Pediatr Infect Dis J, 2002;21:5842

Copyright 2002 by Lippincott Williams & Wilkins, Inc.

Vol. 21, No. 6

Printed in U.S.A.

Management of the febrile child without a

focus of infection in the era of universal
pneumococcal immunization
JEROME O. KLEIN, MD

Should strategies of management of invasive

disease in the febrile child without focus of infection (occult bacteremia) be reconsidered in communities with universal immunization of infants
with the conjugate vaccines for Haemophilus
influenzae type b and Streptococcus pneumoniae
(PCV7)? The incidence of occult bacteremia is
likely to decrease with the virtual elimination of
H. influenzae type b and vaccine serotype pneumococcal invasive diseases. The number of children with fever coming to physicians offices,
however, is unlikely to change. The challenge of
distinguishing the febrile child with invasive
bacterial disease who requires aggressive therapy from the febrile child who has a viral infection and requires only symptomatic therapy will
persist. The bacteriology of invasive disease in
infants and young children in 2002 will include
pneumococcal serotypes not in PCV7; serotypes
in PCV7 that occur in the unimmunized, partially
immunized or fully immunized child (vaccine
failures); Neisseria meningitidis; Salmonella
spp., group A Streptococcus, Staphylococcus aureus and Gram-negative enteric bacilli. Management plans published in the 1990s suggested an
aggressive diagnostic approach to the febrile
child 3 to 36 months old who was toxic or had a
temperature of >39C. Diagnostic tests included
white blood cell counts, cultures of blood and
urine and chest radiograph and lumbar puncture
as indicated by clinical signs and administration
of parenteral ceftriaxone. Although PCV7 was
extraordinarily effective in prevention of serotype-specific invasive pneumococcal disease in

clinical trials, pediatricians need to know

whether the results based on 38 000 enrollees
will be maintained as millions of children are
immunized. In addition questions about change
in serotype of pneumococci causing invasive disease (serotype switching), herd immunity and
durability of protection after immunization need
to be answered. Until more experience is available to answer these questions, the febrile child
without focus of infection should be managed
without consideration of immunization with
PCV7. Evaluation of the organism (serotype) and
the host (acute and convalescent sera) should be
undertaken for each case of invasive pneumococcal disease in this era of universal pneumococcal
immunization.
INTRODUCTION

The management of the febrile child without a focus

of infection, occult bacteremia, has been a subject of
controversy for decades. Radetsky1 noted that more
than 300 articles on management of the febrile infant
had been published in the 36 years beginning in 1960.
Streptococcus pneumoniae is responsible for the vast
majority of episodes of occult bacteremia. With the
availability and demonstrated efficacy of the heptavalent conjugate pneumococcal vaccine (PCV7) in prevention of invasive pneumococcal disease, does the strategy for management of the febrile child who is
immunized with PCV7 need to be reconsidered? The
purpose of this article is to review the microbial
changes that are likely to occur in the era of universal
pneumococcal immunization and the implications of
these changes for altering management strategies for
the febrile child.
MICROBIOLOGY OF OCCULT BACTEREMIA

Bacteriology of occult bacteremia in the 1990s.

The bacterial pathogens responsible for occult bacteremias before the introduction of the conjugate polysaccharide Haemophilus influenzae type b vaccine in 1990
and PCV 7 in 2000 included S. pneumoniae, Haemophilus influenzae type b (Hib), Neisseria meningitidis,
group A Streptococcus, Staphylococcus aureus, Salmonella spp. and Gram-negative enteric bacilli (Fig. 1). S.

From Pediatric Infectious Diseases, Boston Medical Center,

and Department of Medicine, Boston University School of Medicine, Boston, MA.
Key words: Febrile child, management, occult bacteremia,
pneumococcal vaccine.
Address for reprints: Jerome O. Klein, M.D., Maxwell Finland
Laboratory for Infectious Diseases, Boston Medical Center, 774
Albany Street, Boston, MA 02118. Fax 617-414-7230. E-mail
jerome.klein@bmc.org.
DOI: 10.1097/01.inf.0000016385.94483.52

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THE PEDIATRIC INFECTIOUS DISEASE JOURNAL

FIG. 1. Estimated proportions of pathogens responsible for

occult bacteremia, 1990 and 2002.

pneumoniae was responsible for 80% of all episodes of

occult bacteremia2; of the pneumococcal bacteremias
80% were caused by serotypes in PCV 73; thus 64%
of the occult bacteremias were caused by PCV 7 serotypes, and 16% were caused by serotypes not in PCV 7.
Hib was responsible for 10% of the invasive episodes
of occult bacteremia, and N. meningitidis was responsible for 2 to 5%, with only a small proportion of cases
of the other bacterial pathogens.
After introduction of the Hib vaccine, the number of
episodes of Hib bacteremia diminished. Studies from
Boston4 and Philadelphia5 examined the microbiology
of occult bacteremia for the period 1993 to 1996. In the
Boston cohort the rate of occult bacteremia in febrile
children 3 to 36 months of age with a temperature of
39C or greater was 1.57%. The pneumococcus was
responsible for 92% of the positive cultures of blood.
The Philadelphia study used similar criteria for infants
2 to 24 months of age. The prevalence of bacteremia
was 1.9%; S. pneumoniae was responsible for 82.9% of
the bacteremias, Salmonella spp. 5.4% and group A
streptococci 4.5%.
Bacteriology of occult bacteremia in 2002. In
2002 with almost universal use of the conjugate Hib
and pneumococcal vaccines in infants in the United
States, the incidence of invasive disease is likely to
decrease, and the pattern of bacterial pathogens responsible for occult bacteremia will change. Without an
available vaccine, the incidence of meningococcemia,
invasive disease caused by Salmonella, group A Streptococcus, Staphylococcus aureus and Gram-negative
enteric bacilli, is likely to remain constant. Given that
microbial ecology is constantly changing, we need to be
alert for the possibility that one of these pathogens will
become more important as a cause of occult bacteremia.
Invasive disease caused by Hib has been almost
eliminated in communities with high rates of immunization with the conjugate vaccine. The organism may
persist in communities with low rates of immunization
such as those with religious reasons for refusal to
immunize.

585

Although still uncommon the appearance of invasive

disease caused by H. influenzae type a6 and type f7
suggests the possibility that non-b serotypes could
replace Hib as a serious pathogen.
Influence of the conjugate pneumococcal vaccine on the bacteriology of occult bacteremia.
The success of PCV7 in prevention of invasive disease
caused by serotypes in the vaccine in the Northern
California clinical trial8 will likely be replicated as
millions of children are immunized. There are data
that suggest a herd effect; an average of 34% of all
children younger than age 5 years were vaccinated in
Northern California between October, 1995, and
March, 2001; during this time period there was a 62.4%
reduction in invasive disease among children younger
than 5 years.9 Although problems with vaccine supply
occurred in the summer and fall of 2001, by December,
2001, 23 million doses of PCV7 had been distributed in
the United States (M Boken, Wyeth Lederle Vaccines,
personal communication). If the vaccine proves to be
97% effective for prevention of pneumococcal disease
caused by serotypes in the vaccine in fully immunized
children (as occurred in the clinical trial), there will be
a substantial decrease in episodes of occult bacteremia.
Nevertheless invasive pneumococcal disease will persist in infants: (1) disease will occur caused by serotypes not in the vaccine; (2) disease will occur caused
by serotypes in the vaccine and represent vaccine
failures; (3) some children will not have protective
antibodies because they were unimmunized or incompletely immunized; (4) some children will not have
protective antibodies because of immune deficits. The
possibility of vaccine switching in immunized children
exists, i.e. increased incidence of invasive disease
caused by serotypes not in the vaccine. Alternatively
there might be protection for serotypes not in the
vaccine but related to vaccine serotypes. The results of
the microbiologic studies of otitis media in Finnish
children10 identified a reduction in the frequency of
episodes caused by serotypes that cross-reacted with
those in the vaccine (serotypes 6A, 9N, 18B, 19A and
23A). However, there was also a 33% increase in
serotypes not in the vaccine causing otitis media. Thus
even though the PCV7 is likely to be very effective, the
nonvaccine serotypes of pneumococcus (and the uncommon cases of vaccine serotypes of pneumococcus) will
persist as the most frequent pathogen associated with
occult bacteremia (Fig. 1).
SHOULD THE MANAGEMENT OF INFANTS WITH
FEVER WITHOUT SOURCE WHO ARE
IMMUNIZED WITH PCV7 CHANGE?

Fever without source in infants will continue to be a

common cause of office visits to physicians. About
two-thirds of children between the ages of birth and 2
years visit the physician for an acute febrile illness.11

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THE PEDIATRIC INFECTIOUS DISEASE JOURNAL

Fever without source is the diagnosis in 14% of office

visits. Because the overall incidence of invasive disease
among febrile infants was low, the introduction of the
conjugate vaccines will not diminish the number of
office visits for fever without source. The challenge to
the practitioner of distinguishing the few children with
invasive bacterial disease who require aggressive management from the many children who have presumably
viral and spontaneously resolving disease that can be
managed with symptomatic treatment will remain.
The guidelines below are suggestions for current management of the infant with fever without source in the
era of universal Haemophilus and pneumococcal immunizations.
Management of the febrile neonate. Fever in the
first weeks of life is relatively uncommon. However,
when fever does occur the incidence of severe disease
including sepsis is sufficiently high to warrant careful
evaluation and conservative management. Invasive
disease caused by S. pneumoniae, H. influenzae (usually nontypable) and N. meningitidis occurs but is
uncommon. Practice guidelines prepared by Baraff et
al.2 for management of febrile infants younger than 28
days suggest that all should be considered for hospitalization and parenteral antibiotic therapy unless there
is a recognizable alternative and benign diagnosis. The
differential diagnosis of fever in the first month of life
includes five categories based on pathogenesis: in utero
infections; infections acquired at delivery (early and
late onset sepsis); infections acquired in the nursery;
infections acquired in the household; and infections
acquired because of underlying anatomic or physical
disabilities (e.g. urinary tract infections). For presumed bacterial sepsis in the neonate, initial therapy
with ampicillin and gentamicin continues to be appropriate
Management of the infant 29 to 90 days old
with fever without source. Invasive disease after
the first month includes a mix of late onset disease
associated with organisms acquired at delivery including group B streptococci, Gram-negative enteric bacilli
and uncommonly Listeria monocytogenes and enterococci as well as the invasive organisms acquired in the
household, pneumococci, meningococci and H. influenzae. Febrile infants in this age group may be categorized as toxic or nontoxic, and among the nontoxic
group low risk or high risk for invasive bacterial
disease.12 Low risk criteria include: previously being
healthy; having no focal bacterial infection on physical
examination; and having negative laboratory screening. Negative laboratory screening is defined as a white
blood cell (WBC) count of 5000 to 15 000/mm3, 1500
band forms/mm3, normal urinalysis, and when diarrhea is present, 5 WBC per high power field in stool.
The percent of serious bacterial infections in infants 90
days of age or less by clinical and laboratory findings is

Vol. 21, No. 6, June, 2002

1.4% contrasted with 17.3% if the patients appears

toxic. For the toxic or nontoxic but high risk patient,
ceftriaxone (50 mg/kg once daily in the absence of
meningitis) was recommended by Baraff et al.2 and is
still the regimen of choice. Parenteral ampicillin should
be added for the rare cases of invasive disease caused
by enterococci or L. monocytogenes. Because febrile
infants in this age group would have received none or
one dose of PCV7, the vaccine status of the child is
irrelevant to therapeutic decisions.
Management of the child 3 to 36 months of age
with fever without source. The risk of occult bacteremia in children 3 to 36 months of age without source
was reported in the review of Baraff and colleagues to
vary from 1.6 to 11% with a mean probability of 4.3% in
children with a temperature of 39C or more.2, 12 Bacteremia is more frequent in children with higher temperatures and elevated WBC counts. A summary of
studies of WBC counts in children with fever without
source by Baraff et al.2 identified a mean probability of
2.6% in children with WBC 15 000 and 13% in children with WBC 15 000. Recent reports suggest that
C-reactive protein has a better predictive value for
occult bacteremia and serious bacterial infection than
WBC counts.13
An algorithm for management of children 3 to 36
months of age with fever without source was proposed
by Baraff et al.2 and is frequently cited as a useful
guide. Children who were toxic were hospitalized for
sepsis workup and parenteral antibiotics; ceftriaxone
50 mg/kg/day in a single dose was recommended. Children who were not toxic but who had a temperature of
39C or greater had WBC count; cultures of blood,
urine and stool; and chest radiograph if clinical signs of
lower respiratory tract infection were present. Empiric
use of ceftriaxone was recommended for all children
with temperature of 39C or greater or for such febrile
children if the WBC count was 15 000. These guidelines generated much discussion, and viewpoints varied among experts.14 16 Some argued that the expense
and pain for the child of diagnostic tests and parenteral
therapy were unwarranted because the incidence of
invasive bacterial disease was low and many of the
episodes of pneumococcal and Haemophilus influenzae
bacteremia cleared without use of antimicrobial
agents. Other experts countered that the role of the
physician was as gatekeeper to protect the previously
healthy child from the uncommon invasive event that
had potential serious outcomes and that treating many
to protect the few with severe disease was warranted.
The purpose of this article is not to reconcile these
viewpoints but to question whether or not the introduction of the conjugate pneumococcal vaccine alone warrants a change in the concepts of management of
children who are fully immunized and have fever
without source.

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THE PEDIATRIC INFECTIOUS DISEASE JOURNAL

The history of vaccine safety and efficacy after approval and recommendations by authoritative groups
is replete with surprises, most of which are unanticipated adverse events. The most recent example is the
unexpected increased incidence of intussusception associated with rotavirus vaccine. PCV 7 had an excellent
safety record during the clinical trials, but physicians
still need to be alert for the rare adverse event that
may be identified only after hundreds of thousands of
children are immunized. The efficacy documented in
the clinical trials must be corroborated as millions of
children are immunized. In addition questions about
the possibility of serotype switching, incidence of nonvaccine serotypes causing invasive disease and duration of protection will be answered only after sufficient
experience has accumulated. For all these reasons the
strategy of management of the child with fever without
source should be the same irrespective of the history of
PCV immunization. With the passage of time and
greater experience, we can reassess these recommendations and consider change as directed by the data.
Careful and skilled observation remains the
key to management of the febrile child. The key to
management decisions of the febrile child without
source remains the ability of the physician/nurse to
distinguish the child who is toxic from the child who is
not toxic; to distinguish the child who has altered affect
including decreased state of alertness, decreased responsiveness, has difficulty in being consoled from the
child who is playful, responsive, maintains eye contact
and is readily consoled. The art of pediatrics, the
powers of observation of the astute clinician, remains
the key to management of the febrile child. The febrile
illness is dynamic; the child will appear different, for
better or worse, hours after the office visit. The physician needs to maintain contact with the family until
the clinical episode is resolved. Selected laboratory
tests, particularly WBC counts and differential, are of
value if there is ambiguity in the clinical diagnosis, but
if the test is performed the physician must respond to
the results. None of these clinical issues changes in the
era of universal pneumococcal immunization.
RESPONSIBILITY OF THE PHYSICIAN IN
ASSESSING THE CHILD WITH PNEUMOCOCCAL
BACTEREMIA

Physicians will continue to encounter children with

episodes of invasive pneumococcal disease. To further
document the efficacy of PCV 7 as millions of doses are
administered to infants throughout the United States,
thorough evaluation of each child with invasive pneumococcal disease will be necessary. The physician responsible for such a child should consider the following
steps: (1) document the history of immunization with
PCV 7 or pneumococcal polysaccharide vaccine: include
dates of immunization, source of the vaccine and lot

587

number; (2) obtain the pneumococcal isolate and submit for serotyping and susceptibility tests; (3) obtain
acute and convalescent samples of blood: the acute
serum will provide information about protective antibody at the onset of disease and whether or not the
child responded to PCV 7 (if received). The convalescent serum will provide information about the ability of
the patient to respond to the disease causing strain.
If the child has had prior episodes of pneumococcal
disease or syndromes suggesting pneumococcal disease, an assessment of immune functions should be
considered.
The Centers for Disease Control and Prevention has
established a report form for tracking cases of invasive
pneumococcal disease among vaccinated children. The
instruction sheet and case report form can found at
www.cdc.gov/nip.
SUMMARY AND CONCLUSIONS

(1) Fever without source will continue to be a frequent reason for visits to physicians. (2) The microbiology of occult bacteremia will likely change in the era
of universal pneumococcal conjugate vaccine immunization. Nevertheless pneumococcal disease caused by
serotypes not in the vaccine, due to vaccine failure or
occurring in children who were not immunized or
partially immunized or have immune defects will continue to be the most frequent cause of occult bacteremia. The incidence of meningococcemia or bacteremia
caused by group A Streptococcus, Salmonella, Staphylococcus aureus or Gram-negative enteric bacilli will
likely continue at recent rates of disease unless
changes in the ecology of the pathogen occurs. (3) Fever
in the infant to 28 days of life should be aggressively
managed as in the past. (4) Fever in the first 3 months
of life should be aggressively managed. Because the
infant will have received at a maximum one dose of
PCV 7, vaccine history is irrelevant to management
decisions. (5) Management of the febrile infant without
source of infection during ages 3 months to 3 years
should not be changed until more extensive experience
with PCV 7 is available. The history of vaccines is
replete with surprises, and it is still too early in our
understanding of the safety and efficacy of PCV 7 to
warrant a change in strategy of the uncommon but
potentially severe consequences of invasive bacterial
disease in the occult bacteremia syndrome.
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