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Bacteremia

Last Updated: March 15, 2005
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Synonyms and related keywords: bacteriemia, fever, fever without a source, FWS, occult bacteremia, bloodstream infection, serious bacterial infection, systemic bacterial infection, SBI, cytokines, Haemophilus influenzae type b vaccine, Hib vaccine, Hib conjugate vaccine, 7-valent conjugate pneumococcal vaccine, Streptococcus pneumoniae, pneumonia, meningitis, pneumococcal infection, pneumococcal meningitis, Neisseria meningitidis, Salmonella bacteremia, meningococcal bacteremia, hypothermia, hyperthermia, petechiae, white blood cell count, WBC count, sepsis, absolute neutrophil count, ANC, C-reactive protein level, CRP, procalcitonin level, PCT, absolute band count, ABC, erythrocyte sedimentation rate, ESR, urinalysis, urinary tract infection, UTI, Escherichia coli, E coli, antibiotic resistance

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Author: Brian J Holland, MD, Consulting Staff, Department of Pediatrics, US Army Hospital, Wuerzburg, Germany

Coauthor(s): Denise Demers, MD, FAAP, Assistant Professor of Pediatrics, Uniformed Services University of the Health Sciences, Division of Pediatric Infectious Diseases, Department of Pediatrics, Tripler Army Medical Center
Brian J Holland, MD, is a member of the following medical societies: Alpha Omega Alpha
Editor(s): Itzhak Brook, MD, MSc, Professor, Department of Pediatrics, Georgetown University School of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Mark R Schleiss, MD, American Legion Chair of Pediatrics, Professor of Pediatrics, Division Director, Division of Infectious Diseases and Immunology, Department of Pediatrics, University of Minnesota School of Medicine; Robert W Tolan, Jr, MD, Chief of Allergy, Immunology and Infectious Diseases, The Children's Hospital at St Peter's University Hospital, Clinical Associate Professor of Pediatrics, Drexel University College of Medicine; and Russell W Steele, MD, Professor and Vice Chairman, Department of Pediatrics, Head, Division of Infectious Diseases, Louisiana State University Health Sciences Center

Disclosure


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Background: Bacteremia is the presence of viable bacteria in the circulating blood (Spraycar, 1995). Transient bacteremia may develop following dental work or other iatrogenic manipulations, but it is generally clinically benign and self-resolved in children who do not have an underlying illness or a turbulent cardiac blood flow.

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 have an increased heart rate or respiratory rate and may have a change in temperature. Children with sepsis syndrome or severe sepsis have hypotension, hypoperfusion, or organ dysfunction. Septic shock occurs in children who do not respond to adequate volume resuscitation or require vasopressors or inotropes. Bacteria may be present in the bloodstream of children with focal infections, sepsis, severe sepsis, or septic shock; however, those topics are beyond the scope of this article and are addressed in other eMedicine articles. The focus of this article is occult bacteremia.

Patients with occult bacteremia do not have clinical evidence other than fever of a systemic response to infection (Harper, 1993). 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 (Lorin, 1993; Swindell, 1993). A recent review defines occult bacteremia as bacteremia identified in a patient without clinical evidence of sepsis (shock or purpura) or a toxic appearance, without underlying significant chronic medical conditions, without clear foci of infection (other than acute otitis media) on examination, and who is discharged and sent home after an outpatient evaluation (Kuppermann, 1999).

Often, the only manifestation of occult bacteremia is fever or a minor infection (eg, otitis media, upper respiratory tract infection) (Harper, 1993). Therefore, in a busy clinic or emergency department, infants and young children with occult bacteremia are difficult to distinguish from others among the waiting-room throng.

Fever is common in pediatric patients. Children average 4-6 fevers by age 2 years. (McCarthy, 1998). 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 (Harper, 1993; McCarthy, 1998; Baraff and Bass, 1993; Baraff, 2000); 65% of children younger than 3 years visit a physician for acute febrile illness (Baraff and Bass, 1993; Baraff, 1993).

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 (McCarthy, 1998). 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 (McCarthy, 1998).

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 (Baraff, 2000). 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) (Baraff, 2000).

Pathophysiology: Much of the pathophysiology of occult bacteremia is not fully understood. The presumed mechanism begins with bacterial colonization of the respiratory passages; bacteria may egress into the bloodstream of some children because of host- and organism-specific factors. Once viable bacteria have gained access to the bloodstream, they may be cleared spontaneously, 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 (Harper, 1993; Bass, 1993).

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 (McCarthy, 1998). 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 resolves spontaneously 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 (Baker, 1999; Jaskiewicz, 1993).

Frequency:

  • In the US: The risk of bacteremia has been studied by categorizing infants and young children based on age, appearance, temperature, laboratory criteria, a number of low-risk criteria based on a combination of these, 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 (Baraff and Bass, 1993).

    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 (Baraff and Bass, 1993; Baraff, 1992). In children aged 3-36 months who are toxic, the risk of bacteremia or serious bacterial infection ranges from 10-90%, depending on criteria (Baraff and Bass, 1993; Baraff, 1993).

    In the bacteremia literature, studies designed to determine the relationship between temperature and risk of occult bacteremia define fever. Most studies 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 (Baraff, 1993).

    A number of studies published in the early 1990s found that 2-15% of febrile infants younger than 3 months were bacteremic (Baker, 1999; Kadish, 2000; Jaskiewicz, 1993; Baskin, 1993), and the risk of occult bacteremia in children aged 3-36 months with FWS was 2.5-11% (Harper, 1993; Baraff and Bass, 1993; Baraff, 2000; Baraff and Oslund, 1993; Jones, 1993). According to more recent 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 (Alpern, 2001; Lee, 1998; Lee, 2001).

    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 is likely to decrease significantly the overall risk of occult bacteremia (Baraff, 2000; Black, 2001; Kaplan, 2002).

  • Internationally: 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 (Giebink, 2001).

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 administered antibiotics once blood cultures became positive for known bacterial pathogens (Kuppermann, 1999). Occult bacteremia results in morbidity and mortality due to focal infections that arise following the initial bloodstream infection. Most episodes of occult bacteremia resolve spontaneously, and serious sequelae are increasingly uncommon. However, serious bacterial infections occur, including pneumonia, septic arthritis, osteomyelitis, cellulitis, meningitis, and sepsis, and death can result (Kuppermann, 1999; Kramer, 1997).

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 (Harper, 1993; Baraff and Bass, 1993; Baraff, 1993; Harper, 1995).

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 (Harper, 1993; Kuppermann, 1999; Baraff and Bass, 1993; Bauchner, 1997; Baraff, 1993; Lee, 2001).

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 (Kuppermann, 1999; Baraff, 2000). The mortality rate of pneumococcal meningitis is 6.3-15%, and the overall mortality rate of pneumococcal bacteremia is 0.8% (Kuppermann, 1999, Baraff, 2000; Kaplan, 2002).

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 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% (Harper, 1993; Kuppermann, 1999; Baraff, 2000).

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 (Kuppermann, 1999). However, in previously healthy children aged 3-36 months, the risk of meningitis or serious bacterial infection following Salmonella bacteremia is low (Harper, 1993).

Race: Studies of the prevalence of bacteremia in children in diverse settings have identified no racial, geographic, or socioeconomic predisposition (Harper, 1993; Swindell, 1993; Bass, 1993; Fleisher, 1994). However, antibiotic resistance patterns vary in different geographic regions, which may affect the treatment of children with bacteremia.

Sex: No known sex-based difference exists in the prevalence or course of bacteremia (Bass, 1993).

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 (Bass, 1993), while other analyses have found that variations in age-based risk are dependent 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 (Swindell, 1993; Kuppermann, 1999; Lee, 1998), and 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 (Kuppermann, 1999; Bass, 1993). The risk of Salmonella bacteremia is greatest in infants younger than 1 year, especially in those younger than 2 months (Kuppermann, 1999).

A seasonal variation exists in febrile children presenting for evaluation. The peak is from late fall to early spring in children of all ages and is likely because of respiratory and gastrointestinal viral infections. Another peak occurs during the summer in infants younger than 3 months and is likely because of enteroviral infections and thermoregulation during hot weather (McCarthy, 1998). However, most studies do not specifically address seasonal variation associated with bacteremia.


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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 (Kadish, 2000). 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 (Jaskiewicz, 1993).

  • Duration of fever: The duration of fever at presentation has been noted to be shorter in patients whose blood cultures eventually became positive for known bacterial pathogens (mean 18 h) than in those patients with blood cultures negative for known bacterial pathogens (mean 25 h) (Bass, 1993). 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 (Kuppermann, 1999). Overall, duration of fever is inadequate to identify occult bacteremia clinically (Strait, 1999).
  • 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.
    • 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 (Jaskiewicz, 1993; Baraff, 1992). 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
    • Elements of the history that indicate an increased risk for occult bacteremia in infants and children after the neonatal period include the following (Harper, 1993; Baraff and Bass, 1993; Baker, 1999; Dirnberger, 1996):

      • 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, HIV, malnutrition, asplenia)
  • History of underlying medical condition: A recent longitudinal study of invasive pneumococcal infections found 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% (Kaplan, 2002).

  • 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 (Baraff and Bass, 1993). 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.

  • Diarrhea, Salmonella: 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 (Kuppermann, 1999).

  • Epidemiology: Although a history of family members or frequent contacts with obvious viral syndromes such as upper respiratory infections may suggest a viral syndrome (Baraff and Bass, 1993), 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 (Kuppermann, 1999).
  • Risk factors for invasive pneumococcal disease: Recent studies have begun to evaluate the relationship between history and pneumococcal disease. Elements of history that have been associated with an increased risk of pneumococcal bacteremia include daycare attendance (Kuppermann, 1999; Baraff, 2000; Levine, 1999), lack of breastfeeding (Baraff, 2000; Levine, 1999), and underlying illness such as sickle cell disease and AIDS (Baraff, 2000; Levine, 1999). 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 (Levine, 1999).

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 treated appropriately, and children with nonfocal physical examination findings are further evaluated for occult bacteremia (Baraff and Bass, 1993; Baker, 1999; Dirnberger, 1996).

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 Higher*

AgeOrganism†Positive Blood Cultures, %
Neonates <1 moGroup B Streptococcus73
Escherichia coli8
S pneumoniae3
Staphylococcus aureus3
Enterococcus species3
Enterobacter cloacae3
Infants aged 1-2 moGroup B Streptococcus31
E coli20
Salmonella species16
S pneumoniae10
H influenzae type b6
S aureus4
E cloacae4

*Kadish, 2000; Baskin, 1993; Baker, 1999; Jaskiewicz, 1993; Baraff, 1992
†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 from 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 (Baraff, 2000). In addition, with the disappearance of Hib as a cause of occult bacteremia in children, the relative frequency of S pneumoniae has increased in some medical centers to more than 90% (Bass, 1994).

Table 4. Causes of Occult Bacteremia and Changes Over Time in Children Aged 3-36 Months with FWS*

Organism†1975-1993, %1993, %1990 to Present, %1993-1996, %
S pneumoniae83-86938992
H influenzae type b5-13200
N meningitidis1-3………
Salmonella species1-7………

*Harper, 1993; Kuppermann, 1999; Baraff and Bass, 1993; Bass, 1993; Baraff and Oslund, 1993; Alpern, 2001; Fleisher, 1994; Baraff, 1993; Harper, 1995; Lee, 1998
†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 is anticipated to decrease greatly in the near future because of 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 (Alpern, 2001). A recent 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, which is the only pneumococcal vaccine that the Food and Drug Administration (FDA) has approved for infants and young children at the time of this writing (Kaplan, 2002).

A list of strains of S pneumoniae and the percentage of pneumococcal bacteremia caused by each strain is as follows (all except S pneumoniae 6 are 98% covered by the 7-valent conjugate pneumococcal vaccine):

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Lab Studies:

  • Erythrocyte sedimentation rate
    • A number of 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 (Kuppermann, 1999). These studies found that ESR had a better sensitivity than WBC count and similar specificity. A recent review found that the ESR did not predict occult bacteremia, and WBC count and ANC were more sensitive and specific (Kuppermann, 1999). Based on this information, ESR is not currently recommended as a screening test for occult bacteremia (Kuppermann, 1999; Baraff and Bass, 1993).
    • 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 (Baraff and Bass, 1993). Several studies performed before widespread use of conjugate Hib and pneumococcal vaccines found that 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 (Kuppermann, 1999).

    • Several recent studies have reassessed CRP level as a screen for bacterial infection and compared it to other laboratory markers (Lopez, 2003; Pulliam, 2001; Lacour, 2001; Gendrel, 1999; Isaacman, 2002). These were all prospective observational studies of infants and children who presented to the emergency department for evaluation of FWS. As discussed above in the section on WBC count (see White blood cell count), 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 utility in the context of occult bacteremia because they address the evaluation of febrile young children who have no focus of infection on initial examination in an outpatient setting.

    • These 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 2.8-5.0, yielding NPVs of 81-98% and PPVs of 30-69% in distinguishing invasive or serious bacterial infections from noninvasive or benign infections (Lopez, 2003; Pulliam, 2001; Lacour, 2001; Gendrel, 1999; Isaacman, 2002).

      Table 8. Recent Studies Reevaluating CRP Level as a Screen in FWS

      Study
      Screening Goal
      Cutoff
      NPV, %
      PPV, %
      Lopez, 2003
      Invasive bacterial infection *
      2.8
      81
      69
      Pulliam, 2001
      Serious bacterial infection †
      5.0
      98
      Not reported
      Lacour, 2001
      Serious bacterial infection ‡
      4.0
      96
      51
      Gendrel, 1999
      Invasive bacterial infection §
      4.0
      97
      34
      Isaacman, 2002
      Occult bacterial infection ll
      4.4
      94
      30

      * Culture-positive bacteremia/meningitis/sepsis/bone/joint infection; DMSA-positive pyelonephritis; lobar pneumonia; bacterial enteritis in <3 mos

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

      ‡ Culture-positive bacteremia/meningitis/osteomyelitis; DMSA-positive pyelonephritis; lobar pneumonia

      § Culture-positive bacteremia/sepsis/meningitis

      ll Culture-positive bacteremia/UTI; lobar pneumonia

    • WBC count is currently the established standard lab screening test in young children with FWS (Baraff and Bass, 1993). Several of the above studies directly compared WBC count and CRP level as screening lab 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 (Lopez, 2003; Pulliam, 2001; Lacour, 2001; Isaacman, 2002). While one author concluded that CRP level did not have any advantage or additional value compared to WBC count (Isaacman, 2002), CRP-level screening for febrile children in the emergency department is a part of the established protocol at a number of the other medical centers. Potential strengths of CRP level include favorable test characteristics outlined above, 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 (Jaye, 1997). 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 above, 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 lab values studied. The optimal cutoff for CRP level overall, including any duration of fever, was 2.8, giving an NPV of 81% and a PPV of 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, an NPV of 77% and a PPV of 66% (Lopez, 2003). 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 (Pulliam, 2001). 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 (Isaacman, 2002). To complicate the results further, the first study above (Lopez, 2003), 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 lab screening in illnesses of short duration may be problematic, whether WBC count or CRP level is used.
  • Cytokines

    • Interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-a (TNF-a) all increase in the serum and cerebrospinal fluid in gram-negative and gram-positive sepsis; the levels increase with the severity of illness. A recent review found that these levels also increase in bacteremia; sensitivity and PPV are similar to those of WBC count (Kuppermann, 1999). A recent prospective case control study found that IL-6 and TNF-a 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 7.0%, and an NPV of 99.6% (Strait, 1999).

      These cytokines have not been thoroughly investigated; they have marginal clinical utility, unknown cost-effectiveness, and are not recommended as routine screening laboratory studies for occult bacteremia (Kuppermann, 1999).

  • Urinalysis

    • Evaluation of children with FWS often requires laboratory analysis to evaluate for UTI. Children with test results suggesting 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 (Baraff, 1993). All the 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 (Baraff and Bass, 1993).

    • 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 (Baraff and Bass, 1993; Baker, 1999; Jaskiewicz, 1993; Baraff, 1992; Bachur, 2001). 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 (Baraff, 1993).

    • Recent 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 (Baraff, 1993; Herr, 2001). 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 (Bachur, 2001).
  • Salmonella and stool studies

    • Salmonella bacteremia accounts for a small portion of occult bacteremia (see Causes), and the clinical and laboratory findings are different from those in pneumococcal bacteremia. A WBC count is not a useful screening test because most infants and children with Salmonella bacteremia have a WBC count less than 15,000, and only half of patients have a left shift of the WBC count differential (Kuppermann, 1999). Most patients who develop Salmonella bacteremia have gastroenteritis, and 6.5% of children younger than 1 year who have Salmonella gastroenteritis become bacteremic (Kuppermann, 1999). Because of this association, stool cultures are recommended for children with diarrhea (Baraff and Bass, 1993; Baraff, 1993).

    • The initial clinical application of low-risk criteria for infants younger than 3 months with FWS did not include a stool evaluation. However, a number of 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 (Baraff and Bass, 1993; Jaskiewicz, 1993; Baraff, 1992).
  • N meningitidis

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

    • Although the risk of pneumococcal bacteremia is directly related to increasing WBC counts, 6% of children with meningococcal bacteremia have a WBC count per HPF of fewer than 5. Overall, WBC counts and ANCs have not proved consistently useful in determining the risk of meningococcal infection (Kuppermann, 1999; Kuppermann and Malley, 1999).

    • The band count may be the most important component of the CBC in meningococcus (Kuppermann, 1999). 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 (Kuppermann, 1999; Kuppermann and Malley, 1999). However, the clinical utility of an elevated band count is limited because of the low overall prevalence of meningococcal bacteremia. The PPV of a band count greater than 10% is 0.06.

    • The use of plasma clearance rate (PCR) in the evaluation of occult meningococcal bacteremia has not been studied. In studies of known meningococcal disease, PCR is sensitive and specific and may be useful in detecting meningococcal bacteremia (Kuppermann, 1999).

  • Cerebrospinal fluid analysis

    • Infants and children with FWS may require a laboratory analysis to evaluate for meningitis. Febrile infants and children of any age who are toxic require a full sepsis evaluation, including cerebrospinal fluid (CSF) and empiric treatment with parenteral antibiotics (Baraff and Bass, 1993).

    • 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 having fewer than 8-10 WBCs per HPF, no bacteria, and normal glucose and protein levels (Baraff and Bass, 1993; Baker, 1999; Jaskiewicz, 1993; Baraff, 1992). Children with laboratory values suggesting meningitis should be treated for this focal infection. Evaluation and treatment for meningitis is a separate topic and is not fully addressed here.

  • Blood culture

    • A blood culture positive for known bacterial pathogens is the criterion standard used to define bacteremia. Blood cultures should be obtained in infants and young children at risk for occult bacteremia. Blood cultures that are positive for single isolates of known pathogenic bacteria (see Causes) are generally considered to be true positive results; cultures that grow multiple isolates or nonpathogenic bacteria are considered contaminated. How fast the culture becomes positive for known bacterial pathogens is also useful in distinguishing pathogens from contaminants; true pathogens generally grow faster than contaminants, with most pathogens turning positive in less than 24 hours (Kuppermann, 1999; Baraff, 2000). The routine mean detection time for several pathogens are as follows (Kuppermann, 1999):

      • S pneumoniae - 11-15 hours

      • Salmonella species - 9-12 hours

      • N meningitidis - 12-23 hours

    • Whether the quantity of colonies grown is useful in detecting occult bacteremia or in predicting prognosis is unclear. Occult pneumococcal bacteremia may yield fewer than 10 colony-forming units (CFU)/mL, which is lower than in focal disease. The yield in meningococcal infection varies widely, but one study found that patients with yields higher than 700 CFU/mL were at an increased risk for meningitis (Kuppermann, 1999).

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 findings on physical examination include grunting, flaring, retracting, rhonchi, wheezing, rales, and focal decreased breath sounds. These findings are 94-99% specific for pneumonia (Bachur, 1999). 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 (Baraff, 2000; Baraff, 1993).
  • Recent studies suggest that pulse oximetry may be a more reliable predictor of pulmonary infections than is respiratory rate in infants and young children. A recent guideline recommends that chest radiography be used to evaluate for pneumonia if the patient's oxygen saturation is less than 95% (Baraff, 2000).
  • A recent 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. Approximately 20% of febrile children younger than 5 years who had normal physical examination findings and WBC counts higher than 20,000 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 (Bachur, 1999).

Procedures:

  • Blood: Venipuncture is performed to obtain blood for a CBC 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 (Kuppermann, 1999). The recovery rate is 83% with a large (ie, 6 mL) volume of blood and is 60% with a small (ie, 2 mL) volume of blood. 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 (LP): An 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. Although it remains a subject of debate, children with bacteremia who have an LP may possibly have an increased risk of meningitis (Baraff, 2000).
  • Urine specimen: Urine collection is performed for urinalysis, microscopy, Gram stain, cell count, and culture (see Lab Studies and Medical Care). Although UTIs are a separate subject and not fully addressed here, 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.
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Medical Care:

Antipyretics

Most infants and young children who are evaluated for occult bacteremia present with a fever. Some debate exists regarding the use of antipyretics to treat fever. However, while the child is evaluated to determine a source of the fever, fever reduction with medication is reasonable and widely accepted. Studies have shown that ibuprofen 10 mg/kg/dose every 8 hours or acetaminophen 10-15 mg/kg/dose every 4-6 hours are both effective and well tolerated (Walson, 1992).

Infants younger than 3 months

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 distinguish infants at an increased risk for serious bacterial infection clinically (Avner, 1993). Since then, a number of 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 (Baraff and Bass, 1993; Baker, 1993; Baskin, 1992; Dagan, 1985; Bachur, 2001). Following are the low-risk criteria established by groups from Philadelphia, Boston, and Rochester and the 1993 American Academy of Pediatrics (AAP) guideline.

Table 11. Low-Risk Criteria for Infants Younger than 3 Months*

CriterionPhiladelphia BostonRochesterAAP 1993
Age1-2 mo1-2 mo0-3 mo1-3 mo
Temperature38.2°C>38°C>38°C>38°C
AppearanceAIOS† <15WellAnyWell
HistoryImmune No antibiotics in the last 24 h;
No immunizations in the last 48 h 		Previously healthyPreviously healthy
ExaminationNonfocalNonfocalNonfocalNonfocal
WBC count <15,000; band-to-neutrophil ratio
<0.2		<20,000 5-15,000
Band <1,000		 5-15,000;
Band <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 radiographyNo infiltrateWithin normal limits, if obtainedWithin normal limits, if obtained …
Stool culture <5 WBCs per HPF… <5 WBCs per HPF…
*Baker, 1993; Baskin, 1992; Dagan, 1985; Baraff and Bass, 1993
†Acute illness observation score

Low-risk criteria: How well do they 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 exists in patients deemed to be at low risk). The NPV of various low-risk criteria for serious bacterial infection and occult bacteremia are presented as follows (Baker, 1999; Kadish, 2000; Baker, 1993; Baskin, 1992; Baraff, 1992; Dagan, 1985; Baraff and Bass, 1993):

  • Philadelphia NPV - 95-100%

  • Boston NPV - 95-98%

  • Rochester NPV - 98.3-99%

  • AAP 1993 - 99-99.8%

Application of low-risk criteria

See Image 1 for a treatment approach in febrile infants younger than 3 months.

Children aged 3-36 months

Empiric antibiotics: How well do they work?

The first step in the treatment of children with FWS, described above, 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.

A number of studies have compared the effectiveness of oral and parenteral antibiotics in reducing complications of occult bacteremia. Many of these studies were conducted before widespread use of the conjugate Hib vaccine (Kuppermann, 1999); 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 (Baraff and Bass, 1993; Fleisher, 1994).

Table 12. Occult Bacteremia - Relationship Between Outpatient Antibiotic Use and Complications*

Complication No Antibiotic Therapy, %PO Antibiotic Therapy, %IM/IV Antibiotic Therapy, %
Persistent bacteremia18-213.8-50-5
New focal infection135-6.65-7.7
Meningitis9-104.5-8.20.3-1
*Baraff and Bass, 1993; Baraff, 1993; Harper, 1995; Bass, 1993; Fleisher, 1994

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 (Kuppermann, 1999; Baraff and Bass, 1993), but a recent metaanalysis found no statistical change in occurrence of meningitis between patients with and without treatment with oral antibiotics (Rothrock, 1997).

Table 13. Pneumococcal Bacteremia - Relationship Between Outpatient Antibiotic Use and Complications*

ComplicationNo Antibiotic Therapy, % Any Antibiotic Therapy, %PO Antibiotic Therapy, % IM/IV Antibiotic Therapy, %
Persistent bacteremia7-171-1.52.5…
Focal infection/SBI9.7-103.3-4……
Meningitis2.7-60.4-10.4-1.50.4-1

*Kuppermann, 1999; Baraff and Bass, 1993; Baraff, 1993; Jones, 1993; Lee, 2001; Bauchner, 1997; Baraff, 1997; Rothrock, 1997; Baraff, 2000

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/intravenous antibiotic therapy (Baraff, 2000).

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 (Harper, 1993; Kuppermann, 1999). Empiric oral antibiotics have not been proven to prevent focal complications or persistence of bacteremia in children with occult nontyphoidal Salmonella bacteremia (Kuppermann, 1999). 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 (Pickering, 2003).

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 (Baker, 1999; Jones, 1993). 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 (Baraff, 1992).

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 (Baraff and Bass, 1993; Baker, 1999; Jones, 1993). The risk for infection with Listeria is significantly decreased in children older than 4-6 weeks, and debate exists regarding whether coverage for Listeria is required in infants aged 1-3 months at risk for occult bacteremia. All these possible antibiotic regimens have excellent coverage against the other childbirth- 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 (Bass, 1993; Baraff, 1992). 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 (Bass, 1993).

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/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/clavulanic acid have shown that, while amoxicillin/clavulanic acid more commonly causes diarrhea, the overall rate of adverse effects (eg, diarrhea, vomiting, maculopapular exanthems) is similar at approximately 5% (Bass, 1993; Fleisher, 1994). 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 (Fleisher, 1994).

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 day care centers are resistant to penicillin (Nilsson, 2001).

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 (Kaplan, 2002; Friedland, 1995; Arditi, 1998).

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 (Baraff and Bass, 1993; Fleisher, 1994; Friedland, 1995). 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) (Arditi, 1998).

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 (Kaplan, 2002). 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% (Baraff and Bass, 1993; Kaplan, 2002; Fleisher, 1994).

Since the end of the 1980s, researchers have been concerned that penicillin-resistant pneumococcus may also be resistant to third-generation cephalosporins (Kaplan, 2002). At that time, less than 1% of pneumonococci were resistant to ceftriaxone (Fleisher, 1994). Since then, ceftriaxone resistance has increased, but it remains significantly less common than penicillin resistance (Kaplan, 2002; Fleisher, 1994; Arditi, 1998).

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 (Baraff and Bass, 1993; Kaplan, 2002; Fleisher, 1994); highly ceftriaxone-resistant pneumococcus (MIC >1) has increased from 0.5% in 1993 to 2% in 1999 (Kaplan, 2002). 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) (Arditi, 1998). 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 (Fleisher, 1994; Kaplan, 2002).

Morbidity and mortality with resistance

Antibiotic resistance is increasing in pneumococcal disease, but resistance is not necessarily directly correlated with virulence. Several studies have attempted to establish whether infection with antibiotic-resistant pneumococci relates to increased morbidity or mortality.

In two longitudinal studies of invasive pneumococcal disease and pneumococcal meningitis, no difference was observed in clinical presentation, hospital course, morbidity, or mortality among patients with disease caused by antibiotic-resistant pneumococci compared with those caused by antibiotic-susceptible pneumococci (Kaplan, 2002; Arditi, 1998).

A prospective observational study of pneumococcal disease, which did not include meningitis, compared various SBIs, including occult pneumococcal bacteremia. The patients were treated empirically with oral or parenteral antibiotics at the discretion of the attending physician. No significant difference was o