Professional Documents
Culture Documents
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.
1.
Early-Onset Symptoms
o
Late-Onset Symptoms
o
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Sepsis
o
Meningitis Symptoms
o
Pnuemonia Symptoms
o
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.
Overview of Bacterial
Infections in Childhood
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This
Bacterial Infections
Preventable With Routine
Immunization*
Diphtheria
Infection with Haemophilus
Pertussis
Tetanus
Occult Bacteremia
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This
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
.
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]
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]
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
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]
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.
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]
Organism*
Group B Streptococcus
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
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, %
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
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/sepsis/meningitis
ll
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/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;
< 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
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
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
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
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]
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]
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:
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/sepsis/meningitis
ll
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/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]
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.
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]
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
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
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
Age
Neonates < 1 mo
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
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/sepsis/meningitis
ll
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/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;
< 0.2
Urine
assessment
CSF
assessment
Negative for
bacteria
Leukocyte esterase
negative
< 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
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
< 20,000/L
5-15,000/L;
5-15,000/L;
< 5 WBCs
per HPF
< 0.2
Urine
assessment
CSF
assessment
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
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.
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]
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
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]
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.
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
Incidence:
~5% of all children who present with a fever and no clear source is
identified.
Pathogens:
serotypes
have
simply
vaccinated against.
Neisseria meningitidis
Non-typhoidal salmonellae
replaced
those
that
are
now
Low Risk:
o
Temp <39.4oC
High Risk
o
Temp >40oC
more
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
Follow up is essential.
AMH.
Tag:
Training
MRCPath Part2
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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.
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.
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.
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]
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