MD Health, Dallas, TX
UCSF of
School of Medicine; Medical Cincinnati Department of Pediatrics, Associate Chief and Medical
Pediatric Emergency Medicine,
Director, Medicine, Icahn School of
Medicine Cincinnati, OH Director, Assistant Professor
International Editor
UCSF at Mount Sinai; Director, Pediatric

investigational information about pharmaceutical products that is outside Food and Drug
Benioff Children's Hospital, San Emergency Medicine, Goryeb Anupam Kharbanda, MD, of Pediatrics and Emergency Lara Zibners, MD, FAAP, FACEP,
Francisco, CA MS Medicine, Cohen Children's MMed
Children's Hospital, Morristown Chief, Critical Care Services Medical
Richard M. Cantor, MD, FAAP, Medical Center, Morristown, Children's Hospitals and Clinics Center of New York, Donald Honorary Consultant, Paediatric
NJ of and
FACEP Minnesota, Minneapolis, MN Barbara Zucker School of Emergency Medicine, St. Mary's

Administration approved labeling. Information presented as part of this activity is intended

Sandip Godambe, MD, PhD
Professor of Emergency Medicine
Chief Quality and Patient Safety
and Pediatrics; Section Chief,
Officer, Professor of Pediatrics
Pediatric Emergency Medicine; and
Emergency Medicine, Attending
Medical Director, Upstate Poison
Medicine
at Hofstra/Northwell, New Hospital Imperial College Trust,
Tommy Y. Kim, MD, FAAP, Hyde
FACEP Park, NY London, UK; Nonclinical Instructor
Associate Professor of Pediatric of Emergency Medicine, Icahn
Steven Rogers, MD
Emergency Medicine, University School of Medicine at Mount
of

Physician, Children's Hospital
Control Center, Golisano Children's
King's Daughters Health System,
Hospital, Syracuse, NY Norfolk, VA
Steven Choi, MD, FAAP
Ran D. Goldman, MD
solely as continuing medical education and is not intended to promote off-label use of any
California Riverside School of Associate Professor, University Sinai,
of the Medicine, of New York, NY
Riverside Community Hospital, Connecticut School of Medicine,
Attending Emergency Medicine Pharmacology Editor
Department of Emergency Medicine,
Riverside, CA Physician, Connecticut Children's
Aimee Mishler, PharmD, BCPS

Assistant Vice President,
Montefiore Health System;
Director,
Montefiore Network Performance
Improvement; Executive Director,
Montefiore Institute for Performance
Professor, Department of Pediatrics, Melissa Langhan, MD,
University of British Columbia;
Research Director, Pediatric
Emergency Medicine, BC
Children's
Hospital, Vancouver, BC, Canada
MHS
Associate Professor of Pediatrics
and
Emergency Medicine; Fellowship
Director, Director of Education,
Pediatric Emergency Medicine,
Medical Center, Hartford, CT
Christopher Strother, MD
Assistant Professor, Emergency
Medicine, Pediatrics, and Medical
Education; Director, Undergraduate
pharmaceutical product.
Emergency Medicine Pharmacist,
Maricopa Medical Center,
Phoenix, AZ
CME Editor

Faculty Disclosure: It is the policy of EB Medicine to ensure objectivity, balance, independence,

Improvement; Associate Professor Yale and Emergency Department
University School of Medicine, Deborah R. Liu, MD
of Pediatrics, Albert Einstein New Simulation; Icahn School of
College Haven, CT Medicine Associate Professor of Pediatrics,
of Medicine, Bronx, NY at Mount Sinai, New York, NY Keck School of Medicine of
USC;
Division of Emergency Medicine,

transparency, and scientific rigor in all CME-sponsored educational activities. All faculty
Children's Hospital Los Angeles,
Los Angeles, CA

participating in the planning or implementation of a sponsored activity are expected to disclose to

the audience any relevant financial relationships and to assist in resolving any conflict of interest
that may arise from the relationship. Presenters must also make a meaningful disclosure to the
Critical topics coming soon in audience of their discussions of unlabeled or unapproved drugs or devices. In compliance with
all ACCME Essentials, Standards, and Guidelines, all faculty for this CME activity were asked to
complete a full disclosure statement. The information received is as follows: Dr. Palladino, Dr. Woll,
Pediatric Emergency Medicine Dr. Aronson, Dr. Avner, Dr. Williams, Dr. Mishler, Dr. Skrainka, Dr. Claudius, Dr. Horeczko,
and their related parties report no relevant financial interest or other relationship with the
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 Calculated
Decisions
POWERED BY

Clinical Decision Support for Pediatric Emergency Medicine Practice Subscribers

Rochester Criteria for Febrile Infants

The Rochester criteria for febrile infants determine whether or
not febrile infants are at low risk for serious bacterial infection.

Click the thumbnail above

to access the calculator.

Points & Pearls

• While the validation study for the Rochester
criteria included infants aged ≤ 60 days, in
clinical practice, infants aged < 28 days often
are not considered to be at low risk, due to
their age.
• Premature infants should be assessed based
on their corrected age (eg, for an infant born
at 30 weeks gestational age, subtract 7 weeks
from the chronologic age).
Evidence Appraisal
The Rochester criteria were first proposed by
Dagan et al in 1985 at the University of Rochester
Medical Center in New York. In 1994, Jaskiewicz
et al validated the criteria by aggregating data from
3 prospective studies that were conducted between
1984 and 1992. Only infants aged ≤ 60 days who
had rectal temperatures ≥ 38ºC (100.4ºF) at home
or at presentation were included in the validation
study. The clinical environments were an emergen-
cy department and a pediatric outpatient clinic.
The evaluation of each infant included global
assessment, past medical history, physical exami-
nation (including for evidence of skin, soft tissue,
bone, or joint infection), and laboratory assess-
ment (including blood, urine, and cerebrospinal
fluid studies). Chest x-ray and stool studies were
only obtained if clinical symptoms were present. Of
note, cerebrospinal fluid studies were not part of
CALCULATOR REVIEW AUTHOR
Laura Mercurio, MD
Department of Pediatric Emergency Medicine, Brown
University/Hasbro Children’s Hospital, Providence, RI
the Rochester risk stratification criteria. Each infant
was then categorized as low risk or not low risk.
Among 931 evaluable patients, 437 met all of the
low-risk criteria and 511 did not.
The study’s main outcomes were bacteremia
and a larger inclusive category of serious bacte-
rial infection (SBI). SBI was defined as bacteremia,
meningitis, osteomyelitis, suppurative arthritis,
soft tissue infections (cellulitis, abscess, mastitis,
omphalitis), urinary tract infection, gastroenteri-
tis, or pneumonia. SBI was identified in 1% of the
low-risk infants as compared to 12.3% of non–low-
risk infants. The negative predictive value (NPV) of
the low-risk criteria was 99.5% for bacteremia and
98.9% for SBI.
In 2012, Hui et al conducted a review of 84
studies to determine the diagnostic accuracy of
screening tools for SBI and HSV in infants aged
< 3 months. This review also examined the rela-
tionship between viral testing and risk of SBI. The
various clinical and laboratory criteria (including the
Rochester, Philadelphia, Boston, and Milwaukee
screening tools) demonstrated similar overall ac-
curacy (84.4%-100% sensitivity; 93.7%-100% NPV)
for identifying infants with SBI. The Rochester cri-
teria were more accurate in neonates than in older
infants, while the other screening tools were more
accurate in older infants than in neonates.
In 2016, Gomez et al conducted a prospec-
tive study including infants aged < 90 days who
presented to 11 European pediatric emergency
departments between September 2012 and August
2014. The study compared the accuracies of the
new Step-by-Step approach, the Rochester criteria,
and the Lab-score for identifying patients who are
at low risk of invasive bacterial infection (IBI). For

CD1 www.ebmedicine.net
the study population, the sensitivity and NPV for Use the Calculator Now
ruling out IBI were 92.0% and 99.3%, respectively, Click here to access the Rochester criteria on
for the Step-by-Step approach, 81.6% and 98.3% MDCalc.
for the Rochester criteria, and 59.8% and 98.1% for
the Lab-score. Some infants with IBIs were misclas- Calculator Creator
sified by each of the tools in the study: 7 by the Ron Dagan, MD
Step-by-Step approach,16 by the Rochester criteria, Click here to read more about Dr. Dagan.
and 35 by the Lab-score.

Why to Use
• The Rochester criteria identify infants who are at low risk for SBI (defined as bacteremia, meningitis,
osteomyelitis, suppurative arthritis, soft tissue infections [cellulitis, abscess, mastitis, omphalitis],
urinary tract infection, gastroenteritis, or pneumonia).
• Febrile infants aged ≤ 60 days may present with minimal signs and symptoms or may present similarly
to those who have viral infections. The criteria can help identify SBI in these patients; the prevalence of
SBI is 10% to 12% in this group, with urinary tract infections representing > 90% of these SBIs (Biondi
2013, Greenhow 2014).
• Use of the Rochester criteria may reduce overtesting and overtreatment of well-appearing febrile
infants.

When to Use
• The Rochester criteria can be used for well-appearing infants aged ≤ 60 days who present to the ED
for a chief complaint of fever ≥ 38ºC (100.4ºF), or who are found to have fever on presentation for
another complaint.
• Ill-appearing infants should be redirected to the sepsis guidelines.

Next Steps
If the patient is at low risk for SBI according to the Rochester criteria (in the derivation study, SBI occurred
in 1% of low-risk infants):
• Limited testing, including complete blood cell count, blood culture, urinalysis, and urine culture, is
recommended.
• Febrile infants who are considered to be at low risk generally do not require antibiotics.
• It is generally safe to discharge these infants if there are no social concerns or questions about the
caregiver’s ability to follow up with a primary care pediatrician.

If the patient is not considered to be at low risk for SBI according to the Rochester criteria (in the study,
SBI occurred in 12.3% of infants who were identified as not at low risk):
• Further testing is required, including complete blood cell count, blood culture, urinalysis, urine culture,
and cerebrospinal fluid testing.
• Empiric broad spectrum antibiotic coverage is indicated.
• Admission is recommended, pending negative cultures at 24 to 36 hours.

Advice
• Herpes simplex virus risk factors should be carefully assessed, including maternal history of herpes
simplex virus infection or primary lesions at delivery, household contacts with lesions, vesicular rash,
patient presentation with seizures, or pleocytosis on cerebrospinal fluid testing.
• A positive viral test result (eg, respiratory syncytial virus, influenza) reduces the likelihood of SBI by
approximately 50%, but the risk of a concurrent SBI is not 0% (Greenhow 2014, Krief 2009).
• The gold standard for urine culture is a sample obtained via straight catheterization. “Bag” urine
collection introduces the risk of specimen contamination with skin flora. If possible, blood, urine,
and cerebrospinal fluid samples should be obtained before starting antibiotics.
• The differential diagnosis of febrile ill-appearing infants aged < 60 days should also include the fol-
lowing: congenital heart disease, metabolic disease (eg, galactosemia), congenital adrenal hyperpla-
sia with adrenal crisis, and nonaccidental trauma.

Abbreviations: ED, emergency department; SBI, serious bacterial infection.

Pediatric Emergency Medicine Practice • July 2019 CD2 Copyright © 2019 EB Medicine. All rights reserved.
References
Original/Primary Reference
• Dagan R, Powell KR, Hall CB, et al. Identification of
infants unlikely to have serious bacterial infection
although hospitalized for suspected sepsis. J Pediatr.
1985;107(6):855-860.
https://www.ncbi.nlm.nih.gov/pubmed/4067741
Validation Reference
• Jaskiewicz JA, McCarthy CA, Richardson AC, et al.
Febrile infants at low risk for serious bacterial infection
--an appraisal of the Rochester criteria and implications for
management. Febrile Infant Collaborative Study Group.
Pediatrics.1994;94(3):390-396.
https://www.ncbi.nlm.nih.gov/pubmed/8065869
Other References
• Biondi E, Evans R, Mischler M, et al. Epidemiology of
bacteremia in febrile infants in the United States. Pediatrics.
2013;132(6):990-996.
DOI: https://doi.org/10.1542/peds.2013-1759
• Greenhow TL, Hung YY, Herz AM, et al. The changing epi-
demiology of serious bacterial infections in young infants.
Pediatr Infect Dis J. 2014;33(6):595-599.
DOI: https://doi.org/10.1097/INF.0000000000000225
Pediatric Emergency Medicine Practice • July 2019
• Krief WI, Levine DA, Platt SL, et al. Influenza virus infection
and the risk of serious bacterial infections in young febrile
infants. Pediatrics. 2009;124(1):30-39.
DOI: https://doi.org/10.1542/peds.2008-2915
• Hui C, Neto G, Tsertsvadze A, et al. Diagnosis and man-
agement of febrile infants (0-3 months). Evid Rep Technol
Assess (Full Rep). 2012;(205):1-297.
https://www.ncbi.nlm.nih.gov/pubmed/24422856
• Biondi EA, Byington CL. Evaluation and management of
febrile, well-appearing young infants. Infect Dis Clin North
Am. 2015;29(3):575-585.
DOI: https://doi.org/10.1016/j.idc.2015.05.008
• Gomez B, Mintegi S, Bressan S, et al. Validation of the
"Step-by-Step" approach in the management of young
febrile infants. Pediatrics. 2016;138(2):e20154381.
DOI: https://doi.org/10.1542/peds.2015-4381
Copyright © MDCalc • Reprinted with permission.
CD3 Copyright © 2019 EB Medicine. All rights reserved.
 Step-by-Step Approach to
Febrile Infants
The Step-by-Step approach to febrile infants identifies febrile
infants aged ≤ 90 days who are at low risk for invasive bacterial
Click the thumbnail above
to access the calculator. infections.
Points & Pearls
• The Step-by-Step approach was developed with
the goal of identifying febrile infants aged
≤ 90 days who are at low risk of invasive bacterial
infection (defined as bacteremia or meningitis).
• It was only studied in previously healthy infants
and does not apply to infants who have any prior
medical history.
• The Step-by-Step approach should be used in
previously healthy infants aged ≤ 90 days who
present with fever without a source.
• In the original study by Mintegi et al (2014), “fe-
ver without a source” was defined as fever in an
infant with an unremarkable physical examination
and without signs or symptoms of a self-limiting
viral illness such as bronchiolitis or gastroenteritis.
• Differences in the prevalence of invasive bacterial
infection (IBI) versus noninvasive bacterial infec-
tion in each risk subgroup should also be taken
into consideration when interpreting and apply-
ing the results of the original study.
• The Step-by-Step approach performs best when
applied to infants with fever lasting > 2 hours
because the rule relies on the detection of in-
flammatory markers (procalcitonin and C-reactive
protein) that may take time to increase.
Critical Action
No decision rule should trump clinical gestalt. High
suspicion for IBI in a febrile infant should warrant a
full sepsis workup.
Evidence Appraisal
Gomez et al (2016) conducted a prospective valida-
tion study of previously derived criteria, which they ap-
plied to 2185 infants aged ≤ 90 days who presented
to pediatric emergency departments at 11 European
hospitals. Among this group, 3.9% were diagnosed
with an IBI and 19.1% were diagnosed with a noninva-
sive bacterial infection such as urinary tract infection.
CALCULATOR REVIEW AUTHOR
Emily Heikamp, MD, PhD
Department of Pediatrics, Section of Hematology-
Oncology, Baylor College of Medicine/Texas Children's
Hospital, Houston, TX
CD4 www.ebmedicine.net
In a post-hoc analysis, the Step-by-Step ap-
proach demonstrated superior sensitivity and nega-
tive predictive value as compared to other risk as-
sessment tools such as the Rochester criteria and the
Lab-score (Shaughnessy 2016). Sensitivity and nega-
tive predictive value for ruling out IBI were 92.0%
and 99.3% for the Step-by-Step approach, 81.6%
and 98.3% for the Rochester criteria, and 59.8% and
98.1% for the Lab-score, respectively.
Use the Calculator Now
Click here to access Step-by-Step on MDCalc.
Calculator Creator
Santiago Mintegi, MD, PhD.
Click here to read more about Dr. Mintegi.
References
Original/Primary Reference
• Mintegi S, Bressan S, Gomez B, et al. Accuracy of a sequential
approach to identify young febrile infants at low risk for inva-
sive bacterial infection. Emerg Med J. 2014;31(e1):e19-e24.
DOI: https://doi.org/10.1136/emermed-2013-202449
Validation Reference
• Gomez B, Mintegi S, Bressan S, et al. Validation of the
"Step-by-Step" approach in the management of young
febrile infants. Pediatrics. 2016;138(2):e20154381.
DOI: https://doi.org/10.1542/peds.2015-4381
Other References
• Aronson PL, Neuman MI. Should we evaluate febrile young
infants step-by-step in the emergency department?. Pediat-
rics. 2016;138(2):e20161579.
DOI: https://doi.org/10.1542/peds.2016-1579
• Shaughnessy AF. Step-By-Step approach to ruling out infant
infection is accurate. Am Fam Physician. 2016;94(11):933.
https://www.aafp.org/afp/2016/1201/p933.html
• Dieckmann RA, Brownstein D, Gausche-Hill M. The pediatric
assessment triangle: a novel approach for the rapid evalu-
ation of children. Pediatr Emerg Care. 2010;26(4):312-315.
DOI: https://doi.org/10.1097/PEC.0b013e3181d6db37
• Biondi EA, Byington CL. Evaluation and management of
febrile, well-appearing young infants. Infect Dis Clin North
Am. 2015;29(3):575-585.
DOI: https://doi.org/10.1016/j.idc.2015.05.008
• Biondi EA, Mischler MM, Jerardi KE, et al. Blood culture
time to positivity in febrile infants with bacteremia. JAMA
Pediatrics. 2014;168(9): 844-849.
DOI: https://doi.org/10.1001/jamapediatrics.2014.895
• Powell EC, Mahajan PV, Roosevelt G, et al. Epidemiology of
bacteremia in febrile infants aged 60 days and younger. Ann
Emerg Med. 2018;71(2):211-216.
DOI: https://doi.org/10.1016/j.annemergmed.2017.07.488
 Why to Use
The etiology of fever in infants aged ≤ 90 days can range from self-limiting viral illness (eg, bronchiolitis)
to life-threatening IBI (eg, bacteremia or meningitis). The Step-by-Step approach can be used to rule out
IBI with a high negative predictive value (99.3%). If IBI can be safely ruled out, these low-risk infants do not
require hospital admission and intravenous antibiotics.

When to Use
• The Step-by-Step approach can be used in previously healthy infants aged ≤ 90 days who have a fever
≥ 38.0°C (≥ 100.4°F) documented at home or at presentation in the ED.
• Caution is advised when using the Step-by-Step approach in infants with a short duration of fever, as it
takes time for serum inflammatory markers (eg, procalcitonin, to increase). Observation in the ED should
be considered, even if laboratory values are initially normal.
• Caution is advised when using the Step-by-Step approach in infants aged 21 to 28 days, as the
management of this age group remains controversial and the Step-by-Step algorithm did not perform
optimally in this group. In the validation study by Gomez et al (2016), 4 out of the 7 patients (57%) who
were not identified as high risk by the Step-by-Step approach but were diagnosed with an IBI were aged
21 to 28 days. Studies suggest that the prevalence of bacteremia may be higher in infants aged 21 to 28
days as compared to infants aged > 28 days, so a full sepsis workup is recommended for any infant aged
< 28 days (Powell 2018).

Next Steps
Interpretation
Risk Group IBI Risk Recommendation
Low 0.7% Full sepsis workup is likely not needed. Consider a period of ED observation,
especially if the fever lasts < 2 hours, and ensure outpatient follow-up with a
pediatrician.
Intermediate 3.4% Full sepsis workup (including blood, urine, and cerebrospinal fluid cultures),
initiation of broad-spectrum intravenous antibiotics, and inpatient hospital
admission may be indicated, especially if the patient is aged 21 to 28 days.

High 8.1% Full sepsis workup (including blood, urine, and cerebrospinal fluid cultures),
initiation of broad-spectrum intravenous antibiotics, chest x-ray, and inpatient
hospital admission are recommended.

Management of IBI in Infants:

• Prompt initiation of broad-spectrum antibiotics according to local guidelines is strongly recommended.
• Optimization of respiratory support and hemodynamics should be initiated if respiratory distress or signs
of dehydration or shock are present.
• Inpatient hospital admission for a minimum of 36 to 48 hours is recommended if cultures remain
negative. Studies indicate that if IBI is present, 96% of blood cultures will become positive within 36
hours and 99% will become positive within 48 hours (Biondi 2014, Biondi 2015).

Abbreviations: ED, emergency department; IBI, invasive bacterial infection.

Copyright © MDCalc • Reprinted with permission.

Pediatric Emergency Medicine Practice • July 2019 CD5 Copyright © 2019 EB Medicine. All rights reserved.
 PECARN Rule for Low-Risk
Febrile Infants
The PECARN rule for low-risk febrile infants predicts the risk
for urinary tract infection, bacteremia, or bacterial meningitis in
Click the thumbnail above
to access the calculator. febrile infants aged ≤ 60 days.
Points & Pearls
• The PECARN (Pediatric Emergency Care Ap-
plied Research Network) prediction rule does
not apply to ill-appearing infants. The rule is
intended to be one directional: it may help rule
out serious bacterial infection (SBI) in patients
who are “low risk,” but the converse is not true
(ie, patients who are “not low risk” according
to the rule do not necessarily have an SBI).
• Infants with signs of shock or who are oth-
erwise ill-appearing or unstable should be
considered at to be at high risk for SBI and
in most cases should have blood, urine, and
cerebrospinal fluid cultures performed. This
clinical prediction rule would not apply to such
patients.
• A serum procalcitonin level is required for the
PECARN prediction rule, but this test may not
be rapidly available in all settings.
• The majority of infants aged ≤ 60 days are
unvaccinated and have immature immune
systems.
• Infants aged < 28 days warrant special atten-
tion, as they are at elevated risk for herpes
meningoencephalitis as well as a more rapid
progression of disease. These patients almost
always require admission for close monitor-
ing along with a full sepsis workup, including
lumbar puncture.
Critical Actions
Consider a critical congenital heart defect (and
empiric prostaglandin treatment) in a neonate who
presents in shock.
CALCULATOR REVIEW AUTHORS
Derek Tam, MD, MPH
Department of Pediatrics, Maimonides Medical Center,
Brooklyn, NY
Hector Vazquez, MD
Department of Emergency Medicine, Maimonides
Medical Center, Brooklyn, NY
Christopher Tainter, MD, RDMS
Department of Anesthesiology, Division of Critical
Care, Department of Emergency Medicine, University of
California San Diego, San Diego, CA
CD6 www.ebmedicine.net
Evidence Appraisal
The derivation study by Kuppermann et al (2019)
included 1896 previously healthy febrile infants
aged ≤ 60 days who had a serum procalcitonin
level test at the time of their sepsis evaluation;
participants whose procalcitonin samples were
lost or mislabeled were excluded. The overall
cohort was 1821 patients (908 in the derivation
sample and 913 in the validation sample). The
primary outcome was the presence or absence
of an SBI, defined as urinary tract infection,
bacteremia, or bacterial meningitis.
The prediction rule had a sensitivity of 98.8%
(95% confidence interval [CI], 92.5%-99.9%) in
the derivation study and 97.7% sensitivity (95%
CI, 91.3%- 99.6%) in the validation study. The
negative predictive value for SBI was 99.8% (95%
CI, 98.8%-100.0%) and 99.6% (95% CI, 98.4%-
99.9%) in the derivation and validation studies,
respectively. Because the validation study was
not conducted independently, there is a risk of
diminished external validity.
The benefits of using this rule are: (1)
unnecessary admissions may be decreased and
(2) unnecessary lumbar punctures may be
avoided. A key difference in this prediction rule
as compared to other similar rules is that the
sensitivity remained high despite the fact that
lumbar puncture results were not used as criteria
in the rule. However, there is a low prevalence
of bacterial meningitis in the general population
due to the use of Haemophilus influenzae type
B and pneumococcal vaccinations, so there were
few cases of bacterial meningitis included in this
study’s data set.
Finally, 3 infants in the study were
misclassified by the prediction rule as being at low
risk but had SBIs (2 had a urinary tract infection
and 1 had Enterobacter cloacae bacteremia). All
3 were treated appropriately based on culture
results and had uneventful clinical courses.
Use the Calculator Now
Click here to access the PECARN rule on MDCalc.
Calculator Creator
Nathan Kuppermann, MD, MPH
Click here to read more about Dr. Kuppermann.
 Why to Use
A physical examination alone is unreliable in ruling out SBI in febrile infants. The PECARN prediction rule
may help to decrease unnecessary admissions and/or lumbar punctures. It can be used to help determine
the disposition of some well-appearing infants who have reliable access to follow-up with a primary care pe-
diatrician or in the same ED in 24 hours, or whose caregivers can be relied upon to return the patient to the
ED if a pending culture has a positive result.

When to Use
Use the PECARN prediction rule in well-appearing infants aged ≤ 60 days, to stratify the risk of SBI (defined as
urinary tract infection, bacteremia, or bacterial meningitis).

Next Steps
• Patients predicted to be at low risk for SBI might be able to be safely discharged from the ED, as long as
follow up with a primary care pediatrician or in the same ED can be reasonably well assured.
• The decision to admit a febrile infant is multifactorial. Lack of reliable follow-up care may necessitate
admission.

Advice
Some well-appearing infants considered to be at low risk for SBI may be suitable for discharge from the ED
with follow-up with their primary care pediatrician or in the same ED in 24 hours for reassessment, as op-
posed to the traditional practice of admitting all febrile infants aged 0 to 60 days.

Abbreviations: ED, emergency department; PECARN, Pediatric Emergency Care Applied Research Network; SBI, serious bacterial infection.

Reference Copyright © MDCalc • Reprinted with permission.

Original/Primary Reference
• Kuppermann N, Dayan PS, Levine DA, et al. A clinical pre-
diction rule to identify febrile infants 60 days and younger
at low risk for serious bacterial infections. JAMA Pediatr.
2019;173(4):342-351.
DOI: https://doi.org/10.1001/jamapediatrics.2018.5501

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