Clinical Review & Education

Review

Evaluation and Management of Febrile Children

A Review
Leigh-Anne Cioffredi, MD; Ravi Jhaveri, MD

IMPORTANCE Management of febrile children is an intrinsic aspect of pediatric practice.

Febrile children account for 15% of emergency department visits and outcomes range from
the presence of serious bacterial infection to benign self-limited illness.
OBSERVATIONS Studies from 1979 to 2015 examining febrile infants and children were
included in this review. Management of febrile infants younger than 90 days has evolved
considerably in the last 30 years. Increased rates of Escherichia coli urinary tract infections,
increasing resistance to ampicillin, and advances in viral diagnostics have had an effect on the
approach to caring for these patients. Widespread vaccination with conjugate vaccines
against Haemophilus influenzae and Streptococcus pneumoniae has virtually eliminated the
concern for bacterial infections in children aged 3 to 36 months. Urinary tract infections still
remain a concern in febrile infants of all ages.
CONCLUSIONS AND RELEVANCE Advances over the last 30 years allow for more precise risk
stratification for infants at high risk of serious bacterial infection. With appropriate testing at
the initial visit, much of the diagnostic testing and empirical treatment can be avoided for
infants younger than 90 days. In the vaccinated child aged 3 to 36 months, the only bacterial
infection of concern is urinary tract infection.
JAMA Pediatr. doi:10.1001/jamapediatrics.2016.0596
Published online June 20, 2016.

he management of febrile children accounts for 15% of

emergency department visits but remains a controversial
subject among health care professionals.1 Although most
infants with fever have a self-limiting illness that requires supportive care, a small percentage will have serious bacterial illness (SBI)
that, if untreated, could result in significant morbidity or mortality.
This review summarizes the progress made and current practices
in the evaluation and treatment of febrile children, offers guidance
for management, and examines some unanswered questions and
future directions.
The epidemiologic features of infants and children with fever
are markedly different depending on the age at presentation. Given
this fact, the discussion first focuses on patients aged 3 to 36 months
and shifts to those younger than 3 months.

Children Aged 3 to 36 Months

History and Epidemiologic Features
Before universal vaccination for Haemophilus influenzae type b (Hib)
and Streptococcus pneumoniae, 3% to 15% of older infants and toddlers presenting with fever had bacteremia.2-4 The most common
causes were S pneumoniae and Hib, but also included Salmonella
species.2 Occasionally, older infants who had fever without signs or
symptoms had blood cultures positive for Hib and S pneumoniae,
an entity termed occult bacteremia. A small subset of these chiljamapediatrics.com

Author Affiliations: Division of

General Pediatrics and Adolescent
Medicine, University of North
Carolina at Chapel Hill School of
Medicine, Chapel Hill (Cioffredi);
Division of Infectious Diseases,
Department of Pediatrics, University
of North Carolina at Chapel Hill
School of Medicine, Chapel Hill
(Jhaveri).
Corresponding Author: Ravi Jhaveri,
MD, Division of Infectious Diseases,
Department of Pediatrics, University
of North Carolina at Chapel Hill
School of Medicine, 101 Manning Dr,
Campus Box 7509, Chapel Hill, NC
27599 (ravi.jhaveri@unc.edu).

dren developed invasive infections, including pneumonia, osteomyelitis, and meningitis, but most had treatment outcomes that were
benign.5,6 The concern for occult bacteremia and the risk of subsequent associated morbidity led many health care professionals to
obtain blood cultures and start empirical antibiotics in children with
fever without focal examination findings.2,7 With widespread use of
the Hib vaccine, Hib bacteremia nearly disappeared.8,9 Subsequent 7-valent and 13-valent conjugate vaccines for S pneumoniae
led to greater than 50% reductions in S pneumoniaerelated
bacteremia.10 As a result, occult bacteremia has also disappeared.11-13
Routine vaccination against Hib and S pneumoniae also resulted in decreased incidence of bacterial meningitis. After routine
use of the Hib vaccine, the incidence of Hib meningitis decreased
by 99% in children younger than 5 years.14 Subsequently, the development of the pneumococcal vaccines decreased the incidence
of meningitis caused by S pneumoniae considerably. Castelblanco
et al15 describe an 83% decreased incidence between 1997 and 2010.
Olarte et al16 describe continued reductions in S pneumoniae meningitis from 2010 to 2013 with the switch from 7-valent to 13-valent
pneumococcal conjugate vaccine.
Although not directly owing to vaccination, rates of infection
with Neisseria meningitidis have also declined to historically low
levels.17 Although this pathogen was never the most prevalent, meningococcal bacteremia was most likely to lead to meningitis and
many clinicians experienced cases in the past in which children with
fever discharged from the emergency department returned in shock.
(Reprinted) JAMA Pediatrics Published online June 20, 2016

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: http://archpedi.jamanetwork.com/ by a GLASGOW UNIVERSITY LIBRARY User on 06/20/2016

E1

Clinical Review & Education Review

Evaluation and Management of Febrile Children

Cases of meningococcal bacteremia continue to decline and do not

warrant specific changes in management.17-19
Urinary tract infection (UTI) is the most prevalent SBI without
localizing signs of infection in vaccinated children.11 Although UTIs
and pyelonephritis can present symptomatically, they frequently present in children aged 3 to 36 months without specific symptoms. Unrecognized UTIs can result in permanent renal damage, and in severe cases, lead to renal failure. Although the overall prevalence of
UTI in children with fever without a source of infection is 3% to 8%,
certain groups are at higher risk.11,20-22 Prevalence is as high as 17%
in white girls younger than 2 years with fever without a source of
infection. Uncircumcised males are also at increased risk.21,23,24 Although viral infection is the most common overall cause of fever in
this group, identification of a viral infection does not exclude a concurrent UTI.25-28 Therefore, urinalysis and culture should remain a
standard part of the workup for toddlers with fever without a source
of infection.29

Management Recommendations
Children in this age group with fever, evidence of viral illness, and/or
normal findings from the urinalysis do not require empirical therapy.
In patients with localizing signs of infection (otitis media, skin and
soft-tissue infections, enteritis, and pneumonia), evaluation should
be guided by the presenting symptoms. These infections rarely occur without signs and symptoms, particularly in patients older than
3 months. For children with fever without localizing signs of infection, given that the odds of identifying a contaminant is 100 times
more likely than identifying a true pathogen, management has
moved away from evaluation of complete blood cell counts, blood
cultures, and empirical antibiotics of any kind.11-13
When managing a child who has received fewer than 2 doses
each of Hib and S pneumoniae vaccines, management reverts to the
more comprehensive evaluation of complete blood cell counts, blood
cultures, and sometimes examinations of cerebrospinal fluid. The
same guidance applies for children with immune deficiencies, acquired or hereditary, as they are overrepresented among patients
with S pneumoniae bacteremia.30,31 These children also warrant
evaluation for bacteremia or other SBI.

Infants Younger Than 3 Months

History and Epidemiologic Features
Studies estimate the incidence of SBI in febrile infants younger than
3 months is 9% to 14%.22,32,33 Epidemiologic features of SBI in this
population have also changed in the past 10 years. Studies conducted before 2000 reported a higher proportion of bacteremia and
meningitis than do current studies, with UTIs accounting for 30%
to 55% of SBI22; UTIs now account for 75% to 84% of serious infections in infants, while the incidence of isolated bacteremia is 6% to
13%.22,34 With the increase in UTIs, Escherichia coli has become the
dominant pathogen causing SBI in infants.22,33-36
Although the incidence of UTIs remains high, the natural history is strikingly different than in meningitis or bacteremia. With empirical treatment, infants younger than 60 days with UTI typically
become afebrile within 24 hours, and the need for intensive care unit
level care is exceedingly rare.36 However, recognition and treatment of UTIs is crucial, as it can lead to identification of correctable
E2

underlying pathologic conditions such as vesicoureteral reflux or urinary tract anomalies. The most recent revision of the American Academy of Pediatrics guidelines for management of UTIs with fever acknowledges the importance of evaluating children with fever without
localizing symptoms by conducting urinalysis and urine culture before administration of antibiotics.29 In addition, they advise performing renal ultrasonography to evaluate for anatomical anomalies requiring surgical intervention.
Although overall risk for SBI is increased in infants younger than
3 months compared with older infants, there is variation in risk among
this age group as well. Infants younger than 28 days are at higher
risk of SBI than infants aged 28 to 90 days.37-39 Historically, guidelines have acknowledged this increased risk and treated neonates
more conservatively.
Although the mechanism of relative immunodeficiency of the
neonate is unknown, immaturity of T-cell function may play a significant role. Reproducible evidence demonstrates that neonatal
T-cells express significantly less CD40 ligand than do T-cells from
older individuals. CD40 is critical in communication between
T-cells and B-cells that promote antibody class switching in response to antigenic insult, and the deficiency may partially account for the increased neonatal susceptibility to infection.40-43
Although some infants with SBI will appear very ill (toxic), many
present without localizing signs of infection. Owing to concern about
not identifying SBI in infants younger than 3 months, it had been common practice to admit all febrile patients aged 8 weeks or younger,
obtain laboratory evaluation and blood cultures, and treat them empirically for SBI.5,44,45 This practice decreases the risk of failing to treat
infants with a potentially serious illness, but comes with significant
cost and potential complications.
Researchers have continued to investigate better methods of
identifying infants at high risk of SBI and decreasing unnecessary
treatment and hospitalization of those at low risk. One of the first
studies to establish clinical predictors of risk of SBI in infants younger
than 3 months, published in 1985, outlined what became known as
the Rochester criteria.4 Infants were considered low risk if they were
well appearing, did not have evidence of focal infection, and met the
following criteria: white blood cell count of 5 to 15 000/L, with less
than 1500 bands/L (to convert to 109/L, multiply by 0.001) and
normal urinalysis findings. A total of 144 of 233 infants (61.8%) met
low-risk criteria for SBI, and of these, 1 (0.7%) had an SBI, compared with 22 of 89 infants (25%) classified as high risk.
The Rochester criteria continue to be used by many health care
professionals because, even though they do not rely on cerebrospinal fluid parameters, their negative predictive value is 99%.4 A major limitation of the Rochester criteria is that they included only fullterm infants with no significant medical history. For premature infants
or infants with medical conditions, modified criteria (Boston criteria46
and Philadelphia criteria47) are available for those presenting after
28 days of life (Table). In 1993, Baraff et al45 offered expert opinion
recommending a complete evaluation for sepsis, including blood culture, urine culture, and lumbar puncture, followed by admission for
empirical antibiotic treatment for all infants with fever younger than
28 days. These recommendations were used as guidelines by many
but were not endorsed as policy until the American College of Emergency Physicians reiterated this recommendation in 2003.48
There is significant variation among inpatient and outpatient clinicians who evaluate and treat neonates with fever. Pantell et al39

JAMA Pediatrics Published online June 20, 2016 (Reprinted)

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: http://archpedi.jamanetwork.com/ by a GLASGOW UNIVERSITY LIBRARY User on 06/20/2016

jamapediatrics.com

Evaluation and Management of Febrile Children

Review Clinical Review & Education

Table. Summary of Low-Risk Stratification Criteria for Febrile Infants

Criteria
Characteristic

Rochester4

Philadelphia47

Boston46

Benefits

Can use in patients <28 d

Does not require CSF
evaluation

Can use in patients who were

not term or who have
previously diagnosed medical
conditions

Can use in patients who

were not term or who
have previously diagnosed
medical conditions

Drawbacks

Patients must be term

infants without medical
conditions

Patients must be >28 d

Patients must be >28 d

Low-risk criteria

WBC 5000-15 000/L

Bands <1500/mm3
UA <10 WBC/hpf
Fecal leukocytes <5
WBC/hpf (if diarrhea
is present)

WBC <20 000/L

Band-to-neutrophil ratio <0.2
UA <10 WBC/hpf
Urine Gram stain result
negative
CSF <8 WBC/L
CSF Gram stain result negative
Normal chest radiograph result
Fecal leukocytes 0 to few
(if diarrhea is present)

WBC <15 000/L

UA <10 WBC/hpf
CSF <10 WBC/L
Normal chest radiograph
result

published the Pediatric Research in Office Settings study documenting equivalent outcomes for febrile infants who were managed conservatively in office-based settings. A recent retrospective review
across 36 pediatric emergency departments demonstrated that
369 of 2253 neonates with fever (16.4%) were discharged from
the emergency department, with only 1 patient (0.3%) returning
with SBI.49 The ability to assess risk in neonates continues to be
controversial.50-53 Just as much variation exists in the treatment of
patients admitted for evaluation for sepsis, where choice of antibiotics and duration of treatment vary widely between institutions and
among clinicians. Although some clinicians are comfortable observing the patient for 24 hours, others require 72 hours for stable infants who have negative blood culture results before discontinuing
antibiotics. Recent evidence indicates that if pathogenic bacteria are
present, 96% of blood culture results become positive by 36 hours
and 91% are positive by 24 hours.54 Observation for 36 hours while
receiving antibiotics should be adequate to identify nearly all infants infected with SBI.
Several major changes affecting the management of febrile neonates are worth a detailed discussion: greater understanding of a viral diagnosis and the subsequent risk of SBI, decreased incidence of
early-onset group B streptococcal infection, decreased incidence
of Listeria infection, and subsequent increasing incidence of ampicillin-resistant organisms.

Viral Diagnosis and Risk of SBI

Despite relying on older, less-sensitive culture techniques, the Rochester study reported that 101 of 144 infants (70.1%) considered to
be low risk had a viral illness.4 Most infections (78 of 137 [56.9%])
were enterovirus, followed by respiratory syncytial virus (RSV) (32
of 137 [23.4%]) and influenza (15 of 137 [10.9%]). Viral infections were
also common in the high-risk group, with 36 of 89 patients (40%)
having a viral pathogen. The ability to incorporate viral studies into
the risk criteria was limited by the lack of timely results.
Viral detection has now expanded well beyond culture, past
rapid antigen detection and direct fluorescent antibody testing to
polymerase chain reaction (PCR). This change has led many to investigate the rate of concomitant viral infection with SBI. In 2004,
Levine et al27 reported a prospective study investigating risk of SBI
in infants with RSV. Their results demonstrated that infants with RSV
did not have concurrent meningitis or bacteremia, but 5.4% did have
jamapediatrics.com

Abbreviations: CSF, cerebrospinal

fluid; hpf, high power field;
UA, urinalysis; WBC, white blood
cells.
SI conversion factor: To convert WBC
count and bands to 109/L, multiply
by 0.001.

UTIs. These results suggested that once the diagnosis of RSV was
made, the risk of SBI other than UTIs was essentially zero.
Enterovirus is frequently responsible for febrile illness in young
infants, accounting for 40% to 50% of cases during the summer.55
Rittichier et al56 describe a cohort of 214 infants with fever and
enterovirus infection, of whom 12 (5.6%) had concurrent UTI and
3 (1.4%) had bacteremia; most (13 [86.7%]) of the 15 infants with
coexisting SBI were classified as high risk.
The predictive value of influenza and SBI has been investigated in recent years. Studies indicate the rate of SBI in febrile
infants is significantly lower with known influenza infection than in
those negative for influenza.26,57 Analogous to RSV studies, they
confirm very low rates of bacteremia and detectable rates of UTI in
infants with influenza.26,57
With mounting evidence that a confirmed viral infection reduces the risk of SBI, this information has become more codified in
risk stratification criteria. Byington et al25 confirmed evidence that
any viral infection combined with the Rochester criteria further delineates risk of SBI. If results of viral testing are rapidly available, they
can be used with the Rochester criteria to direct the management
of febrile infants. An evaluation algorithm incorporating rapid viral
testing into risk stratification criteria has decreased the length of a
hospital stay, time exposed to antibiotics, and cost.32
In a recent epidemiologic study using new multiplex testing
methods, Byington et al58 reported the prevalence and persistence of respiratory viruses in the general population. Children are
more likely to have positive test results for viral infection in the household, and rates of viral infections increased with the number of children in the household and with decreasing age of children. Most episodes of viral infection detected by PCR persisted for less than
2 weeks, but some viruses were detected by PCR after 3 weeks, well
after symptoms had resolved.58 This finding supports evidence that
most febrile illnesses in children are viral infections but should also
caution health care professionals that not every PCR-positive detection is reliable for management decisions.

Decreasing Incidence of Group B Streptococcus

Screening pregnant women for group B streptococcus (GBS) between 35 and 37 weeks gestation to prevent early-onset sepsis has
been recommended by the Centers for Disease Control and Prevention since 1996.59-61 This screening regimen in combination with in(Reprinted) JAMA Pediatrics Published online June 20, 2016

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: http://archpedi.jamanetwork.com/ by a GLASGOW UNIVERSITY LIBRARY User on 06/20/2016

E3

Clinical Review & Education Review

Evaluation and Management of Febrile Children

trapartum prophylactic antibiotic treatments has decreased incidence of early-onset GBS infection from 1.8 of 1000 live births in
1990 to 0.32 of 1000 live births in 2003.62 However, these efforts
have not changed the incidence of late-onset GBS infection.63 Mothers of infants with late-onset GBS are more likely to be carriers of
GBS at the time of diagnosis than at the time of antenatal screening.63
Although mortality from late-onset GBS is lower than from earlyonset disease, morbidity still involves developmental delay, cerebrovascular changes, hearing loss, or intellectual disability. Empirical treatment for febrile infants who are at high risk of bacterial
infection should continue to cover GBS.

Listeria
Although Listeria infection had been relatively prevalent, with 1.76
cases of perinatal infection per 10 000 children younger than 1 year
in 1989, the incidence has fallen drastically.64 By 1993, surveillance
data indicated the incidence of perinatal listeriosis had decreased
by 51% to 0.86 cases per 10 000 children younger than 1 year. In
the past 10 years, numerous studies examining the causes of neonatal SBI show an absence of Listeria infection in infants younger than
60 days. These studies span the United States and include large academic hospitals and smaller community hospitals.22,27,33,34,37,65-67
We previously hypothesized that widespread use of intrapartum
antibiotics against GBS may have been a contributor to decreased
cases of listeriosis. The Pediatric Health Information Systems database has demonstrated that reductions in rates of listeriosis in infants significantly correlate with decreases in early-onset GBS and
likely represent a collateral benefit.33,68 These results indicate that
Listeria infection is rare in infants; however, most studies represent
retrospective evaluations. Large prospective trials would be necessary to evaluate the true incidence of Listeria infections in the neonatal period.

Ampicillin Resistance
Intrapartum prophylaxis is important in decreasing early-onset GBS,
but the widespread use of ampicillin for prophylaxis has been shown
to increase the risk of early-onset sepsis owing to ampicillinresistant pathogens. Puopolo and Eichenwald69 describe increasing proportions of ampicillin-resistant pathogens cultured from neonates since the widespread use of ampicillin for intrapartum
prophylaxis. The 2 largest risk factors for ampicillin-resistant bacteria were maternal exposure to ampicillin and length of that exposure. The 2010 Centers for Disease Control and Prevention guidelines for intrapartum prophylaxis recommend either penicillin
G potassium or sodium or ampicillin, so use varies based on hospital culture and protocol.59 Infants born to mothers who received prophylaxis with penicillin or other gram-positive agents, such as clindamycin phosphate, did not show an increased risk of infection with
ampicillin-resistant organisms.69
Current literature indicates the rates of ampicillin resistance
in pathogens causing invasive disease in infants younger than
90 days are increasing, with 36% to 60% of pathogens having
resistance.34,37,65 Since E coli represents the most common pathogen causing disease in febrile neonates, the increasing resistance to
ampicillin has sparked debate about the role of ampicillin in empirical treatment of SBI in infants. Those who advocate for it generally
do so because the principles of antibiotic stewardship would dictate that third-generation cephalosporins should not be used in this
E4

situation and ampicillin is first-line treatment for Enterococcus

while also covering Listeria.70 In addition, ampicillin may work synergistically with gentamicin sulfate in the treatment of GBS. Those
who advocate against the use of ampicillin express concern that
with a growing percentage of cases of ampicillin-resistant E coli, the
small percentage of infants with E colirelated UTI and concurrent
bacteremia who receive ampicillin and gentamicin will effectively
be receiving gentamicin monotherapy for bacteremia.33,65 Use of a
third-generation cephalosporin as empirical therapy would offer
adequate coverage for that subset of infants. To our knowledge,
there are no specific outcomes studies directly comparing one regimen with the other in this population of healthy infants. An oftencited study performed in the neonatal intensive care setting
showed increased mortality when a third-generation cephalosporin
was used as empirical therapy.71 The prolonged length of stay,
repeated courses of antibiotics, and potential exposure to resistant
organisms make this study difficult to extrapolate to otherwise
healthy febrile infants seen in the office or emergency department.
Although no answer is immediately forthcoming, with the increasing prevalence of ampicillin-resistant E coli, it is essential to know
local resistance patterns and consider using a third-generation
cephalosporin for empirical treatment of febrile infants if ampicillin
resistance is above 40% to 50%.

Management Recommendations
Despite all the previously described advances and developments,
management recommendations still focus on careful physical
examination, age of the infant, and clinical and laboratory criteria.
For infants younger than 28 to 30 days, the risk of SBI is still higher
and a more conservative approach can be justified. This approach
would include a complete blood cell count, urinalysis, blood and
urine cultures, and lumbar puncture. Empirical antibiotics that
include the combinations of ampicillin and gentamicin or ampicillin
and cefotaxime sodium or cefotaxime alone would all be appropriate. Maximizing the use of available viral diagnostics could preempt
many of the above recommendations if a test result is positive in
the appropriate clinical scenario (eg, positive RSV test result in an
infant in February [peak RSV season] with a toddler sibling with
respiratory tract symptoms). Because of the prolonged detection
of several respiratory viruses (rhinovirus, coronavirus) in a recent
study,58 these results may not allow for infants to be discharged
from care.
Although some are comfortable observing patients for 24 hours,
others require 72 hours for stable infants who have negative blood
culture results before discontinuing antibiotics. Recent evidence indicates if pathogenic bacteria are present, 96% of blood culture results become positive by 36 hours and 91% are positive by 24
hours.54 Therefore, observation while receiving antibiotics for 36
hours is adequate to identify nearly all infants infected with pathogenic organisms.
For infants aged 30 to 90 days, the risk of SBI declines, except
for UTIs. Prioritizing viral testing and urinalysis or urine culture may
preempt the rest of the evaluation. The empirical use of ampicillin
in this group of infants becomes even harder to justify given the lack
of cases of Listeria infection and the rising rate of ampicillin resistance. For an infant of any age who presents with signs and symptoms that suggest sepsis or a toxic appearance, a full evaluation and
prompt empirical antibiotics are indicated.

JAMA Pediatrics Published online June 20, 2016 (Reprinted)

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: http://archpedi.jamanetwork.com/ by a GLASGOW UNIVERSITY LIBRARY User on 06/20/2016

jamapediatrics.com

Evaluation and Management of Febrile Children

Review Clinical Review & Education

Recent Developments and Future Directions

Several advances are taking place that will likely offer meaningful advances in management of febrile infants. Although there have been
meaningful changes in specific viral diagnostics, recent growth of
multiplex testing for respiratory viruses offers the advantage of rapid
and simultaneous detection of many viruses. Although the longitudinal experience continues to grow with these assays for routine detection during acute respiratory illnesses, there are few specific outcomes studies to demonstrate that a positive result for a specific virus
reliably means that no bacterial pathogen is subsequently detected and that the specific virus was the only identified cause of
fever in that infant. These studies are ongoing and likely to yield the
expected outcomes for risk stratification, but until they reach the
same level of evidence that has been achieved by individual testing
for RSV, influenza, and enterovirus, clinicians cannot yet confidently avoid the rest of the evaluation.
In addition to increasing the efficiency of identifying viral
pathogens, new strategies using host-based gene-expression signatures to discern whether a child is infected with a viral or bacterial pathogen are being developed. Zaas et al72 have developed a
reverse transcriptase PCR assay designed to use changes in host
immune response to identify whether an infection is viral or bacterial. They have tested the assay in adults experimentally infected
with influenza and successfully classified patients infection as viral
or nonviral. Similarly, Mejias et al73 used whole blood gene expression to characterize severity of disease in infants infected with RSV
and compare the specificity of gene expression profiles for RSV
against those of infants with influenza and rhinovirus. They demonstrated that gene expression profiles could perform as a biomarker
for RSV infection and had the potential for use as an early diagnos-

ARTICLE INFORMATION
Accepted for Publication: February 25, 2016.
Published Online: June 20, 2016.
doi:10.1001/jamapediatrics.2016.0596.
Author Contributions: Drs Cioffredi and Jhaveri
had full access to all the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Both authors.
Acquisition, analysis, or interpretation of data: Both
authors.
Drafting of the manuscript: Both authors.
Critical revision of the manuscript for important
intellectual content: Jhaveri.
Study supervision: Jhaveri.
Conflict of Interest Disclosures: Dr Jhaveri
reported receiving grant support from GenMark.
No other disclosures were reported.
Additional Contributions: Melissa Miller, PhD,
Department of Pathology and Laboratory Medicine,
University of North Carolina at Chapel Hill School of
Medicine, provided support for research on this
study. She was not compensated for her
contribution.
REFERENCES
1. Niska R, Bhuiya F, Xu J. National Hospital
Ambulatory Medical Care Survey: 2007 emergency

jamapediatrics.com

tic tool. This group has planned prospective studies in febrile

infants and has performed feasibility studies collecting blood from
febrile infants in the emergency department. 74 Given these
advances in rapid diagnostics that are pathogen based and host
based, it is possible that soon, a clinician managing a febrile infant
would be able to obtain a nasopharyngeal swab, small-volume
blood sample, and urine sample. The infant would remain in a
short-stay emergency department or urgent care setting without
formal admission. In a matter of minutes to hours, a result could be
available that would suggest a viral cause for the illness. If that was
the case, the infant could be discharged with supportive care. If
results of the urine sample suggested a UTI, perhaps the infant
could be discharged with appropriate oral therapy. If the host gene
expression signature was suggestive of a bacterial infection that
was not a UTI, the infant would be admitted and empirical therapy
would be started. This approach offers the promise of a much more
precise determination of high risk or low risk and could deliver the
oft-stated goal of a personalized or precision approach to patient
management.

Conclusions
The epidemiologic features of SBI have changed significantly in the
past 20 years with the introduction and widespread use of vaccines against Hib and S pneumoniae. Management strategies must
continue to evolve to identify the few children with SBI. New diagnostic techniques, such as efficient viral testing and evaluation of
host gene expression profiling, will continue to change the landscape of the evaluation of febrile illness and may supplement
current risk stratification criteria to identify those who may be
observed in the outpatient setting safely in the near future.

department summary. Natl Health Stat Report.

2010;(26):1-31.
2. Jaffe DM, Tanz RR, Davis AT, Henretig F,
Fleisher G. Antibiotic administration to treat
possible occult bacteremia in febrile children.
N Engl J Med. 1987;317(19):1175-1180.
3. Baraff LJ, Oslund SA, Schriger DL, Stephen ML.
Probability of bacterial infections in febrile infants
less than three months of age: a meta-analysis.
Pediatr Infect Dis J. 1992;11(4):257-264.
4. Dagan R, Powell KR, Hall CB, Menegus MA.
Identification of infants unlikely to have serious
bacterial infection although hospitalized for
suspected sepsis. J Pediatr. 1985;107(6):855-860.

8. Lee GM, Harper MB. Risk of bacteremia for

febrile young children in the post-Haemophilus
influenzae type b era. Arch Pediatr Adolesc Med.
1998;152(7):624-628.
9. Bisgard KM, Kao A, Leake J, Strebel PM,
Perkins BA, Wharton M. Haemophilus influenzae
invasive disease in the United States, 1994-1995:
near disappearance of a vaccine-preventable
childhood disease. Emerg Infect Dis. 1998;4(2):
229-237.
10. Herz AM, Greenhow TL, Alcantara J, et al.
Changing epidemiology of outpatient bacteremia in
3- to 36-month-old children after the introduction
of the heptavalent-conjugated pneumococcal
vaccine. Pediatr Infect Dis J. 2006;25(4):293-300.

5. Teele DW, Pelton SI, Grant MJ, et al. Bacteremia

in febrile children under 2 years of age: results of
cultures of blood of 600 consecutive febrile
children seen in a walk-in clinic. J Pediatr. 1975;87
(2):227-230.

11. Waddle E, Jhaveri R. Outcomes of febrile

children without localising signs after
pneumococcal conjugate vaccine. Arch Dis Child.
2009;94(2):144-147.

6. Alpern ER, Alessandrini EA, Bell LM, Shaw KN,

McGowan KL. Occult bacteremia from a pediatric
emergency department: current prevalence, time
to detection, and outcome. Pediatrics. 2000;106
(3):505-511.

12. Wilkinson M, Bulloch B, Smith M. Prevalence of

occult bacteremia in children aged 3 to 36 months
presenting to the emergency department with
fever in the postpneumococcal conjugate vaccine
era. Acad Emerg Med. 2009;16(3):220-225.

7. Myers MG, Wright PF, Smith AL, Smith DH.

Complications of occult pneumococcal bacteremia
in children. J Pediatr. 1974;84(5):656-660.

13. Sard B, Bailey MC, Vinci R. An analysis of

pediatric blood cultures in the postpneumococcal
conjugate vaccine era in a community hospital
emergency department. Pediatr Emerg Care. 2006;
22(5):295-300.

(Reprinted) JAMA Pediatrics Published online June 20, 2016

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: http://archpedi.jamanetwork.com/ by a GLASGOW UNIVERSITY LIBRARY User on 06/20/2016

E5

Clinical Review & Education Review

Evaluation and Management of Febrile Children

14. Centers for Disease Control and Prevention

(CDC). Progress toward eliminating Haemophilus
influenzae type b disease among infants and
childrenUnited States, 1987-1997. MMWR Morb
Mortal Wkly Rep. 1998;47(46):993-998.
15. Castelblanco RL, Lee M, Hasbun R.
Epidemiology of bacterial meningitis in the
USA from 1997 to 2010: a population-based
observational study. Lancet Infect Dis. 2014;14(9):
813-819.
16. Olarte L, Barson WJ, Barson RM, et al. Impact of
the 13-valent pneumococcal conjugate vaccine on
pneumococcal meningitis in US children. Clin Infect
Dis. 2015;61(5):767-775.
17. Cohn AC, MacNeil JR, Harrison LH, et al.
Changes in Neisseria meningitidis disease
epidemiology in the United States, 1998-2007:
implications for prevention of meningococcal
disease. Clin Infect Dis. 2010;50(2):184-191.
18. Shapiro ED, Aaron NH, Wald ER, Chiponis D.
Risk factors for development of bacterial meningitis
among children with occult bacteremia. J Pediatr.
1986;109(1):15-19.
19. Wong VK, Hitchcock W, Mason WH.
Meningococcal infections in children: a review of
100 cases. Pediatr Infect Dis J. 1989;8(4):224-227.
20. Hoberman A, Chao HP, Keller DM, Hickey R,
Davis HW, Ellis D. Prevalence of urinary tract
infection in febrile infants. J Pediatr. 1993;123(1):
17-23.
21. Shaw KN, Gorelick M, McGowan KL,
Yakscoe NM, Schwartz JS. Prevalence of urinary
tract infection in febrile young children in the
emergency department. Pediatrics. 1998;102(2):e16.
22. Greenhow TL, Hung YY, Herz AM, Losada E,
Pantell RH. The changing epidemiology of serious
bacterial infections in young infants. Pediatr Infect
Dis J. 2014;33(6):595-599.
23. Roberts KB, Akintemi OB. The epidemiology
and clinical presentation of urinary tract infections
in children younger than 2 years of age. Pediatr Ann.
1999;28(10):644-649.
24. Hoberman A, Wald ER. Urinary tract infections
in young febrile children. Pediatr Infect Dis J. 1997;
16(1):11-17.
25. Byington CL, Enriquez FR, Hoff C, et al. Serious
bacterial infections in febrile infants 1 to 90 days old
with and without viral infections. Pediatrics. 2004;
113(6):1662-1666.
26. Bender JM, Ampofo K, Gesteland P, et al.
Influenza virus infection in infants less than three
months of age. Pediatr Infect Dis J. 2010;29(1):6-9.

E6

febrile infants and children 2 to 24 months. Pediatrics.

2011;128(3):595-610.
30. Kaplan SL, Barson WJ, Lin PL, et al. Early trends
for invasive pneumococcal infections in children
after the introduction of the 13-valent pneumococcal
conjugate vaccine. Pediatr Infect Dis J. 2013;32(3):
203-207.
31. Kaplan SL, Barson WJ, Lin PL, et al. Serotype
19A is the most common serotype causing invasive
pneumococcal infections in children. Pediatrics.
2010;125(3):429-436.
32. Byington CL, Reynolds CC, Korgenski K, et al.
Costs and infant outcomes after implementation of
a care process model for febrile infants. Pediatrics.
2012;130(1):e16-e24.
33. Watt K, Waddle E, Jhaveri R. Changing
epidemiology of serious bacterial infections in
febrile infants without localizing signs. PLoS One.
2010;5(8):e12448.
34. Sadow KB, Derr R, Teach SJ. Bacterial
infections in infants 60 days and younger:
epidemiology, resistance, and implications for
treatment. Arch Pediatr Adolesc Med. 1999;153(6):
611-614.
35. Bonadio W, Maida G. Urinary tract infection in
outpatient febrile infants younger than 30 days of
age: a 10-year evaluation. Pediatr Infect Dis J. 2014;
33(4):342-344.
36. Dayan PS, Hanson E, Bennett JE, Langsam D,
Miller SZ. Clinical course of urinary tract infections
in infants younger than 60 days of age. Pediatr
Emerg Care. 2004;20(2):85-88.
37. Byington CL, Rittichier KK, Bassett KE, et al.
Serious bacterial infections in febrile infants
younger than 90 days of age: the importance of
ampicillin-resistant pathogens. Pediatrics. 2003;111
(5, pt 1):964-968.
38. Jaskiewicz JA, McCarthy CA, Richardson AC,
et al; Febrile Infant Collaborative Study Group.
Febrile infants at low risk for serious bacterial
infectionan appraisal of the Rochester criteria and
implications for management. Pediatrics. 1994;94
(3):390-396.
39. Pantell RH, Newman TB, Bernzweig J, et al.
Management and outcomes of care of fever in early
infancy. JAMA. 2004;291(10):1203-1212.
40. Adkins B. T-cell function in newborn mice and
humans. Immunol Today. 1999;20(7):330-335.
41. Nonoyama S, Penix LA, Edwards CP, et al.
Diminished expression of CD40 ligand by activated
neonatal T cells. J Clin Invest. 1995;95(1):66-75.
42. Schroeder HW Jr, Hillson JL, Perlmutter RM.
Early restriction of the human antibody repertoire.
Science. 1987;238(4828):791-793.

27. Levine DA, Platt SL, Dayan PS, et al; Multicenter

RSV-SBI Study Group of the Pediatric Emergency
Medicine Collaborative Research Committee of the
American Academy of Pediatrics. Risk of serious
bacterial infection in young febrile infants with
respiratory syncytial virus infections. Pediatrics.
2004;113(6):1728-1734.

43. Cuisinier AM, Gauthier L, Boubli L,

Fougereau M, Tonnelle C. Mechanisms that
generate human immunoglobulin diversity operate
from the 8th week of gestation in fetal liver. Eur J
Immunol. 1993;23(1):110-118.

28. Titus MO, Wright SW. Prevalence of serious

bacterial infections in febrile infants with
respiratory syncytial virus infection. Pediatrics.
2003;112(2):282-284.

44. Marshall R, Teele DW, Klein JO. Unsuspected

bacteremia due to Haemophilus influenzae:
outcome in children not initially admitted to
hospital. J Pediatr. 1979;95(5, pt 1):690-695.

29. Roberts KB; Subcommittee on Urinary Tract

Infection, Steering Committee on Quality
Improvement and Management. Urinary tract
infection: clinical practice guideline for the
diagnosis and management of the initial UTI in

45. Baraff LJ, Bass JW, Fleisher GR, et al; Agency

for Health Care Policy and Research. Practice
guideline for the management of infants and
children 0 to 36 months of age with fever without
source. Ann Emerg Med. 1993;22(7):1198-1210.

46. Baskin MN, ORourke EJ, Fleisher GR.

Outpatient treatment of febrile infants 28 to 89
days of age with intramuscular administration of
ceftriaxone. J Pediatr. 1992;120(1):22-27.
47. Baker MD, Bell LM, Avner JR. Outpatient
management without antibiotics of fever in
selected infants. N Engl J Med. 1993;329(20):
1437-1441.
48. American College of Emergency Physicians
Clinical Policies Committee; American College of
Emergency Physicians Clinical Policies
Subcommittee on Pediatric Fever. Clinical policy for
children younger than three years presenting to the
emergency department with fever. Ann Emerg Med.
2003;42(4):530-545.
49. Jain S, Cheng J, Alpern ER, et al. Management
of febrile neonates in US pediatric emergency
departments. Pediatrics. 2014;133(2):187-195.
50. Schwartz S, Raveh D, Toker O, Segal G,
Godovitch N, Schlesinger Y. A week-by-week
analysis of the low-risk criteria for serious bacterial
infection in febrile neonates. Arch Dis Child.
2009;94(4):287-292.
51. Baker MD, Bell LM, Avner JR. The efficacy of
routine outpatient management without antibiotics
of fever in selected infants. Pediatrics. 1999;103(3):
627-631.
52. Marom R, Sakran W, Antonelli J, et al. Quick
identification of febrile neonates with low risk for
serious bacterial infection: an observational study.
Arch Dis Child Fetal Neonatal Ed. 2007;92(1):F15-F18.
53. Huppler AR, Eickhoff JC, Wald ER. Performance
of low-risk criteria in the evaluation of young infants
with fever: review of the literature. Pediatrics.
2010;125(2):228-233.
54. Biondi EA, Mischler M, Jerardi KE, et al;
Pediatric Research in Inpatient Settings (PRIS)
Network. Blood culture time to positivity in febrile
infants with bacteremia. JAMA Pediatr. 2014;168
(9):844-849.
55. Byington CL, Taggart EW, Carroll KC,
Hillyard DR. A polymerase chain reaction-based
epidemiologic investigation of the incidence of
nonpolio enteroviral infections in febrile and
afebrile infants 90 days and younger. Pediatrics.
1999;103(3):E27.
56. Rittichier KR, Bryan PA, Bassett KE, et al.
Diagnosis and outcomes of enterovirus infections in
young infants. Pediatr Infect Dis J. 2005;24(6):
546-550.
57. Krief WI, Levine DA, Platt SL, et al; Multicenter
RSV-SBI Study Group of the Pediatric Emergency
Medicine Collaborative Research Committee of the
American Academy of Pediatrics. Influenza virus
infection and the risk of serious bacterial infections
in young febrile infants. Pediatrics. 2009;124(1):
30-39.
58. Byington CL, Ampofo K, Stockmann C, et al.
Community surveillance of respiratory viruses
among families in the Utah Better Identification of
Germs-Longitudinal Viral Epidemiology (BIG-LoVE)
study. Clin Infect Dis. 2015;61(8):1217-1224.
59. Verani JR, McGee L, Schrag SJ; Division of
Bacterial Diseases, National Center for
Immunization and Respiratory Diseases, Centers for
Disease Control and Prevention (CDC). Prevention
of perinatal group B streptococcal diseaserevised
guidelines from CDC, 2010. MMWR Recomm Rep.
2010;59(RR-10):1-36.

JAMA Pediatrics Published online June 20, 2016 (Reprinted)

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: http://archpedi.jamanetwork.com/ by a GLASGOW UNIVERSITY LIBRARY User on 06/20/2016

jamapediatrics.com

Evaluation and Management of Febrile Children

60. Schrag S, Gorwitz R, Fultz-Butts K, Schuchat A.

Prevention of perinatal group B streptococcal
disease. Revised guidelines from CDC. MMWR
Recomm Rep. 2002;51(RR-11):1-22.
61. Schrag SJ, Verani JR. Intrapartum antibiotic
prophylaxis for the prevention of perinatal group B
streptococcal disease: experience in the United
States and implications for a potential group B
streptococcal vaccine. Vaccine. 2013;31(suppl 4):
D20-D26.
62. Puopolo KM, Madoff LC, Eichenwald EC.
Early-onset group B streptococcal disease in the
era of maternal screening. Pediatrics. 2005;115(5):
1240-1246.
63. Jordan HT, Farley MM, Craig A, et al; Active
Bacterial Core Surveillance (ABCs)/Emerging
Infections Program Network, CDC. Revisiting the
need for vaccine prevention of late-onset neonatal
group B streptococcal disease: a multistate,
population-based analysis. Pediatr Infect Dis J.
2008;27(12):1057-1064.
64. Tappero JW, Schuchat A, Deaver KA,
Mascola L, Wenger JD. Reduction in the incidence
of human listeriosis in the United States:
effectiveness of prevention efforts? the Listeriosis
Study Group. JAMA. 1995;273(14):1118-1122.

jamapediatrics.com

Review Clinical Review & Education

65. Greenhow TL, Hung YY, Herz AM. Changing

epidemiology of bacteremia in infants aged 1 week
to 3 months. Pediatrics. 2012;129(3):e590-e596.

with ampicillin and gentamicin, for neonates at risk

for sepsis is associated with an increased risk of
neonatal death. Pediatrics. 2006;117(1):67-74.

66. Biondi E, Evans R, Mischler M, et al.

Epidemiology of bacteremia in febrile infants in the
United States. Pediatrics. 2013;132(6):990-996.

72. Zaas AK, Burke T, Chen M, et al. A host-based

RT-PCR gene expression signature to identify acute
respiratory viral infection. Sci Transl Med. 2013;5
(203):203ra126.

67. Hassoun A, Stankovic C, Rogers A, et al. Listeria

and enterococcal infections in neonates 28 days of
age and younger: is empiric parenteral ampicillin
still indicated? Pediatr Emerg Care. 2014;30(4):
240-243.
68. Lee B, Newland JG, Jhaveri R. Reductions in
neonatal listeriosis: collateral benefit of group B
streptococcal prophylaxis? J Infect. 2016;72(3):
317-323.
69. Puopolo KM, Eichenwald EC. No change in
the incidence of ampicillin-resistant, neonatal,
early-onset sepsis over 18 years. Pediatrics. 2010;
125(5):e1031-e1038.

73. Mejias A, Dimo B, Suarez NM, et al. Whole

blood gene expression profiles to assess
pathogenesis and disease severity in infants with
respiratory syncytial virus infection. PLoS Med.
2013;10(11):e1001549.
74. Mahajan P, Kuppermann N, Suarez N, et al;
Febrile Infant Working Group for the Pediatric
Emergency Care Applied Research Network
(PECARN). RNA transcriptional biosignature analysis
for identifying febrile infants with serious bacterial
infections in the emergency department: a feasibility
study. Pediatr Emerg Care. 2015;31(1):1-5.

70. Cantey JB, Lopez-Medina E, Nguyen S,

Doern C, Garcia C. Empiric antibiotics for serious
bacterial infection in young infants: opportunities
for stewardship. Pediatr Emerg Care. 2015;31(8):
568-571.
71. Clark RH, Bloom BT, Spitzer AR, Gerstmann DR.
Empiric use of ampicillin and cefotaxime, compared

(Reprinted) JAMA Pediatrics Published online June 20, 2016

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: http://archpedi.jamanetwork.com/ by a GLASGOW UNIVERSITY LIBRARY User on 06/20/2016

E7