Fever in the Pediatric Patient

Robyn Wing,

MD,

Maya R. Dor,

DO,

Patricia A. McQuilkin,

MD*

KEYWORDS
 Fever  Fever without source  Occult pneumonia  Urinary tract infection
 Febrile seizure  Meningococcemia  Sickle cell disease  Febrile neutropenia
KEY POINTS
 Fever is defined as a rectal temperature greater than 38.0 C (>100.4 F). A fever that was
documented recently at home should be considered the same as a temperature documented in the emergency department.
 All febrile infants younger than 28 days should receive a full sepsis workup and be
admitted for parenteral antibiotic therapy. Clinical and laboratory criteria can be used to
identify low-risk febrile infants aged 1 to 3 months, who can be treated on an outpatient
basis with close follow-up.
 The PCV7 (7-valent conjugate pneumococcal vaccine) vaccine has markedly decreased
the incidence of serious bacterial infection in vaccinated infants and children, but children
who are unvaccinated or have received fewer than 2 doses of vaccine are still at risk for
pneumococcal disease. The impact of the new PCV13 vaccine remains to be seen, but
this new medication should decrease the risk even further.
 Occult urinary tract infections occur often in children with fever without a source (FWS);
therefore, a catheterized urine specimen should be obtained for urine testing in girls
and uncircumcised boys younger than 2 years and in circumcised boys younger than
6 months.
 Fever with petechiae below the nipples should lead to consideration of meningococcemia.
Diagnosis and rapid initiation of treatment are critical to decrease mortality from this
devastating illness.

Fever, defined as a rectal temperature greater than 38.0 C (100.4 F), is the most
common complaint for children and infants who are brought to emergency departments (EDs).1,2 The emergency physician must distinguish benign from lifethreatening disease and educate families, as appropriate, about the causes and

Drs Wing and Dor have equally contributed to this article.

Funding Sources: None.
Conflict of Interest: None.
Department of Pediatrics, University of Massachusetts Medical School, 55 Lake Avenue North,
Worcester, MA 01655, USA
* Corresponding author.
E-mail address: [email protected]
Emerg Med Clin N Am 31 (2013) 10731096
http://dx.doi.org/10.1016/j.emc.2013.07.006
0733-8627/13/$ see front matter 2013 Elsevier Inc. All rights reserved.

emed.theclinics.com

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management of fevers. The approach to fevers in children is guided by the patients

age, immunization status, and immune status as well as the results of a careful
physical examination. In this article, the approach to pediatric fever is discussed
and significant causes of both common and dangerous fevers in children are
highlighted.
Although fever is recognized by health care providers as a beneficial physiologic
response that facilitates the fight of the immune system against pathogens, it evokes
fear and anxiety in caregivers.3 In 1980, Schmitt introduced the term fever phobia after
finding, in a survey, that 52% of parents believed that a temperature of 40 C or even
less can cause neurologic damage.4 In an assessment of the incidence of fever phobia
in an urban pediatric ED, Poirier and colleagues5 found that 32% of caregivers named
seizure as the main danger of fever, 18% named death, and 15% named brain damage. These results indicate that many caregivers seem to confuse the beneficial effects of fever with the harmful effects of hyperthermia.6 This phobia prompts many
ED visits for the management of fever in children.
APPROACH TO PEDIATRIC FEVER

The presence of fever in children and young people affects clinical management decisions and therefore must be recorded accurately. This documentation can be challenging, because measuring the temperature in children can be difficult, especially
when they are uncooperative or restless. Also, parents use different methods to measure temperature. Rectal temperature measurement is more accurate than tympanometry and use of the axilla.7,8 Wide fluctuations are noted with tympanometry,
especially in young children, and axillary temperatures can vary by as much as 1 F
(5/9 C).9 A fever documented at home by measuring the temperature with a thermometer should be treated in the same manner as a fever documented in the ED.10 Studies
have found no correlation between fever reduction with antipyretic medication and the
likelihood of a serious bacterial infection (SBI)1116; therefore, this history should not
influence patient management.
FEVER WITHOUT SOURCE IN CHILDREN YOUNGER THAN 3 YEARS

Most children younger than 3 years with fever have a clinically apparent source of
infection. Sources include proven bacterial infections (including otitis media in infants
older than 3 months) or named viral syndromes (croup, stomatitis, herpangina, varicella, and bronchiolitis) in infants older than 1 month.17 However, in 20% of children,
a source of infection cannot be elucidated even after a thorough history is obtained
and a physical examination is performed.18,19 Although most of these children harbor
self-limiting viral illnesses, there should always be concern for the few infants and children in whom complications from invasive bacterial disease might develop.20,21 It is
important to screen and stratify neonates and infants at risk for occult bacteremia.
The incidence of SBI is higher in febrile infants younger than 3 months than in older
children. Fever without a source (FWS) in this age group raises the suspicion of a
serious underlying disease.22
PNEUMOCOCCAL CONJUGATE VACCINE AND THE RISK OF OCCULT BACTEREMIA

Before the introduction of the 7-valent conjugate pneumococcal vaccine (PCV7; Prevnar, Lederle Laboratories/Wyeth-Ayerst, NY) in 2000, the incidence of occult bacteremia in well-appearing children younger than 3 years with FWS and a temperature
39.0 C or higher was 2% to 3%. Effective vaccination programs targeted against

Fever in Pediatric Patient

Haemophilus influenzae and Streptococcus pneumonia have decreased the rate to between 0.25% and 0.91%.2329 Most neonates younger than 2 months have not yet
received these vaccinations and therefore are vulnerable to infections caused H influenzae and Streptococcus pneumoniae. Recent retrospective studies found virtually no
SBI caused by those 2 organisms in neonates younger than 3 months, which the investigators attributed to the herd immunity effect caused by the successful vaccination of
older infants.2931 Occult bacteremia in well-appearing neonates with FWS was found
to be caused by Escherichia coli, Streptococcus hemolyticus, group B streptococci,
Staphylococcus epidermitis, and coagulase-negative staphylococci.30
At the time of its introduction, PCV7 contained isolates of 85% to 97% of the pneumococcal species that cause disease in children younger than 2 years.32 However,
after PCV7 was introduced in the United States, the distribution of pneumococcal
pathogens shifted. Sixty-four percent of invasive pneumococcal disease (IPD) in children younger than 5 years was found to be caused by 6 additional serotypes, which
are now included in the 13-valent pneumococcal conjugate vaccine (PCV13, Pfizer
Vaccines, NY).33 PCV13 was licensed in 2010 for infants older than 6 weeks and contains pneumococcal capsular polysaccharides corresponding to the 6 serotypes
currently causing more than 70% of IPD worldwide.34 Data from England suggest
that the routine use of PCV13 has already decreased the incidence of IPD caused
by serotypes not included in PCV7 but included in PCV13.35
FEVER IN THE NEONATE (YOUNGER THAN 28 DAYS)

Clinicians cannot rely on history and physical examination alone to exclude SBI in the
febrile neonate. ED practice guidelines for the evaluation of febrile neonates younger
than 28 days continue to call for a full sepsis workup, which includes complete blood
count (CBC), blood culture, urinalysis and urine culture, lumbar puncture with evaluation of cerebrospinal fluid (CSF), and administration of antibiotics in the ED followed by
hospitalization pending results of cultures.1,36 Some investigators also advocate
screening transaminases or obtaining a chest radiograph to evaluate for neonatal herpes simplex virus (HSV) infection, given its propensity to involve the liver and the lungs
in this age group.37,38 Studies of the applicability of low-risk criteria to infants between
the ages of 1 and 28 days found that more SBIs were missed in these very young infants compared with older infants, validating the need for a full sepsis evaluation with
hospital admission in this age group.3942 The decision to obtain CSF for HSV polymerase chain reaction (PCR) and to treat with acyclovir is discussed later. The decision to obtain a chest radiograph should be based on clinical symptoms.
Neonatal medications for treatment of presumed SBI include ampicillin (200
300 mg/kg/d intravenously [IV], divided every 8 hours [if the infant is <7 days old] or
every 6 hours [if the infant is >7 days old]) plus a third-generation cephalosporin (cefotaxime, 150 mg/kg/d IV, divided every 8 hours). Ceftriaxone is contraindicated in
neonates because of the risk of albumin displacement and the subsequent increased
risk of hyperbilirubinemia and kernicterus. Vancomycin can be used instead of ampicillin if the neonate has gram-positive cocci on CSF Gram stain or is at risk for Staphylococcus aureus infection. Consider acyclovir (60 mg/kg/d IV divided every 8 hours)
for ill-appearing infants; infants with seizures, skin lesions, or increased transaminase
levels; and those with CSF pleocytosis and a negative Gram stain until an alternative
diagnosis is established or the HSV PCR becomes negative.43 Viral testing and
treatment of influenza in neonates are discussed later. An algorithm for the evaluation
and management of previously healthy infants younger than 28 days with a FWS is
presented as Fig. 1.

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Fig. 1. Algorithm for management of a previously healthy infant 90 days of age or younger with a fever without source. This algorithm is a suggested,
but not exhaustive, approach to management. hpf, high-power field. * optional, see text. (Adapted from Lee B, McCallin T. Microbiology and infectious
disease. In: Tschudy MM, Arcara KM. The Harriet Lane handbook. 19th edition. St Louis (MO): Mosby; 2011; with permission. Modified from Baraff LJ.
Management of fever without source in infants and children. Ann Emerg Med 2000:36(6):60214; and Baraff LJ. Management of infants and young
children with fever without source. Pediatr Ann 2008:37(10):6739.)

Fever in Pediatric Patient

NEONATAL HERPES

Neonatal herpes is an important consideration in the evaluation of a neonate with

FWS. In recent years, the incidence of fetal and neonatal herpes has increased,
concomitant with the increase in HSV infections among women of childbearing
years.37 Risk factors for neonatal HSV infection include maternal primary infection during pregnancy or delivery, exposure to cervical viral shedding, delivery before
38 weeks, fetal scalp monitoring, maternal age younger than 21 years, low birth
weight, and rupture of membranes more than 4 to 6 hours before delivery.4446 It is
therefore crucial to obtain a comprehensive medical and prenatal history from the
mother, specifically about history and timing of HSV infection, for any neonate presenting with FWS. Only 20% to 30% of HSV-infected mothers provide a history of
genital herpes,47,48 but most of them (60%80%) have subclinical infection with
asymptomatic viral shedding at the time of delivery.44,4951 Infants born vaginally to
mothers with a primary HSV infection are exposed to higher viral loads and fewer
maternal antibodies than those born to mothers with secondary infections; the incidence of neonatal HSV is concomitantly higher (33%50% vs 3%5%, respectively).45,48,52,53 HSV has an incubation period of 5 to 21 days. Infected neonates
usually present with symptoms in the first 2 weeks of life, but symptoms can occur
at any time during the first 6 weeks.54,55 Clinicians must therefore have a high level
of suspicion to make an early diagnosis of HSV infection in neonates and thereby
improve the prognosis.37
HSV-2 causes 75% to 85% of neonatal HSV infections. Most of them (85%) are
acquired vertically during the peripartum period, with the remainder (5%10%) contracted before labor or after birth.56 Neonatal HSV infections are divided into 3 clinical
presentations: disseminated disease; disease localized to the skin, eyes, and mouth
(SEM); and central nervous system (CNS) disease.
Disseminated disease presents during the first week of life, accounting for 35% of
neonatal HSV cases, and has the highest mortality.53 Any neonate presenting with
signs of sepsis in the setting of negative bacterial cultures or severe liver dysfunction
should raise concern for disseminated HSV infection. Mortality correlates with increases in aspartate transaminase level more than 10 times the upper limit of normal
and neonatal lethargy at the time of acyclovir initiation.37 Multiple organs can become
involved, including the CNS, adrenal gland, SEM, with a predilection for the liver and
lungs.56
SEM disease often presents late in the first week of life, accounts for 40% of disease, and has the lowest mortality of the 3 presentations.37,57 Neonates with the
SEM form of HSV infection present with vesicular skin lesions, keratitis, or chorioretinitis, with the face and scalp most commonly affected.58
CNS disease presents latest (between weeks 2 and 3 of life) and accounts for 35%
of neonatal HSV infections. Neonates can present with cranial nerve abnormalities,
irritability, a bulging fontanelle, seizures, encephalitis, apnea, bradycardia, and skin
findings. Infant prematurity and seizures are risk factors for death.56
The presence of fever, irritability, abnormal CSF findings, increased transaminase
levels, and skin lesions (especially in the setting of seizures) should raise concern
for neonatal HSV infection.53,56 Only 17% to 39% of neonates infected with HSV present with skin lesions, so their absence does not exclude the diagnosis.56 Diagnostic
evaluation includes HSV PCR, viral culture, electroencephalogram, and liver transaminases. Although viral culture of skin vesicles, mouth, eyes, urine, blood, stool, and
CSF is the gold standard for diagnosis, PCR can confirm it with or without skin lesions
in 24 hours, with a sensitivity of 71% to 100%.56,59 Analysis of PCR results from blood

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and CSF samples increases the sensitivity of PCR testing for HSV DNA.59 A negative
CSF or serum PCR result does not exclude the presence of HSV infection. In addition
to PCR and viral cultures, screening for increases in serum transaminase level and a
chest radiograph to detect pneumonitis are recommended, given the propensity of
HSV infection, especially the disseminated form, to involve the liver and lungs.37
Seventy percent of patients with untreated localized SEM disease progress to CNS
and disseminated disease; therefore, early diagnosis and treatment with acyclovir are
imperative to the prevention of morbidity and mortality in neonates infected with
HSV.60,61 The presence of CSF pleocytosis in the setting of a negative Gram stain necessitates HSV PCR of CSF and serum, with subsequent high-dose acyclovir administration. Acyclovir, given at 60 mg/kg/d in 3 divided doses, improves outcomes in
patients with disseminated disease or CNS manifestations.62
FEVER IN INFANTS 1 TO 3 MONTHS OF AGE

Several protocols, based on the Boston, Philadelphia, and Rochester criteria, have
been developed to help clinicians identify infants and children who are at low risk
for SBI, so that they can be managed safely as outpatients, reducing the number of
unnecessary hospitalizations.41,6365 For this reason, the evaluation of well-appearing
infants between 1 and 3 months of age presenting with FWS varies in EDs. The most
recent recommendations for low-risk criteria and management of fever in nontoxic
appearing infants between 28 and 90 days of age are summarized in Fig. 1.
These protocols do not clarify the role of lumbar puncture in the stratification of lowrisk and high-risk febrile infants. Lumbar puncture, therefore, remains optional in infants 1 to 3 months of age but should be performed if empirical antibiotics are to be
started. If a child returns to the ED and a lumbar puncture performed at that time reveals pleocytosis, a negative culture indicates either aseptic meningitis or only partially
treated bacterial meningitis, necessitating a full course of parenteral antibiotics.66
Similar to the decision to obtain a lumbar puncture, the decision to obtain a chest
radiograph in infants and children presenting with FWS is not always a clear one.
Occult pneumonia is present in up to 26% of children with FWS and a white blood
cell (WBC) count greater than 20,000/mm3 (most lower respiratory infections in children have a viral source).6772 Bacterial lower respiratory tract infections often occur
as a secondary infection after an initial respiratory viral infection.66 A meta-analysis
that evaluated reports of febrile infants younger than 3 months73 showed that
33.2% of all those presenting with at least 1 clinical finding of pulmonary disease
(ie, tachypnea >50 breaths/min, cyanosis or O2 saturation <95%, rales, rhonchi, retractions, wheezing, coryza, grunting, stridor, nasal flaring, or cough) had chest radiographs positive for pneumonia. This evidence supports obtaining a chest radiograph
in febrile infants who are younger than 3 months, have a temperature greater than
38 C, and present with at least 1 clinical sign of pulmonary disease.1
The requirement for hospital admission and IV antibiotic administration in this age
range depends on the laboratory findings. All infants 28 to 90 days of age with CSF
pleocytosis should be admitted to the hospital for IV antibiotic administration while
CSF cultures are followed. Infants 42 days of age or younger with CSF pleocytosis
should also be treated with acyclovir.38 For patients with urinary tract infections
(UTIs) (discussed later), neonates younger than 1 month should be hospitalized for
IV administration of antibiotics, and outpatient management could be appropriate
for infants aged 28 to 60 days.66 Hospital admission should also be considered for
infants in families with social concerns such as transportation challenges, lack of resources, and unreliable follow-up. Cultures should be followed for 36 to 48 hours,

Fever in Pediatric Patient

because 90% of bacterial pathogens grow within the first 24 hours. All infants sent
home must have follow-up within 24 hours by telephone or visit. Infants who received
IV/intramuscular (IM) antibiotics need a second IM dose, pending culture results. Antibiotic management for infants aged 2 to 3 months includes a third-generation cephalosporin (ceftriaxone, 50 mg/kg IM/IV).
UTIS

In the postvaccination era, UTIs are now the most common occult bacterial infections
in children. They occur in 2% of febrile children younger than 5 years and are present
in 6% to 8% of febrile girls and 2% to 3% of febrile boys younger than 12 months.7477
Risk factors for occult UTI include female gender, uncircumcised male, temperature
greater than 39.0 C, FWS in a child younger than 1 year, and FWS in females between
1 and 2 years of age.1,76 Shaikh and colleagues78 found UTI as the diagnosis in 7.5%
of febrile infant girls between 0 and 3 months of age, 2.4% of circumcised boys, and
20.1% of uncircumcised boys. Among febrile children with UTIs, 60% to 65% have evidence of pyelonephritis.79 Studies have also shown a 12.4% incidence of positive
blood cultures from neonates admitted for UTI, emphasizing the importance of
screening for and treating UTIs in febrile infants.80,81
Current guidelines for evaluation and management of UTI in children 2 to 24 months
of age recommend obtaining a urine culture in conjunction with urinalysis before giving antibiotics when UTI is suspected. Because of the low specificity (70%) and high
false-positive rate (85%) of urine culture from a bag collection, urethral catheterization (sensitivity 95%, specificity 99%) and suprapubic aspiration are the best
methods for diagnosing UTIs in young children.1 The diagnosis requires abnormal
urinalysis results (10 WBCs/high-powered field or bacteriuria) and 50,000 or
more colony-forming units/mL of a single uropathogen on culture. Lower colony
counts are often caused by colonization of the distal urethra and periurethral area
and do not represent true UTI. Treatment with antibiotics for 7 to 14 days is recommended (ceftriaxone, cefixime, cephalexin, or bactrim, depending on local antibiotic
sensitivity patterns). On follow-up, a renal and bladder ultrasonographic examination
is indicated after the first febrile UTI, but routine voiding cystourethrography (VCUG)
is no longer recommended. A VCUG might be indicated if an ultrasonographic image
shows abnormalities or the patient has recurrent febrile UTIs. After a childs first
febrile UTI, parents should be advised to seek medical care promptly (within 48 hours)
for future febrile illnesses to ensure that recurrent infections can be diagnosed and
treated quickly.82
VIRAL INFECTIONS

Although SBI testing is crucial in the 1-day to 90-day age group, most infants with
FWS have an underlying viral illness as the cause of fever. As the ability to diagnose
viral illnesses improves, the role of these tests in the management of febrile infants is
being investigated. Many recent studies have investigated whether febrile infants
with viral illnesses could have a concomitant SBI. Studies have shown significantly
lower rates of SBI in infants presenting with FWS with proven viral syndromes,
such as bronchiolitis, influenza, varicella, croup, stomatitis, and herpangina. One
large prospective study22 looked at rates of SBI in infants 1 to 90 days old presenting
with FWS with and without viral syndromes. The incidence of SBI in infants with a
viral syndrome was 4.2% versus 12.3% in febrile infants without a proven viral syndrome. This study also stratified infants into high and low risk according to Rochester criteria and found significantly lower rates of SBI in high-risk infants with viral

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infections (5.5%) compared with high-risk infants without viral infections (16.9%).
The difference in SBI rates between infants with and without a proven virus in
low-risk infants was not statistically significant (1.7% vs 3.1%).22 Another study83
looking at rates of SBI in febrile infants younger than 60 days found significantly
lower rates of SBI in infants diagnosed with influenza virus infection (2.5%) than in
infants presenting with FWS without influenza (11.7%). Other studies84,85 found
significantly lower rates of SBI in infants with bronchiolitis (2.2%7%) compared
with infants without bronchiolitis (9.6%12.5%). Viral testing for respiratory syncytial
virus, influenza, adenovirus, rotavirus, enterovirus, and herpesvirus has proved useful in predicting a low risk for SBI, but detection of rhinovirus alone has not been
significant.86,87
The addition of rapid viral diagnostic testing to commonly used high-risk criteria,
such as the Rochester criteria, could allow more careful categorization of infants
with FWS at risk for SBI. Viral testing of nasal specimens using PCR, enzyme-linked
immunosorbent assay, or direct-fluorescent assay detection (DFA) should be performed when a respiratory virus is suspected. Enteroviral testing with both blood
and CSF PCR provides the best diagnostic yield for enterovirus infections.87 The
risk of SBI in infants with documented viral infections is comparable with that of a
low-risk infant, so physicians should consider treating them as such. The results of
viral testing can be combined with 24-hour bacterial culture results to optimize treatment plans for patients, decrease antibiotic use, and decrease length of stay in patients admitted for FWS.38
The American Academy of Pediatrics recommends antiviral therapy for any child at
high risk of complications of influenza infection, which includes all children younger
than 2 years. Treatment should be initiated as soon as possible after illness onset
and should not be delayed while awaiting definitive influenza test results. Rapid antigen tests have a low sensitivity and should not be used to rule out influenza.88 Dosing
of oseltamivir in infants younger than 12 months is 3 mg/kg/dose by mouth twice a day
for 5 days.88
FEVER IN CHILDREN 3 TO 36 MONTHS OF AGE

Previously healthy and well-appearing children aged 3 to 36 months who present with
FWS account for approximately 6% of all pediatric ED visits.18 Similar to younger infants, most febrile children in this age group have a self-limiting viral illness.89,90 However, it is important to identify infants with occult bacteremia, because of the risk of
subsequent complications, including pneumonia, septic arthritis, osteomyelitis, meningitis, sepsis, and death.91 The prevalence of occult bacteremia among febrile children aged 3 to 36 months is between 0.5% and 2%; the lower rates are observed
in populations with PCV7 vaccination coverage of approximately 80%.1,27,92 The
threshold for when to evaluate the age group for occult SBI is a rectal temperature
39 C or greater (102.2 F). Children at greatest risk for UTI are boys younger than
6 months, uncircumcised males, females younger than 24 months, and patients
with known urinary tract abnormalities. Specimens for urinalysis and urine culture
should be obtained by urethral catheterization in these patients.43,82 If the results
are positive (according to the aforementioned criteria), antibiotics and close followup are warranted.
The recommendation for evaluation of previously healthy, well-appearing children
aged 3 to 36 months with temperature 39.5 C (103.1 F) or greater and FWS is to
consider obtaining a CBC with manual differential in unvaccinated children and children who have received fewer than 2 doses of the pneumococcal vaccine (PCV7 or

Fever in Pediatric Patient

PCV13). A blood culture with empirical antibiotic therapy for children with a peripheral
WBC count of 15,000/mm3 or greater or an absolute neutrophil count greater than or
equal to 10,000 should be considered.66 Guidelines for antibiotic treatment call for
administration of ceftriaxone, 50 mg/kg IM/IV. Twenty-four-hour follow-up by telephone or visit is necessary if antibiotics are given in the ED. In this postvaccination
era, with its changing epidemiology in the pathogens responsible for occult bacteremia, the decrease in the rate of Streptococcus pneumoniae bacteremia has led to
questions about the necessity for traditionally recommended screening tests for
occult bacteremia in children aged 3 to 36 months with FWS.1,93 The newer multivalent
vaccine, PCV13, should provide even more protection for infants and will likely further
lower the risk of occult bacteremia. The most recent recommendations for management of fever in non-toxic appearing infants aged 336 months are summarized in
Fig. 2.
OCCULT PNEUMONIA IN CHILDREN 3 TO 36 MONTHS OF AGE

Seven percent of children younger than 2 years with temperatures higher than 38 C
have pneumonia.94 Most children older than 3 months with pneumonia have clinical
signs of infection (tachypnea, nasal flaring, grunting, oxygen saturation <95%,
cyanosis, abnormal lung sounds), but approximately 3% of young patients without
these symptoms have radiographic evidence of occult pneumonia.93,9597 Studies
have also reported high rates of occult pneumonia (20%30%) among highly febrile
children older than 3 months with temperatures greater than 39 C and WBC counts
greater than 20,000/mm3, without clinical signs of pneumonia.67 Blood cultures yield
positive findings in only 3% to 5% of young children with pneumonia.67,98 Recommendations for when to obtain a chest radiograph in a febrile infant without respiratory
symptoms differ greatly among sources. The American College of Emergency Physicians recommends consideration of a chest radiograph in febrile children 3 months of
age and older with temperatures greater than 39 C and a WBC count greater than
20,000/mm3 without clinical evidence of a lower respiratory tract infection.1 However,
more recent guidelines recommend a chest radiograph in febrile children older than
3 months who have FWS, a temperature of 40 C or greater, or a WBC count greater
than 20,000/mm3.43
FIRST COMPLEX FEBRILE SEIZURE

There is a well-established association between seizures of any type (prolonged, focal,

or recurrent) and acute bacterial meningitis.99102 A complex febrile seizure might be
the sole presenting sign of acute bacterial meningitis.99,100,103110 Simple febrile seizures are described as self-limiting, lasting less than 15 minutes, with tonic-clonic features, no reoccurrences within the next 24 hours, and no postictal features. Complex
febrile seizures are described as seizures lasting longer than 15 minutes; a series of
seizures recurring within a 24-hour period; or focal seizures with tonic or clonic movements, loss of muscle tone, laterality with or without secondary generalization, head or
eye deviation to 1 side, or subsequent transient unilateral paralysis (lasting minutes to
occasionally days).111
The incidence of acute bacterial meningitis in children who present after their first
simple febrile seizure seems to be low.112 Between 12% and 27% of children diagnosed with acute bacterial meningitis have been reported to have had a seizure (of
any type).99,113 A retrospective cohort study looking at the incidence of acute bacterial
meningitis in otherwise healthy children aged 6 to 60 months presenting to the ED after
their first complex febrile seizure found that few of them who had a complex febrile

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Fig. 2. Algorithm for management of a previously healthy, nontoxic appearing child, 3 to 36 months of age, with a fever without source. This algorithm
is a suggested, but not exhaustive, approach to management. (Adapted from Lee B, McCallin T. Microbiology and infectious disease. In: Tschudy MM,
Arcara KM. The Harriet Lane handbook. 19th edition. St Louis (MO): Mosby; 2011; with permission. Modified from Baraff LJ. Management of fever
without source in infants and children. Ann Emerg Med 2000:36(6):60214; and Baraff LJ. Management of infants and young children with fever
without source. Pediatr Ann 2008:37(10):6739.)

Fever in Pediatric Patient

seizure had acute bacterial meningitis in the absence of other signs or symptoms. The
investigators of that study concluded that patients whose only feature of a complex
febrile seizure was 2 brief nonfocal seizures in 24 hours are at particularly low risk
for acute bacterial meningitis.111,112 Therefore, it is recommended that lumbar puncture be performed based on clinical suspicion and additional signs and symptoms that
suggest meningitis, rather than a complex febrile seizure alone.
KAWASAKI DISEASE

Kawasaki disease (KD) is a systemic vasculitis of unknown cause, affecting small and
medium vessels. The leading cause of acquired heart disease in North American and
Japanese children, KD is believed to be an immune-mediated vasculitis that primarily
affects children younger than 5 years.36,114,115 In the United States, the incidence in
2006 was estimated to be 20.8/100,000 among children younger than 5 years.116
The diagnosis of KD is made clinically; there is no diagnostic test for this disease.
The classic presentation of KD is fever for 5 days or more and the presence of at least
4 of the 5 following clinical criteria:
 Bilateral and nonexudative bulbar conjunctivitis
 Oropharyngeal changes: strawberry tongue; diffuse erythema of the oropharyngeal mucosa without exudate; erythema, cracking, fissuring, or bleeding of the
lips
 Cervical lymphadenopathy (>1.5 cm diameter, usually unilateral)
 Polymorphous nonvesicular or bullous rash (most commonly a nonspecific,
diffuse maculopapular eruption)
 Peripheral extremity changes with erythema or edema of the palms or soles
(in the acute phase) or periungal desquamation in the subacute phase
The term incomplete KD is used when a child presents with fever lasting 5 days or
more with only 2 or 3 of the clinical criteria listed earlier. Atypical KD is the term used
for patients who fulfill the criteria for KD and have a clinical feature not usually associated with it (eg, renal impairment).117
Other clinical features that support the diagnosis of KD include severe irritability (a
common finding), aseptic meningitis, mild acute iridocyclitis or anterior uveitis on slit
lamp examination, and oligoarticular and polyarticular arthritis and arthralgias.117121
In 1 study,122 61% of patients had gastrointestinal complaints (diarrhea, vomiting,
abdominal pain) and 35% had respiratory symptoms (rhinorrhea or cough). Otitis media or tympanitis secondary to inflammation can also be seen in KD.118,123 Hydrops of
the gallbladder occurs in approximately 15% of patients in the acute phase and can be
seen on abdominal ultrasonography.117,124 For patients who do not fulfill these diagnostic criteria, abdominal ultrasonography can be useful in supporting the diagnosis.
The criteria can be applied once other diseases with similar presentations have been
excluded.117,118 It is not uncommon to document a concomitant infection in patients
with KD.125,126 In 1 study, 33% of children with typical KD had a confirmed concomitant infection.125 Therefore, suspicion for KD needs to remain high, especially if an
infection does not explain the clinical features.
The fever of KD is usually high and unresponsive to antibiotics and often to antipyretics as well.118 The clinical features might not all be present at once, so it is important
to inquire about all of the clinical features when obtaining the patients history. It is
important to reevaluate a child with a persistent fever or FWS and a child whose fever
is not responding to antibiotics, because the diagnosis may become clear on
reevaluation.

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The results of laboratory investigations in the acute phase of KD are nonspecific but
could support the diagnosis in children who do not fulfill diagnostic criteria. The acutephase reactants (erythrocyte sedimentation rate and C-reactive protein [CRP]) are
almost always increased either in the early febrile period or on later repeat testing.
A high WBC count with a predominance of neutrophils is found frequently. Anemia
might be present, especially with prolonged inflammation. A characteristic feature of
KD is thrombocytosis; however, this finding usually occurs in the second week of
the illness, during the subacute phase. Hypoalbuminemia is common, as are
increased serum transaminase levels. Sterile pyuria might indicate urethritis or
meatitis.118
Children suspected of having KD should be admitted to the hospital and treated
with IV immunoglobulin (IVIG) to reduce the risk of cardiac complications, most
notably, coronary artery aneurysm (CAA). CAA develops in approximately 20% of untreated children and is the most common cause of morbidity and mortality associated
with this disease. The American Heart Association recommends that all children
suspected of having KD be treated with a single dose of 2 g/kg of IVIG infused over
12 hours. It also recommends that high-dose aspirin be initiated at a dose of 80 to
100 mg/kg per day in 4 divided doses as long as the child is febrile, then switching
to low-dose aspirin after the child has been afebrile for 48 to 72 hours.117,127 Mortality
as low as 0.026% has been achieved among children treated with this regimen.128
Although most children respond well to initial treatment, 11.6% to 38.3% have
persistent or a recurrence of fever beyond 48 hours after completion of IVIG, which
is a risk factor for CAA.129131 Children returning to the ED with fever persistence or
recurrence 48 hours after finishing IVIG therapy for KD should be presumed to have
a recurrence until proved otherwise and should be treated with a second infusion of
2 g/kg of IVIG over 12 hours.117
MENINGOCOCCEMIA

Neisseria meningitidis, also known as Meningococcus, is a gram-negative Diplococcus that colonizes the human upper respiratory tract and can cause lifethreatening clinical syndromes. Upper respiratory tract infections and exposure to
active and passive tobacco smoking damages nasopharyngeal cells, increasing susceptibility to invasive disease.132,133 The incidence of invasive meningococcal disease
in the United States is 1.1/100,000, with peak incidence in late winter and early
spring.134 Most cases occur in children, with 46% occurring in children younger
than 2 years.135 Individuals living in crowded living conditions, such as dormitories
and military barracks, are at increased risk for invasive disease.136 Two licensed vaccines are available to reduce the burden of invasive disease. However, the quadrivalent polysaccharide vaccine (Menomune, Sanofi Pasteur, Swiftwater, PA, USA; also
referred to as MPSV4) and the quadrivalent conjugate vaccine (Menactra, Sanofi
Pasteur, Swiftwater, PA, USA; also referred to as MCV4) do not cover serogroup B,
which causes approximately 50% of cases of invasive disease worldwide and 30%
in the United States.137
N meningitidis can cause a rapidly fatal illness. The 2 most common clinical syndromes (acute meningococcal meningitis and fulminant meningococcemia) must be
recognized promptly for immediate diagnosis and treatment. Approximately 50% of
patients with invasive disease present with acute purulent meningitis.138 Its classic
symptoms, like all presentations of bacterial meningitis, include headache, fever,
photophobia, stiff neck, nausea, vomiting, altered mental status, and bulging fontanelle in infants. Meningococcemia, or meningococcal septicemia, without meningitis

Fever in Pediatric Patient

occurs in 5% to 20% of patients with invasive disease.139 It can initially present with
acute onset of fever, chills, arthralgia, and myalgia. Patients can experience a transient
resolution of symptoms within the first 6 hours, and a maculopapular rash, resembling
a viral exanthem, may appear.140 Then the characteristic nonblanching hemorrhagic
(petechial or purpuric) skin lesions may manifest, being more prominent on the extremities. Children with fever and petechial rash merit close examination and consideration by the emergency physician, because they have an 11% chance of having
meningococcemia.141 Patients with petechiae confined to the distribution of the superior vena cava are less likely to have meningococcal infection.142 In addition, in meningococcemia, the hemorrhagic skin lesions generally progress and are larger and bluer
than the pinpoint petechiae associated with thrombocytopenia or coughing.138
Without prompt treatment, 15% to 20% progress to purpura fulminans, which may
necessitate skin grafts or amputations.143 Complications of meningococcemia include
adrenal hemorrhage (Waterhouse-Friderichsen syndrome), stroke, disseminated
intravascular coagulation, and acute respiratory distress syndrome.136
N meningitidis is diagnosed by Gram stain and culture from CSF or blood. Cultures
might be negative if the patient has been pretreated with antibiotics, but PCR can
detect N meningitidis in culture-negative patients.144,145 Rapid bacterial antigen
detection is not reliable, but newer bedside diagnostic tests are being developed.146,147 N meningitidis should be considered in every patient with CSF pleocytosis
and should be treated based on clinical suspicion.
The treatment of meningococcal disease includes aggressive fluid resuscitation and
management of shock and early antibiotic therapy. The mortality associated with invasive disease has dropped from 70% to 90% to 10% as a result of rapid antibiotic treatment.136 Empirical therapy for suspected meningococcal disease should include an
extended-spectrum cephalosporin, such as ceftriaxone (100 mg/kg/d) or cefotaxime
(200 mg/kg/d IV in 3 divided doses). Penicillin (300,000 U/kg/d IV every 46 hours) may
be used for definitive treatment. Patients with a severe penicillin allergy should be
treated with chloramphenicol, when available, or meropenem (but note 2%3%
cross-reactivity with penicillin).148 For patients with unexplained petechial rash and
fever without signs of meningitis or meningococcal septicemia, an increased WBC
count or increased CRP level may indicate an increased risk of meningococcal disease and reason to treat empirically.141,149
Shock should be managed aggressively with fluids and vasopressor medications.
Patients with meningitis should be monitored and treated for increased intracranial
pressure. Although there is conflicting evidence about the benefit of adjuvant corticosteroid therapy in children with septic shock,150,151 steroids are indicated in cases of
adrenal insufficiency, which can occur in association with adrenal hemorrhage from
meningococcemia.
In addition to standard precautions, patients with meningococcal infection require
isolation with droplet precautions until 24 hours after initiation of effective antimicrobial
therapy.148 Chemoprophylaxis is warranted for household and close contacts, regardless of immunization status. These contacts include those who sleep in the same
dwelling, those who could be exposed to oral secretions, and child-care or preschool
contacts during the 7 days preceding the onset of disease in the patient. If possible,
the following medications should be administered to contacts within 24 hours: ciprofloxacin (500 mg by mouth once for adults), rifampin (5 mg/kg every 12 hours for
2 days for infants <1 month old or 10 mg/kg every 12 hours for 2 days for
children >1 month), or ceftriaxone (125 mg IM for children <12 years and 250 mg IM
for children >12 years).148 Postexposure immunoprophylaxis with the meningococcal
vaccine should be considered when an outbreak occurs.152

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SICKLE CELL DISEASE

In children with sickle cell disease (SCD), fever is frequently the first indication of
serious and life-threatening infection. Infection is the leading cause of death in patients
with SCD, and the approach to fever in these patients should be conservative. Children with SCD are at high risk of bacteremia, because of the early and predictable
loss of splenic function. This condition increases the risk of invasive infection by
encapsulated organisms such as H influenzae, Streptococcus pneumoniae, E coli,
and Salmonella.153 Before the availability of the H influenzae type b and pneumococcal
conjugate vaccines, children with SCD had a 13% risk of developing bacterial sepsis.
The PCV7 vaccine has decreased the incidence of IPD by more than 90%.154
The National Institutes of Health recommend the following workup for all children
with SCD who present with FWS: CBC, blood culture, chest radiograph, oxygen saturation measurement, urinalysis, urine culture, and throat culture.36 Children with SCD
who are at particularly high risk for bacteremia include those who are younger than
1 year, those with a history of pneumococcal infection, those with an infiltrate on a chest
film, and those with the following laboratory findings: WBC count greater than 30,000 or
less than 5000, platelet count less than 100,000, and hemoglobin level less than 5 g/dL.
Children with SCD and any of these findings should be admitted and placed on IV antibiotics while awaiting blood culture results. Children who do not meet these high-risk
criteria but meet criteria for outpatient follow-up can be given a long-acting parenteral
antibiotic, such as ceftriaxone, and then be seen on an outpatient basis.
Other sources of infection should also be considered when children with SCD present to the ED. Fever with cough, chest pain, or dyspnea can indicate acute chest syndrome (ACS). In the young child, ACS often presents as fever and cough without
pain.155 This life-threatening condition cannot be excluded by chest radiograph, and
patients who raise a high index of suspicion should be admitted for IV fluid hydration,
IV antibiotics, oxygen therapy when warranted, and close observation. Influenza is
associated with significant morbidity and mortality in patients with SCD. Children
with SCD and suspected influenza should be treated with antiviral medication and
treated conservatively. Osteomyelitis, meningitis, and arthritis are all more commonly
seen in patients with SCD.
Parvovirus infection in children with SCD can constitute an emergency because of
its frequent association with aplastic crisis. Children with parvovirus present with fever, headache, nausea, and the slapped cheek rash that is the hallmark of this infection. Because parvovirus causes bone marrow suppression, it frequently can cause
aplastic crisis in children with SCD. The first sign of crisis is a lowered reticulocyte
count, which can be seen in the first 5 days of illness. The hemoglobin level then decreases accordingly. Children with SCD and suspected parvovirus should be admitted
under isolation, and hemoglobin levels should be observed closely, because transfusion might be warranted.
FEBRILE NEUTROPENIA

Fever and neutropenia are the most frequent and potentially lethal complications
of chemotherapy in children. Management with emergency hospitalization and empirical IV administration of broad-spectrum antibiotics has decreased mortality to less
than 1%.156
Febrile neutropenia is defined as the persistence of a temperature 38.5 C or greater
for more than 2 hours or a single temperature of 39 C in a patient with an absolute
neutrophil count less than 500 cells/mm3.157 Recent studies stratified neutropenic patients into risk groups. Neutropenic children at low risk of bacteremia and serious

Fever in Pediatric Patient

medical complications are those who present as outpatients, who have been neutropenic for less than 7 days, and who have no significant comorbidity. One study
indicated that these children have a 4% risk of bacteremia or serious medical complication versus a 41% risk in children not meeting these criteria.158 Neutropenic children
are vulnerable to bacterial, fungal, and viral infections. Recent epidemiologic trends
have shown an increase in gram-positive bacteria and fungi as causative agents of
infection.159
Guidelines for management of children with febrile neutropenia were published in
2012.160 On the patients presentation in the ED, blood cultures should be obtained
from all lumens of central venous catheters. If possible, blood specimens should
also be obtained from peripheral sites. Urinalysis and urine culture should be performed if a clean-catch midstream specimen can be obtained. Chest radiographs
should be obtained only in symptomatic patients.
Treatment of febrile neutropenia consists of monotherapy with an antipseudomonal
b-lactam IV antibiotic or a carbapenem to provide empirical coverage. Addition of a
second agent to provide gram-negative coverage should be reserved for patients
who are clinically unstable or in centers where resistance exists. Studies have shown
success with treating low-risk patients with oral outpatient regimens such as fluoroquinolones or amoxicillin/clavulinate.161
SUMMARY

Children and infants presenting to the ED with fever can pose a challenge to the emergency physician. Because fever in children provokes much anxiety among caregivers,
it is important to identify children who are at risk for dangerous outcomes.
Important points regarding the management of febrile infants and children are summarized as follows:
 Fever is defined as a rectal temperature greater than 38.0 C (>100.4 F). A fever
that was documented recently at home should be considered the same as a
temperature documented in the ED.
 All febrile infants younger than 28 days should receive a full sepsis workup and be
admitted for parenteral antibiotic therapy.
 Clinical and laboratory criteria can be used to identify low-risk febrile infants
aged 1 to 3 months who can be treated on an outpatient basis with close
follow-up.
 The PCV7 vaccine has markedly decreased the incidence of SBI in vaccinated
infants and children, but children who are unvaccinated or have received fewer
than 2 doses of vaccine are still at risk for pneumococcal disease. The impact
of the new PCV13 vaccine remains to be seen, but this new medication should
decrease the risk even further.
 Neonatal herpes is a potentially devastating illness. Early diagnosis and treatment are essential to reduce mortality. The diagnosis should be strongly considered in the presence of HSV risk factors, atypical sepsis, unexplained acute
hepatitis, and focal seizure activity. Acyclovir therapy should be initiated before
viral dissemination or significant CNS replication occurs.
 The use of rapid flu tests can distinguish influenza from other viral illnesses, assist
in ruling out occult bacteremia in febrile infants, and direct the treatment of highrisk children with antiviral medications.
 Occult UTIs occur often in children with FWS; therefore, a catheterized urine
specimen should be obtained for urine testing in girls and uncircumcised boys
younger than 2 years and in circumcised boys younger than 6 months.

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 Occult pneumonia should be considered in children with a temperature greater than

40 C and a WBC count greater than 20,000 or FWS with respiratory symptoms.
 Fever with petechiae below the nipples should lead to consideration of meningococcemia. Diagnosis and rapid initiation of treatment are critical to decrease
mortality from this devastating illness.
 Children with SCD and neutropenia are at high risk for bacterial infections and
require special evaluation.
ACKNOWLEDGMENTS

We thank Christina Hermos, MD, Pegeen Eslami, MD, Catherine James, MD, Falgun
Wylie, and William (Jerry) Durbin, MD, for review of the fever algorithms.
REFERENCES

1. 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):53045.
2. Slater M, Krug SE. Evaluation of the infant with fever without source: an evidence
based approach. Emerg Med Clin North Am 1999;17(1):97126.
3. Sherman JM, Sood SK. Current challenges in the diagnosis and management of
fever. Curr Opin Pediatr 2012;24(3):4006.
4. Schmitt BD. Fever phobia: misconceptions of parents about fevers. Am J Dis
Child 1980;134(2):17681.
5. Poirier MP, Collins EP, McGuire E. Fever phobia: a survey of caregivers of children seen in a pediatric emergency department. Clin Pediatr (Phila) 2010;49(6):
5304.
6. Betz MG, Grunfeld AF. Fever phobia in the emergency department: a survey of
childrens caregivers. Eur J Emerg Med 2006;13(3):12933.
7. Craig JV, Lancaster GA, Taylor S, et al. Infrared ear thermometry compared with
rectal thermometry in children: a systematic review. Lancet 2002;360(9333):
6039.
8. Craig JV, Lancaster GA, Williamson PR, et al. Temperature measured at the
axilla compared with rectum in children and young people: systematic review.
BMJ 2000;320(7243):11748.
9. Hissink Muller PC, van Berkel LH, de Beaufort AJ. Axillary and rectal temperature measurements poorly agree in newborn infants. Neonatology 2008;94(1):
314.
10. Anbar RD, Richardson-de Corral V, OMalley PJ. Difficulties in universal application of criteria identifying infants at low risk for serious bacterial infection.
J Pediatr 1986;109(3):4835.
11. Torrey SB, Henretig F, Fleisher G, et al. Temperature response to antipyretic therapy in children: relationship to occult bacteremia. Am J Emerg Med 1985;3(3):
1902.
12. Weisse ME, Miller G, Brien JH. Fever response to acetaminophen in viral vs.
bacterial infections. Pediatr Infect Dis J 1987;6(12):10914.
13. Baker MD, Fosarelli PD, Carpenter RO. Childhood fever: correlation of diagnosis
with temperature response to acetaminophen. Pediatrics 1987;80(3):3158.
14. Mazur LJ, Jones TM, Kozinetz CA. Temperature response to acetaminophen
and risk of occult bacteremia: a case-control study. J Pediatr 1989;115(6):
88891.

Fever in Pediatric Patient

15. Baker RC, Tiller T, Bausher JC, et al. Severity of disease correlated with fever
reduction in febrile infants. Pediatrics 1989;83(6):10169.
16. Yamamoto LT, Wigder HN, Fligner DJ, et al. Relationship of bacteremia to antipyretic therapy in febrile children. Pediatr Emerg Care 1987;3(4):2237.
17. Greenes DS, Harper MB. Low risk of bacteremia in febrile children with recognizable viral syndromes. Pediatr Infect Dis J 1999;18(3):25861.
18. Lee GM, Harper MB. Risk of bacteremia for febrile young children in the postHaemophilus influenzae type b era. Arch Pediatr Adolesc Med 1998;152(7):
6248.
19. Soman M. Characteristics and management of febrile young children seen in a
university family practice. J Fam Pract 1985;21(2):11722.
20. Byington CL, Rittichier KK, Bassett KE, et al. Serious bacterial infections in
febrile infants younger than 90 days of age: the importance of ampicillinresistant pathogens. Pediatrics 2003;111(5 Pt 1):9648.
21. Nizet V, Vinci RJ, Lovejoy FH Jr. Fever in children. Pediatr Rev 1994;15(4):
12735.
22. 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):
16626.
23. Klein JO. Management of the febrile child without a focus of infection in the era
of universal pneumococcal immunization. Pediatr Infect Dis J 2002;21(6):5848.
24. Mintegi S, Benito J, Sanchez J, et al. Predictors of occult bacteremia in young
febrile children in the era of heptavalent pneumococcal conjugated vaccine.
Eur J Emerg Med 2009;16(4):199205.
25. 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):295300.
26. Whitney CG, Farley MM, Hadler J, et al. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl
J Med 2003;348(18):173746.
27. 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):
2205.
28. Adams WG, Deaver KA, Cochi SL, et al. Decline of childhood Haemophilus influenzae type b (Hib) disease in the Hib vaccine era. JAMA 1993;269(2):2216.
29. Poehling KA, Talbot TR, Griffin MR, et al. Invasive pneumococcal disease
among infants before and after introduction of pneumococcal conjugate vaccine. JAMA 2006;295(14):166874.
30. Morley EJ, Lapoint JM, Roy LW, et al. Rates of positive blood, urine, and cerebrospinal fluid cultures in children younger than 60 days during the vaccination
era. Pediatr Emerg Care 2012;28(2):12530.
31. Bressan S, Berlese P, Mion T, et al. Bacteremia in feverish children presenting to
the emergency department: a retrospective study and literature review. Acta
Paediatr 2012;101(3):2717.
32. Alpern ER, Alessandrini EA, McGowan KL, et al. Serotype prevalence of occult
pneumococcal bacteremia. Pediatrics 2001;108(2):E23.
33. Johnson HL, Deloria-Knoll M, Levine OS, et al. Systematic evaluation of serotypes causing invasive pneumococcal disease among children under five: the
pneumococcal global serotype project. PLoS Med 2010;7(10). http://dx.doi.
org/10.1371/journal.pmed.1000348.

1089

1090

Wing et al

34. Webster J, Theodoratou E, Nair H, et al. An evaluation of emerging vaccines for

childhood pneumococcal pneumonia. BMC Public Health 2011;11(Suppl 3):S26.
35. Miller E, Andrews NJ, Waight PA, et al. Effectiveness of the new serotypes in the
13-valent pneumococcal conjugate vaccine. Vaccine 2011;29(49):912731.
36. Claudius I, Baraff LJ. Pediatric emergencies associated with fever. Emerg Med
Clin North Am 2010;28(1):6784.
37. Colletti JE, Homme JL, Woodridge DP. Unsuspected neonatal killers in emergency medicine. Emerg Med Clin North Am 2004;22(4):92960.
38. 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):e1624.
39. Ferrera PC, Bartfield JM, Snyder HS. Neonatal fever: utility of the Rochester
criteria in determining low risk for serious bacterial infections. Am J Emerg
Med 1997;15(3):299302.
40. Kadish HA, Loveridge B, Tobey J, et al. Applying outpatient protocols in febrile
infants 1-28 days of age: can the threshold be lowered? Clin Pediatr (Phila)
2000;39(2):818.
41. Baker MD, Bell LM. Unpredictability of serious bacterial illness in febrile infants
from birth to 1 month of age. Arch Pediatr Adolesc Med 1999;153(5):50811.
42. Chiu CH, Lin TY, Bullard MJ. Application of criteria identifying febrile outpatient neonates at low risk for bacterial infections. Pediatr Infect Dis J 1994;13(11):9469.
43. Baraff LJ. Management of infants and young children with fever without source.
Pediatr Ann 2008;37(10):6739.
44. Overall JC Jr. Herpes simplex virus infection of the fetus and newborn. Pediatr
Ann 1994;23(3):1316.
45. Brown ZA, Benedetti J, Ashley R, et al. Neonatal herpes simplex virus infection
in relation to asymptomatic maternal infection at the time of labor. N Engl J Med
1991;324(18):124752.
46. Rudnick CM, Hoekzema GS. Neonatal herpes simplex virus infections. Am Fam
Physician 2002;65(6):113842.
47. Brown ZA, Benedetti JK, Watts DH, et al. A comparison between detailed and
simple histories in the diagnosis of genital herpes complicating pregnancy.
Am J Obstet Gynecol 1995;172(4 Pt 1):1299303.
48. Kesson AM. Management of neonatal herpes simplex virus infection. Paediatr
Drugs 2001;3(2):8190.
49. Diamond C, Mohan K, Hobson A, et al. Viremia in neonatal herpes simplex virus
infections. Pediatr Infect Dis J 1999;18(6):4879.
50. Prahlow JA, Linch CA. A baby, a virus, and a rat. Am J Forensic Med Pathol
2000;21(2):12733.
51. Liesegang TJ. Herpes simplex virus epidemiology and ocular importance.
Cornea 2001;20(1):113.
52. Carey BE. Neonatal herpes simplex: pulmonary and intracranial findings.
Neonatal Netw 2002;21(6):637.
53. American Academy of Pediatrics. Herpes simplex. In: Pickering L, editor. Red
book: 2012 report of the committee on infectious disease. Elk Grove Village
(IL): American Academy of Pediatrics; 2000. p. 30918.
54. Brown ZA. Genital herpes complicating pregnancy. Dermatol Clin 1998;16(4):
80510.
55. American Academy of Pediatrics. Herpes simplex. In: Pickering L, editor. Red
book: 2012 report of the committee on infectious disease. Elk Grove Village
(IL): American Academy of Pediatrics; 2012. p. 398.

Fever in Pediatric Patient

56. Kimberlin DW, Lin CY, Jacobs RF, et al. Natural history of neonatal herpes
simplex virus infections in the acyclovir era. Pediatrics 2001;108(2):2239.
57. Kohl S. The diagnosis and treatment of neonatal herpes simplex virus infection.
Pediatr Ann 2002;31(11):72632.
58. Dhar S, Dhar S. Disseminated neonatal herpes simplex: a rare entity. Pediatr
Dermatol 2000;17(4):3302.
59. Malm G, Forsgren M. Neonatal herpes simplex virus infections: HSV DNA in
cerebrospinal fluid and serum. Arch Dis Child Fetal Neonatal Ed 1999;81(1):
F249.
60. Whitley RJ, Nahmias AJ, Visintine AM, et al. The natural history of herpes simplex virus infection of mother and newborn. Pediatrics 1980;66(4):48994.
61. Whitley RJ. Neonatal herpes simplex virus infections: pathogenesis and therapy.
Pathol Biol (Paris) 1992;40(7):72934.
62. Enright AM, Prober CG. Neonatal herpes infection: diagnosis, treatment and
prevention. Semin Neonatol 2002;7(4):28391.
63. Baker MD, Bell LM, Avner JR. Outpatient management without antibiotics of
fever in selected infants. N Engl J Med 1993;329(20):143741.
64. Jaskiewicz JA, McCarthy CA, Richardson AC, et al. Febrile infants at low risk for
serious bacterial infectionan appraisal of the Rochester criteria and implications for management. Febrile Infant Collaborative Study Group. Pediatrics
1994;94(3):3906.
65. 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):227.
66. Baraff LJ. Management of fever without source in infants and children. Ann
Emerg Med 2000;36(6):60214.
67. Bachur R, Perry H, Harper MB. Occult pneumonias: empiric chest radiographs
in febrile children with leukocytosis. Ann Emerg Med 1999;33(2):16673.
68. Claesson BA, Trollfors B, Brolin I, et al. Etiology of community-acquired pneumonia in children based on antibody responses to bacterial and viral antigens.
Pediatr Infect Dis J 1989;8(12):85662.
69. Bettenay FA, de Campo JF, McCrossin DB. Differentiating bacterial from viral
pneumonias in children. Pediatr Radiol 1988;18(6):4534.
70. Swingler GH. Radiologic differentiation between bacterial and viral lower respiratory infection in children: a systematic literature review. Clin Pediatr (Phila)
2000;39(11):62733.
71. Boyer K, Cherry J. Nonbacterial pneumonia. In: Feigin R, Cherry J, editors. Textbook of pediatric infectious disease. Philadelphia: WB Saunders; 1992.
72. Turner RB. Epidemiology, pathogenesis, and treatment of the common cold.
Ann Allergy Asthma Immunol 1997;78(6):53140.
73. Bramson RT, Meyer TL, Silbiger ML, et al. The futility of the chest radiograph in
the febrile infant without respiratory symptoms. Pediatrics 1993;92(4):5246.
74. Shaw KN, Gorelick M, McGowan KL, et al. Prevalence of urinary tract infection
in febrile young children in the emergency department. Pediatrics 1998;102(2):
e16.
75. Hoberman A, Chao HP, Keller DM, et al. Prevalence of urinary tract infection in
febrile infants. J Pediatr 1993;123(1):1723.
76. Hoberman A, Wald ER. Urinary tract infections in young febrile children. Pediatr
Infect Dis J 1997;16(1):117.
77. Bauchner H, Philipp B, Dashefsky B, et al. Prevalence of bacteriuria in febrile
children. Pediatr Infect Dis J 1987;6(3):23942.

1091

1092

Wing et al

78. Shaikh N, Morone NE, Bost JE, et al. Prevalence of urinary tract infection in
childhood: a meta-analysis. Pediatr Infect Dis J 2008;27(4):3028.
79. Hoberman A, Wald ER, Hickey RW, et al. Oral versus initial intravenous therapy
for urinary tract infections in young febrile children. Pediatrics 1999;104(1 Pt 1):
7986.
80. Magin EC, Garcia-Garcia JJ, Sert SZ, et al. Efficacy of short-term intravenous
antibiotic in neonates with urinary tract infection. Pediatr Emerg Care 2007;
23(2):836.
81. Sastre JB, Aparicio AR, Cotallo GD, et al. Urinary tract infection in the newborn:
clinical and radio imaging studies. Pediatr Nephrol 2007;22(10):173541.
82. Subcommittee on Urinary Tract Infection, Steering Committee on Quality
Improvement and Management, Roberts KB. Urinary tract infection: clinical
practice guideline for the diagnosis and management of the initial UTI in febrile
infants and children 2 to 24 months. Pediatrics 2011;128(3):595610.
83. 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):309.
84. Levine DA, Platt SL, Dayan PS, et al. Risk of serious bacterial infection in young
febrile infants with respiratory syncytial virus infections. Pediatrics 2004;113(6):
172834.
85. Bilavsky E, Shouval DS, Yarden-Bilavsky H, et al. A prospective study of the risk
for serious bacterial infections in hospitalized febrile infants with or without bronchiolitis. Pediatr Infect Dis J 2008;27(3):26970.
86. Doby B, Korgenski K, Reynolds C, et al. Detection of rhinovirus does not
decrease the likelihood of serious bacterial infection in febrile infants younger
than 90 days of age [poster]. Presented at the Annual Meeting of the Pediatric
Academic Society. Denver (Colorado), May 1, 2011.
87. Rittichier KR, Bryan PA, Bassett KE, et al. Diagnosis and outcomes of enterovirus infections in young infants. Pediatr Infect Dis J 2005;24(6):54650.
88. Committee on Infectious Diseases, American Academy of Pediatrics. Recommendations for prevention and control of influenza in children, 20122013.
Pediatrics 2012;130(4):78092.
89. Lee GM, Fleisher GR, Harper MB. Management of febrile children in the age of
the conjugate pneumococcal vaccine: a cost-effectiveness analysis. Pediatrics
2001;108(4):83544.
90. Jaffe DM, Tanz RR, Davis AT, et al. Antibiotic administration to treat possible
occult bacteremia in febrile children. N Engl J Med 1987;317(19):117580.
91. Kuppermann N. Occult bacteremia in young febrile children. Pediatr Clin North
Am 1999;46(6):1073109.
92. Waddle E, Jhaveri R. Outcomes of febrile children without localising signs after
pneumococcal conjugate vaccine. Arch Dis Child 2009;94(2):1447.
93. Baraff LJ, Bass JW, Fleisher GR, et al. Practice guideline for the management of
infants and children 0 to 36 months of age with fever without source. Agency for
Health Care Policy and Research. Ann Emerg Med 1993;22(7):1198210.
94. Taylor JA, Del Beccaro M, Done S, et al. Establishing clinically relevant standards for tachypnea in febrile children younger than 2 years. Arch Pediatr Adolesc Med 1995;149(3):2837.
95. Leventhal JM. Clinical predictors of pneumonia as a guide to ordering chest
roentgenograms. Clin Pediatr (Phila) 1982;21(12):7304.
96. Zukin DD, Hoffman JR, Cleveland RH, et al. Correlation of pulmonary signs and
symptoms with chest radiographs in the pediatric age group. Ann Emerg Med
1986;15(7):7926.

Fever in Pediatric Patient

97. Singal BM, Hedges JR, Radack KL. Decision rules and clinical prediction of
pneumonia: evaluation of low-yield criteria. Ann Emerg Med 1989;18(1):1320.
98. Hickey RW, Bowman MJ, Smith GA. Utility of blood cultures in pediatric patients
found to have pneumonia in the emergency department. Ann Emerg Med 1996;
27(6):7215.
99. Rosman NP, Peterson DB, Kaye EM, et al. Seizures in bacterial meningitis: prevalence, patterns, pathogenesis, and prognosis. Pediatr Neurol 1985;1(5):
27885.
100. Rosman NP. Evaluation of the child who convulses with fever. Paediatr Drugs
2003;5(7):45761.
101. Nigrovic LE, Kuppermann N, Malley R. Development and validation of a multivariable predictive model to distinguish bacterial from aseptic meningitis in
children in the post-Haemophilus influenzae era. Pediatrics 2002;110(4):
7129.
102. Nigrovic LE, Kuppermann N, Macias CG, et al. Clinical prediction rule for identifying children with cerebrospinal fluid pleocytosis at very low risk of bacterial
meningitis. JAMA 2007;297(1):5260.
103. Chin RF, Neville BG, Scott RC. Meningitis is a common cause of convulsive status epilepticus with fever. Arch Dis Child 2005;90(1):669.
104. Fetveit A. Assessment of febrile seizures in children. Eur J Pediatr 2008;167(1):
1727.
105. Armon K, Stephenson T, MacFaul R, et al. An evidence and consensus based
guideline for the management of a child after a seizure. Emerg Med J 2003;
20(1):1320.
106. Green SM, Rothrock SG, Clem KJ, et al. Can seizures be the sole manifestation
of meningitis in febrile children? Pediatrics 1993;92(4):52734.
107. Kneen R, Appleton R. Status epilepticus with fever: how common is meningitis?
Arch Dis Child 2005;90(1):34.
108. Offringa M, Moyer VA. Evidence based paediatrics: evidence based management of seizures associated with fever. BMJ 2001;323(7321):11114.
109. Warden CR, Zibulewsky J, Mace S, et al. Evaluation and management of febrile
seizures in the out-of-hospital and emergency department settings. Ann Emerg
Med 2003;41(2):21522.
110. Akpede GO, Sykes RM. Convulsions with fever as a presenting feature of bacterial meningitis among preschool children in developing countries. Dev Med
Child Neurol 1992;34(6):5249.
111. Kimia A, Ben-Joseph EP, Rudloe T, et al. Yield of lumbar puncture among children who present with their first complex febrile seizure. Pediatrics 2010;126(1):
629.
112. Kimia AA, Capraro AJ, Hummel D, et al. Utility of lumbar puncture for first simple
febrile seizure among children 6 to 18 months of age. Pediatrics 2009;123(1):
612.
113. Rosenberg NM, Meert K, Marino D, et al. Seizures associated with meningitis.
Pediatr Emerg Care 1992;8(2):679.
114. Taubert KA, Rowley AH, Shulman ST. Nationwide survey of Kawasaki disease
and acute rheumatic fever. J Pediatr 1991;119(2):27982.
115. Yanagawa H, Nakamura Y, Ojima T, et al. Changes in epidemic patterns of Kawasaki disease in Japan. Pediatr Infect Dis J 1999;18(1):646.
116. Holman RC, Belay ED, Christensen KY, et al. Hospitalizations for Kawasaki syndrome among children in the United States, 19972007. Pediatr Infect Dis J
2010;29(6):4838.

1093

1094

Wing et al

117. Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and longterm management of Kawasaki disease: a statement for health professionals
from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease,
Council on Cardiovascular Disease in the Young, American Heart Association.
Circulation 2004;110(17):274771.
118. Lang B. Recognizing Kawasaki disease. Paediatr Child Health 2001;6(9):
63843.
119. Ohno S, Miyajima T, Higuchi M, et al. Ocular manifestations of Kawasakis disease
(mucocutaneous lymph node syndrome). Am J Ophthalmol 1982;93(6):7137.
120. Burns JC, Joffe L, Sargent RA, et al. Anterior uveitis associated with Kawasaki
syndrome. Pediatr Infect Dis 1985;4(3):25861.
121. Gong GW, McCrindle BW, Ching JC, et al. Arthritis presenting during the acute
phase of Kawasaki disease. J Pediatr 2006;148(6):8005.
122. Baker AL, Lu M, Minich LL, et al. Associated symptoms in the ten days before
diagnosis of Kawasaki disease. J Pediatr 2009;154(4):5925.
123. Yoskovitch A, Tewfik TL, Duffy CM, et al. Head and neck manifestations of
Kawasaki disease. Int J Pediatr Otorhinolaryngol 2000;52(2):1239.
124. Suddleson EA, Reid B, Woolley MM, et al. Hydrops of the gallbladder associated with Kawasaki syndrome. J Pediatr Surg 1987;22(10):9569.
125. Benseler SM, McCrindle BW, Silverman ED, et al. Infections and Kawasaki disease: implications for coronary artery outcome. Pediatrics 2005;116(6):e7606.
126. Jordan-Villegas A, Chang ML, Ramilo O, et al. Concomitant respiratory viral infections in children with Kawasaki disease. Pediatr Infect Dis J 2010;29(8):
7702.
127. Dajani AS, Taubert KA, Gerber MA, et al. Diagnosis and therapy of Kawasaki
disease in children. Circulation 1993;87(5):177680.
128. Nakamura Y, Yashiro M, Uehara R, et al. Epidemiologic features of Kawasaki
disease in Japan: results of the 20072008 nationwide survey. J Epidemiol
2010;20(4):3027.
129. Durongpisitkul K, Soongswang J, Laohaprasitiporn D, et al. Immunoglobulin failure and retreatment in Kawasaki disease. Pediatr Cardiol 2003;24(2):1458.
130. Tremoulet AH, Best BM, Song S, et al. Resistance to intravenous immunoglobulin in children with Kawasaki disease. J Pediatr 2008;153(1):11721.
131. Burns JC, Capparelli EV, Brown JA, et al. Intravenous gamma-globulin treatment
and retreatment in Kawasaki disease. US/Canadian Kawasaki Syndrome Study
Group. Pediatr Infect Dis J 1998;17(12):11448.
132. Caugant DA, Tzanakaki G, Kriz P. Lessons from meningococcal carriage
studies. FEMS Microbiol Rev 2007;31(1):5263.
133. Stephens DS. Uncloaking the meningococcus: dynamics of carriage and disease. Lancet 1999;353(9157):9412.
134. Kirsch EA, Barton RP, Kitchen L, et al. Pathophysiology, treatment and outcome
of meningococcemia: a review and recent experience. Pediatr Infect Dis J 1996;
15(11):96778.
135. Riedo FX, Plikaytis BD, Broome CV. Epidemiology and prevention of meningococcal disease. Pediatr Infect Dis J 1995;14(8):64357.
136. Rosenstein NE, Fischer M, Tappero JW. Meningococcal vaccines. Infect Dis Clin
North Am 2001;15(1):15569.
137. Girard MP, Preziosi MP, Aguado MT, et al. A review of vaccine research and
development: meningococcal disease. Vaccine 2006;24(22):4692700.
138. Brigham KS, Sandora TJ. Neisseria meningitidis: epidemiology, treatment and
prevention in adolescents. Curr Opin Pediatr 2009;21(4):43743.

Fever in Pediatric Patient

139. van Deuren M, Brandtzaeg P, van der Meer JW. Update on meningococcal disease with emphasis on pathogenesis and clinical management. Clin Microbiol
Rev 2000;13(1):14466.
140. Yung AP, McDonald MI. Early clinical clues to meningococcaemia. Med J Aust
2003;178(3):1347.
141. Klinkhammer MD, Colletti JE. Pediatric myth: fever and petechiae. CJEM 2008;
10(5):47982.
142. Wells LC, Smith JC, Weston VC, et al. The child with a non-blanching rash: how
likely is meningococcal disease? Arch Dis Child 2001;85(3):21822.
143. Herrera R, Hobar PC, Ginsburg CM. Surgical intervention for the complications
of meningococcal-induced purpura fulminans. Pediatr Infect Dis J 1994;13(8):
7347.
144. Taha MK, Alonso JM. Molecular epidemiology of infectious diseases: the
example of meningococcal disease. Res Microbiol 2008;159(1):626.
145. Cummings KC, Louie J, Probert WS, et al. Increased detection of meningococcal infections in California using a polymerase chain reaction assay. Clin
Infect Dis 2008;46(7):11246.
146. Perkins MD, Mirrett S, Reller LB. Rapid bacterial antigen detection is not clinically useful. J Clin Microbiol 1995;33(6):148691.
147. Chanteau S, Dartevelle S, Mahamane AE, et al. New rapid diagnostic tests for
Neisseria meningitidis serogroups A, W135, C, and Y. PLoS Med 2006;3(9):e337.
148. American Academy of Pediatrics. Meningococcal infections. In: Pickering L,
editor. Red Book: 2012 Report of the Committee on Infectious Diseases. Elk
Grove Village (IL): American Academy of Pediatrics; 2012. p. 5009.
149. Visintin C, Mugglestone MA, Fields EJ, et al. Management of bacterial meningitis and meningococcal septicaemia in children and young people: summary of
NICE guidance. BMJ 2010;340:c3209.
150. Markovitz BP, Goodman DM, Watson RS, et al. A retrospective cohort study of
prognostic factors associated with outcome in pediatric severe sepsis: what is
the role of steroids? Pediatr Crit Care Med 2005;6(3):2704.
151. Zimmerman JJ, Williams MD. Adjunctive corticosteroid therapy in pediatric
severe sepsis: observations from the RESOLVE study. Pediatr Crit Care Med
2011;12(1):28.
152. Bilukha OO, Rosenstein N, National Center for Infectious Diseases, et al. Prevention and control of meningococcal disease. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep
2005;54(RR-7):121.
153. Leikin SL, Gallagher D, Kinney TR, et al. Mortality in children and adolescents
with sickle cell disease. Cooperative Study of Sickle Cell Disease. Pediatrics
1989;84(3):5008.
154. Halasa NB, Shankar SM, Talbot TR, et al. Incidence of invasive pneumococcal
disease among individuals with sickle cell disease before and after the introduction of the pneumococcal conjugate vaccine. Clin Infect Dis 2007;44(11):
142833.
155. Vichinsky EP, Styles LA, Colangelo LH, et al. Acute chest syndrome in sickle cell
disease: clinical presentation and course. Cooperative Study of Sickle Cell
Disease. Blood 1997;89(5):178792.
156. Koh A, Pizzo PA. Infectious complications in pediatric cancer patients. In:
Pizzo PA, Poplack DG, editors. Principles and practice of pediatric oncology.
6th edition. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins; 2011.
p. 1190242.

1095

1096

Wing et al

157. Binz P, Bodmer N, Leibundgut K, et al. Different fever definitions and the rate of
fever and neutropenia diagnosed in children with cancer: a retrospective twocenter cohort study. Pediatr Blood Cancer 2013;60(5):799805.
158. Alexander SW, Wade KC, Hibberd PL, et al. Evaluation of risk prediction criteria
for episodes of febrile neutropenia in children with cancer. J Pediatr Hematol
Oncol 2002;24(1):3842.
159. Crokaert F. Febrile neutropenia in children. Int J Antimicrob Agents 2000;16(2):
1736.
160. Lehrnbecher T, Phillips R, Alexander S, et al. Guideline for the management of
fever and neutropenia in children with cancer and/or undergoing hematopoietic
stem-cell transplantation. J Clin Oncol 2012;30(35):442738.
161. Manji A, Beyene J, Dupuis LL, et al. Outpatient and oral antibiotic management
of low-risk febrile neutropenia are effective in childrena systematic review of
prospective trials. Support Care Cancer 2012;20(6):113545.