Introduction 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 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
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Introduction
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
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.
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 38°C (100.4°F) in infants younger than 3 months and at least 39°C (102.2°F) 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
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.9,22,23
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.
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.24
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.25 The widespread adoption of vaccines to the most common childhood bacteria pathogens (H influenzae 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 2-15% risk of developing important focal infections such as meningitis.4,8,10,26
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. 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.4,2,8,27,10,21
Of all focal infections that develop because of pneumococcal bacteremia, pneumococcal meningitis carries the highest risk for significant morbidity and mortality, including a 25-30% risk of neurologic sequelae such as deafness, mental retardation, seizures, and paralysis.25,9 The mortality rate of pneumococcal meningitis is 6.3-15%, and the overall mortality rate of pneumococcal bacteremia is 0.8%.25,9,23
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%.4,25,9
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.4,6,11,28 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.
Clinical
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.25 Overall, duration of fever is inadequate to clinically identify occult bacteremia.29
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.25
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:4,8,12,30
Age, which determines the cutoff used to define fever Febrile temperature ( 3 mo and temperature >38°C
[100.4°F], 3-36 mo and temperature 39-39.5°C [102.2-103.1°F])
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 reported 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%.23
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,2,9,31 lack of breastfeeding,9,31 and underlying illness such as sickle cell disease or acquired immunodeficiency syndrome (AIDS).9,31 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.31
Physical
Evaluation of a febrile infant or young child begins by establishing whether the patient truly has an 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.8,12,30
General appearance o 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.11,32
o 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.4,11,12,29,32 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.32,2
o 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 o 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.
o 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 o Most studies designed to determine the relationship between
temperature and risk of occult bacteremia define fever as a temperature of at least 38°C (100.4°F) in infants younger than 3 months and a temperature of at least 39°C (102.2°F) 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 36°C (96.8°F).8
o 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.33
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 a infant or child. Home measurement of fever based on a thermometer reading has generally been accepted as true and accurate.
Febrile temperature o 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 Infection33
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Table
AgeTemperature, 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
AgeTemperature, 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
Table 2. Children Aged 3-36 Months - Fever and Occult Bacteremia2,4,6,9,34
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Table
Temperature, Degrees Celsius
Occult Pneumococcal Bacteremia, %
Positive Blood Culture, %
Positive Blood Culture, %
Occult Pneumococcal 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
Temperature, Degrees Celsius
Occult Pneumococcal Bacteremia, %
Positive Blood Culture, %
Positive Blood Culture, %
Occult Pneumococcal 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
o Children aged 2-3 years who have a temperature lower than 39.5°C have less than a 1% risk of occult pneumococcal bacteremia.2
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.4,2,33
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.35 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.4,2,8,20,3,26
Pneumonia o 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.27 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
o 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.36 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.4,2,36
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 38°C or Higher15,16,12,13,14
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Table
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
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
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%.37 Since the introduction and widespread use of the pneumococcal vaccines, the rate of vaccine-specific 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 FWS4,2,8,11,17,26,20
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Table
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 … … …
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.23 Rates of heptavalent vaccine-serotype invasive pneumococcal infection postlicensure have dropped by 56%-100%, depending on location and age.38,39,40,41
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 33.42,43,41
Differential Diagnoses
Other Problems to Be Considered
Viremia, viral syndromeAutoimmune disorderPoor thermoregulation, environmental problemsTumorAcute subdural hematomaFocal bacterial infection
Workup
Laboratory Studies
WBC count o 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.2,8,9,17,11,34
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.2,8,9,17,11,34
o 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.2,21,29 Table 5. Studies Evaluating the Established WBC More Than 15 per HPF Screen for Occult Bacteremia in FWS
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Table
Study Cutoff NPV, % PPV, %
Kuppermann, 1999 2 WBC >15 99 6
Lee, 2001 21 WBC >15 99 5
Strait, 1999 29 WBC >15 98 6
Study Cutoff NPV, % PPV, %
Kuppermann, 1999 2 WBC >15 99 6
Lee, 2001 21 WBC >15 99 5
Strait, 1999 29 WBC >15 98 6
o Several studies have reassessed the use of the WBC count as a screen for bacterial infection and compared it with other laboratory markers44,45,46,47 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.44,45,46,47 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.44,45,46,47 Table 6. Recent Studies Reevaluating WBC Count as a Screen in FWS
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Table
Study Screening Goal
Cutoff, per HPF
NPV, %
PPV, %
Fernandez Lopez, 2003 44
Invasive bacterial infection*
WBC >17 69 69
Pulliam, 2001 45
Serious bacterial infection†
WBC >15 89 30
Lacour, 2001 46
Serious bacterial infection‡
WBC >15 89 46
Isaacman, 2002 47
Occult bacterial infection§
WBC >17 95 30
Study Screening Goal
Cutoff, per HPF
NPV, %
PPV, %
Fernandez Lopez, 2003 44
Invasive bacterial infection*
WBC >17 69 69
Pulliam, 2001 45
Serious bacterial infection†
WBC >15 89 30
Lacour, Serious WBC >15 89 46
2001 46 bacterial infection‡
Isaacman, 2002 47
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.
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 o 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.
o 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 76-82% sensitivity, a 74-78% specificity, a 7-8% PPV, and a 99% NPV for occult bacteremia.2,29 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 Bacteremia2,29
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Table
ANC Sensitivity, % Specificity, % PPV, % NPV, %
10,000 76 78 8 99.2
>7,200 82 74 7.5 99.4
ANC Sensitivity, % Specificity, % PPV, % NPV, %
10,000 76 78 8 99.2
>7,200 82 74 7.5 99.4
Band count o 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.
o Elevated band counts have also been found in 21-29% of patients with culture-proven viral infections.48 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%
o Bandemia (band >15%) is related to cases of viral infections as follows:48
Influenza A and B - 29% Enterovirus - 23% Respiratory syncytial virus - 22% Rotavirus - 22%
o 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 o 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 o 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.25
o Several studies have reassessed CRP level as a screen for bacterial infection and compared it with other laboratory markers.44,45,46,49,47 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.44,45,46,49,47 Table 8. Studies Reevaluating CRP level as a Screen in FWS
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Table
Study Screening Cutoff NPV, PPV, %
Goal %
Lopez, 2003 44
Invasive bacterial infection*
2.8 81 69
Pulliam, 2001 45
Serious bacterial infection†
5 98 Not reported
Lacour, 2001 46
Serious bacterial infection‡
4 96 51
Gendrel, 1999 49
Invasive bacterial infection§
4 97 34
Isaacman, 2002 47
Occult bacterial infectionll
4.4 94 30
Study Screening Goal
Cutoff NPV, %
PPV, %
Lopez, 2003 44
Invasive bacterial infection*
2.8 81 69
Pulliam, 2001 45
Serious bacterial infection†
5 98 Not reported
Lacour, 2001 46
Serious bacterial infection‡
4 96 51
Gendrel, 1999 49
Invasive bacterial infection§
4 97 34
Isaacman, 2002 47
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/meningitisll 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.44,45,46,47 Although one author concluded that CRP level did not have any advantage or additional value compared to WBC count,47 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.50 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.44 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.45
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.47 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 o Interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α) 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-α 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%.29
o 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 o Several reviews have described what is currently known
about PCT.51,52,53 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.44,46,49 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.44,46,49 Table 9. Recent Studies Evaluating PCT level as a Screen in FWS
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Table
Study Screening Goal Cutoff NPV, %
PPV, %
Lopez, 2003 44
Invasive bacterial infection*
0.6 90 91
Lacour, 2001 46
Serious bacterial infection†
1 97 55
Gendrel, 1999 49
Invasive bacterial infection‡
2 99 52
Study Screening Goal Cutoff NPV, %
PPV, %
Lopez, 2003 44
Invasive bacterial infection*
0.6 90 91
Lacour, 2001 46
Serious bacterial infection†
1 97 55
Gendrel, 1999 49
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.44
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 FWS44
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Table
Illness Duration
Screening Goal
Optimal Cutoff
NPV, %
PPV, %
Any (<12 h and >12 h)
Invasive bacterial infection*
0.6 90 91
<12 h Invasive bacterial infection*
0.7 90 97
Illness Duration
Screening Goal
Optimal Cutoff
NPV, %
PPV, %
Any (<12 h and >12 h)
Invasive bacterial infection*
0.6 90 91
<12 h Invasive bacterial infection*
0.7 90 97
*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.54 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.44
o Potential weaknesses of PCT level tests include cost (currently estimated at twice that of CRP level tests);53
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 o 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
o 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.8,12,13,14,55 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
o 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.10,56 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.55
Salmonella and stool studies o 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.
o 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/μ 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
o 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 o 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.
o 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.25,2
o 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.25,2 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.
o 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 o 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
o 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.8,12,13,34 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 o A blood culture positive for known bacterial pathogens is the
criterion standard used to define bacteremia. o 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
o 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
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.55 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.57 Approximately 20% of febrile children younger than 5 years who had normal physical examination findings and WBC counts higher than 20,000/μL 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/μL.
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.
Treatment
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.58
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.59
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.8,60,61,62,55
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 Months60,61,62,8
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Table
Criterion Philadelphia Boston Rochester AAP 1993
Age 1-2 mo 1-2 mo 0-3 mo 1-3 mo
Temperature 38.2°C 38°C 38°C 38°C
Appearance AIOS* <15 Well Any Well
History Immune No antibiotics in the last 24 h;No immunizations in the last 48 h
Previously healthy
Previously healthy
Examination Nonfocal Nonfocal Nonfocal Nonfocal
WBC count <15,000/μL; band-to-neutrophil ratio<0.2
<20,000/μL 5-15,000/μL;ABC <1,000
5-15,000/μ L;ABC <1,000
Urine assessment
<10 WBCs per HPF;Negative for bacteria
<10 WBCs per HPF;Leukocyte esterase negative
<10 WBCs per HPF
<5 WBCs per HPF
CSF assessment
<8 WBCs per HPF;Negative for bacteria
<10 WBCs per HPF
<10-20 WBCs per HPF
…
Chest radiography
No infiltrate Within reference range, if obtained
Within reference range, if obtained
…
Stool culture <5 WBCs per HPF
… <5 WBCs per HPF
…
Criterion Philadelphia Boston Rochester AAP 1993
Age 1-2 mo 1-2 mo 0-3 mo 1-3 mo
Temperature 38.2°C 38°C 38°C 38°C
Appearance AIOS* <15 Well Any Well
History Immune No antibiotics in the last 24 h;No immunizations in the last 48 h
Previously healthy
Previously healthy
Examination Nonfocal Nonfocal Nonfocal Nonfocal
WBC count <15,000/μL; band-to-neutrophil ratio<0.2
<20,000/μL 5-15,000/μL;ABC <1,000
5-15,000/μ L;ABC <1,000
Urine assessment
<10 WBCs per HPF;Negative for bacteria
<10 WBCs per HPF;Leukocyte esterase negative
<10 WBCs per HPF
<5 WBCs per HPF
CSF assessment
<8 WBCs per HPF;Negative for bacteria
<10 WBCs per HPF
<10-20 WBCs per HPF
…
Chest radiography
No infiltrate Within reference range, if obtained
Within reference range, if
…
obtained
Stool culture <5 WBCs per HPF
… <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:12,15,60,61,14,62,8
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.31
See Media file 1 for a treatment approach in febrile infants younger than 3 months.
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.8,28
Table 12. Occult Bacteremia - Relationship Between Outpatient Antibiotic Use and Complications8,10,26,11,63
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Table
ComplicationNo Antibiotic Therapy, %
Oral Antibiotic Therapy, %
Intramuscular/Intravenous Antibiotic Therapy, %
Persistent bacteremia
18-21 3.8-5 0-5
New focal infection
13 5-6.6 5-7.7
Meningitis 9-10 4.5-8.2 0.3-1
ComplicationNo Antibiotic Therapy, %
Oral Antibiotic Therapy, %
Intramuscular/Intravenous Antibiotic Therapy, %
Persistent bacteremia
18-21 3.8-5 0-5
New focal infection
13 5-6.6 5-7.7
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.64
Table 13. Pneumococcal Bacteremia - Relationship Between Outpatient Antibiotic Use and Complications2,8,10,18,21,27,34,64,9
Open table in new window
Table
Complication
No Antibiotic Therapy, %
Any Antibiotic Therapy, %
Oral Antibiotic Therapy, %
Intramuscular/Intravenous Antibiotic Therapy, %
Persistent bacteremia
7-17 1-1.5 2.5 …
Focal infection/SBI
9.7-10 3.3-4 … …
Meningitis 2.7-6 0.4-1 0.4-1.5 0.4-1
Complication
No Antibiotic Therapy, %
Any Antibiotic Therapy, %
Oral Antibiotic Therapy, %
Intramuscular/Intravenous Antibiotic Therapy, %
Persistent bacteremia
7-17 1-1.5 2.5 …
Focal infection/SBI
9.7-10 3.3-4 … …
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.65
Choice of drug
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.
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 community-acquired 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 broad-spectrum 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%.11,28 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-resistant pneumococcus
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.66 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 penicillin-resistant infections, other than meningitis, are achieved with oral therapy.63
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.23,63,67
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 1999.8,28,63 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).67
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.23 The rate of invasive disease from intermediately penicillin-resistant (MIC 0.1-1) S pneumoniae in 1993 was 5.3-10%, and the rate for highly resistant (MIC >1) S pneumoniae was 4%. In 1999, the rate of invasive disease from intermediately penicillin-resistant S pneumoniae was 22%, and the rate for highly resistant S pneumoniae was 15%.8,23,28
Since the end of the 1980s, researchers have been concerned that penicillin-resistant pneumococcus may also be resistant to third-generation cephalosporins.23 At that time, less than 1% of pneumonococci were resistant to ceftriaxone.28 Since then, ceftriaxone resistance has increased but remains significantly less common than penicillin resistance.23,28,67
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 1999.8,23,28 Highly ceftriaxone-resistant pneumococcus (MIC >1) has increased from 0.5% in 1993 to 2% in 1999.23 A survey of pneumococcal meningitis in the mid 1990s found 4.4% intermediately ceftriaxone-resistant pneumococcus (MIC 0.1-1) and 2.8% highly ceftriaxone-resistant pneumococcus (MIC >1).67 The risk of invasive disease from intermediately ceftriaxone-resistant (MIC 0.1-1) S pneumoniae from 1987-1991 was 0.6%; it was 2.6% in 1993, and it was 9% in 1999. The risk of invasive disease from highly ceftriaxone-resistant (MIC >1) S pneumoniae was 0.5% in 1993 and was 2% in 1999.28,23
Effectiveness and cost-effectiveness
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.60
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 39°C. One used a WBC count greater than 15,000/μ L and found an NNT of 500 to prevent one case of meningitis, and the other used an ANC greater than 10,000/μ 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.9,24,21 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.2,8,17,12,32 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.3,27,34,68,18
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 39°C and a nontoxic appearance. For children aged 3-36 months with a temperature of at least 39°C 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/μ 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 39.5°C and for children aged 3 months to 2 years with a nontoxic appearance and with a temperature of less than 39°C.2 For children aged 3 months to 2 years with a temperature of at least 39°C and a nontoxic appearance and for those aged 2-3 years with a temperature of at least 39.5°C and a nontoxic appearance, a blood culture and empiric antibiotics were recommended if the ANC was greater than 10,000/μ 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 39.5°C.
A blood culture and empiric antibiotics is recommended for children with an ANC of greater than 10,000/μ L or a WBC count of greater than 15,000/μ L if the child's temperature is at least 39.5°C 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.69 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.
For application of the algorithm approach to febrile infants and young children aged 3-36 months, see Media file 2.
Medication
Antibiotic agents
Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.
Amoxicillin (Amoxil, Biomox, Trimox)
Interferes with synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria.
Dosing Interactions Contraindications Precautions
Adult
250-500 mg/dose PO tid; not to exceed 3 g/d
Pediatric
40-80 mg/kg/d PO divided tid; not to exceed 2-3 g/d
Dosing Interactions Contraindications Precaution s
Dosing Interactions Contraindications Precaution sDosing Interactions Contraindications Precautions Ampicillin (Marcillin, Omnipen, Polycillin, Principen, Totacillin)Bactericidal activity against susceptible organisms. Alternative to amoxicillin when unable to take medication PO. Until recently, the HACEK bacteria were uniformly susceptible to ampicillin. Recently, however, beta-lactamase–producing strains of HACEK have been identified.Dosing
Interactions Contraindications Precautions
Adult
500-3000 mg IV/IM q4-6h; not to exceed 12 g/d
Pediatric
100-200 mg/kg/d IV/IM divided q6h
Dosing Interactions Contraindications Precaution s
Dosing Interactions Contraindications Precaution sDosing Interactions Contraindications Precautions Ceftriaxone (Rocephin)Third-generation cephalosporin with broad-spectrum gram-negative activity, lower efficacy against gram-positive organisms, and higher efficacy against resistant organisms. Arrests bacterial growth by binding to one or more penicillin-binding proteins.Dosing
Interactions Contraindications Precautions
Adult
1-4 g/d IV/IM divided q12-24d; not to exceed 4 g/d
Pediatric
50-100 mg/kg/d IV/IM divided q12-24h; not to exceed 4 g/d
Dosing Interactions Contraindications Precaution s
Dosing Interactions Contraindications Precaution sDosing Interactions Contraindications Precautions Cefotaxime (Claforan)For septicemia and treatment of gynecologic infections caused by susceptible organisms. Arrests bacterial cell wall synthesis, which, in turn, inhibits bacterial growth. Third-generation cephalosporin with gram-negative spectrum. Lower efficacy against gram-positive organisms.Dosing
Interactions Contraindications Precautions
Adult
1-2 g/dose IV/IM q6-8h; not to exceed 12 g/d
Pediatric
100-200 mg/kg/d IV/IM divided q6-8h; not to exceed 12 g/d
Dosing Interactions Contraindications Precaution s
Dosing Interactions Contraindications Precaution sDosing Interactions Contraindications Precautions Gentamicin
(Garamycin, I-Gent, Jenamicin)Aminoglycoside antibiotic used for gram-negative coverage. Used in combination with both an agent against gram-positive organisms and one that covers anaerobes. Consider if penicillins or other less-toxic drugs are contraindicated, when clinically indicated, and in mixed infections caused by susceptible staphylococci and gram-negative organisms. Dosing regimens are numerous; adjust dose based on CrCl and changes in volume of distribution. May be administered IV/IM.Dosing
Interactions Contraindications Precautions
Adult
Serious infections and normal renal function: 3 mg/kg/dose IV q8hLoading dose: 1-2.5 mg/kg IVMaintenance dose: 1-1.5 mg/kg IV q8hExtended dosing regimen for life-threatening infections: 5 mg/kg/d IV divided q6-8hFollow each regimen by at least a trough level drawn 0.5 h prior to the fourth dose; may draw a peak level 0.5 h after 30-min infusion
Pediatric
<5 years: 2.5 mg/kg/dose IV q8h>5 years: 1.5-2.5 mg/kg/dose IV q8h or 6-7.5 mg/kg/d divided q8h; not to exceed 300 mg/d; monitor as in adults
Dosing Interactions Contraindications Precaution s
Dosing Interactions Contraindications Precaution sDosing Interactions Contraindications Precautions Vancomycin (Vancocin, Vancoled, Lyphocin)Potent antibiotic directed against gram-positive organisms and active against Enterococcus species. Useful in the treatment of septicemia and skin structure infections. Indicated for patients who cannot receive or who have not responded to penicillins and cephalosporins or who have infections with resistant staphylococci. For abdominal penetrating injuries, it is combined with an agent active against enteric flora and/or anaerobes.To avoid toxicity, current recommendation is to assay vancomycin trough levels after third dose drawn 0.5 h prior to next dosing. Use CrCl to adjust dose in patients diagnosed with renal impairment.Used in conjunction with gentamicin for prophylaxis in penicillin-allergic patients undergoing gastrointestinal or genitourinary procedures.Dosing
Interactions Contraindications Precautions
Adult
500 mg q6-8h IV for 7-10 d; alternatively, 1 g IV q12h for 7-10 d
Pediatric
<1 month:<1200 g: 15 mg/kg/d IV
1200-2000 g: 10-15 mg/kg IV q12-18h>2000 g: 15-20 mg/kg IV q8-12h>1 month: 40-60 mg/kg/d IV divided tid/qid for 7-10 d
Dosing Interactions Contraindications Precaution s
Dosing Interactions Contraindications Precaution sDosing Interactions Contraindications Precautions Nafcillin (Unipen, Nafcil, Nallpen)Initial therapy for suspected penicillin G–resistant streptococcal or staphylococcal infections.Initially use parenteral therapy in severe infections. Change to PO therapy as condition warrants.Because of thrombophlebitis, particularly in children or elderly patients, administer parenterally only for short term (1-2 d); change to PO route as clinically indicated.Dosing
Interactions Contraindications Precautions
Adult
250 mg to 1 g PO q4-6h500 mg to 1 g IV/IM q4-6h
Pediatric
<1 month: 50-100 mg/kg/d IV divided q6-12h>1 month:100-200 mg/kg/d IV divided q4-6h; not to exceed 12 g/d50-100 mg/kg/d PO divided qid
Dosing Interactions Contraindications Precaution s
Dosing Interactions Contraindications Precaution sDosing Interactions Contraindications Precautions Meropenem (Merrem)Bactericidal broad-spectrum carbapenem antibiotic that inhibits cell wall synthesis. Effective against most gram-positive and gram-negative bacteria.Has slightly increased activity against gram-negative organisms and slightly decreased activity against staphylococci and streptococci compared to imipenem.Dosing
Interactions Contraindications Precautions
Adult
Mild-to-moderate infection: 1 g IV q8hMeningitis: 2 g IV q8h
Pediatric
<3 months: Not established>3 months:
Mild-to-moderate infection: 60 mg/kg/d IV divided q8hMeningitis: 120 mg/kg/d IV divided q8h; not to exceed 6 g/d
Dosing Interactions Contraindications Precaution s
Dosing Interactions Contraindications Precaution sDosing Interactions Contraindications Precautions Imipenem and cilastatin (Primaxin)For treatment of multiple organism infections in which other agents do not have wide spectrum coverage or are contraindicated because of potential for toxicity.Dosing
Interactions Contraindications Precautions
Adult
Base initial dose on severity of infection and administer in equally divided doses250-500 mg IV q6h; not to exceed 3-4 g/d500-750 mg IM q12h or intra-abdominally
Pediatric
<1 month: 20-40 mg/kg/d IV divided q12h1-3 months: 100 mg/kg/d IV divided q6h3 months to 12 years: 60-100 mg/kg/d IV divided q6h; not to exceed 4 g/d>12 years: Administer as in adults
Dosing Interactions Contraindications Precaution s
Dosing Interactions Contraindications Precaution sDosing Interactions Contraindications Precautions Cefepime (Maxipime)Fourth-generation cephalosporin with good gram-negative coverage. Similar to third-generation cephalosporins but has better gram-positive coverage.Dosing
Interactions Contraindications Precautions
Adult
Mild-to-moderate infection: 1-2 g IV q12h for 5-10 dSevere infection (eg, pseudomonal, neutropenic fever): 2 g IV q8h
Pediatric
<2 months: Not established2 months to 16 years (<40 kg): 50 mg/kg IV q8h; not to exceed 2 g>16 years or >40 kg: Administer as in adults
Dosing Interactions Contraindications Precaution s
Dosing Interactions Contraindications Precaution sDosing Interactions Contraindications Precautions Antipyretic
agentsInhibits central synthesis and release of prostaglandins that mediate the effect of endogenous pyrogens in the hypothalamus; thus, promotes the return of the set-point temperature to normal.Ibuprofen (Advil, Excedrin IB, Ibuprin, Motrin)One of the few NSAIDs indicated for reduction of fever.Dosing
Interactions Contraindications Precautions
Adult
200-400 mg PO q4-6h while symptoms persist; not to exceed 3.2 g/d
Pediatric
10 mg/kg PO q8h; not to exceed 2.4 g/d
Dosing Interactions Contraindications Precaution s
Dosing Interactions Contraindications Precaution sDosing Interactions Contraindications Precautions Acetaminophen (Aspirin Free Anacin, Feverall, Tempra, Tylenol)Reduces fever by acting directly on hypothalamic heat-regulating centers, which increases dissipation of body heat via vasodilation and sweating.Dosing
Interactions Contraindications Precautions
Adult
325-650 mg PO q4-6h or 1000 mg tid/qid; not to exceed 4 g/d
Pediatric
<12 years: 10-15 mg/kg/dose PO q4-6h prn; not to exceed 2.6 g/d>12 years: Administer as in adults; not to exceed 5 doses in 24 h
Dosing Interactions Contraindications Precaution s
Dosing Interactions Contraindications Precaution sDosing Interactions Contraindications Precautions Follow-upFurther Inpatient CareHospitalization
o Neonates younger than 1 month: Most guidelines recommend hospitalization, with or without antibiotic therapy, for all febrile infants younger than 1 month pending culture results.8,12
o Infants aged 1-3 months: Most guidelines recommend hospitalization for infants in this age group who do not meet low-risk criteria (ie, they are ill-appearing, appear toxic, are hypotensive, or were not previously healthy or they have a focal infection, high-risk petechiae, UTI, or WBC count per HPF of <5 or >15). Infants who need supportive care such as oxygen and intravenous fluids should also be treated as inpatients, as well as those who cannot be treated as outpatients because of caregiver, transportation,
communication, or other logistics.8,13 Outpatients whose blood or CSF cultures are positive for known bacterial pathogens should be readmitted for intravenous antibiotic therapy.8
o Children aged 3-36 months: Infants and young children in this age group should be hospitalized if sepsis is a concern because of toxic appearance, unstable vital signs, or high-risk petechiae upon examination. They may also be admitted if they cannot be treated as outpatients because of caregiver, transportation, communication, or other logistics.8,13 Many infants and young children in this age group are initially treated as outpatients. They may need to be admitted if a blood culture is positive for known pathogens, depending on the clinical status of the patient and the specific organism grown (see Further Outpatient Care).
Tailored antibiotic therapy o Although this article focuses on the management of
bacteremia caused by S pneumoniae, which is the most common isolated organism, occult bacteremia can be caused by rare pathogens, such as Enterobacteriaceae species and S aureus, which are not optimally covered by most common empiric antibiotics. As microbiologic laboratory data become available, antibiotic coverage may be tailored for improved coverage against specific organisms. Carbapenems, vancomycin, and cefepime should be considered when pathogens that are resistant to other antibiotics are recovered or suspected. Although these antibiotics have not been studied or suggested as empiric coverage in patients with FWS, they may be very useful when tailoring antibiotic treatment.
o Microbiology, antibiotic coverage, and the clinical situation should be considered together when tailoring antibiotic therapy. A full discussion of focal infections and treatment approaches to rare pathogens is beyond the scope of this article, but 2 important situations warrant mention. First, vancomycin should be added upon clinical concern for meningitis to cover possible penicillin-resistant and ceftriaxone-resistant gram-positive organisms. Second, any infant or child with occult S aureus bacteremia should have an evaluation for a likely underlying source of infection, such as osteomyelitis or endocarditis, and should be covered with vancomycin or nafcillin.
Further Outpatient Care
Follow-up care: Febrile infants and young children who have a known source for their fever, such as a recognizable viral infection, soft tissue infection, pneumonia, or UTI, should be monitored based on guidelines for those specific infections. Febrile infants and young children who have been evaluated and found to have FWS should be closely observed and reevaluated in 24 hours. This can be conducted on an inpatient (see Further Inpatient Care) or outpatient basis, with or without blood cultures and antibiotics.
Antibiotic treatment at follow-up: The 1993 AAP guidelines recommend that all children at risk for occult bacteremia be reevaluated in 18-24 hours. For children who remained asymptomatic, continued to have nonfocal examination findings, and had blood cultures that were negative for known bacterial pathogens at 24 hours, a second dose of intramuscular ceftriaxone (50 mg/kg) is recommended to cover for a total of 48 hours of negative cultures.8
Monitoring blood cultures: In addition to reevaluating the patient in 24 hours, monitoring blood cultures is important in detecting occult bacteremia and preventing sequelae of subsequent focal infections. A recent review stated that 50% of patients with serious complications from occult bacteremia returned for evaluation and treatment because of a blood culture positive for known bacterial pathogens; only 12% returned because of illness.2 For adequate outpatient follow-up and monitoring of blood culture results, the laboratory must be able to contact the physician, the physician must be able to contact the family, and the family must be able to seek care as soon as the blood culture becomes positive for known bacterial pathogens.
Blood cultures positive for known bacterial pathogens: Patients who are evaluated for FWS and are monitored as outpatients with blood cultures must be reevaluated if the blood cultures become positive with a known pathogen. The appropriate treatment depends on the clinical situation and the specific bacteria present.
o S pneumoniae Infants and young children with occult pneumococcal
bacteremia may be treated and monitored as outpatients if they are well-appearing and afebrile on follow-up.8,4,2 Treatment recommendations include a second dose of ceftriaxone with the addition of an oral antibiotic when sensitivities are known or with the empiric addition of an oral antibiotic on day 2.8,4,2
Therapy with ceftriaxone is recommended if concern penicillin-resistant pneumococcus is a concern because of recent antibiotic use.8 An alternate choice for oral antibiotic coverage may be necessary if the patient is allergic to penicillin.
If a patient with pneumococcal bacteremia is febrile or ill appearing on follow-up, the treatment should include a complete evaluation with LP, parenteral antibiotics, and hospitalization pending culture sensitivities. Serious bacterial infection (eg, meningitis) and pneumococcus resistant to third-generation cephalosporins are concerns; thus, hospitalization and close monitoring are recommended, with adjustment of antibiotic coverage as indicated by sensitivities and clinical course.8,4,2
o Salmonella: Patients with Salmonella bacteremia should be treated with a course of antibiotics and appropriately monitored. Appropriate therapy depends on the clinical
situation; patients who are ill appearing, febrile, younger than 3 months, or immunocompromised should receive a full sepsis evaluation and parenteral antibiotics, whereas immunocompetent afebrile children aged 3-36 months may be treated with a course of oral antibiotics.2
o N meningitidis: As many as 50% of children who develop meningococcal disease are evaluated 2-3 days before the diagnosis and are treated on an outpatient basis for FWS.2
Meningococcal disease has a high rate of occult presentation, and meningococcal bacteremia has a high potential morbidity and mortality rate because of focal complications such as meningitis, shock, and extremity necrosis. Treatment in patients with meningococcal bacteremia, regardless of clinical appearance, should involve a full sepsis evaluation, parenteral antibiotics, and hospitalization.4,2
Inpatient & Outpatient Medications
Amoxicillin, ampicillin, ceftriaxone, cefotaxime (See Medication.)
Transfer
Transfer is not likely unless complications such as sepsis or focal infections are present.
Deterrence/Prevention
Secondary prevention: Early identification of outpatients by screening and empiric antibiotic treatment of febrile infants and young children at risk for occult bacteremia is a form of secondary prevention. This approach does not prevent bacteria from entering the bloodstream in the first place, but it does prevent subsequent focal bacterial illness, morbidity, and mortality.11
Judicious antibiotic use: Approximately 30% of children with invasive pneumococcal infections received antibiotic treatment in the month before the infection, and children who have received antibiotics within the last month are at increased risk for invasive pneumococcal disease with antibiotic-resistant strains.23 This suggests that judicious use of antibiotics for upper respiratory infections, bronchitis, acute otitis media, and sinusitis can prevent pneumococcal infections by decreasing the antibiotic pressure that selects for invasive and resistant pneumococcal strains.
Recent history o Widespread use of the conjugate Hib vaccine in the early
1990s is a recent example of the potential effects of vaccines as primary prevention. Before this vaccine, invasive Hib disease accounted for 10% of occult bacteremia in children aged 3-36 months; children with untreated bacteremia had approximately 20% risk for persistent bacteremia and as much as 15% risk for important focal infections such as meningitis.8,11,26,4
o Introduction of the vaccine decreased the incidence of invasive Hib disease by 90% shortly after its widespread
use.9,10 Use of the vaccine has now essentially eliminated Hib as a cause of invasive disease in immunized children.20 This success story serves as not only an example of prevention in occult bacteremia, but also (the authors hope) a roadmap for expectations following widespread use of the conjugate 7-valent pneumococcal vaccine.
S pneumoniae vaccine o The 7-valent conjugate pneumococcal vaccine was designed
to cover 98% of the strains of S pneumoniae responsible for occult bacteremia. A multicenter surveillance found that isolates that are contained in the 7-valent conjugate pneumococcal vaccine cause 82-94% of S pneumoniae invasive disease.23 See Causes.
o Results of initial efficacy studies of the 7-valent pneumococcal vaccine are encouraging. Published reports of the phase II US trials in 37,000 children found that that the vaccine was 97% effective for vaccine-associated strains in fully vaccinated children and 89% effective overall.9,24 A study of the efficacy of this vaccine during the first year of its licensure indicates that 34-58% of children received at least one dose of vaccine and 14-16% of children were fully vaccinated; a 58-87% reduction in invasive pneumococcal disease occurred.22 Further studies have reinforced these findings over the last decade.39,40,38,41
o More recent studies have highlighted a dampening in the overall rate of decline in invasive pneumococcal disease, with a rise in nonvaccine serotypes in some age groups.43,42,41
These findings have confirmed concerns by some authors that reducing nasopharyngeal carriage of the vaccine serotypes may leave an ecologic niche that invasive serotypes not included in the vaccine may fill.9 Early studies in the United States and a study in East Africa using a 5-valent conjugate pneumococcal vaccine revealed evidence of serotype replacement in nasopharyngeal carriage.9,70
However, the connection between colonization and virulence is not necessarily direct. No evidence indicates that nonvaccine strains in vaccinated children increase the rates of invasive disease.9,22
o Some authors are also concerned that use of the 7-valent conjugate pneumococcal vaccine may alter antibiotic resistance patterns. Early studies show that the most common serogroups associated with penicillin resistance are all included in the vaccine.23 Strain 19A has become important in recent years because it is a nonvaccine strain with high antibiotic resistance that has been found in a large percentage of recent pneumococcal isolates.42
o Although the indications and dosing schedule for the 7-valent conjugate pneumococcal vaccine are a separate topic and not fully addressed here, evidence suggests that the vaccine should be administered to all children younger than 5 years and priority should be given to children with underlying
illnesses because of increased risk of morbidity and mortality associated with invasive pneumococcal infections.23
N Meningitidis vaccine o The conjugated multivalent polysaccharide vaccine to strains
A, C, Y and W-135 of N meningitidis has had success in Europe and Canada and was approved for use in the United States in 2005.
o The vaccine was approved for use in children as young as 2 years in 2007.
o Clinical trials are ongoing to judge efficacy and safety in children younger than 2 years.
o No vaccine for the group B strain of the bacteria is available.
Complications
Complications of bacteremia (see Mortality/Morbidity) o Occult bacteremia results in morbidity and mortality due to
focal infections that arise following the initial bloodstream infection. 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; death may result.3,2
o Of all focal infections that develop because of pneumococcal bacteremia, pneumococcal meningitis carries the highest risk for significant morbidity and mortality, including a 25-30% risk of neurologic sequelae such as deafness, mental retardation, seizures, and paralysis.9,2
Complications of hospitalization o In addition to complications associated with bacteremia and
its sequelae, numerous possible complications are associated with evaluation and empiric treatment of infants and young children at risk for occult bacteremia.
o A study of hospitalized febrile infants younger than 2 months found that complications were common, many complications were preventable, and most infants were hospitalized longer than necessary.71 In this study, 20% of all admissions resulted in at least one complication, and 60% of these complications were believed to be preventable (eg, medications overdose, fluid overload, intravenous infiltrate, intravenous skin sloughing, a kidnapped infant [a preventable complication of hospitalization in general, unrelated to the reason for admission], culture contamination that required follow-up). Of the infants in this study who were evaluated and found not to have bacterial disease based on cultures negative for known bacterial pathogens, 98% were hospitalized longer than 72 hours.
o The risk of complications should be considered when weighing the risks and benefits of evaluation and empiric treatment of febrile infants and young children at risk for occult bacteremia and its sequelae. Because the overall risk of occult bacteremia decreases with widespread use of the
conjugate pneumococcal vaccine, this balance between risk and benefit may need to be reevaluated.
Prognosis
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; death may result.3,2
Evaluation, treatment, and follow-up of febrile infants and young children at risk for occult bacteremia significantly decrease the risk for serious bacterial infections and sequelae.
Patient Education
For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Sepsis (Blood Infection).
Miscellaneous
Medicolegal Pitfalls
Lawsuits may be directed at physicians who have performed the initial evaluations of young febrile children with occult bacteremia before the development of focal complications or overt signs of disease are well described.2
Appropriate evaluation, screening, treatment, and follow-up care can significantly decrease sequelae.
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