Sections

Bacteremia

Presentation

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.^[17]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.^[15]

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).^[12]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.^[40]Overall, duration of fever is inadequate to clinically identify occult bacteremia.^[46]
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.^[40]
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.^{[15, 16]}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:^{[6, 10, 14, 47]}
  - 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 revealed that a history of an underlying medical condition was a significant risk factor for increased mortality. Children with invasive pneumococcal infections and an underlying medical condition had a mortality rate of 3.4%, whereas previously healthy children with invasive pneumococcal infections had a mortality rate of 0.84%.^[24]
History of prematurity: Premature infants may be at a higher risk for invasive bacterial infection when presenting with an apparent life-threatening event (ALTE), perhaps because of reduced maternal-derived antibodies giving some passive immunity.^[48]
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.^[10]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.^[1]
Epidemiology: Although a history of family members or frequent contacts with obvious viral syndromes such as upper respiratory infections may suggest a viral syndrome,^[10]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.^[1]
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,^{[1, 2, 49]}lack of breastfeeding,^{[2, 49]}and underlying illness such as sickle cell disease or acquired immunodeficiency syndrome (AIDS).^{[2, 49]}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.^[49]
A study by Oestergaard et al found a higher rate of Staphylococcus aureus bacteremia among first-degree relatives (specifically in siblings) of those who were once hospitalized with S aureus bacteremia than in the rest of the population.^[50]

Physical Examination

Evaluation of a febrile infant or young child begins by establishing whether the patient truly has a fever without a source (FWS). Toxic or lethargic children and patients with focal infection and sepsis are appropriately treated, and children with nonfocal physical examination findings are further evaluated for occult bacteremia.^{[10, 14, 47]}

General appearance

Numerous investigators have formally defined the initial aspect of the physical examination, the assessment of general appearance, in an attempt to assess its utility in determining the presence of bacterial disease. The Yale Observation Scale (YOS)/Acute Illness Observation Scale (AIOS) has been widely used to assess an infant's quality of cry, reaction to parents, state variation, color/perfusion, hydration, and response to social cues in the environment.^{[8, 15]} Other authors have examined irritability, consolability, and social smile.^{[12, 51]}

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.^{[6, 12, 14, 46, 51]} General appearance based on observation scores had a sensitivity of 74% and specificity of 75% in detecting serious illness in older children^{[10, 11]}; it had a sensitivity of 33% in detecting bacterial disease in infants younger than 2 months.^[14] General appearance had 5.2% sensitivity for detecting occult bacteremia, and social smile was 45% sensitive and 51% specific for bacteremia.^{[1, 51]}

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.^[35]

Vital signs

Temperature, pulse, respiratory rate, and blood pressure can be very useful in raising clinical suspicion for sepsis or pneumonia and for establishing the risk for occult bacteremia. Studies have also suggested that pulse oximetry should be used routinely as a fifth vital sign.^[2] In younger infants, poor perfusion as judged by a capillary-refill time of less than 2 seconds is a more sensitive measure of cardiovascular status than pulse or blood pressure in the early phase of sepsis.

In studies of occult bacteremia, children were not excluded based on specific vital sign parameters; in very young infants, the presence of a serious bacterial infection may not significantly correlate with differences in pulse, respiratory rate, or blood pressure.^[17] However, tachycardia, tachypnea, or hypotension in a febrile or hypothermic infant are signs of sepsis and warrant a complete evaluation.^[6]

Fever defined

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).^[10]

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.^[9] Tactile fever has been found to poorly correlate with the presence of actual fever documented by a healthcare professional using rectal or oral thermometry.^[52] Thus, a parent who reports a child as having a fever because the child feels warm should not be used as part of the evaluation of an infant or child. Home measurement of fever based on a thermometer reading has generally been accepted as true and accurate.

Febrile temperature

The upper extreme of the febrile temperature alone is inadequate to distinguish occult bacteremia; however, the risk of bacteremia has consistently been found to increase with increases in temperature.^[21] Studies have shown a variation in risk at given temperatures based on age; this has led to the fever cutoffs listed above.

Table 3. Age, Fever, and Bacterial Infection^[52] (Open Table in a new window)

Age	Temperature, Degrees Celsius	Rate of Bacterial Infection, %
Neonates < 1 mo	38-38.9	5
	39-39.9	7.5
	≥ 40	18
Infants aged 1-2 mo	38-38.9	3
	39-39.9	5
	≥ 40	26

Table 4. Children Aged 3-36 Months - Fever and Occult Bacteremia^{[1, 2, 6, 8, 53]} (Open Table in a new window)

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

Children aged 2-3 years who have a temperature lower than 39.5°C have less than a 1% risk of occult pneumococcal bacteremia.^[1]

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.^{[1, 6, 52]}

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.^[10]

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.^{[2, 10]} 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.^[54] 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.^{[1, 5, 6, 10, 21, 22]}

Pneumonia

Consider the diagnosis of pneumonia in febrile children who have no other source of infection. Specific physical examination findings such as tachypnea, grunting, flaring, retracting, rhonchi, wheezing, rales, and focal decreased breath sounds have 94-99% specificity for pneumonia.^[42] 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.^[2]

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.^{[1, 5, 15]}

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.^[1] 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.^[55] Group A streptococcal bacteremia sporadically occurs in children with varicella, but these children are usually toxic or have focal findings.^[1] 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.^{[1, 6, 55]}

Workup

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Media Gallery

Application of low-risk criteria and approach for the febrile infant: A reasonable approach for treating febrile infants younger than 3 months who have a temperature of greater than 38°C.
Application of algorithms for children aged 3-36 months: A reasonable approach for treating infants and young children aged 3-36 months who have a temperature of at least 39.5°C.

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

Organism^*	1975-1993, %	1993, %	1993-1996, %	1990 to present, %
S pneumoniae	83-86	93	92	89
H influenzae type b	5-13	2	0	0
N meningitidis	1-3	…	…	…
Salmonella species	1-7	…	…	…
^* Also, less frequently (< 1%), E coli, S aureus, Streptococcus pyogenes, group B Streptococcus, Moraxella species, Kingella species, Yersinia species, and Enterobacter species

Study	Cutoff	NPV, %	PPV, %
Kuppermann, 1999^[1]	WBC >15	99	6
Lee, 2001^[35]	WBC >15	99	5
Strait, 1999^[46]	WBC >15	98	6

Study	Screening Goal	Cutoff, per HPF	NPV, %	PPV, %
Fernandez Lopez, 2003^[56]	Invasive bacterial infection^*	WBC >17	69	69
Pulliam, 2001^[57]	Serious bacterial infection^†	WBC >15	89	30
Lacour, 2001^[58]	Serious bacterial infection^‡	WBC >15	89	46
Isaacman, 2002^[59]	Occult bacterial infection^§	WBC >17	95	30
^* Culture-positive bacteremia/meningitis/sepsis/bone/joint infection; dimercaptosuccinic acid (DMSA)–positive pyelonephritis; lobar pneumonia; bacterial enteritis in infants younger than 3 months ^† Culture-positive bacteremia/meningitis/septic arthritis/urinary tract infection (UTI); focal infiltrate on chest radiograph ^‡ Culture-positive bacteremia/meningitis/osteomyelitis; DMSA-positive pyelonephritis; lobar pneumonia ^§ Culture-positive bacteremia/UTI; lobar pneumonia

ANC	Sensitivity, %	Specificity, %	PPV, %	NPV, %
10,000	76	78	8	99.2
>7,200	82	74	7.5	99.4

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

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/μL; 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

Complication	No 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

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

Bacteremia Clinical Presentation