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 Author Affiliations: Division of
against Haemophilus influenzae and Streptococcus pneumoniae has virtually eliminated the General Pediatrics and Adolescent
Medicine, University of North
concern for bacterial infections in children aged 3 to 36 months. Urinary tract infections still Carolina at Chapel Hill School of
remain a concern in febrile infants of all ages. Medicine, Chapel Hill (Cioffredi);
Division of Infectious Diseases,
Department of Pediatrics, University
CONCLUSIONS AND RELEVANCE Advances over the last 30 years allow for more precise risk
of North Carolina at Chapel Hill
stratification for infants at high risk of serious bacterial infection. With appropriate testing at School of Medicine, Chapel Hill
the initial visit, much of the diagnostic testing and empirical treatment can be avoided for (Jhaveri).
infants younger than 90 days. In the vaccinated child aged 3 to 36 months, the only bacterial Corresponding Author: Ravi Jhaveri,
infection of concern is urinary tract infection. MD, Division of Infectious Diseases,
Department of Pediatrics, University
of North Carolina at Chapel Hill
JAMA Pediatr. doi:10.1001/jamapediatrics.2016.0596 School of Medicine, 101 Manning Dr,
Published online June 20, 2016. Campus Box 7509, Chapel Hill, NC
27599 (ravi.jhaveri@unc.edu).

T
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 support-
ive 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 tod-
dlers 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 chil-
dren developed invasive infections, including pneumonia, osteo-
myelitis, and meningitis, but most had treatment outcomes that were
benign.5,6 The concern for occult bacteremia and the risk of subse-
quent 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 Subse-
quent 7-valent and 13-valent conjugate vaccines for S pneumoniae
led to greater than 50% reductions in S pneumoniae–related
bacteremia.10 As a result, occult bacteremia has also disappeared.11-13
Routine vaccination against Hib and S pneumoniae also re-
sulted 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 de-
velopment 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 men-
ingitis 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, me-
ningococcal 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.

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 Clinical Review & Education Review
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 pre-
sent in children aged 3 to 36 months without specific symptoms. Un-
recognized UTIs can result in permanent renal damage, and in se-
vere 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 Al-
though viral infection is the most common overall cause of fever in
this group, identification of a viral infection does not exclude a con-
current 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 oc-
cur without signs and symptoms, particularly in patients older than
3 months. For children with fever without localizing signs of infec-
tion, 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, ac-
quired 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 con-
ducted 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 infec-
tions 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 his-
tory is strikingly different than in meningitis or bacteremia. With em-
pirical 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 treat-
ment of UTIs is crucial, as it can lead to identification of correctable
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Evaluation and Management of Febrile Children
underlying pathologic conditions such as vesicoureteral reflux or uri-
nary tract anomalies. The most recent revision of the American Acad-
emy of Pediatrics guidelines for management of UTIs with fever ac-
knowledges the importance of evaluating children with fever without
localizing symptoms by conducting urinalysis and urine culture be-
fore administration of antibiotics.29 In addition, they advise per-
forming renal ultrasonography to evaluate for anatomical anoma-
lies 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, guide-
lines 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 sig-
nificant 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 re-
sponse to antigenic insult, and the deficiency may partially ac-
count 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 com-
mon practice to admit all febrile patients aged 8 weeks or younger,
obtain laboratory evaluation and blood cultures, and treat them em-
pirically 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/μL, with less
than 1500 bands/μL (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, com-
pared 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 cerebrospi-
nal fluid parameters, their negative predictive value is 99%.4 A ma-
jor limitation of the Rochester criteria is that they included only full-
term 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 cul-
ture, 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 Emer-
gency Physicians reiterated this recommendation in 2003.48
There is significant variation among inpatient and outpatient cli-
nicians who evaluate and treat neonates with fever. Pantell et al39
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 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 Can use in patients who were Can use in patients who
Does not require CSF not term or who have were not term or who
evaluation previously diagnosed medical have previously diagnosed
conditions medical conditions
Drawbacks Patients must be term Patients must be >28 d Patients must be >28 d
infants without medical
conditions
Low-risk criteria WBC 5000-15 000/μL WBC <20 000/μL WBC <15 000/μL
Bands <1500/mm3 Band-to-neutrophil ratio <0.2 UA <10 WBC/hpf
UA <10 WBC/hpf UA <10 WBC/hpf CSF <10 WBC/μL Abbreviations: CSF, cerebrospinal
Fecal leukocytes <5 Urine Gram stain result Normal chest radiograph fluid; hpf, high power field;
WBC/hpf (if diarrhea negative result UA, urinalysis; WBC, white blood
is present) CSF <8 WBC/μL
cells.
CSF Gram stain result negative
Normal chest radiograph result SI conversion factor: To convert WBC
Fecal leukocytes 0 to few count and bands to ×109/L, multiply
(if diarrhea is present)
by 0.001.

published the Pediatric Research in Office Settings study document-
ing equivalent outcomes for febrile infants who were managed con-
servatively 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 antibi-
otics and duration of treatment vary widely between institutions and
among clinicians. Although some clinicians are comfortable observ-
ing the patient for 24 hours, others require 72 hours for stable in-
fants 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 in-
fants infected with SBI.
Several major changes affecting the management of febrile neo-
nates are worth a detailed discussion: greater understanding of a vi-
ral 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 ampi-
cillin-resistant organisms.
Viral Diagnosis and Risk of SBI
Despite relying on older, less-sensitive culture techniques, the Roch-
ester 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 in-
vestigate 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
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 investi-
gated 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 re-
duces 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 de-
lineates 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 persis-
tence of respiratory viruses in the general population. Children are
more likely to have positive test results for viral infection in the house-
hold, and rates of viral infections increased with the number of chil-
dren in the household and with decreasing age of children. Most epi-
sodes 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 de-
tection is reliable for management decisions.
Decreasing Incidence of Group B Streptococcus
Screening pregnant women for group B streptococcus (GBS) be-
tween 35 and 37 weeks’ gestation to prevent early-onset sepsis has
been recommended by the Centers for Disease Control and Preven-
tion since 1996.59-61 This screening regimen in combination with in-

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 Clinical Review & Education Review
trapartum prophylactic antibiotic treatments has decreased inci-
dence 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 Moth-
ers 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 early-
onset disease, morbidity still involves developmental delay, cere-
brovascular changes, hearing loss, or intellectual disability. Empiri-
cal 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 neo-
natal SBI show an absence of Listeria infection in infants younger than
60 days. These studies span the United States and include large aca-
demic 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 data-
base has demonstrated that reductions in rates of listeriosis in in-
fants 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 neces-
sary to evaluate the true incidence of Listeria infections in the neo-
natal 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 ampicillin-
resistant pathogens. Puopolo and Eichenwald69 describe increas-
ing proportions of ampicillin-resistant pathogens cultured from neo-
nates since the widespread use of ampicillin for intrapartum
prophylaxis. The 2 largest risk factors for ampicillin-resistant bacte-
ria were maternal exposure to ampicillin and length of that expo-
sure. The 2010 Centers for Disease Control and Prevention guide-
lines for intrapartum prophylaxis recommend either penicillin
G potassium or sodium or ampicillin, so use varies based on hospi-
tal culture and protocol.59 Infants born to mothers who received pro-
phylaxis with penicillin or other gram-positive agents, such as clin-
damycin 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 patho-
gen causing disease in febrile neonates, the increasing resistance to
ampicillin has sparked debate about the role of ampicillin in empiri-
cal treatment of SBI in infants. Those who advocate for it generally
do so because the principles of antibiotic stewardship would dic-
tate that third-generation cephalosporins should not be used in this
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Evaluation and Management of Febrile Children
situation and ampicillin is first-line treatment for Enterococcus
while also covering Listeria.70 In addition, ampicillin may work syn-
ergistically 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 coli–related 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 regi-
men with the other in this population of healthy infants. An often-
cited 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 increas-
ing 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 appropri-
ate. 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 in-
dicates if pathogenic bacteria are present, 96% of blood culture re-
sults 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 patho-
genic 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 resis-
tance. For an infant of any age who presents with signs and symp-
toms that suggest sepsis or a toxic appearance, a full evaluation and
prompt empirical antibiotics are indicated.
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 Evaluation and Management of Febrile Children Review Clinical Review & Education

tic tool. This group has planned prospective studies in febrile

Recent Developments and Future Directions
Several advances are taking place that will likely offer meaningful ad-
vances 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 longitu-
dinal experience continues to grow with these assays for routine de-
tection during acute respiratory illnesses, there are few specific out-
comes studies to demonstrate that a positive result for a specific virus
reliably means that no bacterial pathogen is subsequently de-
tected 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 confi-
dently avoid the rest of the evaluation.
In addition to increasing the efficiency of identifying viral
pathogens, new strategies using host-based gene-expression sig-
natures to discern whether a child is infected with a viral or bacte-
rial 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 bacte-
rial. 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 expres-
sion 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 demon-
strated that gene expression profiles could perform as a biomarker
for RSV infection and had the potential for use as an early diagnos-
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 vac-
cines against Hib and S pneumoniae. Management strategies must
continue to evolve to identify the few children with SBI. New diag-
nostic techniques, such as efficient viral testing and evaluation of
host gene expression profiling, will continue to change the land-
scape 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.

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.
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