Content uploaded by Jeffrey R Avner
Author content
All content in this area was uploaded by Jeffrey R Avner on Jul 16, 2018
Content may be subject to copyright.
PEDIATRIC EMERGENCY MEDICINE:
CURRENT CONCEPTS AND CONTROVERSIES 0733–8627/02 $15.00 .00
MANAGEMENT OF FEVER IN
INFANTS AND CHILDREN
Jeffrey R. Avner, MD, and M. Douglas Baker, MD
It is a curious observation, but it is true that fever rarely goes
unnoticed. Of the many symptoms of disease, it is one that consistently
causes alarm in parents and generates discussion among physicians. For
many reasons, the management of fever has been and is likely to remain
a passionately debated topic. Although laboratory research suggests that
fever has antimicrobial actions, clinical evidence to support the hypothe-
sis that fever is beneficial during infection and that fever reduction is
harmful remains elusive.
Myths and misconceptions about fever abound. As a result, children
with fever have withstood overfeeding, bloodletting, bundling, bowel-
bathing, and administration of a variety of chemical concoctions, includ-
ing herbal salves, tonics, synthetic antipyretics, and antibiotics. Not
surprisingly, an equivalent number and diversity of approaches to man-
agement of fever have evolved in pediatric, family medicine, and emer-
gency medicine practice settings.
29, 39, 63
All are defended with equal vigor
by their advocates.
What follows is an overview of the evaluation and management of
fever in young children. Because in children of different ages there are
substantial differences in the cause and outcome of fever-generating
illnesses, the authors have stratified the discussion accordingly. Al-
though the authors have personal biases on the topic, they intend to
From the Division of Pediatric Emergency Medicine, Children’s Hospital at Montefiore;
the Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York
(JRA); the Section of Emergency Medicine, Department of Pediatrics, Yale-New Haven
Children’s Hospital; and the Department of Pediatrics, Yale University School of
Medicine, New Haven, Connecticut (MDB)
EMERGENCY MEDICINE CLINICS OF NORTH AMERICA
VOLUME 20 •NUMBER 1 •FEBRUARY 2002 49
50 AVNER & BAKER
present a broad perspective of the issues involved. That stated, there are
some approaches to fever management that should be avoided. The
relative worthiness of the remainder is a topic around which debate will
likely continue.
FEVER IN INFANTS
Although there is some variability in opinion,
4, 12, 23, 29, 37, 39, 63
most
researchers define fever in infants younger than 2 months of age as body
temperature greater than or equal to 38C. That number represents a
two-standard deviation (SD) from the norm of 37C, which is the average
body temperature of well children. Some investigators
12
have extended
the age range to 3 months, and others
4
have raised the temperature
threshold to 38.2C.
Infants younger than 2 months differ from older children in several
important ways. Younger infants seem to be less immunocompetent,
and, as a result of their recent birth, are exposed to an unique group of
bacterial pathogens. As a result, infections from group B streptococcus,
gram-negative bacteria, and (less commonly) Listeria sp. are seen in
addition to those caused by pneumococcus and meningococcus, which
are more common in older children.
4, 12, 37
The exact epidemiology of febrile illnesses in young infants is some-
what difficult to ascertain. Most large studies have focused on subsets
of febrile infants rather than on the group as a whole. One group of
investigators based in the emergency department (ED) of an urban
pediatric referral center in Philadelphia found the incidence of bacterial
disease to be approximately 10% in febrile infants from 1 to 2 months of
age,
5
and 13% in febrile infants younger than 1 month of age.
6
Research-
ers in Salt Lake City
40
also reported the latter rate of bacterial disease.
The relative frequencies of specific bacterial diseases in infants show
similar consistency. In infants younger than 3 months of age, urinary
tract infections account for one third of all bacterial diseases.
5, 6, 12, 40
Bacterial gastroenteritis, bacteremia, meningitis, cellulitis, and other bac-
terial diseases are also seen with regularity. Although older reports of
bacteremia suggested a direct inverse relationship between incidence
and age in weeks, current data indicate that the rate of bacteremia is
between 2% and 3% in all febrile infants younger than 2 months.
5, 6, 40
A further distinguishing characteristic of young infants deserves
special mention—their relative inability to demonstrate clinical evidence
of illness. The ability of a child to engage in social interaction with an
adult is age related and inconsistent, if not absent in infants younger
than 2 months. Although clinical scoring systems have been developed
to help to identify infants and toddlers at low risk for bacterial disease,
49
they have been found to be unreliable when applied to infants younger
than 2 months of age.
3, 4, 6, 12, 40
In one study of 747 infants with fever, two
thirds of those with bacterial diseases appeared well to the examining
attending pediatrician.
4
Although ill appearance should always raise
MANAGEMENT OF FEVER IN INFANTS AND CHILDREN 51
considerable concern, in this age range, well appearance does not imply
absence of bacterial disease.
Preliminary Research
Preliminary investigations of fever in infants focused on identifica-
tion of clinical or laboratory factors that would identify a subset of
young infants who were at increased risk of bacterial infection.
19, 22, 53
These studies demonstrated that single laboratory parameters, such as
the complete blood count or the erythrocyte sedimentation rate, or
clinical parameters, such as the observed appearance of the infant, were
not entirely predictive of the presence of bacterial disease. They laid the
groundwork for the development of more complex screening tools to
identify infants who are at low risk of having serious bacterial diseases
as the cause of fever, however.
4–6, 12, 23, 37
Screening for Low-risk Infants
Several investigators have used prospective consecutive cohort
study designs to test the effectiveness of screening tools to identify
infants with fever who are at low risk for bacterial disease.
4, 12, 37
Re-
searchers in Boston tested the safety and efficacy of outpatient manage-
ment with IM ceftriaxone of fever in 1- to 3-month-old infants whom
they judged to be at low risk of having serious bacterial disease. In this
study, the 503 1- to 3-month-old infants were judged to be at low risk
for bacterial disease, according to screening criteria used (Table 1). All
were treated with ceftriaxone and managed as outpatients. Even in this
low-risk cohort, 27 (5%) had culture-positive bacterial diseases, including
bacteremia, urinary tract infections (UTIs), and gastroenteritis. All in-
fants recovered uneventfully from their illnesses and seemed to have no
Table 1. COMPONENTS OF FEVER MANAGEMENT PROTOCOLS
Boston
12
Philadelphia
4, 5
Rochester
37
Age (days) 28–89 29–56 0–60
Temperature (Celsius) ⬎37.9 ⬎38.1* ⬎37.9
Infant Observation Score Yes† Yes No
Peripheral WBC ⬍20,000 ⬍15,000 5,0000–15,000
CSF obtained from all Yes Yes No
Antibiotics administered Yes No No
SBI in low-risk group (%) 5.4 0 1.1
Negative Predictive Value (%) 94.6 100 98.9
Sensitivity (%) Not stated 100 92.4
WBC, white blood cell count; CSF, cerebrospinal fluid.
*Temperature criteria was changed to ⬎37.9C in follow-up study.
5
†IOS was assigned but not indicated by the authors to be a screening criteria.
52 AVNER & BAKER
substantial complications attributable to their initial outpatient manage-
ment. All nine infants with initial bacteremia had repeat blood cultures
that were negative. Few differences in initial screening parameters were
detected between those with bacterial disease and those without. Consis-
tent with the findings of others, however, was a significantly higher
percentage of bands in the peripheral blood samples of those with
bacterial diseases.
4, 37, 41, 51
In Philadelphia, investigators tested the efficacy and safety of outpa-
tient management without antibiotics of fever in a selected low-risk
group of 1- to 2-month-old infants.
4
Using a clinical screening tool
similar to but more restrictive than that used in the Boston study, 287
(40%) of 747 consecutive infants with fever were judged to be at low
risk for bacterial disease (see Table 1). All but one of these infants were
documented to have nonbacterial diseases, yielding a negative predictive
value (NPV) of 99% (95% CI: 98, 100) to the screening tool. Using revised
screening criteria that incorporated band-to-neutrophil ratio limits, the
investigators were able prospectively to exclude all febrile 1- to 2-month-
old infants with bacterial disease from consideration for management
without antibiotics. A follow-up study by this group demonstrated that
in their cumulative data set of 1169 1- to 2-month-old infants with fever,
no infant classified as low risk had bacterial disease.
5
These authors
concluded that fever in carefully selected infants could be managed
safely without antibiotics on an outpatient basis, provided that a com-
plete evaluation for sepsis was performed, and that follow-up within 24
hours by a qualified physician was ensured.
Another research group in Rochester used a slightly less restrictive
screening tool to attempt to identify infants younger than 60 days of age
who are unlikely to have serious bacterial infections as the cause of their
fevers.
37
Of the 931 well-appearing infants included in their study, 437
(47%) were classified as low risk for bacterial illness. Although the NPV
of the screen was 98.9% (95% CI: 97.2, 99.6), the sensitivity of their
screening tool was only 92.4% (95% CI: 83, 97). There were other im-
portant limitations to their findings. Unlike the studies from Boston and
Philadelphia, they used no uniform sepsis evaluation (3% of enrolled
infants did not have spinal fluid cultures, and 25% did not have urine
cultures sent). There were multiple observers, and the assessment of the
infants’ general appearance was poorly specified. In addition, treatment
with antibiotics was inconsistent.
It is likely that the reason for the difference in performance of the
three screening tools lies in the differences in their composition (see
Table 1). The Philadelphia group chose a slightly higher temperature
cut-off point, a lower peripheral white blood cell count, and included a
band-to-neutrophil ratio. The Boston group chose a higher peripheral
white blood cell cut-off point, no band criteria, and was less specific
about their use of assessment of clinical appearance. The Rochester
group did not include spinal fluid analysis as part of their low-risk
criteria, added a low-end cut-off point for peripheral white blood cell
counts, did not require urine cultures for all infants, did not use a
MANAGEMENT OF FEVER IN INFANTS AND CHILDREN 53
uniform assessment of appearance, and included infants younger than 1
month of age. All three studies had high NPVs, largely related to
the low overall incidence of bacterial disease in febrile infants. The
Philadelphia group demonstrated both high NPV and high sensitivity,
thereby ensuring that the risk of misclassifying an infant with bacterial
disease as low risk is very unlikely. The Boston group, which used a
screening tool that produced a relatively low NPV value, supports the
routine use of ceftriaxone to manage fever in their outpatient low-risk
group. The Philadelphia and Rochester groups, both of which used
screening tools that led to higher NPVs do not advocate routine use of
antibiotics to manage fever in infants.
Any of the three approaches to management of fever in infants is
defensible. The results of the evaluation of these techniques are pub-
lished and should be reviewed by those choosing to use them. It is,
however, clearly a mistake to knowingly shortcut these protocols in the
absence of proper supportive data. For instance, one cannot at this point
abandon proper evaluation of fever based on well appearance or clinical
suspicion of viral disease. Data published in the ‘‘posthemophilus vac-
cine’’ period clearly indicate that well-appearing infants with fever can
harbor serious bacterial disease. No recent studies have shown it safe to
omit from the routine evaluation of fever in infants the complete blood
count (and differential), urinalysis, blood culture, urine culture, and
regimented assessment of clinical appearance. Some debate does exist
regarding the necessity of obtaining spinal fluid for analysis from some
well-appearing infants with fever.
37
Although the incidence of bacterial
meningitis is low in this group of patients, (bordering on 1%), investiga-
tors have reported occasional patients with documented bacterial menin-
gitis who have appeared well and have had complete blood counts
within acceptable norms.
4, 5
Chest Radiographs
There is also debate about the need to obtain a chest radiograph in
every infant with fever. Several investigators have stated their opinion
that this test can be omitted from the work-up of those infants who
have no clinical indications of respiratory disease.
17, 21, 32
Infants free of
respiratory signs or symptoms are those who demonstrate no evidence
of tachypnea (respiratory rate [RR] ⬍50–60), crackles, rhonchi, wheez-
ing, retractions, nasal flaring, grunting, cough, or rhinitis. Unfortunately,
selected omission of the chest radiograph would allow a small number of
radiographic lung densities in febrile infants to go unrecognized.
4, 5, 21, 32
For instance, in the 8-year data set from Philadelphia, 36 febrile 1- to 2-
month-old infants had positive chest radiographs. Of those, five had no
signs or symptoms of respiratory disease at the time of evaluation.
Although it is likely that many radiographically demonstrable lung
densities in febrile infants result from nonbacterial disease, it is also
possible that some represent bacterial infections. The conservative ap-
54 AVNER & BAKER
proach favors obtaining this study as part of the initial evaluation of
fever in infants.
INFANTS YOUNGER THAN 1 MONTH
Management of fever in infants younger than 1 month of age
deserves special mention. Because of reported higher rates of bacterial
disease in very young infants with fever
19, 41, 53
and their limited abilities
to exhibit ill appearance,
3
some researchers
5, 7, 8
have chosen to exclude
febrile infants younger than 1 month from their outpatient management
schemes. Proponents of the Rochester screening tool have included these
young infants in their study sample,
37
and have provided some prelimi-
nary insight into this issue. In one group of 227 febrile infants younger
than 1 month (who by Rochester criteria were at low risk for bacterial
disease), two had bacterial disease. Although the screen performed rea-
sonably well, the group studied was not composed entirely of consecu-
tively presenting eligible infants, which makes questionable the applica-
bility of the results to the population as a whole.
Two more recent studies demonstrated that the published Boston
and Philadelphia screening tools, which were designed for use in infants
older than 1 month, are not reliable when applied to infants younger
than 1 month. In a retrospective study of 225 febrile 0- to 1-month-old
infants in Salt Lake City, 39 were proved to have serious bacterial
illnesses. Of those, 19.4% by Philadelphia criteria and 25.8% by Boston
criteria met low risk (for bacterial disease) standards. In a similar study
of 0- to 1-month-old febrile infants in Philadelphia, 5 of 32 (15.6%) who
had serious bacterial illnesses also met the Philadelphia low risk (for
bacterial disease) criteria. Those investigators found that applying the
Philadelphia screening criteria to neonates younger than 1 month would
falsely identify as low risk for bacterial illness as many as one in ten
with fever. Thus, the initial management of fever in infants younger
than 1 month should include a complete evaluation for bacterial illness,
and the empirical administration of antibiotics, pending the results of
bacterial cultures. This approach is different and more conservative than
the outpatient options demonstrated safe for selected older, 1- to 2-
month-old febrile infants.
FEVER IN OLDER INFANTS AND TODDLERS
Unlike very young infants (less than 2 months of age), older infants
and toddlers have better-developed social skills, which aids the physi-
cian in the assessment of the child’s risk of serious illness. By 3 months,
almost all infants smile responsively and make laughing sounds, and by
1 year most infants can stand, walk, play simple interactive games (eg,
‘‘slapping five’’) and wave bye-bye. Thus, clinical observation scales that
are not reliable in young infants
3, 49
work particularly well in this age
MANAGEMENT OF FEVER IN INFANTS AND CHILDREN 55
group. An experienced practitioner, therefore, is usually able to deter-
mine, by clinical appearance, whether a child is ‘‘ill’’ or ‘‘well’’ ap-
pearing. Clearly, if the child looks ill and has signs consistent with
invasive bacterial illness or sepsis, emergent management, including
stabilization of the ABCs and empiric treatment with intravenous antibi-
otics, is the rule. Most causes of fever in children are of relatively benign
origin, however, and need only parental reassurance and careful follow-
up. Nevertheless, physician fears of missing a rare serious illness, com-
bined with parental anxiety and ‘‘fever phobia,’’ set in the stressful
atmosphere of an ED, often give way to a series of laboratory tests,
antibiotic treatment, and possible admission to the hospital.
Unfortunately, this type of routine approach often does not serve
children well. Unlike adults, children do not have the cognitive ability
to understand why the blood tests are being done, and furthermore, the
procedure is more difficult, often requiring several attempts at venipunc-
ture. The risk of serious bacterial illness in well-appearing febrile chil-
dren is very low, and some entities like pneumococcal bacteremia and
otitis media often resolve spontaneously.
2, 9, 11, 24, 30, 36, 38
The goal of the
emergency physician, therefore, should be to identify which febrile chil-
dren are likely to have a benign illness and thus spare them a variety of
invasive testing and empiric treatments.
Many febrile children have a source for their fevers clearly identifi-
able on physical examination (e.g., otitis media, viral stomatitis, pneumo-
nia) and can be managed accordingly. Others have associated clinical
findings that place them at higher risk for invasive bacterial illness. For
example, 2% to 20% of children with fever and petechiae (below the
nipple line) have invasive bacterial illness usually caused by meningo-
coccus.
7, 25, 47
The problem for the practitioner is how to manage the well-
appearing febrile child without a source of infection. For these children,
the risks and benefits of obtaining laboratory tests center on the inci-
dence of and the consequence of not identifying, occult or unsuspected
infection. Although occult bacteremia is the most feared and controver-
sial entity, other occult infections also can occur.
OCCULT URINARY TRACT INFECTION
Young children rarely have the ability to complain of typical symp-
toms of UTIs (e.g., dysuria, suprapubic pain, and hesitancy) and because
they are not yet toilet trained, frequency and or foul-smelling urine can
be difficult to identify. Thus, children with UTIs usually present with
nonspecific findings; fever is often the only presenting symptom.
28, 56, 57
A large study
56
of 2411 children (boys ⬍1 year and girls ⬍2 years) who
presented to an urban ED with fever ⱖ38.5C found a prevalence of UTI
of 3.3%. Girls were more likely to have UTI (4.3% vs 1.8%, P⬍0.001) and
white children were 9.7 times more likely to have UTI than nonwhites.
In particular, 16.1% of white girls had UTI. Other significant factors
associated with a higher prevalence of UTI included no potential source
56 AVNER & BAKER
of infection (5.9% vs 2.7%), ill appearance (5.7% vs. 2.4%), circumcision
(8.0% vs. 1.2%), and fever ⬎39C (3.9% vs 2.2%). Based on their data,
the authors concluded that UTI is prevalent in young children, particu-
larly white girls, without a definite source of fever, and that the presence
of potential sources of fever such as upper respiratory infection (URI) or
otitis media, does not reliably rule out the presence of UTI.
It is noteworthy that the prevalence of UTI in febrile children is
about twice that of occult bacteremia
1, 56
and is exceptionally high in the
subgroups of white girls and uncircumcised boys. There is some concern
that these data could overestimate the true prevalence of occult UTIs
because the eventual sequelae of missed pyelonephritis (e.g., hyperten-
sion and renal failure) seem much less common than would be expected.
There are a few possible explanations to this dichotomy. Perhaps these
occult UTIs are being treated presumptively when concurrent otitis
media is diagnosed, the incidence of asymptomatic bacteria is higher
than expected, the morbidity of missing a UTI is lower than expected,
or these result just cannot be generalized to other populations. Neverthe-
less, the issue of occult UTI in febrile young children is an important
and often unrecognized source of infection. In any practice setting, the
clinician should consider obtaining urine from these children, especially
in those at particularly high risk for UTI.
OCCULT BACTEREMIA
In the early 1970s, several studies
18, 50, 62
found that about 3% of well-
appearing febrile children had unsuspected bacteremia usually caused
by pneumococcus. In most of these children (90%–97%), who were initially
managed as outpatients, the bacteremia resolved spontaneously and
there were no sequelae. Nevertheless, the realization that unsuspected
(or occult) bacteremia did exist, coupled with the fear that affected
children could develop invasive disease such as meningitis, led many
practitioners to advocate obtaining blood cultures when managing fever
in young well-appearing children. By the 1980s, the most common
organisms and their characteristic pattern of disease were identified.
The common pathogens at that time were predominately S. pneumoniae
(65%–75%), H. influenzae type b (HIB, 10%–20%), N. meningitidis (5%–
15%), and Salmonella sp. (5%–15%).
18, 36, 38, 50
Although Pneumococcus was
the most common cause of occult bacteremia, the rate of spontaneous
resolution was very high (⬎90%). Occult bacteremia caused by HIB and
meningococcus was of greater concern because these bacteria had higher
rates of invasive sequelae ranging from 7% to 35%. Thereafter, studies
showed that certain clinical and laboratory signs associated with the host
inflammatory response can be useful for risk assessment and monitoring
outcome. Many investigators have shown that as the height of the fever
rises, so does the risk of bacteremia.
1, 35, 36, 45
Similarly, higher peripheral
white blood cell counts were associated with increased risk of bacter-
emia.
1, 35, 45
These findings set the foundation for the practice of obtaining
MANAGEMENT OF FEVER IN INFANTS AND CHILDREN 57
a complete blood count and blood culture as part of the routine manage-
ment of fever in these children.
The importance of early identification of occult bacteremia rests on
the premise that antibiotic treatment during the period of bacteremia
reduces the risk of sequelae. There have been several retrospective
studies but few prospective studies that have addressed that issue. In a
study of 995 children, Jaffe found no difference in ‘‘major’’ morbidity
associated with occult bacteremia between amoxicillin and placebo.
36
Fleisher
27
randomized 6,733 children between 3 and 36 months of age
with temperature over 39.0C and either no focal findings or otitis media
to receive either IM ceftriaxone or PO amoxicillin. Probable or definite
infections at follow-up were classified on the basis of physical examina-
tion, leukocyte counts, antigen detection, cultures of blood or other
body fluids, and ancillary tests. These results suggested that ceftriaxone
eradicated bacteremia, prevented definite focal bacterial complications,
and was associated with less persistent fever. The study had several
limitations, however, including debatable definitions of definite and
probable infection.
2, 46
These studies formed the basis for the publication
of an article in 1993 containing practice guidelines for the management
of fever in infants and children without a source of infection.
8
These
guidelines represented an opinion of a group of experts but did not
constitute guidelines endorsed by a major organization or general con-
sensus, however. These guidelines suggested that children 3 to 36
months of age with fever of 39.0C or more and whose white blood cell
count is 15,000/mm
3
or more should have a blood culture and be treated
with antibiotics pending culture results. The authors also recommended
obtaining urine cultures from boys 6 months of age or younger and all
girls 2 years of age or younger who are treated with antibiotics. The
authors of these guidelines also offered the following caveat, ‘‘the prac-
tice guidelines are meant to assist the physician in managing infants and
children with fever without source . . . they are not intended to be
applied rigidly to every child with fever without source.’’
8
In deciding among various management strategies, the physician
must weigh the risks and benefits of each approach:
Risks
Unnecessary hospitalization
Unnecessary antibiotic therapy
Discomfort of venipuncture
Potential negative psychosocial impact on physician-child-parent
relationship
Unnecessary resource utilization
Cost
Emotional distress
Increased waiting time
Benefits
Possible prevention of localized infection
Possible prevention of severe illness
58 AVNER & BAKER
Early recognition of severe illness
Possible prevention of sequelae
Hearing loss
Neurologic deficit
Learning/behavior problems
Death
Those who think that testing is hazardous, unpleasant, and expensive
relative to the rare chance that a child has bacteremia and even rarer
chance that the bacteremia will progress to severe illness, support a
‘‘watch-and-wait’’ approach. Others who think that missing even one
case of bacteremia is a costly event support testing and empiric treat-
ment. Regardless of one’s preference for a particular approach, new data
and changing environmental circumstances continue to alter the relative
costs and benefits. There have been several recent developments already
in this new century that will have a major impact on this controversial
area:
1. Declining incidence of HIB disease
2. Increasing emphasis on resource use
3. New techniques for rapid identification of bacteremia
4. Parental values given more consideration
5. Usefulness of antibiotics to prevent serious sequelae of occult
bacteremia remains unclear
6. Increasing antibiotic resistance to common bacterial pathogens
7. Use of the pneumococcal vaccine
Declining Incidence of Hemophilus influenzae Type B
Disease
Widespread use of the HIB vaccine in the early 1990s has had a
profound impact on the incidence of both bacteremia and serious bacte-
rial illness (especially meningitis) in children. When the practice guide-
lines
8
were published in 1993, most of the data used to support the
decision tree were obtained from studies prior to widespread use of the
HIB vaccine. The prevalence of occult bacteremia ranged from 3% to
10%
13, 27, 36, 50, 62
; HIB bacteremia accounted for 10% to 20% of the bacter-
emia and up to 40% to 50% of the complications.
31
From 1987 to 1997,
the incidence of invasive HIB disease in children younger than 5 years
of age decreased by 97%.
20
Recent studies of occult bacteremia have
shown a virtual elimination of HIB and a resultant decline in both the
prevalence of occult bacteremia and subsequent sequelae.
1, 45
In two large
post-HIB occult bacteremia studies, the prevalence of occult bacteremia
in young children with fever was reported as 1.6% to 1.9%. Pneumococ-
cus accounted for 83% to 92% of those cases of bacteremia.
1, 45
There
were no reported cases of HIB bacteremia in either study. In the study
by Alpern,
1
95.7% of children with occult pneumococcal bacteremia had
resolution of their bacteremia without the use of parenteral antibiotics,
and the rate of severe adverse outcome (meningitis or death) was only
MANAGEMENT OF FEVER IN INFANTS AND CHILDREN 59
0.03%. Thus, decision-making management schemes in the new millen-
nium must take into account the lower rate of occult bacteremia and the
decline in serious invasive disease in the post-HIB vaccine era.
Increasing Emphasis on Resource Utilization
Although most studies have focused on the prevalence of occult
bacteremia, the rate of contaminated blood culture results is as high as
the true positive rate.
1, 45, 50
How these false-positive results are handled
is an important consideration when one is weighing the risks and
benefits of any management strategy. In a study by Segal,
55
85 (41%) of
209 children with positive blood cultures who were evaluated for occult
bacteremia had cultures that grew contaminants only. Follow-up of these
85 children generated 106 telephone calls, 102 additional diagnostic tests,
18 doses of parenteral antibiotics, and 12 hospital admissions. Other
than the direct monetary costs, the authors also note that there were
several other costs not included in their study: time spent by the ED
attending physicians contacting family members and primary care pro-
viders (PCPs), follow-up visits with PCPs, and societal costs related to
time lost from work by parents.
55
Thus, in an era when medical care is
often driven by managed care and cost-benefit analysis, the opportunity
costs related to shifting some resources to the follow-up of contaminated
blood cultures must be considered.
New Techniques for Rapid Identification of Bacteremia
Part of the difficulty in deciding management strategies for children
at risk for occult bacteremia is its low prevalence; therefore, most chil-
dren who receive empiric treatment have only benign viral illness. If a
child with bacteremia could be identified at the time of initial presenta-
tion, however, then antibiotic use could be restricted to only those
children at risk for invasive illness. This type of approach requires a
rapid test with both high sensitivity (so that no child with bacteremia is
missed) as well as high predictive values (so that a child with a positive
test result probably has bacteremia, whereas a child with a negative test
result probably does not). The ideal test is a blood culture that becomes
positive immediately. Although instant blood culture results are not yet
a reality, methods that shorten the delay to positive culture results are
already in place. Automated blood culture techniques, which can moni-
tor continuously for the presence of most pathogens, can reduce the
laboratory detection time to less than 24 hours.
44, 60
These techniques can
aid in the prevention of serious illness. In a study by Joffe,
38
children
whose diagnosis of serious illness was facilitated by blood culture results
had shorter delay in identifying cultures as positive than did children
notified of positive results who did not develop serious illness (16.2 vs
31.6 hours; P⬍0.05).
60 AVNER & BAKER
In addition to faster blood culture results, newer methods of risk
stratification for occult bacteremia are also being studied. The peripheral
white blood cell count (WBC) is the most popular test used to identify
children at higher risk for occult bacteremia. As the WBC increases, the
positive predictive value (PPV) increases, but the sensitivity decreases.
For example, in the study by Lee,
45
a WBC count threshold of 15,000/
mm
3
had a sensitivity of 86% and a PPV of 5.1%. In other words,
whereas 86% of children with bacteremia had an elevated WBC count,
only 5.1% of those children with an elevated WBC count actually had
bacteremia. If that WBC level were used to determine the use of empiric
antibiotics, almost 95% of those children treated would not have had
bacteremia. Increasing the WBC threshold to 20,000/mm
3
improved the
positive predictive value to 8.1%, but the sensitivity decreased to 48%.
45
Recent research has focused on the use of newer laboratory tests.
Strait
61
found that an enzyme-linked immunosorbent assay (ELISA) for
interleukin-6 was more predictive for occult bacteremia than were height
of fever, duration of fever, absolute band count, or white blood cell
count. The lack of rapid processing and clinical availability limits its
present applicability, however. The polymerase chain reaction (PCR) has
also been thought to be both a sensitive and specific means for detecting
specific bacterial DNA or RNA sequences. PCR reactions can be auto-
mated, rapid, relatively inexpensive, and allow for detection of very-
low-density infection.
34
These theoretical advantages have yet to be
realized in clinical practice, however. Isaacman
33
found that their PCR-
based assay for pneumococcal DNA was less sensitive and specific
than those reported for the WBC count for predicting pneumococcal
bacteremia. Furthermore, clinicians detecting a positive PCR result can-
not be sure that this represents DNA from a living organism or whether
it is just the fossilized remains of killed bacteria (e.g., from nasopharyn-
geal carriage or recent otitis media), the DNA fragments of which were
shed into the bloodstream.
34
Parental Values Given More Consideration
Because there is no clear and certain management strategy for fever
in the well-appearing child, it seems reasonable to involve parents in
the decision-making process. To be sure, factors associated with the
discomfort of venipuncture and possible emotional distress to the parent
and child are difficult to quantify. In fact, parents and physicians show
fundamental value differences concerning diagnostic testing, diagnostic
error, and short- and long-term morbidity.
42
In a survey of parents and
physicians concerning the values of clinical outcomes in febrile young
children, Kramer
42
found that parents emphasize the short-term pain,
discomfort, and inconvenience of the diagnostic tests and are more
willing to risk rare but severe long-term morbidity to avoid the short-
term risks of testing. Perhaps a working parent with other children at
home places a high value on the additional waiting time and pain
MANAGEMENT OF FEVER IN INFANTS AND CHILDREN 61
incurred with venipuncture, whereas the physician is more likely to
discount such ‘‘inconvenience.’’ Conversely, Bennett
16
found just the
opposite preference. In that study, a convenience sample of parents of 3-
to 36-month-old children were asked to order eight outcomes from
treatment of occult bacteremia: blood drawing, localized infection, hospi-
talization for antibiotics, meningitis with recovery, and meningitis re-
sulting in deafness, minor brain damage, severe brain damage, and
death. The utilities for these outcomes were determined using a series
of standard gambles based on their rank order from a visual analogue
scale. The results showed that most parents preferred that their child
have blood drawn, or have a local infection that resolves, or be hospital-
ized for intravenous antibiotics, rather than face a one in a million
chance of death. This suggests that parents prefer these tests (despite
the pain, discomfort, and inconvenience) rather than risk very rare but
severe long-term morbidity.
The choices offered the parents in these studies
16, 42
were theoretical.
The way that parents rate each outcome could change if for example,
they had to, witness multiple venipuncture attempts on their child and
wait hours for the results or wait hours even to see the physician.
Parents might not adequately understand the adverse effects of testing,
such as unnecessary hospitalizations because of false-positive results.
Furthermore, the potential negative psychosocial impact on the physi-
cian–patient relationship is difficult to quantify. These negative factors
include anxiety experienced by children undergoing blood sampling and
parenteral medication administration, and the fostered dependence on
the medical system through implication that blood tests and antibiotics
are necessary components of all evaluations of fever.
64
The latter has a
self-perpetuating effect on parents and encourages more physician visits
for febrile illnesses and more unnecessary tests and treatments.
64
Finally,
intangible factors such as wait-time and cost were not addressed. Never-
theless, this demonstrates an effort to quantify parental values into the
decision-making process.
Relative Usefulness of Antibiotics in Preventing
Serious Sequelae from Occult Bacteremia Remains
Unclear
Most of the controversy in the management of occult bacteremia
centers on whether empiric administration of antibiotics prevents serious
sequelae. From a purely methodologic view, the best scientific design is
a randomized, double-blind, placebo-controlled clinical trial. There are
several barriers to achieving this methodology in the real world, how-
ever. First, the prevalence of occult bacteremia is low, and furthermore,
the prevalence of the most serious sequelae, meningitis, is very low.
Thus, to achieve adequate power, the study must have a large sample
size. In addition, the sample must include all eligible subjects and
involve a strict protocol, including objective parameters for measuring
clinical appearance. The fact that this task is difficult to achieve is
62 AVNER & BAKER
evidenced by the many retrospective chart reviews. One meta-analysis
of these studies found that the overall risk of meningitis was 0.3% in
children receiving empiric antibiotics versus 8% to 10% in untreated
children.
10
Although these reviews can show trends, the methodologic
faults limit the usefulness of their conclusions. There have been only a
few prospective trials that have enrolled a large number of patients. As
cited previously, Fleisher
27
studied 6,733 children between 3 and 36
months of age with temperature over 39.0C and either no focal findings
or otitis media, and randomly administered to them either IM ceftriax-
one or PO amoxicillin. The study did not include a nontreatment arm
and did include children with otitis media as well as those who required
a lumbar puncture as part of their initial evaluation. Bacteremia was
present in 2.9% of children, 84% of whom had S. pneumoniae. There was
no difference between the ceftriaxone and amoxicillin groups in terms
of number of probable or definite infections (3 vs 6, P0.31), although
there were significantly fewer definite infections in the ceftriaxone group
(0 vs 5, P0.02). There were only five cases of meningitis (two probable
infections in the ceftriaxone group and three definite infections in the
amoxicillin group). Because HIB caused four of the five cases of meningi-
tis, one must at least question the applicability of these data in the post-
HIB vaccine era.
Some studies have restricted their analysis to patients infected with
S. pneumoniae. Harper
30
reviewed the records of 467 children with pneu-
mococcal bacteremia treated as outpatients, of which 382 were consid-
ered to have occult bacteremia. The group was not randomized: 48
received no antibiotic, 205 received an oral antibiotic, and 129 received
a parenteral antibiotic. Children in the no-antibiotic group were more
likely to be febrile at follow-up, be admitted, have a new diagnosis
made at follow-up, and have persistent bacteremia. There were only
four cases of meningitis however: two (0.98%) in the oral antibiotic
group and one each in the no-antibiotic (2.1%) and the parenteral antibi-
otic (0.78%) groups. In the study by Alpern,
1
in which 1.8% of the 111
children with bacteremia had a serious adverse outcome, oral antibiotics
did not affect the rate of persistent bacteremia (RR34; 95% CI: 0.06,
1.93).
Increasing Antibiotic Resistance to Common Bacterial
Pathogens
The use of empiric antibiotic treatment in a large number of children
to prevent possible unexpected potential serious sequelae must be bal-
anced against the risk of inducing increasing numbers of drug-resistant
bacteria. In the United States, pneumococcus was almost universally sensi-
tive to penicillin until the 1980s.
26
Now, up to 35% of Pneumococcus sp.
are nonsusceptible to penicillin and approximately one half of those
strains are also nonsusceptible to cephalosporins.
52
Furthermore, among
patients with invasive pneumococcal disease, recent antibiotic use has
been identified as a risk factor for infection with multiple drug-resistant
MANAGEMENT OF FEVER IN INFANTS AND CHILDREN 63
strains.
26
It is therefore a priority for all physicians to avoid antibiotics
in situations for which antibiotics are unlikely to provide benefit. If
used, the antibiotic should be narrow spectrum to minimize selective
pressure.
15
Overuse of antibiotics is likely to be in viral illnesses (e.g.,
URIs and bronchiolitis). Viruses cause the vast majority of febrile ill-
nesses in children during the first two years of life. Empiric treatment
of these children with a broad-spectrum antibiotic like ceftriaxone surely
increases the selection of resistant organisms.
Parental pressure for the physician to ‘‘do something’’ is often a
determining factor in the use of antibiotics. In a survey of 610 pediatri-
cians, Bauchner
14
reported that 48% of parents always, most of the time,
or often pressure the physician to prescribe antibiotics when their child
is ill but antibiotics are not indicated. Furthermore, approximately one
third of physicians reported that they occasionally or more frequently
comply with these requests. Perhaps parents must be enlisted in a
partnership of care for the child with more time spent emphasizing
continued observation and follow-up rather than routine administration
of unnecessary chemicals.
Use of the Pneumococcal Vaccine
In light of the increase in antibiotic resistance and the concern
about treating most well-appearing febrile children with an unnecessary
intramuscular antibiotic, the best option remains prevention of the dis-
ease. To this end, the recent approval of routine immunization with a
heptavalent pneumococcal conjugate vaccine is expected both to prevent
bacteremia and to reduce the amount of disease caused by resistant
organisms. The current vaccine offers protection against 83% to 85% of
pneumococcal disease in children in the United States.
58
Furthermore,
the vaccine recently has been approved for children under 2 years of
age, the group that is at highest risk for occult bacteremia and invasive
disease. If the efficacy of this vaccine is at all close to that of the HIB
vaccine, the impact on the reduction of pneumococcal bacteremia and
its sequelae could eventually make discussion of occult bacteremia and
empiric antibiotic therapy moot.
FEVER PHOBIA
Finally, no discussion about fever in children would be complete
without a reference to the issue of fever phobia. Parental fear of fever is
certainly responsible for many ED visits and phone calls requesting
advice and diagnosis. As adeptly noted by Smith,
59
‘‘since the advent
of modern clinical thermometry by Wunderlich in 1871, the ritual of
temperature taking has been surpassed only by Alexander Graham Bell’s
invention in 1874 as the major curse of pediatrics.’’ This fear is based on
the four Rs: Radio and television, Reading advertisements, Relatives, and
64 AVNER & BAKER
Recollections. Advertising for ‘‘fever medicines’’ is a multimillion-dollar
industry intended to convince parents of the import of reducing fever.
In addition, friends and relatives recount stories of exceedingly rare
events such as febrile illnesses causing death. These concerns focus the
parents on fever control and away from the more important issue, which
is that fever is the symptom of a disease process but not the disease
itself. Physicians can aggravate this fear by their directives such as ‘‘call
me if fever develops,’’ ‘‘give some fever medicine,’’ or ‘‘let me know if
the fever gets higher.’’
Schmidt
54
used the term fever phobia in 1980 to describe an overconc-
ern about low-grade fever (⬍38.9C). In his survey of 81 parents, 48%
said that fever could rise over 41.7C (107F) without treatment, and
16% believed that the fever could rise over 43.3C(110F). Parents’
understanding of the harmful effects of fever were also skewed; 46%
thought fever by itself could cause brain damage.
54
Furthermore, fever
phobia is not just a concern of those with limited education or resources.
In fact, Kramer
43
found that increasing socioeconomic status was associ-
ated with increased fever phobia.
Ideally, education about the role and importance of fever should be
part of anticipatory guidance provided at well-child visits. Unfortu-
nately, it seems that education is lacking, and the ED physician must
then counsel the parents about fever at a time of stress and anxiety.
Nevertheless, there are certain principles that physicians can impart:
Counteracting Fever Phobia
48, 54
1. Fever is a normal response.
2. Fever is a symptom, not a disease.
3. Assume a calm approach to fever.
4. Fever persists until the disease process resolves.
5. Fever determination need not always be exact.
6. Fever is often a useful body defense.
7. Fever (especially low grade) need not always be treated.
8. Antipyretics should be used as ‘‘therapy’’ for fever rather than
‘‘control.’’
9. Clinical appearance is usually more important than the height of
the fever.
SUMMARY
There is no question that fever is a source of great consternation for
parent and physician alike; however, it is impossible to predict with
certainty the outcome of every febrile illness. Inherent in the words
diagnostic impression is a degree of uncertainty. The only question re-
maining is how much uncertainty is in the best interest of the child.
Physicians try to use the existing scientific data to best determine the
prevalence of disease and outcome. At the same time, they must recog-
nize the limitations of both the data and their ability to be generalized
MANAGEMENT OF FEVER IN INFANTS AND CHILDREN 65
to every population. Everything clinicians do has risks and costs, which
they must balance against the incidence of complications and the benefits
of testing. To take away clinical judgment makes physicians technicians
not clinicians.
References
1. Alpern ER, Alessandrini EA, Bell LM, et al: Occult bacteremia from a pediatric
emergency department: Current prevalence, time to detection, and outcome. Pediatrics
106:505–511, 2000
2. Avner JR: Occult bacteremia: How great the risk? Contemp Pediatr 14:53–65, 1997
3. Baker MD, Avner JR, Bell LM: Failure of infant observation scales in detecting serious
illness in febrile 4–8 week old infants. Pediatrics 85:1040–1043, 1990
4. Baker MD, Bell LM, Avner JR: Outpatient management without antibiotics of fever in
selected infants. N Engl J Med 329:1437–1441, 1993
5. Baker MD, Bell LM, Avner JR: The efficacy of routine outpatient management without
antibiotics of fever in selected infants. Pediatrics 103:660–665, 1999
6. Baker MD, Bell LM: Unpredictability of serious bacterial illness in febrile infants from
birth to 1 month of age. Arch Pediatr Adolesc Med 153:508–511, 1999
7. Baker RC, Seguin JH, Leslie N, et al: Fever and petechiae in children. Pediatrics
84:1051–1055, 1989
8. Baraff LJ, Bass JW, Fleisher GR, et al: Practice guidelines for management of infants
and children 0–36 months of age with fever without source. Pediatrics 92:1–12, 1993
9. Baraff LJ, Lee SI: Fever without source: Management of children 3 to 36 months of
age. Pediatr Infect Dis J 11:146–151, 1992
10. Baraff LJ, Oslund S, Prather M: Effect of antibiotic therapy and etiologic microorganism
on the risk of bacterial meningitis in children with occult bacteremia. Pediatrics
92:140–143, 1993
11. Baraff LJ: Management of fever without source in infants and children. Ann Emerg
Med 36:620–614, 2000
12. Baskin MN, O’Rourke EJ, Fleisher GR: Outpatient treatment of febrile infants 28 to 89
days of age with intramuscular administration of ceftriaxone. J Pediatr 120:22–27, 1992
13. Bass JW, Steele RW, Wittler RR, et al: Antimicrobial treatment of occult bacteremia: A
multicenter cooperative study. Pediatr Infect Dis J 12:466–473, 1993
14. Bauchner H, Pelton SI, Klein JO: Parents, physicians, and antibiotic use. Pediatrics
103:395–401, 1999
15. Bennett J, St. Geme JW: Bacterial resistance and antibiotic use in the emergency
department. Pediatr Clin North Am 46:1125–43, 1999
16. Bennett JE, Summer W, Downs SM, et al: Parents’ utilities for outcomes of occult
bacteremia. Arch Pediatr Adolesc Med 154:43–48, 2000
17. Bramson RT, Meyer TL, Silbiger ML, et al: The futility of the chest radiograph in the
febrile infant without respiratory symptoms. Pediatrics 92:524–526, 1993
18. Burke JP, Klein JO, Gezon HM, et al: Pneumococcal bacteremia. Am J Dis Child
121:353–359, 1971.
19. Caspe WB, Chamudes O, Louie B: The evaluation and treatment of the febrile infant.
Pediatr Infect Dis 2:131–135, 1983
20. CDC: Progress toward eliminating Haemophilus influenza type B disease among infants
and children—United States, 1987–1997. MMWR 47:993–998, 1998
21. Crain EF, Bulas D, Bijur PE, et al: Is a chest radiograph necessary in the evaluation of
every infant less than 8 weeks of age? Pediatrics 88:821–824, 1991
22. Crain EF, Shelov SP: Febrile infants: predictors of bacteremia. J Pediatr 101:686–689,
1982
23. Dagan R, Sofer S, Phillip M, et al: Ambulatory care of febrile infants younger than 2
months of age classified as being low risk for having serious bacterial infection. J
Pediatr 112:355–360, 1988
66 AVNER & BAKER
24. Damoiseaux RA, van Balen FA, Hoes AW, et al: Primary care–based randomized
double blind trial of amoxicillin vs. placebo for acute otitis media in children aged
under 2 years. Br Med J 320:350–354, 2000
25. Digullio GA: Fever and petechiae: No time for a rash decision. Clin Pediatr Emerg
Med 1:132–137, 2000
26. Dowell SF, Marcy SM, Phillips WR, et al: Principles of judicious use of antimicrobial
agents for pediatric upper respiratory tract infections. Pediatrics 101:163–165, 1998
27. Fleisher GR, Rosenberg N, Vinci R, et al: Intramuscular versus oral antibiotic therapy
for the prevention of meningitis and other bacterial sequelae in young, febrile children
at risk for occult bacteremia. J Pediatr 124:504–512, 1994
28. Ginsburg CM, McCracken GH: Urinary tract infections in young infants. Pediatrics
69:409–412, 1982
29. Green JW, Hara C, O’Connor S, et al: Management of febrile outpatient neonates. Clin
Pediatr 20:375–380, 1981
30. Harper MB, Bachur R, Fleisher GR: Effects of antibiotic therapy on the outcome of
outpatients with unsuspected bacteremia. Pediatr Infect Dis J 14:760–767, 1995
31. Harper MB, Fleisher GR. Occult bacteremia in the 3-month-old to 3-year-old age
group. Pediatr Ann 22:484–493, 1993
32. Heulitt M, Ablow R, Santos C, et al: Febrile infants less than 3 months old: Value of
chest radiography. Radiology 167:135–137, 1988
33. Isaacman DJ, Zhang Y, Reynolds EA, et al: Accuracy of polymerase chain reaction–
based assay for detection of pneumococcal bacteremia in children. Pediatrics 101:813–
816, 1998
34. Isaacman DJ: The occult bacteremia controversy. Clin Pediatr Emerg Med 1:109–116,
2000
35. Jaffe DM, Fleisher GR: Temperature and total white blood cell count as indicators of
bacteremia. Pediatrics 87:670–674, 1991
36. Jaffe DM, Tanz RR, Todd-Davis A, et al: Antibiotic administration to treat possible
occult bacteremia in febrile children. N Engl J Med 317:1175–1180, 1987
37. Jaskiewicz JA, McCarthy CA, Richardson AC, et al: Febrile infants at low risk for
serious bacterial infection—an appraisal of the Rochester Criteria and implications for
management. Pediatrics 94:390–396, 1994
38. Joffe M, Avner JR: Follow-up of patients with occult bacteremia in pediatric emergency
departments. Pediatr Emerg Care 8:258–261, 1992
39. Jones RG, Bass JW: Febrile children with no focus of infection: A survey of their
management by primary care physicians. Pediatr Infect Dis J 12:179–183, 1993
40. Kadesh JA, Bolte RB, Tobey J, et al: Applying outpatient protocols in febrile infants
1–29 days of age: Can the threshold be lowered? [Abstract]. Annual Meeting of the
Ambulatory Pediatric Association, New Orleans, LA, May 4, 1998
41. King JC, Berman ED, Wright PF. Evaluation of fever in infants less than 8 weeks old.
South Med J 80:948–952, 1987
42. Kramer MS, Etezadi-Amoli J, Ciampi A, et al: Parents’ vs physicians’ values for clinical
outcomes in young febrile children. Pediatrics 93:697, 1994
43. Kramer MS, Naimark L, Leduc DG: Parental fever phobia and its correlates. Pediatrics
75:1110–1113, 1985
44. Krisher KK, Whyburn DR, Koepnick FE: Comparison of the BacT/Alert pediatric
blood culture system, Pedi-BacT, with conventional culture using the 20-ml Becton-
Dickinson supplemented peptone broth tube. J Clin Microbiol 31:793–797, 1993
45. Lee GM, Harper MB: Risk of bacteremia for febrile young children in the post-
haemophilus influenzae type B era. Arch Pediatr Adolesc Med 152:624–628, 1998
46. Long SS: Antibiotic therapy in febrile children: ‘‘Best laid schemes...’’ J Pediatr 124:584–
588, 1994
47. Mandl KD, Stack AM, Fleisher GR: Incidence of bacteremia in infants and children
with fever and petechiae. J Pediatr 131:398–404, 1997
48. May A, Bauchner H: Fever phobia: The pediatrician’s contribution. Pediatrics 90:851–
854, 1992
49. McCarthy PL, Sharpe MR, Spiesel SZ, et al: Observation scales to identify serious
illness in febrile children. Pediatrics 70:802–809, 1982
MANAGEMENT OF FEVER IN INFANTS AND CHILDREN 67
50. McGowan JE, Bratto L, Klein JO, et al: Bacteremia in febrile children seen in a walk-
in pediatric clinic. N Engl J Med 288:1309–1312, 1973
51. Philip AGS, Hewitt JR: Early diagnosis of neonatal sepsis. Pediatrics 65:1036–1041, 1980
52. Rennels M: Resistant pneumococcal disease: Treatment and prevention. Contemp Pedi-
atr 16(Suppl):4–10, 1999
53. Roberts KB, Borzy MS: Fever in the first eight weeks of life. Johns Hopkins Med J
141:9–13, 1977
54. Schmidt BD: Fever phobia: Misconceptions of parents about fevers. Am J Dis Child
134:176–181, 1980
55. Segal GS, Chamberlan JM: Resource utilization and contaminated blood cultures in
children at risk for occult bacteremia. Arch Pediatr Adolesc Med 154:469–473, 2000
56. Shaw KN, Gorelick M, McGowan KL, et al: Prevalence of urinary tract infection in
febrile young children in the emergency department. Pediatrics 102: 1998 http://
www.pediatrics.org/cgi/contnet/full/102/2/el6
57. Shaw KN, Gorelick MH: Fever as a sign of urinary tract infection. Clin Pediatr Emerg
Med 1:117–123, 2000
58. Shinefield HR: Safety and efficacy of the hepatovalent pneumococcal conjugate vaccine.
Infect Dis Child 2000
59. Smith DS: Fever and the pediatrician. J Pediatr 77:935–936, 1970
60. Stevens CM, Swaine D, Butler C, et al: Development of o.a.s.i.s., a new automated
blood culture system in which detection is based on measurement of bottle headspace
pressure changes. J Clin Microbiol 34:1750–1756, 1994
61. Strait RT, Kelly KJ, Kurup VP: Tumor necrosis factor-a, interleukin-1b, and interleukin-
6 levels in febrile, young children with and without occult bacteremia. Pediatrics
104:1321–1326, 1999
62. Teele DW, Pelton SI, Grant MJA, et al: Bacteremia in febrile children under 2 years of
age: Results of cultures of 600 consecutive febrile children seen in a walk-in clinic. J
Pediatr 87:227–230, 1975
63. Wittler RR, Cain KK, Bass JW: A survey about management of febrile children without
source by primary care physicians. Pediatr Infect Dis J 17:271–277, 1998
64. Yamamoto LG, Worthley RG, Melish ME, et al: A revised decision analysis of strategies
in the management of febrile children at risk for occult bacteremia. Am J Emerg Med
16:193–207, 1998
Address reprint requests to
Jeffrey R. Avner, MD
Pediatric Emergency Medicine
Children’s Hospital at Montefiore
111 East 210th Street
Bronx, NY 10467
e-mail: jravner@montefiore.org