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Signs & Symptoms of Strep B in

Infants
By Stephanie Wickliffe, eHow Contributor
Strep B, also known as Group B strep, is a bacteria that can grow in the bladder,
intestines or genitals of some adults. Most healthy adults who have this bacteria
show no symptoms, but if an infant acquires this bacteria, she will develop strep B
disease. An infant can come into direct contact with the bacteria in the uterus or as
she is coming through the birth canal during delivery.

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Strep B Infections in Babies

Group B Strep Symptoms

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1.

Early-Onset Symptoms
o

Symptoms of early-onset strep B disease usually appear within 12


hours after birth, but can appear as late as one week after birth. Signs that
a baby has strep B disease include fever, difficulty feeding and lethargy.
An infant with an early-onset strep B infection may develop sepsis,
pneumonia or meningitis. These complications can be life threatening.
Early-onset strep B disease is more serious than late-onset strep B
disease.

Late-Onset Symptoms
o

Infants with late-onset strep B disease may exhibit symptoms, such


as fever, difficulty feeding, lethargy and seizures, anywhere from one
week to three months after delivery. He may also show signs of an upperrespiratory infection that may include nasal congestion and a cough.
Meningitis is a complication associated with late-onset strep B disease.

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Sepsis
o

Sepsis, also known as "bacteremia," is an infection of the blood and


is a serious complication of strep B disease. An infant with sepsis may
have a fever or a low and unstable temperature, an irregular heartbeat
and irregular breathing. Her skin may be cold, clammy and pale, and she
may seem irritable, listless and floppy. She may eat poorly or experience
vomiting and diarrhea.

Meningitis Symptoms
o

Meningitis, an infection of the lining and fluid of the brain, is a


complication of both early- and late-onset strep B disease. An infant with
meningitis may be irritable and lethargic. She may cry inconsolably and
have a high-pitched cry. She may have fever or low body temperature,
may have a stiff body, and her soft spot or fontanels may seem to bulge.
Untreated meningitis can lead to brain damage or even death.

Pnuemonia Symptoms
o

Pneumonia, a complication of early-onset strep B disease, is an


infection of the lungs that causes inflammation. Symptoms such as a rapid
heart beat, fatigue, restlessness, irritability, fever, coughing, rapid
breathing and trouble breathing may be observed in an infant with
pneumonia. An infant who is having trouble breathing will have flared
nostrils and a sinking chest as he breathes. An infant with pneumonia may
also have vomiting and diarrhea.

Diagnosis and Treatment


o

Doctors will note the infant's symptoms and do blood work to


determine if an infant has strep B disease. They might also do a spinal tap
and test the spinal fluid for signs of the bacteria. If an infant has strep B
disease, she will be treated with intravenous antibiotics. Meningitis,
pneumonia and sepsis caused by the strep B bacteria will also be treated
with antibiotics.

Prevention
o

Women who are expecting are routinely tested for the strep B
bacteria when they are between 35 and 37 weeks pregnant. A mother who
has tested positive for strep B will be treated with IV antibiotics while she
is in labor to help prevent her infant from getting strep B disease. Mothers
who go into labor before 37 weeks, whose amniotic sacs have been
ruptured for more the 18 hours before delivery, who have had a previous
infant with strep B disease or who have a fever greater than 100 degrees
F during labor are also given IV antibiotics as a preventive measure.

Read more: Signs & Symptoms of Strep B in Infants | eHow.com


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Overview of Bacterial
Infections in Childhood

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Bacteria are microscopic, single-celled organisms (see Bacterial Infections:


Overview of Bacteria). Only some bacteria cause disease in people. The most
common bacterial infections among children are skin infections (including
impetigo), ear infections, and throat infections (strep throat). These and
many other less common bacterial disorders are treated similarly in adults
and children and are discussed elsewhere in the book. Other infections
occur at all ages but have specific considerations in children. Several severe
bacterial infections are preventable by routine immunization early in
childhood.
Certain children are at particular risk of bacterial infections. These children
include infants younger than 2 months, children who have no spleen or who
have an immune system disorder, and children who have sickle cell disease.

Bacterial Infections
Preventable With Routine
Immunization*

Diphtheria
Infection with Haemophilus

influenzae type b (meningitis, epiglottitis,


some severe eye infections, and occult
bacteremia)

Infection with Streptococcus


pneumoniae (pneumonia, meningitis,
occult bacteremia, and ear infections)

Infection with Neisseria meningitidis


(meningitis, sepsis, and occult
bacteremia)

Pertussis

Tetanus

*Note: Many viral infections can


also be prevented with routine
immunization (see Newborns and
Infants: Vaccination of Infants and
Children ).
Sometimes doctors diagnose bacterial infections by the typical symptoms
they cause. Usually, however, bacteria must be identified in samples of
tissue or body fluids, such as blood, urine, pus, or cerebrospinal fluid.
Sometimes bacteria from these samples can be recognized under a
microscope or identified with a rapid detection test. Usually, however, they
are too few or too small to see, so doctors must try to grow (culture) them in
the laboratory. It typically takes 24 to 48 hours to culture the bacteria.
Cultures can also be used to test the susceptibility of particular bacteria to
various antibiotics. The results can help a doctor determine which drug to
use in treating an infected child. Doctors may treat certain potentially serious
childhood infections with antibiotics before they have the culture results.
When results are obtained, the antibiotics are continued or changed as

needed. If no bacteria are found, antibiotics may be stopped.

Occult Bacteremia

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Occult (hidden) bacteremia is the presence of bacteria in the bloodstream of


a child who has a fever but who may not appear particularly sick and who
has no apparent other source of infection.

Most commonly, occult bacteremia is caused by the bacteria Streptococcus


pneumoniae.

Typically, children have no symptoms other than fever.

The diagnosis is based on blood tests.

Antibiotics can eliminate the infection.

Children younger than 3 years commonly develop fevers. Most of the time,
they have other symptoms, such as a cough and runny nose, which allow
doctors to diagnose the cause. About one third of the time, children have no
symptoms besides fever. Most of these children have viral infections that go
away without treatment. However, about 3% of such children have bacteria
circulating in the bloodstream (bacteremia). Streptococcus pneumoniae is
the most common type of bacteria causing occult bacteremia. Circulating
bacteria are almost never present in older children or adults with fever and
no other symptoms. These circulating bacteria may attack various organs
and result in serious illnesses, such as pneumonia or meningitis. Although
only about 5 to 10% of children with occult bacteremia develop these serious
problems, doctors perform blood cultures to identify the bacteria before such
problems develop. An elevated white blood cell count indicates a higher risk
of bacterial infection. In this case, a doctor may choose to start antibiotics
before blood culture results are available.
Because doctors cannot tell with certainty which children who have a fever
have bacteremia, doctors may perform a complete blood cell count and

blood cultures if children are younger than 3 years, have a temperature


higher than 102 F (38.9 C), and do not have an apparent reason for their
fever. Because occult bacteremia is much less common among children
older than 3 years, these children do not usually require blood cultures.
If children may have occult bacteremia, doctors reevaluate them in 24 to 48
hours, when culture results are available. Children with positive culture
results are given oral antibiotics at home if they do not appear very ill.
Children who show signs of serious illness are typically given intravenous
antibiotics in the hospital. Sometimes before obtaining culture results,
doctors treat children who have a fever and who appear seriously ill or have
risk factors for bacteremia (such as an elevated white blood cell count) with
a single injection of an antibiotic, such as ceftriaxoneSOME TRADE NAMES
ROCEPHIN

.
The Haemophilus influenzae type b conjugate vaccine, now given to nearly
all children in the United States, has nearly eliminated occult bacteremia due
to Haemophilus influenzae type b. The relatively new conjugate vaccine
against Streptococcus pneumoniae, given to infants, has greatly reduced the
incidence of occult pneumococcal bacteremia. Newer conjugate vaccines
against Neisseria meningitidis are being tested for use in young children.
The use of these vaccines is expected to essentially eliminate occult
bacteremia in children.

History
Many studies have been performed to determine if elements of the past medical history
and history of the acute illness may help in deciding whether a given febrile child is at a
high risk for bacterial infection.
The significance of history varies based on age. In neonates younger than 1 month with a
fever, elements of the past medical history are not useful in determining whether the
bacterial infection is serious.[15] The history of the acute febrile illness is also not useful
because nonspecific symptoms such as feeding intolerance, temperature instability, mild
respiratory distress, or irritability may indicate a serious bacterial infection in a very
young infant.[13]

Duration of fever: The duration of fever at presentation has been noted to be


shorter in patients whose blood culture findings eventually became positive for

known bacterial pathogens (mean 18 h) than in those patients with blood culture
findings negative for known bacterial pathogens (mean 25 h).[11] However, this
difference is not statistically significant, and screening for bacteremia based on
duration of fever less than 2 days would include 80% of patients with bacteremia
and 74% of those without bacteremia.[26] Overall, duration of fever is inadequate to
clinically identify occult bacteremia.[31]
History that indicates specific illness: Although meningococcal infections are
uncommon causes of bacteremia (see Causes), patients with meningococcemia are
at high risk for morbidity and mortality (see Mortality/Morbidity). Knowledge of
local epidemiology involving an outbreak of meningococcus, along with a history
of contact with someone with known meningococcal disease, can raise clinical
suspicion and help confirm an important diagnosis.[26]
History that indicates risk for occult bacteremia: Numerous studies have
attempted to establish elements of the history that can help distinguish which
febrile infants and young children are at an increased risk for bacterial infection,
including occult bacteremia.
o The Rochester criteria are formal elements of the history that have been
widely accepted as indicating a decreased risk for occult bacteremia in
infants aged 60 days or younger.[13, 14] These criteria include the following:
Was previously healthy
Had a term of at least 37 weeks' gestation
Did not receive perinatal antibiotics
Was not hospitalized longer than the mother following delivery
Did not receive treatment for unexplained hyperbilirubinemia
Not currently using antibiotics
Has no previous hospitalizations
Has no chronic or underlying illness
o Elements of the history that indicate an increased risk for occult
bacteremia in infants and children after the neonatal period include the
following:[4, 8, 12, 32]
Age, which determines the cutoff used to define fever
Febrile temperature ( 3 mo and temperature >38C [100.4F], 336 mo and temperature 39-39.5C [102.2-103.1F])
Current antibiotic use
Previous hospitalizations
Chronic or underlying illness
Immunodeficiency (eg, hypogammaglobulinemia, sickle cell
anemia, human immunodeficiency virus [HIV], malnutrition,
asplenia)
History of underlying medical condition: A longitudinal study of invasive
pneumococcal infections revealed that a history of an underlying medical
condition was a significant risk factor for increased mortality. Children with
invasive pneumococcal infections and an underlying medical condition had a
mortality rate of 3.4%, whereas previously healthy children with invasive
pneumococcal infections had a mortality rate of 0.84%.[24]

History of prematurity: Premature infants may be at a higher risk for invasive


bacterial infection when presenting with an apparent life-threatening event
(ALTE), perhaps because of reduced maternal-derived antibodies giving some
passive immunity.[33]
History of other reason for increased temperature: The history may also indicate
possible explanations for increased temperature other than fever in response to an
acute infection, such as recent vaccinations, overbundling, or environmental
exposure to heat involving a young infant.[8] A thorough evaluation for illness or
infection should be performed in all febrile children before determining that
increased temperature is caused by any extrinsic factor.
History of gastroenteritis: A history of gastroenteritis should increase the clinical
suspicion for Salmonella bacteremia. Salmonella is an uncommon cause of
gastroenteritis, but most patients who develop Salmonella bacteremia have
gastroenteritis, and 6.5% of children younger than 1 year with Salmonella
gastroenteritis become bacteremic.[2]
Epidemiology: Although a history of family members or frequent contacts with
obvious viral syndromes such as upper respiratory infections may suggest a viral
syndrome,[8] children with common cold symptoms were generally not excluded
from studies of occult bacteremia. Results suggest that the risk of bacteremia in
febrile children is the same whether common cold symptoms are present.[2]
Risk factors for invasive pneumococcal disease: Studies have evaluated the
relationship between history and pneumococcal disease. Elements of history that
have been associated with an increased risk of pneumococcal bacteremia include
daycare attendance,[2, 9, 34] lack of breastfeeding,[9, 34] and underlying illness such as
sickle cell disease or acquired immunodeficiency syndrome (AIDS).[9, 34] Although
recent antibiotic use does not affect the overall rate of infection, children who
were treated with antibiotics in the last 30 days are more likely to be infected with
S pneumoniae that is resistant to penicillin.[34]

Physical
Evaluation of a febrile infant or young child begins by establishing whether the patient
truly has a fever without a source (FWS). Toxic or lethargic children and patients with
focal infection and sepsis are appropriately treated, and children with nonfocal physical
examination findings are further evaluated for occult bacteremia.[8, 12, 32]

General appearance
Numerous investigators have formally defined the initial aspect of the physical
examination, the assessment of general appearance, in an attempt to assess its utility in
determining the presence of bacterial disease. The Yale Observation Scale (YOS)/Acute
Illness Observation Scale (AIOS) has been widely used to assess an infant's quality of
cry, reaction to parents, state variation, color/perfusion, hydration, and response to social
cues in the environment.[6, 13] Other authors have examined irritability, consolability, and
social smile.[11, 35]

Rigorous studies by numerous authors have found that the use of clinical scores,
observation scores, social smile, and general appearance have not been clinically useful
in distinguishing occult bacteremia, especially in young infants.[4, 11, 12, 31, 35] General
appearance based on observation scores had a sensitivity of 74% and specificity of 75%
in detecting serious illness in older children;[8, 10] it had a sensitivity of 33% in detecting
bacterial disease in infants younger than 2 months.[12] General appearance had 5.2%
sensitivity for detecting occult bacteremia, and social smile was 45% sensitive and 51%
specific for bacteremia.[35, 2]
A cost-effectiveness analysis suggested that clinical judgment of general appearance
(YOS < 6 is low risk), with an estimated sensitivity of 28% and specificity of 82%, may
be a useful screening criterion because the overall prevalence of occult pneumococcal
bacteremia falls with widespread use of the conjugate pneumococcal vaccine.[21]

Vital signs
Temperature, pulse, respiratory rate, and blood pressure can be very useful in raising
clinical suspicion for sepsis or pneumonia and for establishing the risk for occult
bacteremia. Studies have also suggested that pulse oximetry should be used routinely as a
fifth vital sign.[9] In younger infants, poor perfusion as judged by a capillary-refill time of
less than 2 seconds is a more sensitive measure of cardiovascular status than pulse or
blood pressure in the early phase of sepsis.
In studies of occult bacteremia, children were not excluded based on specific vital sign
parameters; in very young infants, the presence of a serious bacterial infection may not
significantly correlate with differences in pulse, respiratory rate, or blood pressure.[15]
However, tachycardia, tachypnea, or hypotension in a febrile or hypothermic infant are
signs of sepsis and warrant a complete evaluation.[4]

Fever defined
Most studies designed to determine the relationship between temperature and risk of
occult bacteremia define fever as a temperature of at least 38C (100.4F) in infants
younger than 3 months and a temperature of at least 39C (102.2F) in children aged 3-36
months. Hypothermia may be the presenting sign of bacterial infection in young infants.
One guideline defined hypothermia as a temperature less than 36C (96.8F).[8]
Although the proper method to use when measuring temperature is continuously debated,
a rectal temperature taken with a glass mercury thermometer remains the criterion
standard.[7] Tactile fever has been found to poorly correlate with the presence of actual
fever documented by a healthcare professional using rectal or oral thermometry.[36] Thus, a
parent who reports a child as having a fever because the child feels warm should not be
used as part of the evaluation of an infant or child. Home measurement of fever based on
a thermometer reading has generally been accepted as true and accurate.

Febrile temperature
The upper extreme of the febrile temperature alone is inadequate to distinguish occult
bacteremia; however, the risk of bacteremia has consistently been found to increase with

increases in temperature.[20] Studies have shown a variation in risk at given temperatures


based on age; this has led to the fever cutoffs listed above.
Table 1. Age, Fever, and Bacterial Infection[36] (Open Table in a new window)
Age
Neonates < 1 mo

Temperature, Degrees Celsius Rate of Bacterial Infection, %


38-38.9
5
39-39.9
7.5
40
18
Infants aged 1-2 mo
38-38.9
3
39-39.9
5
40
26
[2, 4, 6, 9, 37]
Table 2. Children Aged 3-36 Months - Fever and Occult Bacteremia
(Open Table
in a new window)
Occult
Positive
Positive
Occult
Pneumococcal
Blood
Blood
Pneumococcal
Bacteremia, %
Culture, % Culture, %
Bacteremia, %
39
Very low
1.6
1

39-39.4
1.2
1.6
5

39.5-39.7
2.5
2.8
5

39.8-39.9
2.5
2.8
5

40-40.2
3.2
3.7
5
10-10.4
40.3-40.5
3.2
3.7
5
10-10.4
40.5-40.9
4.4
3.8
12
10-10.4
41
9.3
9.2
12
10-10.4
Children aged 2-3 years who have a temperature lower than 39.5C have less than a 1%
risk of occult pneumococcal bacteremia.[2]
Temperature,
Degrees Celsius

Response to antipyretics
Patients with bacterial and viral sources of infection respond similarly to antipyretics; no
significant difference in temperature decrease or clinical appearance after defervescence
is noted. Both groups experience the same decrease in temperature in response to
antipyretic therapy.[4, 2, 36]

Focal infection on physical examination


Thoroughly examine the patient for signs of infection of the skin, soft tissue, bone, or
joints. A patient with any of these focal infections should be appropriately treated and
does not require evaluation for occult bacteremia.[8]

Petechiae
A febrile child with a petechial rash upon physical examination has a 2-8% risk of serious
bacterial infection. The clinical suspicion for meningococcemia should be increased if a
petechial rash is found.[8, 9] However, a prospective cohort of children with fever and
petechiae found a 1.6% risk of bacteremia or sepsis and a 0.5% risk of meningococcal

infection.[38] The children with serious bacterial infection in this study had additional
findings from the history and physical examination that suggest a bacterial cause for
petechiae. These findings include ill appearance, purpura, petechiae below the nipple line,
and no mechanical explanation (eg, cough, vomiting, tourniquet application) for
petechiae.

Acute otitis media or upper respiratory tract infection


An evaluation for bacteremia is warranted in children with acute otitis media or upper
respiratory tract infection. In most studies of occult bacteremia, these children were
included for evaluation. The results of these studies show that the risk of bacteremia is
the same in children with acute otitis media or upper respiratory infection as in children
without these findings.[4, 2, 8, 20, 3, 27]

Pneumonia
Consider the diagnosis of pneumonia in febrile children who have no other source of
infection. Specific physical examination findings such as grunting, flaring, retracting,
rhonchi, wheezing, rales, and focal decreased breath sounds have 94-99% specificity for
pneumonia.[29] Febrile children who have none of these findings rarely have pneumonia.
Studies suggest that pulse oximetry may be a more reliable predictor of pulmonary
infections than respiratory rate in infants and young children; one guideline recommends
that patients with oxygen saturation of less than 95% should be evaluated for pneumonia
by means of chest radiography.[9]
Evaluation for occult bacteremia is still warranted in febrile children with clinical or
radiographic pneumonia. Mild respiratory distress may indicate a serious bacterial
infection in a very young infant, and studies of occult bacteremia found that patients with
pneumonia have the same prevalence of bacteremia as do patients without a focus of
infection.[13, 2, 3]

Recognizable viral infections


Although symptoms of upper respiratory tract infection should not be accepted as an
explanation of fever in an infant or young child, numerous other recognizable viral
infections are generally accepted as a fever source. Children with varicella, croup,
gingivostomatitis, herpangina, or bronchiolitis have less than a 1% chance of concomitant
bacteremia.[2] A retrospective study of children with these recognizable viral syndromes
found a risk of 0.2% for true pathogens and a risk of 1.4% for contaminants.[39] Group A
streptococcal bacteremia sporadically occurs in children with varicella, but these children
are usually toxic or have focal findings.[2] Physical examination findings consistent with
these viral infections generally remove children from studies of bacteremia; these
children should be treated for viral infection without further evaluation for occult
bacteremia.[4, 2, 39]
Previous
Next Section: Causes
Age
Neonates < 1 mo

Organism*
Group B Streptococcus

Positive Blood Cultures, %


73

Escherichia coli
8
S pneumoniae
3
Staphylococcus aureus
3
Enterococcus species
3
Enterobacter cloacae
3
Infants aged 1-2 mo
Group B Streptococcus
31
E coli
20
Salmonella species
16
S pneumoniae
10
H influenzae type b
6
S aureus
4
E cloacae
4
*
Also, less frequently (< 1%), Listeria species, Klebsiella species, group A Streptococcus,
Staphylococcus epidermis, Streptococcus viridans, and N meningitidis
Organism*
1975-1993, % 1993, % 1993-1996, % 1990 to present, %
S pneumoniae
83-86
93
92
89
H influenzae type b
5-13
2
0
0
N meningitidis
1-3

Salmonella species
1-7

*
Also, less frequently (< 1%), E coli, S aureus, Streptococcus pyogenes, group B
Streptococcus, Moraxella species, Kingella species, Yersinia species, and Enterobacter
species
Previous

Table 1. Age, Fever, and Bacterial Infection[36]


Table 2. Children Aged 3-36 Months - Fever and Occult Bacteremia[2, 4, 6, 9, 37]
Table 3. Causes of Occult Bacteremia in Neonates and Infants with a Temperature
of 38C or Higher[15, 16, 12, 13, 14]
Table 4. Causes of Occult Bacteremia and Changes Over Time in Children Aged
3-36 Months with FWS[4, 2, 8, 11, 17, 27, 20]
Table 5. Studies Evaluating the Established WBC More Than 15 per HPF Screen
for Occult Bacteremia in FWS
Table 6. Recent Studies Reevaluating WBC Count as a Screen in FWS
Table 7. ANC as a Screen for Occult Bacteremia[2, 31]
Table 8. Studies Reevaluating CRP level as a Screen in FWS
Table 9. Recent Studies Evaluating PCT level as a Screen in FWS
Table 10. Effect of Illness Duration - PCT level as a Screen in FWS[47]
Table 11. Low-Risk Criteria for Infants Younger than 3 Months[65, 66, 67, 8]
Table 12. Occult Bacteremia - Relationship Between Outpatient Antibiotic Use
and Complications[8, 10, 27, 11, 68]
Table 13. Pneumococcal Bacteremia - Relationship Between Outpatient Antibiotic
Use and Complications[2, 8, 10, 18, 21, 29, 37, 69, 9]
Age

Temperature, Degrees Celsius Rate of Bacterial Infection, %

Neonates < 1 mo

38-38.9
5
39-39.9
7.5
40
18
Infants aged 1-2 mo
38-38.9
3
39-39.9
5
40
26
Occult
Positive
Positive
Occult
Temperature,
Pneumococcal
Blood
Blood
Pneumococcal
Degrees Celsius
Bacteremia, %
Culture, % Culture, %
Bacteremia, %
39
Very low
1.6
1

39-39.4
1.2
1.6
5

39.5-39.7
2.5
2.8
5

39.8-39.9
2.5
2.8
5

40-40.2
3.2
3.7
5
10-10.4
40.3-40.5
3.2
3.7
5
10-10.4
40.5-40.9
4.4
3.8
12
10-10.4
41
9.3
9.2
12
10-10.4
*
Age
Organism
Positive Blood Cultures, %
Neonates < 1 mo
Group B Streptococcus
73
Escherichia coli
8
S pneumoniae
3
Staphylococcus aureus
3
Enterococcus species
3
Enterobacter cloacae
3
Infants aged 1-2 mo
Group B Streptococcus
31
E coli
20
Salmonella species
16
S pneumoniae
10
H influenzae type b
6
S aureus
4
E cloacae
4
*
Also, less frequently (< 1%), Listeria species, Klebsiella species, group A Streptococcus,
Staphylococcus epidermis, Streptococcus viridans, and N meningitidis
Organism*
1975-1993, % 1993, % 1993-1996, % 1990 to present, %
S pneumoniae
83-86
93
92
89
H influenzae type b
5-13
2
0
0
N meningitidis
1-3

Salmonella species
1-7

*
Also, less frequently (< 1%), E coli, S aureus, Streptococcus pyogenes, group B
Streptococcus, Moraxella species, Kingella species, Yersinia species, and Enterobacter
species
Study
Cutoff
NPV, % PPV, %

Kuppermann, 1999[2] WBC >15 99


6
Lee, 2001[21]
WBC >15 99
5
[31]
Strait, 1999
WBC >15 98
6
Study
Screening Goal
Fernandez Lopez,
2003[47]
Pulliam, 2001[48]

Cutoff, per
HPF
WBC >17

NPV, % PPV, %

Invasive bacterial
69
69
*
infection
Serious bacterial
WBC >15
89
30
infection
Lacour, 2001[49]
Serious bacterial
WBC >15
89
46
infection
Isaacman, 2002[50]
Occult bacterial infection WBC >17
95
30
*
Culture-positive bacteremia/meningitis/sepsis/bone/joint infection; dimercaptosuccinic
acid (DMSA)positive pyelonephritis; lobar pneumonia; bacterial enteritis in infants
younger than 3 months

Culture-positive bacteremia/meningitis/septic arthritis/urinary tract infection (UTI); focal


infiltrate on chest radiograph

Culture-positive bacteremia/meningitis/osteomyelitis; DMSA-positive pyelonephritis;


lobar pneumonia

Culture-positive bacteremia/UTI; lobar pneumonia

ANC Sensitivity, % Specificity, % PPV, % NPV, %


10,000
76
78
8
99.2
>7,200
82
74
7.5
99.4
Study
Screening Goal
Cutoff
NPV, % PPV, %
[47]
*
Lopez, 2003
Invasive bacterial infection 2.8
81
69
[48]

Pulliam, 2001
Serious bacterial infection
5
98
Not reported
[49]

Lacour, 2001
Serious bacterial infection
4
96
51
[52]

Gendrel, 1999
Invasive bacterial infection 4
97
34
Isaacman, 2002[50]
Occult bacterial infectionll
4.4
94
30
*
Culture-positive bacteremia/meningitis/sepsis/bone/joint infection; DMSA-positive
pyelonephritis; lobar pneumonia; bacterial enteritis in infants younger than 3 months

Culture-positive bacteremia/meningitis/septic arthritis/UTI; focal infiltrate on chest


radiography

Culture-positive bacteremia/meningitis/osteomyelitis; DMSA-positive pyelonephritis;


lobar pneumonia

Culture-positive bacteremia/sepsis/meningitis

ll

Culture-positive bacteremia/UTI; lobar pneumonia

Study
Screening Goal
Cutoff
NPV, %
PPV, %
[47]
*
Lopez, 2003
Invasive bacterial infection
0.6
90
91
[49]

Lacour, 2001
Serious bacterial infection
1
97
55
Gendrel, 1999[52]
Invasive bacterial infection
2
99
52
*
Culture-positive bacteremia/meningitis/sepsis/bone/joint infection; DMSA-positive
pyelonephritis; lobar pneumonia; bacterial enteritis in infants younger than 3 months

Culture-positive bacteremia/meningitis/osteomyelitis; DMSA-positive pyelonephritis;


lobar pneumonia

Culture-positive bacteremia/sepsis/meningitis

Illness Duration
Screening Goal
Optimal Cutoff NPV, % PPV, %
Any (< 12 h and >12 h) Invasive bacterial
0.6
90
91
*
infection
< 12 h
Invasive bacterial
0.7
90
97
infection*
*Culture-positive bacteremia/meningitis/sepsis/bone/joint infection; DMSA-positive
pyelonephritis; lobar pneumonia; bacterial enteritis in infants younger than 3 months
Criterion
Philadelphia
Boston
Rochester
AAP 1993

Age
Temperature
Appearance
History

1-2 mo
38.2C
AIOS* < 15
Immune

1-2 mo
38C
Well
No antibiotics in the
last 24 h;

0-3 mo
38C
Any
Previously
healthy

1-3 mo
38C
Well
Previously
healthy

Nonfocal
5-15,000/L;

Nonfocal
5-15,000/L;

ABC < 1,000

ABC < 1,000

< 10 WBCs per


HPF

< 5 WBCs
per HPF

No immunizations
in the last 48 h

Examination
WBC count

Nonfocal
< 15,000/L; bandto-neutrophil ratio

Nonfocal
< 20,000/L

< 0.2

Urine
assessment

CSF
assessment

< 10 WBCs per


HPF;

< 10 WBCs per


HPF;

Negative for
bacteria

Leukocyte esterase
negative

< 8 WBCs per HPF; < 10 WBCs per HPF < 10-20 WBCs
per HPF

Negative for
bacteria

Chest
radiography
Stool culture

No infiltrate
< 5 WBCs per HPF

Within reference
range, if obtained

Within reference
range, if obtained
< 5 WBCs per
HPF

Acute illness observation score


No Antibiotic Oral Antibiotic
Intramuscular/Intravenous
Complication
Therapy, %
Therapy, %
Antibiotic Therapy, %
Persistent
18-21
3.8-5
0-5
bacteremia
New focal
13
5-6.6
5-7.7
infection
Meningitis
9-10
4.5-8.2
0.3-1
No
Any
Oral
Intramuscular/Intravenous
Complication Antibiotic Antibiotic Antibiotic
Antibiotic Therapy, %
Therapy, % Therapy, % Therapy, %
Persistent
7-17
1-1.5
2.5

bacteremia
Focal
9.7-10
3.3-4

infection/SBI
Meningitis
2.7-6
0.4-1
0.4-1.5
0.4-1
*

Causes
Causes of occult bacteremia vary depending on the age of the infant or child. Very young
infants most commonly acquire infections from the mother during childbirth. As a
patient's age increases, a gradual shift occurs toward community-acquired infections.
Table 3. Causes of Occult Bacteremia in Neonates and Infants with a Temperature of
38C or Higher[15, 16, 12, 13, 14] (Open Table in a new window)
Age
Neonates < 1 mo

Organism*
Positive Blood Cultures, %
Group B Streptococcus
73
Escherichia coli
8
S pneumoniae
3
Staphylococcus aureus
3
Enterococcus species
3
Enterobacter cloacae
3
Infants aged 1-2 mo
Group B Streptococcus
31
E coli
20
Salmonella species
16
S pneumoniae
10
H influenzae type b
6
S aureus
4
E cloacae
4
*
Also, less frequently (< 1%), Listeria species, Klebsiella species, group A Streptococcus,
Staphylococcus epidermis, Streptococcus viridans, and N meningitidis

Older infants and children are at risk for bacteremia due to colonization of the
nasopharynx or community-acquired organisms. Hib conjugate vaccine has decreased the
prevalence of invasive Hib disease by 90% or more in industrialized countries.[9] With the
disappearance of Hib as a cause of occult bacteremia in children, the relative frequency
of S Pneumoniae increased in some medical centers to more than 90%.[40] Since the
introduction and widespread use of the pneumococcal vaccines, the rate of vaccinespecific strains has dropped considerably, leading to significant changes in the patterns of
causative organisms in more recent studies.
Table 4. Causes of Occult Bacteremia and Changes Over Time in Children Aged 3-36
Months with FWS[4, 2, 8, 11, 17, 27, 20] (Open Table in a new window)
Organism*
1975-1993, % 1993, % 1993-1996, % 1990 to present, %
S pneumoniae
83-86
93
92
89
H influenzae type b
5-13
2
0
0
N meningitidis
1-3

Salmonella species
1-7

*
Also, less frequently (< 1%), E coli, S aureus, Streptococcus pyogenes, group B
Streptococcus, Moraxella species, Kingella species, Yersinia species, and Enterobacter
species
The prevalence of occult bacteremia caused by pneumococcus has greatly decreased
since the introduction of the 7-valent conjugate pneumococcal vaccine, which was
designed to cover 98% of the strains of S pneumoniae responsible for occult bacteremia.
[19]
A multicenter surveillance found that 82-94% of S pneumoniae invasive disease was
caused by isolates that are contained in the 7-valent conjugate pneumococcal vaccine.[24]
Rates of heptavalent vaccine-serotype invasive pneumococcal infection postlicensure
have dropped by 56%-100%, depending on location and age.[41, 42, 43, 44]
S pneumoniae types 4, 6B, 9V, 14, 18C, 19F, and 23F are 98% covered by the 7-valent
conjugate pneumococcal vaccine. The pattern of serotypes isolated from patients has
undergone considerable change since the introduction of the pneumococcal vaccines. In
the first few years of use, the number of cases decreased; more recently, the number of
reports of nonvaccine strains replacing vaccine strains as causes of invasive
pneumococcal infection has increased. In particular, strain 19A is a drug-resistant strain
that has been highlighted in several studies, along with serotypes 15 and 33.[45, 46, 44]
The new Prevnar 13 includes serotypes 1, 3, 5, 6A, 7F, and 19A in addition to those
already in Prevnar, and was is expected to further reduce the rate of pneumococcal
disease.
A recent study from the Kaiser Permanente group looked at 4255 blood cultures from
neonates. They found a significant pathogen in 2% of cultures, of which 56% were E coli,
21% were group B streptococci, and 8% were S aureus, with other infections making up
lower percentages. They found no N meningitidis or Listeria monocytogenes infections
and only one case of Enterococcus

Laboratory Studies

WBC count
The WBC count is the most widely studied laboratory parameter in occult bacteremia.
The risk of occult bacteremia and occult pneumococcal bacteremia has been consistently
found to increase with an increased WBC count.[2, 8, 9, 17, 11, 37] Randomized control trials,
retrospective reviews, prospective cohorts, and metaanalyses have been performed. Many
have used slightly different inclusion and exclusion criteria, age ranges, and fever cutoffs.
A consistent trend has been that children aged 3-36 months with FWS and a WBC count
of more than 15 per high-powered field (HPF) are at an increased risk for occult
bacteremia.[2, 8, 9, 17, 11, 37]
Most young febrile children with increased WBC counts do not have underlying bacterial
infections as a cause of fever. The goal of screening criteria and laboratory tests in
evaluation of infants and young children with fever has been to determine which patients
are at a low risk (ie, which patients can be safely managed as outpatients without
antibiotic treatment). Thus, established screening criteria have been chosen to maximize
sensitivity and negative predictive value (NPV) as the primary objective.[8] Subsequent
studies have shown a WBC count of 15 per HPF to yield an NPV of 98-99% and a
positive predictive value (PPV) of 5-6% in distinguishing occult bacteremia from benign
or noninvasive causes of FWS.[2, 21, 31]
Table 5. Studies Evaluating the Established WBC More Than 15 per HPF Screen for
Occult Bacteremia in FWS (Open Table in a new window)
Study
Cutoff
NPV, % PPV, %
[2]
Kuppermann, 1999 WBC >15 99
6
[21]
Lee, 2001
WBC >15 99
5
[31]
Strait, 1999
WBC >15 98
6
Several studies have reassessed the use of the WBC count as a screen for bacterial
infection and compared it with other laboratory markers[47, 48, 49, 50] These were all
prospective observational studies of infants and children who presented to the emergency
department for evaluation of FWS. The ability to distinguish bacteremia and other serious
invasive bacterial infections from noninvasive or benign infections based on WBC count
was evaluated. The direct application of these results to the evaluation and treatment of
occult bacteremia has some limitations.
This group of studies includes patients with bacteremia but also patients with other
invasive bacterial infections, such as meningitis and sepsis. The results show relatively
high rates of infection in the study populations. Previous studies have found a 1.5-2.3%
prevalence of occult bacteremia in infants and young children with FWS.[19, 21, 20] However,
the newer studies found an 11-38% prevalence of serious or invasive bacterial infections.
[47, 48, 49, 50]
These studies have clinical use in the context of occult bacteremia because they
address the evaluation of febrile young children who have no focus of infection upon
initial examination in an outpatient setting.
These studies have reported optimal screening values based on receiving operator
characteristics (ROC) curves to determine the best balance of sensitivity and specificity.
The results show an optimal cutoff for WBC count of 15-17 per HPF, yielding NPVs of

69-95% and PPVs of 30-69% in distinguishing invasive or serious bacterial infections


from noninvasive or benign infections.[47, 48, 49, 50]
Table 6. Recent Studies Reevaluating WBC Count as a Screen in FWS (Open Table in a
new window)
Study

Screening Goal

Fernandez Lopez,
2003[47]
Pulliam, 2001[48]

Cutoff, per
HPF
WBC >17

NPV, % PPV, %

Invasive bacterial
69
69
*
infection
Serious bacterial
WBC >15
89
30

infection
[49]
Lacour, 2001
Serious bacterial
WBC >15
89
46
infection
Isaacman, 2002[50]
Occult bacterial infection WBC >17
95
30
*
Culture-positive bacteremia/meningitis/sepsis/bone/joint infection; dimercaptosuccinic
acid (DMSA)positive pyelonephritis; lobar pneumonia; bacterial enteritis in infants
younger than 3 months

Culture-positive bacteremia/meningitis/septic arthritis/urinary tract infection (UTI); focal


infiltrate on chest radiograph

Culture-positive bacteremia/meningitis/osteomyelitis; DMSA-positive pyelonephritis;


lobar pneumonia

Culture-positive bacteremia/UTI; lobar pneumonia

These studies and others have compared the test characteristics of WBC count with other
laboratory tests in screening for occult bacterial infections. The results suggest that
absolute neutrophil count (ANC), C-reactive protein (CRP) level, and procalcitonin
(PCT) level have also been favorable test characteristics when screening for occult
bacterial infections in infants and young children. See the Absolute Neutrophil Count
calculator.
In several studies, these other laboratory tests were equal or superior to WBC count as
screening tools, as discussed below. Currently, screening with WBC count remains the
established standard, as set by guidelines published in 1993.[8]

ANC
ANC has also been evaluated as a screen for occult bacteremia; the risk of occult
bacteremia increases with increases in ANC.[2] Although guidelines before the conjugate
Hib vaccine did not recommend ANC as a screen for bacteremia,[8] more recent studies
and guidelines suggest that an ANC higher than 7-10 has favorable screening
characteristics.
ROC curves for ANC are equal to the WBC count; one analysis found that the screening
characteristics of ANC remained significant when adjusting for other variables, such as
WBC count, temperature, age, and YOS.[2] An ANC higher than 7,000-10,000 has a 7682% sensitivity, a 74-78% specificity, a 7-8% PPV, and a 99% NPV for occult
bacteremia.[2, 31] The ANC is related to cases of occult pneumococcal bacteremia as
follows:[2]

Less than 5,000 - 0%


5,000-9,000 - 1.4%
10,000-14,900 - 5.8%
Greater than 15,000 - 12.2%

Table 7. ANC as a Screen for Occult Bacteremia[2, 31] (Open Table in a new window)
ANC Sensitivity, % Specificity, % PPV, % NPV, %
10,000
76
78
8
99.2
>7,200
82
74
7.5
99.4

Band count
The absolute band count (ABC) has been found to have poor test characteristics as a
screen for occult bacteremia and is not recommended as a screening test.[2, 8] In febrile
children, the risk for occult bacteremia generally tends to increase with increasing ABC;
however, no well-defined cutoff is recognized, ROC curve characteristics are poor
compared with those of ANC and WBC count, and any changes in ABC are not
significant when adjusting for other variables.
Elevated band counts have also been found in 21-29% of patients with culture-proven
viral infections.[51] The ABC may be the most important component of the CBC counts for
identifying meningococcal bacteremia, but the low overall prevalence limits its clinical
use. The ABC (X 103/mL) is related to cases of occult pneumococcal bacteremia as
follows:[2]

Less than 0.5 - 1.5%


0.5-0.99 - 1.7%
1-1.5 - 1.7%
1.5-1.9 - 5.2%
Greater than 2 - 6.3%

Bandemia (band >15%) is related to cases of viral infections as follows:[51]

Influenza A and B - 29%


Enterovirus - 23%
Respiratory syncytial virus - 22%
Rotavirus - 22%

In most studies of bacteremia, infants younger than 3 months are considered separately.
Groups in Rochester, Boston, and Philadelphia have established guidelines aimed at
defining populations of infants who are at a low risk for bacterial infection. These
guidelines were published in Pediatrics in 1993. Most of these guidelines use band count
as part of the low-risk criteria. Low-risk band criteria according to these guidelines are as
follows:

Boston guideline - None


Philadelphia guideline - Less than 0.2 band-to-neutrophil ratio
Rochester guideline - Less than 1,500 ABC
1993 Pediatrics - Less than 1,000 ABC

Erythrocyte sedimentation rate


Numerous studies have evaluated erythrocyte sedimentation rate (ESR) as a marker for
bacterial infection. Most studies were performed before widespread use of the conjugate
Hib vaccine and included hospitalized patients and patients with focal infections.[2] These
studies found that ESR had a better sensitivity than WBC count and similar specificity.
One review found that the ESR did not predict occult bacteremia, and WBC count and
ANC were more sensitive and specific.[2] Based on this information, ESR is not currently
recommended as a screening test for occult bacteremia.[2, 8]

CRP level
CRP level is not currently an established standard screening test for occult bacteremia, as
set by the guidelines published in 1993 in Pediatrics and Annals of Emergency Medicine.
[8]
Several studies performed before widespread use of conjugate Hib and pneumococcal
vaccines found that the CRP level had better sensitivity than WBC count and similar
specificity. However, an analysis in 1999 found that CRP level could not be used to
predict occult bacteremia in young children.[26]
Several studies have reassessed CRP level as a screen for bacterial infection and
compared it with other laboratory markers.[47, 48, 49, 52, 50] These were all prospective
observational studies of infants and children who presented to the emergency department
for evaluation of FWS. As discussed above, the application of these results to bacteremia
is somewhat limited by the inclusion of other invasive infections and by the relatively
high prevalence of infection in the study populations. However, these studies have
clinical use in the context of occult bacteremia because they address the evaluation of
febrile young children who have no focus of infection upon initial examination in an
outpatient setting.
Recent studies have reported optimal screening values using ROC curves to determine
the best balance of sensitivity and specificity. The results show an optimal cutoff for CRP

level from 2.8-5, yielding NPVs of 81-98% and PPVs of 30-69% in distinguishing
invasive or serious bacterial infections from noninvasive or benign infections.[47, 48, 49, 52, 50]
Table 8. Studies Reevaluating CRP level as a Screen in FWS (Open Table in a new
window)
Study
Screening Goal
Cutoff
NPV, % PPV, %
[47]
*
Lopez, 2003
Invasive bacterial infection 2.8
81
69
Pulliam, 2001[48]
Serious bacterial infection 5
98
Not reported
[49]

Lacour, 2001
Serious bacterial infection
4
96
51
[52]

Gendrel, 1999
Invasive bacterial infection 4
97
34
[50]
ll
Isaacman, 2002
Occult bacterial infection
4.4
94
30
*
Culture-positive bacteremia/meningitis/sepsis/bone/joint infection; DMSA-positive
pyelonephritis; lobar pneumonia; bacterial enteritis in infants younger than 3 months

Culture-positive bacteremia/meningitis/septic arthritis/UTI; focal infiltrate on chest


radiography

Culture-positive bacteremia/meningitis/osteomyelitis; DMSA-positive pyelonephritis;


lobar pneumonia

Culture-positive bacteremia/sepsis/meningitis

ll

Culture-positive bacteremia/UTI; lobar pneumonia

WBC count is currently the established standard laboratory screening test in young
children with FWS.[8] Several of the studies above directly compared WBC count and
CRP level as screening laboratory tests in febrile young children with FWS. In each of
these comparisons, CRP level had NPVs and PPVs better than or equal to WBC count.[47,
48, 49, 50]
Although one author concluded that CRP level did not have any advantage or
additional value compared to WBC count,[50] CRP level screening for febrile children in
the emergency department is a part of the established protocol at numerous medical
centers. Potential strengths of CRP level screening include favorable test characteristics,
timely availability of results, and an ability to perform tests reliably on a capillary blood
sample.

The time course for changes in serum CRP levels after onset of inflammation and acute
tissue injury is fairly well understood. The CRP level begins to increase within 6 hours,
doubles every 8 hours, and peaks from 36-48 hours.[53] Based on this known delay
between stimulus and CRP level response, some have been concerned that CRP level
would have decreased sensitivity early in the course of an illness.
This issue was assessed in a few of the studies without a clear and consistent conclusion.
In one study, children with a fever duration of less than 12 hours were analyzed
separately, and ROC curves were created for each of the laboratory values studied.[47] The
optimal cutoff for CRP level overall, including any duration of fever, was 2.8; the NPV
was 81%, and the PPV was 69% in distinguishing invasive bacterial infection. The
optimal CRP level cutoff in children with a fever of less than 12 hours was lower (1.9)
and gave less optimal screening test characteristics; the NPV was 77%, and the PPV was
66%. In a smaller study, a CRP level cutoff of 7 was analyzed and was found to miss 3
patients with serious bacterial infections, all of whom had a fever duration of less than 8
hours.[48] These results support the concern that CRP level is lower and less useful as a
screen early in an infection.
However, this finding is not universal. A third study separately analyzed patients with
fever durations of less than and greater than 12 hours and found that, in both groups, CRP
level has a similar optimal cutoff and similar favorable screening characteristics.[50] To
complicate the results further, the first study above also analyzed WBC count in patients
with a fever duration of less than 12 hours. In the first 12 hours of illness, the WBC count
did not differ between invasive bacterial infections and other localized, benign, or viral
infections. This suggests that laboratory screening in illnesses of short duration may be
problematic, whether WBC count or CRP level is used.

Cytokines
Interleukin (IL)-1, IL-6, and tumor necrosis factor- (TNF-) all increase in the serum
and cerebrospinal fluid (CSF) in gram-negative and gram-positive sepsis; the levels
increase with the severity of illness. One review found that these levels also increase in
bacteremia; sensitivity and PPV are similar to those of WBC count.[2] One prospective
case control study found that IL-6 and TNF- were not significantly different between
study groups; however, IL-6 had screening test and ROC curve characteristics similar to
those of WBC count and ANC. IL-6 as a test for occult bacteremia had a sensitivity of
88%, a specificity of 70%, a PPV of 7%, and an NPV of 99.6%.[31]
These cytokines have not been thoroughly investigated; they have marginal clinical use,
unknown cost-effectiveness, and are not recommended as routine screening laboratory
studies for occult bacteremia.[2]

Procalcitonin level
Several reviews have described what is currently known about PCT.[54, 55, 56] PCT is a
prohormone of calcitonin. In studies, PCT levels increase rapidly in the serum following
exposure to bacterial endotoxin. This increase begins at approximately 2-4 hours and is
more rapid than that seen in CRP levels. How PCT level fits into the acute phase cascade
is unclear, and the sites of production and function of PCT level are also unclear. PCT

levels remain low in viral infections and in systemic inflammatory diseases such as
systemic lupus erythematosus (SLE) and Crohn disease, but PCT levels significantly
increase in bacterial infections and superinfections. PCT levels also increase in some
nonbacterial diseases that involve major tissue injury (eg, major surgery, burns,
cardiogenic shock, acute transplant rejection).
Numerous studies in ICU settings have assessed PCT levels. These seem to confirm the
above findings and show that an increase in PCT level is directly correlated with an
increased severity of infection. Serial PCT levels correlate well with response to
treatment. PCT levels decrease with successful antibiotic treatment, and a persistent
elevation of PCT levels correlates with poor outcomes in the ICU.
A few studies have assessed PCT level as a screen for bacterial infection and compared it
with other laboratory markers, including WBC count and CRP.[47, 49, 52] These were all
prospective observational studies of infants and children who presented to the emergency
department for evaluation of FWS. The application of these results to bacteremia is
somewhat limited by the inclusion of other invasive infections and by the relatively high
prevalence of infection in the study populations. However, these studies have clinical use
in the context of occult bacteremia because they address the evaluation of febrile young
children who have no focus of infection upon initial examination in an outpatient setting.
These recent studies have reported optimal screening values based on ROC curves to
determine the best balance of sensitivity and specificity. The results show an optimal
cutoff for PCT level from 0.6-2, yielding NPVs of 90-99% and PPVs of 52-91% in
distinguishing invasive or serious bacterial infections from noninvasive or benign
infections.[47, 49, 52]
Table 9. Recent Studies Evaluating PCT level as a Screen in FWS (Open Table in a new
window)
Study
Screening Goal
Cutoff
NPV, %
PPV, %
[47]
*
Lopez, 2003
Invasive bacterial infection
0.6
90
91
[49]

Lacour, 2001
Serious bacterial infection
1
97
55
Gendrel, 1999[52]
Invasive bacterial infection
2
99
52
*
Culture-positive bacteremia/meningitis/sepsis/bone/joint infection; DMSA-positive
pyelonephritis; lobar pneumonia; bacterial enteritis in infants younger than 3 months

Culture-positive bacteremia/meningitis/osteomyelitis; DMSA-positive pyelonephritis;


lobar pneumonia

Culture-positive bacteremia/sepsis/meningitis

In these studies, PCT level had favorable test characteristics when compared to WBC
count and CRP level as a screen for serious or invasive bacterial infections. PCT level
had better NPVs and PPVs than both WBC count and CRP level in each of these studies.
As mentioned above, laboratory screening in illnesses of short duration may be
problematic. In one of these studies, children with a fever duration of less than 12 hours
were analyzed separately, and ROC curves were created for each of the laboratory values
studied.[47] WBC count had no use as a screening test for illness lasting less than 12 hours,
and CRP level had a lower optimal cutoff value with lower predictive values as a screen
in these recently onset illnesses. Analysis of PCT level screening in illness lasting less
than 12 hours found an optimal cutoff value and screening characteristics that were
similar to those found in illness of longer duration. This information fits with the known
rapid increase in serum PCT level following a stimulus and suggests that PCT level may
be useful as a screen for illnesses of short duration.
Table 10. Effect of Illness Duration - PCT level as a Screen in FWS[47] (Open Table in a
new window)
Illness Duration
Screening Goal
Optimal Cutoff NPV, % PPV, %
Any (< 12 h and >12 h) Invasive bacterial
0.6
90
91
infection*
< 12 h
Invasive bacterial
0.7
90
97
*
infection
*Culture-positive bacteremia/meningitis/sepsis/bone/joint infection; DMSA-positive
pyelonephritis; lobar pneumonia; bacterial enteritis in infants younger than 3 months
Bacteremia is a concern because it can lead to focal bacterial infections, most importantly
meningitis. In a prospective observational study of 59 infants and young children
hospitalized with meningitis, serum PCT level was a perfect screen for bacterial
meningitis. A PCT level cutoff of 2 had a 100% NPV and a 100% PPV in distinguishing
bacterial meningitis from viral meningitis.[57] This suggests that PCT level may have use
as a screen for bacteremia and for sequelae such as meningitis in young febrile children.
In summary, PCT level appears to be more sensitive and more specific for bacterial
infection than are other laboratory values currently used as screening tests and has good
results in illnesses of short duration. Other potential strengths include the need for a small
amount of serum or plasma and the availability of a rapid qualitative colorimetric bedside
PCT level test, which showed similar test characteristics when compared with the
instrument-based laboratory PCT level test.[47]
Potential weaknesses of PCT level tests include cost (currently estimated at twice that of
CRP level tests);[56] increased PCT levels found in some nonbacterial diseases as
mentioned above; and current familiarity and availability limited to research laboratories.
Also, studies of PCT level as a screening test have focused on patients in intensive care
units or patients with serious, invasive, or focal infections. Currently, PCT level shows
promise as a screening test in febrile infants and young children. Further study is needed
to show more direct application to children with FWS, at risk for occult bacteremia, in
the emergency department, or in the pediatric clinic setting.

Urinalysis
Evaluation of children with FWS often requires laboratory analysis to evaluate for UTI.
Children with test results that suggest a UTI are generally treated for this focal infection
and do not require further evaluation for occult bacteremia. Of children evaluated for
FWS, approximately 7% of boys younger than 6 months and approximately 8% of girls
younger than 1 year have a UTI.[10] All published guidelines for evaluation of FWS in
infants younger than 1 month recommend a laboratory evaluation for UTI, and most
guidelines also recommend urine studies in girls younger than 1-2 years and boys
younger than 6 months.[8]
Although UTI is a separate topic and is not fully addressed here, traditional guidelines for
urine studies in infants and children with FWS include urinalysis, microscopy, and urine
culture. A negative screening test result is defined as fewer than 5-10 WBCs per HPF, no
bacteria, and negative nitrite and leukocyte esterase.[8, 12, 13, 14, 58] Application of these
guidelines revealed that, in infants and children, approximately 20% of UTIs established
based on findings from a urine culture were not detected by the screening urinalysis.[10]
Studies using enhanced urinalysis (cell count by hemocytometer and urine Gram stain)
and Gram stain of urine sediment showed 99-100% sensitivity and a 100% NPV for UTI.
[10, 59]
Improvement in sensitivity of urine studies has great potential for improving
detection of systemic bacterial infection (SBI) in young febrile infants during the initial
evaluation.[58]

Salmonella and stool studies


Salmonella bacteremia accounts for a small portion of occult bacteremia (see Causes),
and the clinical and laboratory findings are different from those in pneumococcal
bacteremia.
A WBC count is not a useful screening test because most infants and children with
Salmonella bacteremia have a WBC count less than 15,000/ L, and only half of patients
have a left shift of the WBC count differential.[2] Most patients who develop Salmonella
bacteremia have gastroenteritis, and 6.5% of children younger than 1 year who have
Salmonella gastroenteritis become bacteremic.[2] Because of this association, stool
cultures are recommended for children with diarrhea.[8, 10]
The initial clinical application of low-risk criteria for infants younger than 3 months with
FWS did not include a stool evaluation. However, numerous patients with Salmonella
bacteremia were improperly identified as being at low risk by these guidelines, and
current guidelines recommend a screening stool evaluation in young infants with
diarrhea. Patients with fewer than 5 WBCs per HPF are considered at low risk for
bacterial infection.[8, 13, 14]

N meningitidis
Meningococcus is also an uncommon cause of occult bacteremia, but the morbidity and
mortality associated with meningococcemia are high (see Causes and
Mortality/Morbidity). Laboratory findings in meningococcal bacteremia are also different
from those in pneumococcal bacteremia.

Although the risk of pneumococcal bacteremia is directly related to increasing WBC


counts, 6% of children with meningococcal bacteremia have a WBC count per HPF of
fewer than 5. Overall, WBC counts and ANCs have not proved consistently useful in
determining the risk of meningococcal infection.[26, 2]
The band count may be the most important component of the CBC count in
meningococcus.[2] Approximately 60% of patients with meningococcal bacteremia have a
band count of greater than 10%, and a retrospective review of FWS found that the band
count was the only laboratory value that was significantly higher in patients with
meningococcal bacteremia than in those without bacteremia.[26, 2] However, the clinical use
of an elevated band count is limited because of the low overall prevalence of
meningococcal bacteremia. The PPV of a band count greater than 10% is 0.06.
The use of plasma clearance rate (PCR) in the evaluation of occult meningococcal
bacteremia has not been studied. In studies of known meningococcal disease, PCR is
sensitive and specific and may be useful in detecting meningococcal bacteremia.[2]

CSF analysis
Infants and children with FWS may require a laboratory analysis to evaluate for
meningitis. Febrile infants and children of any age who are toxic require a full sepsis
evaluation, including CSF and empiric treatment with parenteral antibiotics.[8]
Guidelines by groups in Rochester, Boston, and Philadelphia for the treatment of infants
younger than 3 months who have FWS all include screening CSF laboratory tests and a
CSF culture; the guidelines published in Pediatrics in 1993 recommend that a CSF
evaluation be performed in certain situations (see Medical Care). Negative screening test
results were defined as fewer than 8-10 WBCs per HPF, no bacteria, and normal glucose
and protein levels.[8, 12, 13, 37] Children with laboratory values suggesting meningitis should
be treated for this focal infection. Evaluation and treatment for meningitis is a separate
topic and is not fully addressed here.

Blood culture
A blood culture positive for known bacterial pathogens is the criterion standard used to
define bacteremia.
Blood cultures should be obtained in infants and young children at risk for occult
bacteremia. Blood cultures that are positive for single isolates of known pathogenic
bacteria (see Causes) are generally considered to be true positive results; cultures that
grow multiple isolates or nonpathogenic bacteria are considered contaminated. How fast
the culture becomes positive for known bacterial pathogens is also useful in
distinguishing pathogens from contaminants; true pathogens generally grow faster than
contaminants, with most pathogens turning positive in less than 24 hours.[2, 9] The routine
mean detection time for several pathogens are as follows:[2]

S pneumoniae - 11-15 hours


Salmonella species - 9-12 hours
N meningitidis - 12-23 hours

Whether the quantity of colonies grown is useful in detecting occult bacteremia or in


predicting prognosis is unclear. Occult pneumococcal bacteremia may yield fewer than
10 colony-forming units (CFU)/mL, which is lower than in focal disease. The yield in
meningococcal infection widely varies, but one study found that patients with yields
higher than 700 CFU/mL were at an increased risk for meningitis.[2]
Testing for respiratory syncytial virus and influenza may help in the evaluation of infants
with symptoms typical of viral respiratory infection and fever. Positive test results for
these viruses is associated with a lower risk of occult bacteremia and meningitis, although
no significant different in bacterial UTI is seen.[60, 61] This could have implications for the
use of empiric antibiotics and how aggressively a SBI is investigated, although how this
testing would fit into one of the clinical algorithms is unclear.

Imaging Studies
The only imaging study routinely used in infants and children with FWS is chest
radiography to evaluate for pneumonia. Consider pneumonia in febrile children with no
other source of infection. Specific physical examination findings include grunting,
flaring, retracting, rhonchi, wheezing, rales, and focal decreased breath sounds. These
findings are 94-99% specific for pneumonia.[58] Obtain a chest radiograph as part of the
evaluation of children with any of these findings; evaluation for pneumonia in febrile
children without any of these findings is of very low yield.[9, 17]
Some studies suggest that pulse oximetry may be a more reliable predictor of pulmonary
infections than is respiratory rate in infants and young children. One guideline
recommends that chest radiography be used to evaluate for pneumonia if the patient's
oxygen saturation is less than 95%.[9]
One study found that a subset of febrile children who did not have physical examination
findings suggestive of pneumonia were at an increased risk for occult pneumonia.[62]
Approximately 20% of febrile children younger than 5 years who had normal physical
examination findings and WBC counts higher than 20,000/L had chest radiographic
findings consistent with pneumonia. This guideline recommends that a chest radiograph
be obtained in febrile infants and children with signs and symptoms of pneumonia and in
febrile infants and children without signs and symptoms of pneumonia who have WBC
counts higher than 20,000/L

Procedures

Blood: Venipuncture is performed to obtain blood for a CBC count and blood
cultures. This should be performed using a sterile technique to limit
contamination. The recovery rate associated with blood cultures is improved with
larger volumes of blood and a shorter period between the blood draw and
incubation in the laboratory.[2] The recovery rate is 83% with a large volume of
blood (6 mL) and is 60% with a small volume of blood (2 mL). The recovery rate

is 95% after 2 hours between blood draw and incubation and is 70% after 3 hours
between blood draw and incubation.
Lumbar puncture: A lumbar puncture (LP) is performed to obtain CSF for cell
count, glucose and protein levels, microscopy, and Gram stain and culture (see
Lab Studies and Medical Care). This should be performed using a sterile
technique to limit contamination. Children with bacteremia who have an LP may
have an increased risk of meningitis, although this theory is controversial.[9]
Urine specimen: Urine collection is performed for urinalysis, microscopy, Gram
stain, cell count, and culture (see Lab Studies and Medical Care). Urine collection
should be performed using a sterile technique to limit contamination. Suprapubic
bladder aspiration and in-and-out bladder catheterization are best in young infants
and children.

Background
Bacteremia is the presence of viable bacteria in the circulating blood.[1] This may or may
not have any clinical significance because harmless, transient bacteremia may occur
following dental work or other minor medical procedures; however, this bacteremia is
generally clinically benign and self-resolving in children who do not have an underlying
illness or immune deficiency or a turbulent cardiac blood flow. The concern with occult
bacteremia is that it could progress to a more severe local or systemic infection if left
untreated. Most episodes of occult bacteremia spontaneously resolve, and serious
sequelae are increasingly uncommon. However, serious bacterial infections occur,
including pneumonia, septic arthritis, osteomyelitis, cellulitis, meningitis, and sepsis,
possibly resulting in death.[2, 3]
With the development and widespread use of effective vaccines to the common serious
bacterial infections of infancy (Haemophilus influenzae type B and Streptococcus
pneumoniae), the rate of infectious caused by these pathogens has dramatically declined.
Many of the studies in children with occult bacteremia were done prior to the
introduction of one or both of these vaccines and, as such, may overestimate the
likelihood of occult bacteremia.
Patients with occult bacteremia do not have clinical evidence other than fever (a systemic
response to infection).[4] First described in the 1960s in young febrile children with
unsuspected pneumococcal infection, bacteremia is defined as the presence of bacteria in
the bloodstream of a febrile child who was previously healthy; the child does not
clinically appear to be ill and has no apparent focus of infection.[5, 6] Occult bacteremia has
been defined as bacteremia not associated with clinical evidence of sepsis (shock or

purpura) or toxic appearance, underlying significant chronic medical conditions, or clear


foci of infection (other than acute otitis media) upon examination in a patient who is
discharged and sent home after an outpatient evaluation.[2]
Often, the only manifestation of occult bacteremia is fever or a minor infection (eg, otitis
media, upper respiratory tract infection).[4] Therefore, in a busy clinic or emergency
department, infants and young children with occult bacteremia are difficult to distinguish
from others in the waiting-room.
Fever is common in pediatric patients. Children average 4-6 fevers by age 2 years.[7] Fever
also prompts many visits to the pediatric clinic and emergency department.
Approximately 8-25% of doctor's visits by children younger than 3 years are for fever;[4, 7,
8, 9]
65% of children younger than 3 years visit a physician for acute febrile illness.[8, 10]
Fever is less common in infants younger than 3 months than in those aged 3 months to 3
years. Young infants may not mount a fever response and may also be hypothermic in
response to illness or stress.[7] Approximately 1% of infants younger than 2 months
present with fever, and fever is twice as common in infants aged 1-2 months as it is in
newborns younger than 1 month.[7]
Of all pediatric patients presenting for evaluation of fever, 20% have fever for which the
source of infection is undetermined after a history and physical examination.[9] Of all
infants and young children who present to the hospital for any reason, 1.6% appear
nontoxic, were previously healthy, are older than 3 months, and have a fever without a
source (FWS).[9]
Bacteremia may also occur in children with focal infections or in children who have
sepsis (ie, clinical evidence other than fever of a systemic response to infection). Children
with sepsis generally appear ill, have an increased heart rate or respiratory rate and may
have a change in temperature (typically fever, although hypothermia is often seen in very
young infants and newborns). Severe sepsis results in hypotension, hypoperfusion, or
organ dysfunction. Septic shock occurs in children who do not respond to adequate
volume resuscitation or require vasopressors or inotropes. Although bacteria may be
present in the bloodstream of children with focal infections, sepsis, severe sepsis, or
septic shock, the focus of this article is occult bacteremia.

Pathophysiology
Much of the pathophysiology of occult bacteremia is not fully understood. The presumed
mechanism begins with bacterial colonization of the respiratory passages or other
mucosal surface; bacteria may egress into the bloodstream of some children because of
host-specific and organism-specific factors. Once viable bacteria have gained access to
the bloodstream, they may be spontaneously cleared, they may establish a focal infection,
or the infection may progress to septicemia; the possible sequelae of septicemia include
shock, disseminated intravascular coagulation, multiple organ failure, and death.[4, 11]
Often, fever is the only presenting sign in patients with occult bacteremia and is defined
as increased temperature caused by resetting the thermoregulatory center in the

hypothalamus by action of cytokines.[7] The cytokines may be produced in response to


viral or bacterial pathogens or by immune complexes. An increased temperature does not
always represent a fever. Hyperthermia may also be due to increased heat production as
occurs in exercise or decreased heat loss as occurs in overbundling, neither of which
involves resetting of the hypothalamic thermostat.
A child's immune system helps determine which bacteria gain initial access to the
bloodstream, whether bacteremia spontaneously resolves or progresses to serious
bacterial illness, and whether cytokines are produced to mount a fever response. The risk
of life-threatening bacterial disease is greatest in young infants when their immune
system is least mature; they have poor immunoglobulin G (IgG) antibody response to
encapsulated bacteria and decreased opsonin activity, macrophage function, and
neutrophil activity.[12, 13]
Clearly, some children are more susceptible to bacterial infection, which may initially be
uncomplicated bacteremia but could rapidly lead to more serious complications.
Immunosuppression due to neoplastic disease or its treatment or defects in antibody
responses or neutrophil responses predispose certain children to invasive infection.
Bacteremia should be considered, with a low threshold for evaluation and treatment, in
patients with impaired immunity or invasive medical devices such as indwelling central
venous lines.
The pathogens implicated in occult bacteremia change in response to vaccination against
the common pathogenic strains. These changes govern the choices for empiric therapy of
suspected bacteremia.

Epidemiology
Frequency

United States
The risk of bacteremia has been studied by categorizing infants and young children based
on age, appearance, temperature, laboratory criteria, numerous low-risk criteria based on
a combination of these factors, and past medical history. These studies are part of an
ongoing attempt to decide which children require evaluation and treatment and which
children can be safely observed without intervention.
Numerous investigators have loosely and specifically defined the terms toxic and
lethargic (see Physical). A child who is toxic or lethargic is generally described as making
poor eye contact; having poor interactions with parents and the environment; and
showing signs on global assessment of poor perfusion, hypoventilation or
hyperventilation, or cyanosis.[8]
In children younger than 3 months, the risk of bacteremia is 1.2-2% in infants who are
not toxic and 10-11% in infants who are toxic.[8, 14] In children aged 3-36 months who are
toxic, the risk of bacteremia or serious bacterial infection ranges from 10-90%, depending
on criteria.[8, 10]

Most studies designed to determine the relationship between temperature and risk of
occult bacteremia define fever as a temperature of at least 38C (100.4F) in infants
younger than 3 months and at least 39C (102.2F) in children aged 3-36 months.
Because these studies were designed to predict occult bacteremia, they include children
who have only FWS, which is defined as an acute febrile illness in which the etiology is
not apparent after history is obtained and a careful physical examination is performed.[10]
Numerous studies published in the early 1990s found that 2-15% of febrile infants
younger than 3 months had bacteremia.[12, 15, 13, 16] These studies also determined that the risk
of occult bacteremia in children aged 3-36 months with FWS was 2.5-11%.[4, 8, 9, 17, 18]
According to studies performed after the introduction of the conjugate Haemophilus
influenzae type b (Hib) vaccine, the risk of occult bacteremia was 1.5-2.3% in children
aged 3-36 months with FWS.[19, 20, 21] A recent study from the Kaiser Permanente group
gave a risk of 2.2%, but the majority of positive cultures were judged to be contaminants
(247 contaminants vs 93 pathogens out of 4255 cultures), giving a true bacteremia rate of
2%.[22]
Clinical trials and postlicensure studies suggest that the 7-valent conjugate pneumococcal
vaccine is 90% effective in preventing invasive disease caused by Streptococcus
pneumoniae. Widespread use has significantly decreased the overall risk of occult
bacteremia, especially with regards to vaccine-specific strains of streptococcus.[9, 23, 24]
The appearance of the nonvaccine pneumococcus strain 19A, which has been responsible
for some particularly invasive (and drug-resistant) infections, is a concern. This is
discussed in more detail below, and it is expected that the widespread use of the 13-valent
conjugate pneumococcal vaccine will help control this.

International
According to the World Health Organization, at least 6 million children die each year of
pneumococcal infections (eg, pneumonia, meningitis, bacteremia); most of these fatalities
occur in developing countries.[25]

Mortality/Morbidity
The natural history, morbidity, and mortality associated with occult bacteremia alone are
not clearly understood. In prospective studies of occult bacteremia, although many
children were initially observed untreated, all were given antibiotics once blood culture
findings became positive for known bacterial pathogens.[26] The widespread adoption of
vaccines to the most common childhood bacteria pathogens (Hinfluenzae and S
pneumoniae) have further complicated assessment because contemporary data are not
directly comparable to historical studies.
In studies performed before the introduction of the Hib conjugate vaccine, children with
untreated bacteremia had an 18-21% risk of developing persistent bacteremia and a 215% risk of developing important focal infections such as meningitis.[4, 8, 10, 27]
Because widespread use of the Hib vaccine has virtually eliminated invasive Hib disease
in the developed world, recent reviews, analyses, and studies have focused on invasive S
pneumoniae disease.[28] Children with occult pneumococcal bacteremia have a 6-17% risk

of persistent bacteremia, a 2-5.8% risk of meningitis, and a 6-10% risk of other focal
complications.[4, 2, 8, 29, 10, 21]
Of all focal infections that develop because of pneumococcal bacteremia, pneumococcal
meningitis carries the highest risk for significant morbidity and mortality, including a 2530% risk of neurologic sequelae such as deafness, mental retardation, seizures, and
paralysis.[26, 9] The mortality rate of pneumococcal meningitis is 6.3-15%, and the overall
mortality rate of pneumococcal bacteremia is 0.8%.[26, 9, 24]
Neisseria meningitidis also causes bacteremia in infants and young children. Although the
prevalence of meningococcal bacteremia is much lower than that of pneumococcal
disease (see Causes), the morbidity and mortality rates are much greater. Children with
meningococcal bacteremia have a 42-50% risk of developing meningitis; a 50% risk of
developing serious bacterial infection such as septic shock, pneumonia, and neurologic
changes; a 3% risk of developing extremity necrosis; and an overall mortality rate of 4%.
[4, 26, 9]

When untreated, Salmonella bacteremia carries a 50% risk of persistent bacteremia and
can cause meningitis, sepsis, and death in infants younger than 3 months or in persons
who are debilitated or immunocompromised.[2] However, in previously healthy children
aged 3-36 months, the risk of meningitis or serious bacterial infection following
Salmonella bacteremia is low.[4]

Race
Studies of the prevalence of bacteremia in children in diverse settings have identified no
racial, geographic, or socioeconomic predisposition.[4, 6, 11, 30] However, antibiotic resistance
patterns vary in different geographic regions, which may affect the treatment of children
with bacteremia.

Sex
No sex-based difference in the prevalence or course of bacteremia is known.[11]

Age
Studies of occult bacteremia focus on children younger than 3 years. Some studies show
that age does not affect the risk of developing occult bacteremia,[11] whereas other analyses
have found that variations in age-based risk depend on the infecting organism.
Pneumococcal bacteremia is observed in children of all ages; however, children aged 6
months to 2 years are at an increased risk.[6, 2, 20] The prevalence of pneumococcal
meningitis peaks in infants aged 3-5 months. Meningococcal bacteremia occurs most
frequently in infants aged 3-12 months; the highest risk of meningococcal meningitis is in
infants aged 3-5 months.[2, 11] The risk of Salmonella bacteremia is greatest in infants
younger than 1 year, especially in those younger than 2 months.[2]
A seasonal variation in febrile children presenting for evaluation is recognized. The peak
is from late fall to early spring in children of all ages and is likely because of respiratory
and GI viral infections. Another peak occurs during the summer in infants younger than 3
months and is likely due to enteroviral infections and thermoregulation during hot

weather.[7] However, most studies do not specifically address seasonal variation associated
with bacteremia.
Previous
Proceed to Clinical Presentation

Table 1. Age, Fever, and Bacterial Infection[36]


Table 2. Children Aged 3-36 Months - Fever and Occult Bacteremia[2, 4, 6, 9, 37]
Table 3. Causes of Occult Bacteremia in Neonates and Infants with a Temperature
of 38C or Higher[15, 16, 12, 13, 14]
Table 4. Causes of Occult Bacteremia and Changes Over Time in Children Aged
3-36 Months with FWS[4, 2, 8, 11, 17, 27, 20]
Table 5. Studies Evaluating the Established WBC More Than 15 per HPF Screen
for Occult Bacteremia in FWS
Table 6. Recent Studies Reevaluating WBC Count as a Screen in FWS
Table 7. ANC as a Screen for Occult Bacteremia[2, 31]
Table 8. Studies Reevaluating CRP level as a Screen in FWS
Table 9. Recent Studies Evaluating PCT level as a Screen in FWS
Table 10. Effect of Illness Duration - PCT level as a Screen in FWS[47]
Table 11. Low-Risk Criteria for Infants Younger than 3 Months[65, 66, 67, 8]
Table 12. Occult Bacteremia - Relationship Between Outpatient Antibiotic Use
and Complications[8, 10, 27, 11, 68]
Table 13. Pneumococcal Bacteremia - Relationship Between Outpatient Antibiotic
Use and Complications[2, 8, 10, 18, 21, 29, 37, 69, 9]

Age
Neonates < 1 mo

Temperature, Degrees Celsius Rate of Bacterial Infection, %


38-38.9
5
39-39.9
7.5
40
18
Infants aged 1-2 mo
38-38.9
3
39-39.9
5
40
26
Occult
Positive
Positive
Occult
Temperature,
Pneumococcal
Blood
Blood
Pneumococcal
Degrees Celsius
Bacteremia, %
Culture, % Culture, %
Bacteremia, %
39
Very low
1.6
1

39-39.4
1.2
1.6
5

39.5-39.7
2.5
2.8
5

39.8-39.9
2.5
2.8
5

40-40.2
3.2
3.7
5
10-10.4
40.3-40.5
3.2
3.7
5
10-10.4
40.5-40.9
4.4
3.8
12
10-10.4
41
9.3
9.2
12
10-10.4
*
Age
Organism
Positive Blood Cultures, %

Neonates < 1 mo

Group B Streptococcus
73
Escherichia coli
8
S pneumoniae
3
Staphylococcus aureus
3
Enterococcus species
3
Enterobacter cloacae
3
Infants aged 1-2 mo
Group B Streptococcus
31
E coli
20
Salmonella species
16
S pneumoniae
10
H influenzae type b
6
S aureus
4
E cloacae
4
*
Also, less frequently (< 1%), Listeria species, Klebsiella species, group A Streptococcus,
Staphylococcus epidermis, Streptococcus viridans, and N meningitidis
Organism*
1975-1993, % 1993, % 1993-1996, % 1990 to present, %
S pneumoniae
83-86
93
92
89
H influenzae type b
5-13
2
0
0
N meningitidis
1-3

Salmonella species
1-7

*
Also, less frequently (< 1%), E coli, S aureus, Streptococcus pyogenes, group B
Streptococcus, Moraxella species, Kingella species, Yersinia species, and Enterobacter
species
Study
Cutoff
NPV, % PPV, %
[2]
Kuppermann, 1999 WBC >15 99
6
[21]
Lee, 2001
WBC >15 99
5
[31]
Strait, 1999
WBC >15 98
6
Study
Screening Goal
Cutoff, per
NPV, % PPV, %
HPF
Fernandez Lopez,
Invasive bacterial
WBC >17
69
69
2003[47]
infection*
Pulliam, 2001[48]
Serious bacterial
WBC >15
89
30

infection
Lacour, 2001[49]
Serious bacterial
WBC >15
89
46

infection
[50]
Isaacman, 2002
Occult bacterial infection WBC >17
95
30
*
Culture-positive bacteremia/meningitis/sepsis/bone/joint infection; dimercaptosuccinic
acid (DMSA)positive pyelonephritis; lobar pneumonia; bacterial enteritis in infants
younger than 3 months

Culture-positive bacteremia/meningitis/septic arthritis/urinary tract infection (UTI); focal

infiltrate on chest radiograph

Culture-positive bacteremia/meningitis/osteomyelitis; DMSA-positive pyelonephritis;


lobar pneumonia

Culture-positive bacteremia/UTI; lobar pneumonia

ANC Sensitivity, % Specificity, % PPV, % NPV, %


10,000
76
78
8
99.2
>7,200
82
74
7.5
99.4
Study
Screening Goal
Cutoff
NPV, % PPV, %
[47]
*
Lopez, 2003
Invasive bacterial infection 2.8
81
69
Pulliam, 2001[48]
Serious bacterial infection 5
98
Not reported
[49]

Lacour, 2001
Serious bacterial infection
4
96
51
[52]

Gendrel, 1999
Invasive bacterial infection 4
97
34
[50]
ll
Isaacman, 2002
Occult bacterial infection
4.4
94
30
*
Culture-positive bacteremia/meningitis/sepsis/bone/joint infection; DMSA-positive
pyelonephritis; lobar pneumonia; bacterial enteritis in infants younger than 3 months

Culture-positive bacteremia/meningitis/septic arthritis/UTI; focal infiltrate on chest


radiography

Culture-positive bacteremia/meningitis/osteomyelitis; DMSA-positive pyelonephritis;


lobar pneumonia

Culture-positive bacteremia/sepsis/meningitis

ll

Culture-positive bacteremia/UTI; lobar pneumonia

Study
Screening Goal
Cutoff
NPV, %
PPV, %
Lopez, 2003[47]
Invasive bacterial infection*
0.6
90
91
[49]

Lacour, 2001
Serious bacterial infection
1
97
55
[52]

Gendrel, 1999
Invasive bacterial infection
2
99
52
*
Culture-positive bacteremia/meningitis/sepsis/bone/joint infection; DMSA-positive
pyelonephritis; lobar pneumonia; bacterial enteritis in infants younger than 3 months

Culture-positive bacteremia/meningitis/osteomyelitis; DMSA-positive pyelonephritis;


lobar pneumonia

Culture-positive bacteremia/sepsis/meningitis

Illness Duration
Screening Goal
Optimal Cutoff NPV, % PPV, %
Any (< 12 h and >12 h) Invasive bacterial
0.6
90
91
infection*
< 12 h
Invasive bacterial
0.7
90
97
*
infection
*Culture-positive bacteremia/meningitis/sepsis/bone/joint infection; DMSA-positive
pyelonephritis; lobar pneumonia; bacterial enteritis in infants younger than 3 months
Criterion
Philadelphia
Boston
Rochester
AAP 1993
Age
1-2 mo
1-2 mo
0-3 mo
1-3 mo
Temperature
38.2C
38C
38C
38C
*
Appearance
AIOS < 15
Well
Any
Well
History
Immune
No antibiotics in the
Previously
Previously
last 24 h;
healthy
healthy

No immunizations
in the last 48 h

Examination
WBC count

Nonfocal
< 15,000/L; bandto-neutrophil ratio

Nonfocal
< 20,000/L

Nonfocal
5-15,000/L;

Nonfocal
5-15,000/L;

ABC < 1,000

ABC < 1,000

< 0.2

Urine
assessment

CSF
assessment

< 10 WBCs per


HPF;

< 10 WBCs per


HPF;

Negative for
bacteria

Leukocyte esterase
negative

< 10 WBCs per


HPF

< 8 WBCs per HPF; < 10 WBCs per HPF < 10-20 WBCs
per HPF

< 5 WBCs
per HPF

Negative for
bacteria

Chest
radiography
Stool culture

No infiltrate
< 5 WBCs per HPF

Within reference
range, if obtained

Within reference
range, if obtained
< 5 WBCs per
HPF

Acute illness observation score


No Antibiotic Oral Antibiotic
Intramuscular/Intravenous
Complication
Therapy, %
Therapy, %
Antibiotic Therapy, %
Persistent
18-21
3.8-5
0-5
bacteremia
New focal
13
5-6.6
5-7.7
infection
Meningitis
9-10
4.5-8.2
0.3-1
No
Any
Oral
Intramuscular/Intravenous
Complication Antibiotic Antibiotic Antibiotic
Antibiotic Therapy, %
Therapy, % Therapy, % Therapy, %
Persistent
7-17
1-1.5
2.5

bacteremia
Focal
9.7-10
3.3-4

infection/SBI
Meningitis
2.7-6
0.4-1
0.4-1.5
0.4-1
*

Medical Care
Most infants and young children who are evaluated for occult bacteremia present with a
fever. The use of antipyretics to treat fever is somewhat controversial. However, while the
child is evaluated to determine a source of the fever, fever reduction with medication is
reasonable and is widely accepted. Studies have shown that ibuprofen (10 mg/kg/dose
every 8 h) or acetaminophen (10-15 mg/kg/dose every 4-6 h) are both effective and well
tolerated.[63]
Low-risk criteria: Who should be treated?
As recently as 1984, guidelines for treating febrile young infants recommended
evaluation, treatment, and hospitalization because of the increased risk of bacterial
infection and the inability to clinically distinguish infants at an increased risk for serious
bacterial infection.[64] Since then, numerous studies have evaluated combinations of age,
temperature, history, examination findings, and laboratory results to determine which
young infants are at a low risk for bacterial infection.[8, 65, 66, 67, 58]
The following are the low-risk criteria established by groups from Philadelphia, Boston,
and Rochester and the 1993 American Academy of Pediatrics (AAP) guideline.
Table 11. Low-Risk Criteria for Infants Younger than 3 Months[65, 66, 67, 8] (Open Table in a
new window)
Criterion
Age
Temperature
Appearance
History

Philadelphia
1-2 mo
38.2C
AIOS* < 15
Immune

Boston
1-2 mo
38C
Well
No antibiotics in the
last 24 h;

Rochester
0-3 mo
38C
Any
Previously
healthy

AAP 1993
1-3 mo
38C
Well
Previously
healthy

Nonfocal

Nonfocal

No immunizations
in the last 48 h

Examination

Nonfocal

Nonfocal

WBC count

< 15,000/L; bandto-neutrophil ratio

< 20,000/L

5-15,000/L;

5-15,000/L;

ABC < 1,000

ABC < 1,000

< 10 WBCs per


HPF

< 5 WBCs
per HPF

< 0.2

Urine
assessment

CSF
assessment

< 10 WBCs per


HPF;

< 10 WBCs per


HPF;

Negative for
bacteria

Leukocyte esterase
negative

< 8 WBCs per HPF; < 10 WBCs per HPF < 10-20 WBCs
per HPF

Negative for
bacteria

Chest
radiography
Stool culture
*

No infiltrate
< 5 WBCs per HPF

Within reference
range, if obtained

Within reference
range, if obtained
< 5 WBCs per
HPF

Acute illness observation score

How well do low-risk criteria work?


The above guidelines are presented to define a group of febrile young infants who can be
treated without antibiotics. Statistically, this translates into a high NPV (ie, a very high
proportion of true negative cultures is observed in patients deemed to be at low risk). The
NPV of various low-risk criteria for serious bacterial infection and occult bacteremia are
as follows:[12, 15, 65, 66, 14, 67, 8]

Philadelphia NPV - 95-100%


Boston NPV - 95-98%
Rochester NPV - 98.3-99%
AAP 1993 - 99-99.8%

In basic terms, even by the most stringent criteria, somewhere between 1 in 100 and 1 in
500 low-risk, but bacteremic, febrile infants are missed. Many centers still choose to
admit and treat young febrile infants.
A helpful clinical finding is that of a diagnostic viral syndrome, in particular respiratory
syncytial virus bronchiolitis. In this setting, the likelihood of a concomitant bacterial is
lower in nearly all instances, with the exception of a concurrent UTI.[34]
See the image below for a treatment approach in febrile infants younger than 3 months.

Application of low-risk criteria and approach for the febrile infant: A


reasonable approach for treating febrile infants younger than 3 months who have a
temperature of greater than 38C.

Empiric antibiotics: How well do they work?


The first step in the treatment of children with FWS is to use a combination of age,
temperature, and screening laboratory test results to determine the risk for serious
bacterial infection or occult bacteremia. Low-risk children are generally monitored as
outpatients. Children who do not fit low-risk criteria are treated with empiric antibiotics
either as inpatients or as outpatients.
Numerous studies have compared the effectiveness of oral antibiotics and parenteral
antibiotics in reducing complications of occult bacteremia. Many of these studies were
conducted before widespread use of the conjugate Hib vaccine.[2] Parenteral antibiotics
were generally found to be significantly more effective than oral treatment or no
treatment in reducing the sequelae of occult bacteremia, most importantly meningitis.[8, 30]
Table 12. Occult Bacteremia - Relationship Between Outpatient Antibiotic Use and
Complications[8, 10, 27, 11, 68] (Open Table in a new window)
Complication

No Antibiotic Oral Antibiotic


Therapy, %
Therapy, %
18-21
3.8-5

Intramuscular/Intravenous
Antibiotic Therapy, %
0-5

Persistent
bacteremia
New focal
13
5-6.6
5-7.7
infection
Meningitis
9-10
4.5-8.2
0.3-1
Recent studies and analyses have focused on specific causes of occult bacteremia other
than Hib, information more applicable to current evaluation, and treatment of febrile
children.
Several studies and analyses have concluded that oral antibiotics and parenteral
antibiotics are equally effective in reducing complications of pneumococcal bacteremia.[2,
8]
However, a metaanalysis found no statistical change in occurrence of meningitis
between patients with and without treatment with oral antibiotics.[69]

Table 13. Pneumococcal Bacteremia - Relationship Between Outpatient Antibiotic Use


and Complications[2, 8, 10, 18, 21, 29, 37, 69, 9] (Open Table in a new window)
No
Any
Oral
Intramuscular/Intravenous
Complication Antibiotic Antibiotic Antibiotic
Antibiotic Therapy, %
Therapy, % Therapy, % Therapy, %
Persistent
7-17
1-1.5
2.5

bacteremia
Focal
9.7-10
3.3-4

infection/SBI
Meningitis
2.7-6
0.4-1
0.4-1.5
0.4-1
Meningococcal bacteremia is rare but important because of its high rates of morbidity
and mortality. Studies have found that parenteral antibiotics are significantly more
effective than no treatment or oral antibiotics in reducing complications. The risk of
developing meningitis with no antibiotic therapy is 50%, the risk is 29% with oral
antibiotic therapy, and it is 0% with intramuscular and/or intravenous antibiotic therapy.[9]
In young infants and debilitated or immunocompromised patients, Salmonella bacteremia
can have serious complications. The risk of serious complications in previously healthy
children aged 3-36 months with Salmonella bacteremia is small.[4, 2] Empiric oral
antibiotics have not been proven to prevent focal complications or persistence of
bacteremia in children with occult nontyphoidal Salmonella bacteremia.[2] However, some
form of antibiotic treatment, oral or intravenous, is recommended for all children with
Salmonella bacteremia and for young infants and immunocompromised children with
Salmonella gastroenteritis.[70]
The choice of empiric antibiotic treatment is primarily based on the likely causes of
bacteremia for a given patient and the likelihood of resistance.
In very young infants, bacterial causes are most commonly acquired from the mother
during childbirth. For neonates younger than 1 month, Streptococcus species and E coli
are the most common pathogens. Other gram-positive and gram-negative infections are
also observed; including infections with Listeria species (see Causes). Treatment with
ampicillin and gentamicin is widely accepted for patients in this age group; ampicillin
and cefotaxime may also be used.[12, 18] This combination has good gram-positive and
gram-negative coverage for the most likely pathogens, and ampicillin is effective against
Listeria.
In the recent Kaiser Permanente study, fully 36% of their pathogens were ampicillin
resistant, and, if so, were usually gentamicin resistant as well. They recommended
ampicillin/cefotaxime as the combination of choice, and with a very low rate of Listeria
and Enterococcus (the only 2 organisms for which ampicillin would be the preferred drug
in that setting) called into question whether cefotaxime alone would be sufficient. They
did not go so far as to recommend this, but called for further research in other centers.[22]
Third-generation cephalosporins are useful in older infants and children, but they are not
active against Listeria and are not recommended as a single-agent therapy in the empiric
treatment of neonates younger than 1 month who are at risk for occult bacteremia.[14]

A gradual shift toward community-acquired causes occurs as age increases; the causes of
bacteremia in infants aged 1-3 months are a combination of organisms (see Causes).
Empiric antibiotics used in practice vary in this age group. Some practitioners use
ampicillin and gentamicin, some use ampicillin and cefotaxime, and others use
ceftriaxone.[8, 12, 18] The risk for infection with Listeria is significantly decreased in children
older than 4-6 weeks; whether coverage for Listeria is required in infants aged 1-3
months at risk for occult bacteremia is controversial. All these possible antibiotic
regimens have excellent coverage against the other childbirth-acquired or communityacquired bacterial pathogens in this age group.
The empiric treatment of infants and children aged 3-36 months at risk for occult
bacteremia usually involves ceftriaxone. This third-generation cephalosporin has broadspectrum gram-positive and gram-negative coverage, is active against all likely
community-acquired pathogens in this age group, and is resistant to beta-lactamases
produced by some pathogenic organisms.[11, 14] Ceftriaxone has the longest half-life of the
third-generation cephalosporins, and high serum concentrations can be sustained for 24
hours with a single dose. Most body tissues and fluids are penetrated, including the CSF.
[11]

Early studies of empiric coverage with oral antibiotics examined various agents,
including amoxicillin and penicillin. Because of concern for infection with Hib positive
for beta-lactamase, later studies focused on amoxicillin and clavulanic acid.
Other than antibiotic spectrum coverage, adverse effects and compliance are also
considered when choosing an antibiotic treatment. Studies evaluating adverse effects of
ceftriaxone and amoxicillin and clavulanic acid have shown that, whereas amoxicillin and
clavulanic acid more commonly cause diarrhea, the overall rate of adverse effects (eg,
diarrhea, vomiting, maculopapular exanthems) is similar at approximately 5%.[11, 30]
Regarding compliance, the administration of antibiotic treatment is essentially witnessed
when the antibiotic is intramuscularly administered. However, in a study of compliance
with 2 days of amoxicillin taken 3 times per day as outpatient treatment, approximately
10% of families reported missing at least one dose.[11]
Antibiotic resistance, most importantly in S pneumoniae infection, also affects the choice
of empiric treatment for occult bacteremia. Studies in Sweden, Greece, Israel, Portugal,
Russia, and Nebraska have shown that 40-50% of cases of S pneumoniae in children
attending daycare centers are resistant to penicillin.[71] Unlike the beta-lactamase of
staphylococcal penicillin resistance, streptococcal resistance is mediated by altered
penicillin-binding protein affinity for the drug. This resistance can be overcome by
sufficiently high doses of antibiotic. Tissue concentrations sufficient to treat penicillinresistant infections, other than meningitis, are achieved with oral therapy.[68]
To understand the role of penicillin-resistant pneumococcus in serious bacterial infection
and occult bacteremia, realize that all pneumococci are not equal, antibiotic resistance
patterns are not static, and resistance does not necessarily equal virulence. Penicillin
resistance varies from mildly resistant (minimal inhibitory concentration [MIC] < 0.1), to
intermediately resistant (MIC 0.1-1), to highly resistant (MIC >1). The prevalence of
penicillin resistance is increasing over time, and no change in mortality seems to be

associated with invasive pneumococcal disease due to the increase in antibiotic-resistant


pneumococcus.[24, 68, 72]
Longitudinal studies of invasive pneumococcal disease show that the prevalence of
intermediately penicillin-resistant pneumococcus (MIC 0.1-1) has increased from 5-10%
in 1993 to 22% in 1999, and highly penicillin-resistant pneumococcus (MIC >1) has
increased from 4% in 1993 to 15% in 1999.[8, 30, 68] A survey of pneumococcal meningitis in
the mid 1990s found 13% intermediately penicillin-resistant pneumococcus (MIC 0.1-1)
and 7% highly penicillin-resistant pneumococcus (MIC >1).[72]
Antibiotic pressure likely has a large role in selecting for antibiotic-resistant
pneumococci, and a longitudinal study of invasive pneumococcal disease found an
increased risk of penicillin resistance in patients who have used antibiotics in the last 30
days.[24]
Since the end of the 1980s, researchers have been concerned that penicillin-resistant
pneumococcus may also be resistant to third-generation cephalosporins.[24] At that time,
less than 1% of pneumonococci were resistant to ceftriaxone.[30] Since then, ceftriaxone
resistance has increased but remains significantly less common than penicillin resistance.
[24, 30, 72]

Longitudinal studies of invasive pneumococcal disease show that the prevalence of


intermediately ceftriaxone-resistant pneumococcus (MIC 0.1-1) has increased from 3% in
1993 to 9% in 1999.[8, 24, 30] Highly ceftriaxone-resistant pneumococcus (MIC >1) has
increased from 0.5% in 1993 to 2% in 1999.[24] A survey of pneumococcal meningitis in
the mid 1990s found 4.4% intermediately ceftriaxone-resistant pneumococcus (MIC 0.11) and 2.8% highly ceftriaxone-resistant pneumococcus (MIC >1).[72]
Because of the frequency with which children with fever present to emergency
departments and clinics for evaluation, the cost of evaluating and treating children with
FWS can be considerable. Several authors have examined how well screening works in
identifying infants and young children with occult bacteremia and how efficient empiric
treatment is in preventing sequelae of bacteremia, namely meningitis. Costs of treatment
and cost savings in preventing hospitalization, morbidity, and mortality have also been
addressed to assess whether screening and empiric treatment are cost-effective strategies.
Screening febrile infants younger than 3 months by means of history, physical
examination, and laboratory tests and treating low-risk infants as outpatients has been
shown to be cost-effective.[8] Furthermore, an analysis of the Philadelphia criteria in 1993
found that outpatient treatment based on these low-risk criteria costs $3,100 less per
patient than with inpatient treatment.[65]
Screening febrile infants and children aged 3-36 months based on age, degree of fever,
and laboratory results has also been found to be a cost-effective and reasonable approach.
[2, 8, 17, 20]
See Lab Studies for statistics associated with different laboratory values used as
screening tools for occult bacteremia; most studies determined that ROC curves were
most favorable for WBC counts fewer than 15 per HPF or ANCs fewer than 10, criteria
that were used to define low-risk children. Although these values have an NPV of
approximately 99% for occult bacteremia, numerous reviews have noted that these cutoff

values may still miss 25% of children with occult bacteremia because of the large
numbers of febrile children presenting for evaluation.[2, 17, 20]
Determining the number needed to treat (NNT) to prevent a given event is another
method used to assess the effectiveness of screening criteria. Two studies have analyzed
the NNT to prevent meningitis for different laboratory screening criteria in febrile
children aged 3-36 months with a temperature of more than 39C. One used a WBC
count greater than 15,000/L and found an NNT of 500 to prevent one case of meningitis,
and the other used an ANC greater than 10,000/L and found an NNT of 240.[2, 20]
A recent formal estimate of cost-effectiveness compares the cost of screening and
treatment of febrile children using numerous criteria.[21] This analysis also estimates the
cost of complications associated with treatment and hospitalization and estimates the
costs incurred while treating patients with sequelae from untreated infections. For the rate
of occult bacteremia in febrile young children, this analysis uses an estimate of 1.5%,
which is consistent with other current estimates.[19, 20] At this rate of bacteremia, empiric
testing and treatment were found to be the most cost-effective approaches for treatment of
febrile children; the cost is $72,000 per life-year saved. This strategy also favorably
compares with other medical treatments that are considered cost-effective.
Many authors, including the authors of this article, anticipated that the rate of occult
bacteremia would markedly decrease following widespread use of the 7-valent conjugate
pneumococcal vaccine.[9, 25, 21] Using an estimate of 0.5% for the predicted rate of occult
bacteremia, the authors have also calculated the cost-effectiveness of several approaches
to treat febrile children. At this rate of bacteremia, the cost of empiric testing and
treatment of febrile children increases markedly from $72,000 to more than $300,000 per
life-year saved. With the changes in pneumococcal disease (an initial decline followed by
a resurgence of nonvaccine strains), the final outcome is uncertain. What is clear is that
risk-based estimates of likelihood of bacteremia were almost without exception obtained
in a largely prevaccination era.
The sensitivity and specificity of clinical judgment in predicting occult bacteremia and
serious bacterial infections have widely varied in previous studies, with a consensus that
clinical judgment is not a reliable indicator of occult bacteremia.[2, 8, 17, 12, 35] Clinical
judgment has been estimated to be 28% sensitive and 82% specific in predicting occult
bacteremia, not inconsistent with previous studies performed on children aged 3-36
months. At a decreased predicted rate of occult bacteremia of 0.5%, treatment of febrile
children based on clinical judgment was found to be considerably more cost-effective
than other approaches; the cost is $38,000 per life-year saved.
The cost-effectiveness analysis indicating cost per life-year saved per intervention is as
follows:[21]

Tissue plasminogen activator (TPA) for acute myocardial infarction - $32,678


Medical treatment for hypertension - $20,000
Coronary artery bypass grafting (CABG) for myocardial infarction - $7,000
Empiric testing and treatment in febrile children when rate of occult bacteremia is
1.5% - $72,300

Empiric testing and treatment in febrile children when rate of occult bacteremia is
0.5% - Over $300,000
Treatment based on clinical judgment, sensitivity 28% and specificity 82%, when
rate of OB is 0.5% - $38,000

If the rate of bacteremia declines to 0.5%, this analysis concluded that clinicians should
reevaluate their approach to highly febrile children and eliminate strategies that use
empiric testing and treatment.[21]

Treatment algorithms
The 1993 Practice Guidelines, published jointly in Pediatrics and Annals of Emergency
Medicine, has dominated the US approach to febrile patients aged 3-36 months.[8]
Considerable debate in the medical literature has followed the publication of these
guidelines, and surveys indicate that considerable variation from the guidelines occurs in
practice among pediatricians, family practitioners, and emergency department physicians.
[3, 29, 37, 73, 18]

For febrile infants and young children aged 3-36 months, the 1993 Practice Guidelines
recommended no tests or antibiotics for children with a temperature of less than 39C and
a nontoxic appearance. For children aged 3-36 months with a temperature of at least 39C
and a nontoxic appearance, a blood culture and empiric antibiotics were recommended,
either for all children (option 1) or for children with a WBC count higher than 15,000/L
(option 2).
All children who appeared toxic were admitted to the hospital for sepsis workup and
parenteral antibiotics pending culture results. Urine cultures were recommended for
males younger than 6 months and females younger than 2 years, stool cultures were
recommended for children with blood or mucus in the stool or more than 5 WBCs per
HPF on stool smear, and chest radiography was recommended for children with dyspnea,
tachypnea, rales, or decreased breath sounds. Follow-up in 24-48 hours was
recommended for children who had cultures drawn.
In response to the 1993 Practice Guidelines, Kramer and Shapiro published an alternate
approach that involved less laboratory screening and no empiric antibiotic treatment.[3]
Febrile children aged 3-36 months were carefully assessed for bacterial foci; children
with a toxic appearance were admitted to the hospital for sepsis workup, and focal
infections were appropriately treated. Children who appeared well and had no focus of
infection received a urinalysis if appropriate for age, whereas all children received no
other laboratory tests and no antibiotics and were followed up in 24 hours to assess for
worsening or persistence of signs and symptoms of infection.
A 1999 review by Kuppermann proposed an approach to the febrile child aged 3-36
months that was based on the risk of occult bacteremia during a time after Hib had been
eliminated but before the introduction of pneumococcal vaccine.[2] His algorithm divided
children into the following 2 groups based on risk: those aged 3 months to 2 years and
those aged 2-3 years. He also recommended laboratory screening with ANC rather than a
WBC count.

Kuppermann recommended no laboratory tests and no antibiotics for children aged 2-3
years with a nontoxic appearance and with a temperature of less than 39.5C and for
children aged 3 months to 2 years with a nontoxic appearance and with a temperature of
less than 39C.[2] For children aged 3 months to 2 years with a temperature of at least
39C and a nontoxic appearance and for those aged 2-3 years with a temperature of at
least 39.5C and a nontoxic appearance, a blood culture and empiric antibiotics were
recommended if the ANC was greater than 10,000/L.
In 2000, Baraff published a review that included immunization status in the decision
analysis of FWS.[9] Because of the low overall risk of occult bacteremia in children aged
3-36 months with FWS who have received the 7-valent conjugate pneumococcal vaccine,
Baraff recommended that no blood work be performed in these patients irrespective of
the degree of fever. He also recommended that no blood work be performed for FWS in
children with a temperature of less than 39.5C.
A blood culture and empiric antibiotics is recommended for children with an ANC of
greater than 10,000/L or a WBC count of greater than 15,000/L if the child's
temperature is at least 39.5C and he or she has not received the pneumococcal vaccine.
Baraff stated that for children who have received the pneumococcal vaccine, the overall
prevalence of occult pneumococcal bacteremia should decrease by 90%, making
screening of the WBC count or ANC impractical.
In 2004, Nigrovic and Malley published a management guideline, currently in use at the
Children's Hospital Boston's emergency department.[74] This guideline is also based on the
low risk of occult bacteremia in infants immunized against H influenza type b and S
pneumoniae. It recommends that routine screening laboratory tests should not be
performed for well-appearing febrile infants who have received 3 doses of 7-valent
pneumococcal vaccine and 3 doses of Hib vaccine. Although acknowledging the ongoing
concerns over the appropriate approach to infants and children with FWS, the authors
conclude that this new approach is reasonable based on the best available information.
With the use of Prevnar 13, new studies of current risks and pathogens involved in occult
bacteremia are needed, and updated practice guidelines are probably overdue.
For application of the algorithm approach to febrile infants and young children aged 3-36
months, see the image below.

Application of algorithms for children aged 3-36 months:


A reasonable approach for treating infants and young children aged 3-36 months who
have a temperature of at least 39.5C.
1. Definition
1. Age under 36 months old
2. Highest risk in younger infants (esp. <29 days)
3. Fever (38 C or 100.4 F) without localizing signs
4. Acute onset of fever persisting <1 week
5. Assess for Occult Bacteremia
2. Causes: Common etiologies of Occult Bacteremia
1. Newborns and first 1-3 months
1. Group B Beta-hemolytic Streptococcus (Group B Strep)
2. Escherichia coli K1 (ECK1)
3. Listeria monocytogenes
1. Rare in the United States
2. Predominant in Spain
4. Also consider Herpes Simplex Virus
2. Children 3-36 months
1. Most common prior to vaccines (much fewer cases now)
1. Streptococcus Pneumoniae (covered by Prevnar)
2. HaemophilusInfluenzae (covered by Hib Vaccine)
2. Group A Beta-hemolytic Streptococcus
3. Neisseria Meningitidis
3. Causes: Common conditions assoc. with Occult Bacteremia
1. Otitis Media
2. Bacterial Pneumonia
3. Streptococcal Pharyngitis
4. Meningitis
4. Signs: Toxic Findings suggestive of Occult Bacteremia
1. See Yale Observation Scale
2. See Rochester Criteria for Febrile Infants
3. Cyanosis or other signs of poor perfusion
4. Decreased activity
5. Hyperventilation or Hypoventilation
6. Does not interact with parents or environment
7. Irritability
8. Lethargy

5.

6.

7.

8.

9. Hypotonic
10. Tachycardia
11. Weak eye contact
Diagnosis: Predictors of Occult Bacteremia
1. Pre-Hib Era: Fever in non-toxic child ages 3-36 months
1. Temperature <39.5 C: 1.6% Positive Blood Culture
2. Temperature <34.0 C: 2.1% Positive Blood Culture
3. Temperature <41.0 C: 3.5% Positive Blood Culture
4. Temperature >41.0 C: 9.3% Positive Blood Culture
2. Post-Hib Era: Fever in non-toxic child ages 3-36 months
1. Temperature <39.5 C: 0.9% Positive Blood Culture
2. Temperature <34.0 C: 1.1% Positive Blood Culture
3. Temperature <40.5 C: 1.7% Positive Blood Culture
4. Temperature <41.0 C: 2.4% Positive Blood Culture
5. Temperature >40.9 C: 2.8% Positive Blood Culture
3. Post-Hib Era: WBC in non-toxic child ages 3-36 months
1. WBC <5k C: 0.0% Positive Blood Culture
2. WBC <10k C: 0.1% Positive Blood Culture
3. WBC <15k C: 0.5% Positive Blood Culture
4. WBC <20k C: 3.5% Positive Blood Culture
5. WBC <25k C: 6.8% Positive Blood Culture
6. WBC <30k C: 7.2% Positive Blood Culture
7. WBC >30k C: 18.3% Positive Blood Culture
Diagnosis: Findings suggestive of Occult Bacteremia
1. Fever > 40 degrees Celsius
2. White Blood Cell Count
1. Leukopenia <5000
2. Leukocytosis >15,000
3. Absolute Neutrophil Count (ANC) > 10,000
4. History of exposure to serious infection
5. Rapid urine pneumococcal antigen assay
1. Currently being researched for clinical application
2. Test Sensitivity in pneumococcal bacteremia: 96%
3. High false positive rate
4. Neuman (2003) Pediatrics 112:1279-82
Pitfalls
1. Urinalysis alone is insufficient
1. Urine Culture in all cases
2. Catheter or suprapubic specimen preferred
Management
1. Age 0 months to 3 months
1. See Fever Without Focus Management Birth to 3 Months
2. Age 3 months to 36 months
1. See Fever Without Focus Management 3 to 36 months

Occult Bacteraemia: Children


<36 months
Definition:

Occult bacteremia1 is the condition in which bacteremia is identified in


patients without clinical evidence of sepsis (e.g., shock or purpura) or a
toxic ppearance, who have neither significant underlying chronic
medical conditions nor clear foci of infection on examination (other than
otitis media), and who are discharged to home after outpatient evaluation.
These are usually in patients whom a positive result is not anticipated.

Incidence:

~5% of all children who present with a fever and no clear source is
identified.

Although most episodes of occult bacteremia resolve spontaneously,


serious complications, such as pneumonia, septic arthritis, osteomyelitis,
meningitis, sepsis, and death, may occasionally occur.

Pathogens:

Streptococcus pneumonia is responsible for 66%-75% of all cases.


o

Peak prevalence between 6 and 24 months.

Association with high fever(39.4C or 103F).

High WBC count(>15,000).

Absence of evident focal soft tissue infection.

Whilst these incidences may have changed after introduction of the


7-valent conjuugate vaccine, there is evidence to suggest that
other

serotypes

have

simply

vaccinated against.

Neisseria meningitidis

Haemophilus influenzae type b

Non-typhoidal salmonellae

replaced

those

that

are

now

Risks of Occult Bacteraemia:

Low Risk:
o

Age >3 yrs

Temp <39.4oC

WBC >5 & <15

High Risk
o

Age <2 yrs

Temp >40oC

WBC <5 or >15

Contact with H.influenzae or N. meningitidis.

Occult bacteraemia has a low prevalence, so even though WBC is a


sensitive and specific screening test, it has a low PPV. The test does not
discriminate between children who have PUO who are bacteremic
and those who are not.

Therefore, blood culture is the gold standardstill has a high number of


false positives, take 24-48hrs, and most cases of occult pneumococcal
bacteremia clear without treatment.

Utility of Blood Cultures:

Studies2 have demonstrated that, although some patients (12%) with


bacteremia return for follow-up before culture results are known because
of persistent or worsening illness, most (68%) are seen for follow-up as a
result of positive blood cultures. Of patients with serious complications of
occult bacteremia, half returned as a direct result of notification for a
positive blood culture. Since the time of these studies, improved blood
culture technology has significantly reduced the time to detection of
positive cultures (see earlier discussion), so the utility of obtaining blood
cultures in the prevention and early treatment of patients with significant
complications of occult bacteremia may be greater than that previously
suggested. In addition, investigators have demonstrated that blood
cultures of children infected with true pathogens become positive
significantly

more

rapidly than do cultures growing contaminants.

Scheduling 24- hour follow-up for children at risk for occult bacteremia
may also be of use in the early detection of complication.
Management:3

The benefits of laboratory screening and selective empiric antibiotic


treatment of febrile children at risk for occult bacteremia have to be
weighed against the costs of screening tests and blood cultures,
inconvenience, temporary discomfort to patients, risks for side effects of
antibiotics, and the role of antibiotics in the development of bacterial
resistance4. Although great debate exists concerning the role of empiric
antibiotics, a strategy for obtaining blood cultures and empirically
administering antibiotics on the basis of an increased neutrophil count, in
addition to close clinical followup, may be effective in reducing the
frequency and severity of uncommon but adverse sequelae. The "highly
effective" pneumococcal vaccine may have exerted a selection pressure
on Str. pneumoniae - and may alter the ways that clinicians evaluate fully
immunized young, febrile children.

If empiric antibiotics are used, they should be targetted against Str.


pneumoniae, N. menigitidis and H. influenzae.

Follow up is essential.

AMH.
Tag:
Training
MRCPath Part2

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Comments
wafaa4micro (not verified)
22 July, 2008 - 22:11
Permalink

Well, thank you again for


Well, thank you again for useful data and attractive presentation. I just want to
say that the word " appearance" in the 3rd line missed an "a" :)
Wafaa

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greek.god (not verified)


19 June, 2009 - 06:22

Occult bacteremia in young febrile


children.

Permalink

Kuppermann N.

Source
Department of Internal Medicine, University of California, Davis School of Medicine,
USA. nkuppermann@ucdavis.edu

Abstract
The evaluation of nontoxic-appearing, young, febrile children has been a subject of
considerable debate. Of young, nontoxic-appearing children aged 3 to 36 months with
temperatures of 39 degrees C or more and no clear source, approximately 2% to 3% have
occult bacteremia. Of these bacteremias, approximately 90% are caused by S.
pneumoniae, 5% by nontyphoidal Salmonella sp., and 1% by N. meningitidis. Most
children with occult pneumococcal bacteremia improve spontaneously, but approximately
25% of untreated patients have persistent bacteremia or develop new focal infections,
including 3% to 6% who develop meningitis. Occult meningococcal bacteremia, although
rare, has frequent complications, including meningitis in approximately 40% and death in
approximately 4%. Less is known about the natural history of untreated occult
nontyphoidal Salmonella bacteremia. Empiric antibiotic treatment of children with occult
bacteremia decreases the rate of complications, including meningitis. Few disagree that
febrile, young children at risk for occult bacteremia require a careful clinical evaluation
and close follow-up. The benefits of laboratory screening and selective empiric antibiotic
treatment of febrile children at risk for occult bacteremia have to be weighed against the
costs of screening tests and blood cultures, inconvenience, temporary discomfort to
patients, risk for side effects of antibiotics, and the role of antibiotics in the development
of bacterial resistance. Although great debate exists concerning the role of empiric
antibiotics, a strategy for obtaining blood cultures and empirically administering
antibiotics on the basis of an increased ANC, in addition to close clinical follow-up, may

be effective in reducing the frequency and severity of uncommon but adverse sequelae. A
highly effective S. pneumoniae bacterial conjugate vaccine will soon be available, which
will benefit all children, and will alter the ways that clinicians evaluate fully immunized
young, febrile children.

Promising Research in Treating HIV and AIDS


A 2004 report by the Joint United Nations Programme on HIV/AIDS estimates that
in 2003 alone around 4.8 million people became infected with HIV, while around
37.8 million people overall were living with HIV. In 2003 this viral infection killed
2.9 million people, and over 20 million people have died since the first cases of
AIDS were identified in 1981.
HIV is a chronic and deadly infection that can take years to cause damage to the
person's immune system. Eventually, the immune system cannot keep up with
the amount of damage and the host becomes an AIDS patient. Many people don't
know they are infected until having unusual health problems or following routine
testing can be done by going there or the condition could be explain via voip if
there is the facility available in your area.
The virus can be transmitted through sexual interactions, sharing of
contaminated intravenous needles, and exposure in the womb from HIV-infected
mothers. HIV methodically kills most of the cells important in helping the immune
system respond to infection.
These cells are called T-helper cells (T-lymphocytes or CD-4 cells). T-helper cells
help other cells (B-lymphocytes, B-cells) in our body to make antibiotics and
others (CD-8 cells, T-cytotoxic cells, and other T-lymphocytes) to eliminate virusinfected cells and tumor cells.
Promising Research: HAART Therapy and Valproate
Highly Active Anti-Retroviral Therapy (HAART; HIV is in the retrovirus family of
viruses) is able to slow the persistent and systemic multiplication of HIV in the Thelper cells. Unfortunately, whenever someone on HAART therapy stops taking
the medications the HIV virus starts up again.

In 1997, researchers learned that not all T-helper cells become activated and
produce HIV virus following infection. Some become resting cells. These contain
the HIV virus genome in their DNA and it is believed that these HIV infected
resting T-helper cells are the source for renewed multiplication of the HIV virus
following termination of HAART therapy.
Recently some scientists at the University of Texas Southwestern Medical School
in Dallas have found that the drug valproate used in treating epilepsy might be
useful in eliminating these HIV-infected resting T-cells.
Valproate inhibits an enzyme in the resting T-cells that keeps the HIV virus from
multiplying, and allows viruses to commence virus replication. The medication
does this without activating all the T-helper cells and causing too much virus
replication.
By intensifying their HAART therapy and adding in a new medication called
Enfuvirtide they were able to lower the number of HIV-infected resting T-cells by
greater than 70% in 3 out of the 4 patients tested. However, not all the HIVinfected resting T-cells were eliminated and much more work still needs to be
done, but there is now more hope that other less toxic inhibitors might be found.

Streptococcus pneumoniae, or pneumococcus, is an encapsulated gram-positive


bacterium that is the major cause of bacteremia and upper respiratory infections (eg, otitis
media and sinusitis) in children and a common cause of serious invasive infections.
Because pneumococcus commonly and asymptomatically colonizes the upper respiratory
tract of children, a breakdown of the normal mucosal barrier is believed to play a major
role in the development of bacteremia.
Occult bacteremia is defined as the presence of bacteria in the bloodstream of a febrile
child who has no apparent focus of infection[1] and clinically does not appear to be ill.
Some experts include in this definition children who have otitis media at their initial
presentation and are subsequently found to have positive blood cultures.
Pneumococcal bacteremia was termed pneumococcal fever during the 1970s and
1980s, when S pneumoniae was recovered in approximately 5% of blood cultures from
young febrile children with mild upper respiratory tract changes (see the table below).[2]
Such changes included inflammation of the tympanic membranes, pharyngeal erythema,
sinus clouding, and interstitial markings on chest roentgenograms.
Table 1. Incidence of Bacteremia in Febrile Children (Open Table in a new window)

Study
Incidence
McGowan (1973)[3] 4% (outpatients)
Teele (1975)[4]
3.2%
[5]
McCarthy (1977)
7.3%
[6]
Waskerwitz (1981) 5.8%
Dershewitz (1983)[7] 4.3%
Carroll (1983)[8]
10.4%
[9]
Bennish (1984)
4.3%
[10]
Jaffe (1987)
2.8%
[11]
Lee (1998)
1.6%
In studies conducted before 1990, S pneumoniae,Haemophilus influenzae type b (Hib)
and Neisseria meningitidis were recovered from approximately 75%, 20%, and 5%,
respectively, of positive blood cultures in patients with occult bacteremia, with occasional
isolates of Salmonella and Staphylococcus aureus.[3, 4, 12, 13, 14]
Subsequently, Salmonella bacteremia has been shown to occur in children with
Salmonella gastroenteritis much more commonly than was previously thought. This
organism is now the second most common pathogen in children with identified
bacteremia.[11]
Severe infections, predominantly meningitis, occur in fewer than 6% of pneumococcal
occult bacteremia casesa figure that is much lower than the 50% reported with
meningococcal bacteremia and the 20% reported with H influenza.[15]
Occult bacteremia now occurs in only 1 of 200 children who present with acute fever
(temperature of 39o C [102.2o F] or higher) and white blood cell counts of 15,000/L or
higher. The most likely cause of bacteremia remains S pneumoniae; when there is no
evidence of toxicity, such bacteremia is generally a benign, self-limited event.
Because of the extremely low yield, blood cultures are no longer routinely warranted in
children aged 3-36 months who have no obvious source of infection, and empiric
treatment of occult bacteremia is no longer appropriate. Almost all cases will
spontaneously resolve with a low rate of subsequent focal infection. If a child remains
febrile and worsens clinically, further diagnostic evaluation and possible empiric
treatment with antibiotics pending results of cultures may be considered.
The identification of patients at risk for bacteremia and the formulation of strategies to
prevent secondary complications (eg, meningitis, pneumonia, septic arthritis,
osteomyelitis, and cellulitis) remain important aspects of general pediatric practice.
For patients with focal infection and pneumococcal bacteremia, treatment of the focal
infection and monitoring for improvement are standard. For outpatients with proven
pneumococcal bacteremia, reevaluation of their clinical status and identification of any
new focus of infection is essential.

Clinical Presentation and Laboratory Features

The most likely cause of bacteremia remains S pneumoniae. In the absence of apparent
toxicity, pneumococcal bacteremia is a benign, transient, and self-limited event.[18, 19, 11, 20, 7]
It should be differentiated both from bacteremia involving more virulent organisms and
from sepsis, in which blood cultures are repeatedly positive and the patient exhibits signs
and symptoms of severe illness.[21, 22] Repeated positive cultures also suggest the
development of a focal infection.[21, 22, 23]
Earlier studies of pneumococcal bacteremia in children identified a significantly higher
incidence of infection in patients aged 7-12 months with temperatures of 39.4C to
40.6C (103F to 105F) and white blood cell (WBC) counts higher than 20,000/L.[4]
Another study reported a 3-fold greater incidence of bacteremia when the WBC count
was over 15,000/L and the erythrocyte sedimentation rate (ESR) exceeded 30 mm/hr.[5]
Other studies, however, varied in their support of and conclusions about whether the
WBC is a useful indicator for bacterial disease.[6] In one report, only 6.9% of patients with
a WBC count higher than 15,000/L were found to have positive blood cultures, whereas
35% of the bacteremic patients had counts below 15,000/L.[3, 10]
Febrile seizures have been a presenting symptom in as many as 67% of patients with
pneumococcal bacteremia.[1, 2, 3, 4, 24] This association is difficult to interpret, in that both
febrile seizures and pneumococcal bacteremia are independently most common in infants
and children between 6 and 36 months of age.
Occult bacteremia is also more frequent in febrile children with an initial diagnosis of an
upper respiratory tract infection/fever of unknown origin or pneumonia[20] than in those
with otitis media or pharyngitis. Invasion of the respiratory passes by pneumococcus
apparently predisposes to bacteremia.
Among the factors that have not been found to have a significant effect on the incidence
of occult bacteremia are sickle cell disease,[25, 26] hemoglobin sickle cell disease, and sickle
cell trait.[27] Most reports have not shown a gender-, race-, or socioeconomic-related
predominance of the disease.[1]

History and Physical Examination


History
In young patients with high fever, a careful history and physical examination are needed
to identify possible sources of infection. In children with positive blood cultures, the
duration of fever has usually been brief. Approximately 40% of patients with
pneumococcal bacteremia have had fever for less than 1 day, and 82% of patients have
had fever for less than 2 days.[1, 2, 3, 4]
Elements of the history that have been associated with an increased risk of pneumococcal
bacteremia include daycare attendance, lack of breastfeeding, and underlying illness (eg,
asplenia, immunodeficiency, or AIDS).[28] Although recent antibiotic use does not affect
the overall rate of infection, children who were treated with antibiotics in the preceding
30 days are more likely to be infected with S pneumoniae that is resistant to penicillin.[28]

A longitudinal study of invasive pneumococcal infections revealed that a history of an


underlying medical condition was a significant risk factor for increased mortality.
Children with invasive pneumococcal infections and underlying comorbidity had a
mortality of 3.4%, whereas previously healthy children with invasive pneumococcal
infections had a mortality of 0.84%.[29, 28]

Physical examination
By definition, occult pneumococcal bacteremia occurs in children who are febrile and
may have some degree of irritability or lethargy but do not show signs of focal infection
and do not have a toxic appearance. Patients with recognizable viral illnesses (eg,
stomatitis, croup, bronchiolitis, varicella, and mononucleosis) are at lower risk for
pneumococcal bacteremia.
Potential underlying causes of pneumococcal bacteremia that should be apparent on
physical examination include the following:

Meningitis
Sepsis
Cellulitis
Osteomyelitis
Septic arthritis
Pneumonia

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