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Occult Bacteremia and Fever Without Apparent Source in Infants and Young Children

By

Geoffrey A. Weinberg

, MD, Golisano Children’s Hospital

Reviewed/Revised Feb 2024
View PATIENT EDUCATION

Occult bacteremia is the presence of bacteria in the bloodstream of febrile young children who have no apparent foci of infection and look well. Diagnosis is by blood culture and exclusion of focal infection. Treatment is with antibiotics, either inpatient or outpatient; select children are treated pending blood culture results.

Children 3 to 36 months of age

In the era before conjugate vaccines, approximately 3 to 5% of children aged 3 to 36 months with a febrile illness (temperature > 38.5° C) and no localizing abnormalities (ie, fever without a source) had occult bacteremia. In contrast, children > 36 months with bacteremia almost always looked ill and had an identifiable (ie, non-occult) focus of infection. The majority (80%) of occult bacteremia prior to the introduction of routine conjugate immunization was caused by Streptococcus pneumoniae Streptococcal Infections Streptococci are gram-positive aerobic organisms that cause many disorders, including pharyngitis, pneumonia, wound and skin infections, sepsis, and endocarditis. Symptoms vary with the organ... read more Streptococcal Infections . A smaller percentage (10%) was caused by Haemophilus influenzae type b Haemophilus Infections The gram-negative bacteria Haemophilus species cause numerous mild and serious infections, including bacteremia, meningitis, pneumonia, sinusitis, otitis media, cellulitis, and epiglottitis... read more , and an even smaller percentage (5%) was caused by Neisseria meningitidis Meningococcal Diseases Meningococci (Neisseria meningitidis) are gram-negative diplococci that cause meningitis and meningococcemia. Symptoms, usually severe, include headache, nausea, vomiting, photophobia... read more Meningococcal Diseases .

Currently in the United States and Europe, routine vaccination of infants with polysaccharide conjugate vaccines against S. pneumoniae Pneumococcal Vaccine Pneumococcal disease (eg, otitis media, pneumonia, sepsis, meningitis) is caused by some of the > 90 serotypes of Streptococcus pneumoniae (pneumococci). Vaccines are directed against... read more and H. influenzae type b Haemophilus influenzae Type b (Hib) Vaccine Haemophilus influenzae type b conjugate vaccine helps prevent Haemophilus infections but not infections caused by other strains of H. influenzae bacteria. H. influenzae... read more has eliminated > 99% H. influenzae type b infections and substantially reduced ≥ 70% (overall) and ≥ 90% (vaccine-type) invasive S. pneumoniae infections. Thus, in this age group, occult bacteremia has become rare except in underimmunized or nonimmunized children, and in children with immunodeficiency.

Even with the decreased rates of infection, the risk of invasive bacterial infections (IBIs) is still a concern in young children with fever without apparent source or occult bacteremia (1 General references Occult bacteremia is the presence of bacteria in the bloodstream of febrile young children who have no apparent foci of infection and look well. Diagnosis is by blood culture and exclusion of... read more ). IBIs typically are defined as sepsis Neonatal Sepsis Neonatal sepsis is invasive infection, usually bacterial, occurring during the neonatal period. Signs are multiple, nonspecific, and include diminished spontaneous activity, less vigorous sucking... read more , meningitis Bacterial Meningitis in Infants Over 3 Months of Age Bacterial meningitis in infants is a serious infection of the meninges and subarachnoid space. Infants may present with nonspecific symptoms and signs (eg, lethargy, irritability, poor feeding... read more , and urinary tract infection Urinary Tract Infection (UTI) in Children Urinary tract infection (UTI) in children is defined by ≥ 5 × 104 colonies/mL in a catheterized urine specimen or, in older children, by repeated voided specimens with ≥ 105... read more (UTI) but also include septic arthritis Acute Infectious Arthritis Acute infectious (septic) arthritis is a joint infection that evolves over hours or days. The infection resides in synovial or periarticular tissues and is usually bacterial—in younger adults... read more Acute Infectious Arthritis and osteomyelitis Osteomyelitis Osteomyelitis is inflammation and destruction of bone caused by bacteria, mycobacteria, or fungi. Common symptoms are localized bone pain and tenderness with constitutional symptoms (in acute... read more Osteomyelitis . In a prospective study of 203 previously healthy 3- to 24-month-old children with a high fever (≥ 40.5° C) without a source, 99% of whom had received at least 1 dose of a pneumococcal conjugate vaccine, 3% were diagnosed with bacteremia and 12% had either a UTI or pneumonia (1 General references Occult bacteremia is the presence of bacteria in the bloodstream of febrile young children who have no apparent foci of infection and look well. Diagnosis is by blood culture and exclusion of... read more ). Such infections could be minimized by early identification and treatment of the bacteremia. The likelihood of progression to an IBI depends on the cause: 7 to 25% for bacteremia caused by H. influenzae type b but 4 to 6% for bacteremia caused by S. pneumoniae.

Children < 3 months of age

In contrast, febrile infants < 3 months of age continue to have a greater risk of IBI than older infants, approximately 8 to 10%. In the past, IBIs in young infants < 3 months of age were more commonly caused by group B beta-hemolytic Streptococcus, S. pneumoniae, and H. influenzae type b. However, chemoprophylaxis during labor Maternal indications for group B streptococcus prophylaxis Neonatal sepsis is invasive infection, usually bacterial, occurring during the neonatal period. Signs are multiple, nonspecific, and include diminished spontaneous activity, less vigorous sucking... read more in pregnant women colonized with group B beta-hemolytic Streptococcus has reduced early-onset (infection occurring at < 7 days of age) group B streptococcal disease by > 80% (2 General references Occult bacteremia is the presence of bacteria in the bloodstream of febrile young children who have no apparent foci of infection and look well. Diagnosis is by blood culture and exclusion of... read more ). In addition, routine conjugate immunization has decreased colonization among older siblings immunized against S. pneumoniae and H. influenzae type b such that the rate of IBI caused by those organisms has decreased as well (herd immunity). Finally, improvements in food safety also may have reduced the rate of Listeria monocytogenes infection in young infants.

Notably, late-onset (infection occurring at > 7 days of age) group B streptococcal infection is not affected by chemoprophylaxis during labor, and other serious bacterial illnesses such as UTI Urinary Tract Infection (UTI) in Children Urinary tract infection (UTI) in children is defined by ≥ 5 × 104 colonies/mL in a catheterized urine specimen or, in older children, by repeated voided specimens with ≥ 105... read more (most commonly caused by Escherichia coli) and occasional cases of Salmonella and Staphylococcus aureus bacteremia continue to be important causes of fever without apparent source on physical examination in infants < 3 months of age.

Current rates of bacteremia in febrile infants 8 to 60 days of age are closer to 2 to 5%, as opposed to 8 to 10% in the past (3 General references Occult bacteremia is the presence of bacteria in the bloodstream of febrile young children who have no apparent foci of infection and look well. Diagnosis is by blood culture and exclusion of... read more ), and a greater proportion is due to UTI rather than to meningitis or undifferentiated bacteremia.

General references

Symptoms and Signs

The major symptom of occult bacteremia is fever. In infants < 3 months of age, high fever is defined as a temperature 39° C ( 102.2° F) or, according to recent guidelines, 38.0° C ( 100.4° F) (1 Symptoms and signs reference Occult bacteremia is the presence of bacteria in the bloodstream of febrile young children who have no apparent foci of infection and look well. Diagnosis is by blood culture and exclusion of... read more ).

By definition, children with apparent focal disease (eg, cough, dyspnea, and pulmonary crackles suggesting pneumonia; skin erythema suggesting cellulitis or septic arthritis) are excluded (ie, because their disease is not occult).

A toxic appearance (eg, limpness and listlessness, lethargy, signs of poor perfusion, cyanosis, marked hypoventilation or hyperventilation) suggests sepsis or septic shock; bacteremia in such children is also not classified as occult or fever without a source. However, early sepsis can be difficult to distinguish from occult bacteremia.

Symptoms and signs reference

  • 1. Pantell RH, Roberts KB, Adams WG, et al: Evaluation and Management of Well-Appearing Febrile Infants 8 to 60 Days Old [published correction appears in Pediatrics. 2021 Nov;148(5):]. Pediatrics 148(2):e2021052228, 2021. doi: 10.1542/peds.2021-052228

Diagnosis

  • Blood cultures

  • Urine culture and urinalysis

  • Complete blood count (CBC) and differential

  • Serum inflammatory markers (C-reactive protein [CRP], procalcitonin [PCT])

  • Depending on age and clinical circumstances, lumbar puncture for examination of cerebrospinal fluid

Diagnosis of bacteremia requires blood cultures; ideally, 2 samples are taken from separate sites, which helps minimize the problem of false-positive results due to skin contaminants, and results should be made available within 24 hours.

Recommendations for testing and choice of tests vary with age, temperature, and clinical appearance; the goal is to minimize testing without missing an IBI. Children who have indications of focal infection on history or physical examination are evaluated based on those findings.

When available, rapid diagnostic tests for enteroviruses Diagnosis Enteroviruses, along with rhinoviruses (see Common Cold) and human parechoviruses, are a genus of picornaviruses (pico, or small, RNA viruses). All enteroviruses are antigenically heterogeneous... read more , respiratory syncytial virus Diagnosis Respiratory syncytial virus and human metapneumovirus infections cause seasonal lower respiratory tract disease, particularly in infants and young children. Disease may be asymptomatic, mild... read more , and influenza virus Diagnosis Influenza is a viral respiratory infection causing fever, coryza, cough, headache, and malaise. Mortality is possible during seasonal epidemics, particularly among high-risk patients (eg, those... read more (eg, respiratory virus PCR panels) are useful in the evaluation of infants > 30 days of age with fever without apparent source, because infants whose test results are positive for these viruses likely have fever resulting from that virus and require few or no further tests for IBI. There also are rapid tests for other viruses, but these have not been studied sufficiently to justify using their results to alter testing for IBI. Not all studies have found that viral infection lessens the risk of IBI, especially in infants < 30 days of age.

In infants with IBI, the CBC usually shows an elevated white blood cell count (WBC), but the absolute neutrophil count (ANC) is more predictive. If elevated, the inflammation markers CRP and PCT also tend to indicate IBI. The combination of fever, elevated ANC, elevated CRP, and elevated PCT has been used to guide decision making (regarding hospital admission and administration of antimicrobials) for well-appearing term infants 8 to 60 days of age who have fever (1 Diagnosis references Occult bacteremia is the presence of bacteria in the bloodstream of febrile young children who have no apparent foci of infection and look well. Diagnosis is by blood culture and exclusion of... read more , 2 Diagnosis references Occult bacteremia is the presence of bacteria in the bloodstream of febrile young children who have no apparent foci of infection and look well. Diagnosis is by blood culture and exclusion of... read more , 3 Diagnosis references Occult bacteremia is the presence of bacteria in the bloodstream of febrile young children who have no apparent foci of infection and look well. Diagnosis is by blood culture and exclusion of... read more ).

Children 3 to 36 months of age

It is important to note that any febrile infant, regardless of immunization history, who appears seriously ill or toxic requires complete clinical and laboratory evaluation (CBC with differential, blood cultures, urine cultures, lumbar puncture, and, in most cases, admission to the hospital with empiric antimicrobial therapy). Unimmunized, underimmunized, and immunocompromised febrile infants in this age range are more susceptible to IBI than their peers and also typically require the same full clinical and laboratory evaluation for IBI and empiric antibiotics. Children with dyspnea or low oxygen saturation should also have a chest x-ray.

In previously immunized febrile infants aged 3 to 36 months who appear well (nontoxic), the risk of bacteremia is now as low or even lower than the rate of false-positive blood cultures due to skin contaminants, leading many experts to forego blood cultures in these children. However, a urinalysis with microscopic examination and urine culture is typically recommended, but additional laboratory examination (eg, CBC, chest x-ray) is not. Although the vast majority of these children have a viral infection, a very small number of well-appearing children have an early IBI, so caretakers should be advised to monitor the child's symptoms, give antipyretics, and follow up with the clinician (by visit or telephone depending on the circumstances and the caretakers' reliability) in 24 to 48 hours. Children who worsen or remain febrile should have testing done (eg, CBC with differential, blood cultures, possibly chest x-ray or lumbar puncture).

Children < 3 months of age

Toxic-appearing or seriously ill-appearing infants require immediate clinical evaluation, collection of blood, urine, and spinal fluid cultures, and hospitalization for empiric antibiotic therapy. Unlike in older infants, in those < 3 months of age, a nontoxic clinical appearance does not routinely allow deferral of testing.

Algorithms have been developed to help guide evaluation of infants in this age group. Older algorithms (eg, the Rochester criteria) relied on a combination of a priori clinical and laboratory criteria that were developed somewhat arbitrarily and tested among large series of febrile, otherwise well-appearing infants. These algorithms had modest diagnostic sensitivity for IBI (90 to 95%) and, more importantly, had very high negative predictive values (97 to 99%). Thus, they were used to predict which infants were at low risk of IBI, allowing them to be safely monitored without hospitalization or antimicrobials. The advantage of these algorithms was their simplicity; the disadvantage was the relatively low specificity for IBI, meaning that many children without IBI nevertheless ended up being treated with antimicrobials. Also, these algorithms were developed during an era of higher rates of occult bacteremia and bacterial meningitis, before the start of routine conjugate immunization, so they may no longer be as accurate in the current era.

Newer algorithms for the detection of IBI have been developed that rely on prediction rules based on data analyzed with sophisticated statistical modelling techniques and take into account the changing epidemiology of bacterial infections in infants (ie, a greater proportion of bacteremia in a vaccinated patient population results from Escherichia coli UTI rather than pneumococcal infection). A greater emphasis on sensitivity and specificity of diagnosis has been considered to maximize accurate diagnoses and minimize unnecessary treatment of infants without IBI. Finally, the newer algorithms take into account advances in diagnostic testing and pathogen identification. An advantage is increased sensitivity for IBI; a notable disadvantage is the significantly increased complexity of the clinical guidelines for decision making.

Many pediatric hospitals in the United States are using these newer algorithms. The American Academy of Pediatrics 2021 guidelines for the evaluation and management of well-appearing febrile infants 8 to 60 days of age stratifies children into 3 age-based algorithms: infants 8 to 21 days of age, infants 22 to 28 days of age, and infants 29 to 60 days of age (1 Diagnosis references Occult bacteremia is the presence of bacteria in the bloodstream of febrile young children who have no apparent foci of infection and look well. Diagnosis is by blood culture and exclusion of... read more ).

New definitions for abnormal inflammatory markers also help clinicians make decisions regarding hospitalization, administration of antimicrobials, or both (1 Diagnosis references Occult bacteremia is the presence of bacteria in the bloodstream of febrile young children who have no apparent foci of infection and look well. Diagnosis is by blood culture and exclusion of... read more , 2 Diagnosis references Occult bacteremia is the presence of bacteria in the bloodstream of febrile young children who have no apparent foci of infection and look well. Diagnosis is by blood culture and exclusion of... read more , 3 Diagnosis references Occult bacteremia is the presence of bacteria in the bloodstream of febrile young children who have no apparent foci of infection and look well. Diagnosis is by blood culture and exclusion of... read more ). Definition of high risk includes patients with the following (1 Diagnosis references Occult bacteremia is the presence of bacteria in the bloodstream of febrile young children who have no apparent foci of infection and look well. Diagnosis is by blood culture and exclusion of... read more , 2 Diagnosis references Occult bacteremia is the presence of bacteria in the bloodstream of febrile young children who have no apparent foci of infection and look well. Diagnosis is by blood culture and exclusion of... read more , 3 Diagnosis references Occult bacteremia is the presence of bacteria in the bloodstream of febrile young children who have no apparent foci of infection and look well. Diagnosis is by blood culture and exclusion of... read more ):

  • Abnormalities of cerebrospinal fluid

  • Fever 38.0° C ( 100.4° F)

  • CRP > 2 mg/dL (> 20 mg/L)

  • PCT > 0.5 ng/mL (> 0.5 mcg/L)

  • ANC > 4000/mcL (> 4 × 109/L) when used in conjunction with PCT, or > 5200/mcL (> 5.2 × 109/L) if serum PCT is not available

Diagnosis references

  • 1. Pantell RH, Roberts KB, Adams WG, et al: Evaluation and Management of Well-Appearing Febrile Infants 8 to 60 Days Old [published correction appears in Pediatrics. 2021 Nov;148(5):]. Pediatrics 148(2):e2021052228, 2021. doi: 10.1542/peds.2021-052228

  • 2. Kuppermann N, Mahajan P, Dayan PS: Fever, Absolute Neutrophil Count, Procalcitonin, and the AAP Febrile Infant Guidelines. Pediatrics151(2):e2022059862, 2023. doi: 10.1542/peds.2022-059862

  • 3. Yaeger JP, Richfield C, Schiller E, et al: Performance of AAP Clinical Practice Guideline for Febrile Infants at One Pediatric Hospital. Hosp Pediatr 13(3):e47-e50, 2023. doi: 10.1542/hpeds.2022-006820

Treatment

  • Antibiotics (empirically, for select patients pending culture results, as well as for those patients with positive cultures)

  • Antipyretics for discomfort

  • Adequate hydration (because of increased losses with fever and possible anorexia); oral hydration if possible, parenteral if not

Children who receive antibiotics before bacteremia is confirmed by blood culture seem less likely to develop focal infections, but data are inconsistent. However, because of the low overall incidence of bacteremia, many children would receive unnecessary treatment if all who were tested were empirically treated. As above, management varies by age and other clinical factors.

Regardless of age, all children are reevaluated in 24 hours either at a repeat clinical visit or, for selected children depending on age and clinical circumstances, with a telephone call. Those with persistent fever or positive blood or urine cultures who have not been treated already have more cultures done and are hospitalized for evaluation of possible sepsis and parenteral antibiotic therapy. If new signs of focal infection are found on reexamination, evaluation and therapy are directed by the findings.

Children 3 to 36 months of age

Antipyretics in weight-based dosages are given. Antibiotics are not given unless cultures are positive. For urinary tract infection, well-appearing children may receive oral antibiotics for pediatric UTI Treatment Urinary tract infection (UTI) in children is defined by ≥ 5 × 104 colonies/mL in a catheterized urine specimen or, in older children, by repeated voided specimens with ≥ 105... read more as outpatients; others (eg, those who appear more ill, those in whom adequate follow-up is not assured) may require admission for parenteral antibiotics.

Children < 3 months of age

The American Academy of Pediatrics 2021 guidelines suggest that all febrile infants 8 to 21 days of age who are being evaluated for IBI should be hospitalized and given parenteral antimicrobials and that those with risk factors for herpes simplex virus (HSV) infection should be given parenteral acyclovir as well (1 Treatment reference Occult bacteremia is the presence of bacteria in the bloodstream of febrile young children who have no apparent foci of infection and look well. Diagnosis is by blood culture and exclusion of... read more ).

The guidelines suggest that a diagnostic lumbar puncture and blood and urine cultures should be done and that inflammatory marker levels should be sought even with routine hospitalization.

For infants 22 to 60 days of age, decisions concerning inpatient vs at-home care and administration of antimicrobials or expectant management are based on abnormal urinalysis results, inflammatory markers, and, if performed, lumbar puncture results.

Current clinical guidelines will likely continue to be adjusted as the likelihood of IBI and epidemiology of causes of IBI change, and as more data accrue on predictors of IBI based upon combinations of clinical and laboratory markers.

Treatment reference

  • 1. Pantell RH, Roberts KB, Adams WG, et al: Clinical Practice Guideline: Evaluation and Management of Well-Appearing Febrile Infants 8 to 60 Days Old. Pediatrics 148(2):e2021052228, 2021. doi: 10.1542/peds.2021-052228

Key Points

  • Febrile infants and young children < 36 months of age, who have been appropriately immunized with H. influenzae type b and pneumococcal conjugate vaccines, and who look well and have no apparent foci of infection, are unlikely to have occult bacteremia or invasive bacterial infection (IBI; eg, sepsis, meningitis).

  • Use blood cultures (2 samples from 2 separate sites) to diagnose occult bacteremia in selected febrile children.

  • All febrile infants < 36 months of age should be evaluated for urinary tract infection (UTI) with urinalysis and urine culture because UTI is now the most common cause of IBI with fever.

  • Toxic-appearing children (and perhaps all febrile infants < 1 month of age of age) also require cultures of blood and spinal fluid and hospitalization for empiric antibiotic therapy.

  • In children 3 to 36 months of age with a temperature ≥ 39° C and who have been appropriately immunized, testing other than urine culture is not indicated for those who appear well; others should have testing based on clinical findings and other circumstances (eg, rapid viral testing for influenza virus, respiratory syncytial virus, and enterovirus during the appropriate seasons).

  • In infants < 3 months of age with a temperature ≥ 38° C, good clinical appearance does not completely exclude an IBI, so testing, including urinalysis, complete blood count with differential, blood and urine cultures, lumbar puncture (especially for the youngest infants), serum C-reactive protein, and, if available, serum procalcitonin (and perhaps rapid viral testing for influenza virus, respiratory syncytial virus, and enterovirus, or PCR panel) is indicated for all in this age range.

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