Intended for healthcare professionals

Clinical Review

Unexplained fever in young children: how to manage severe bacterial infection

BMJ 2003; 327 doi: https://doi.org/10.1136/bmj.327.7423.1094 (Published 06 November 2003) Cite this as: BMJ 2003;327:1094
  1. Itzhak Brook, professor (ib6{at}georgetown.edu)1
  1. 1Department of Pediatrics, Georgetown University School of Medicine, Washington, DC 20057, USA
  1. Correspondence to: 4431 Albemarle St NW, Washington DC 20016, USA

    Fever with no clear source of infection in children under 3 years old carries a small but important risk of sepsis and meningitis. This review describes the bacterial causes of such infection and the appropriate management in different age groups

    Introduction

    Fever in infants has been defined as a rectal temperature of 38°C (100.4°F) or higher. In older children, a rectal temperature of 38.4°C (101.1°F) or an oral temperature of 37.8°C (100°F) is generally considered abnormal.1 Most young children with fever and no focus of infection present with a self limiting viral illness that does not need any treatment and disappears without sequelae. Urinary tract infection is another important cause of fever in young children who are febrile with no focus of infection.2 However, a few children may eventually develop occult bacteraemia that may be associated with serious bacterial infection. Multiple studies have tried to identify children who seem well but have a serious infection and to evaluate the potential treatments. This review discusses the bacterial causes, essential diagnostic tests, clinical assessment, judicious use of antibiotics, and follow up in unexplained, difficult to diagnose bacterial infection causing fever in young children.

    Sources and selection criteria

    I gathered information by searching Medline, using personal archives, and reading relevant literature. The review and recommendations are based on observational studies and systematic reviews.

    Microbiology

    Many organisms can cause febrile occult infection in young children. Their distribution is seasonal and varies in different age groups. Substantial overlap exists, however (box 1).

    The main bacterial causes of infection in children aged under 1 month are listed in box 1. Viral agents (mostly Herpes simplex and enteroviruses) can also cause life threatening febrile infection in this age group.3 Most infections in children over 3 months are caused by Streptococcus pneumoniae (in non-immunised children), Neisseria meningitidis, or Salmonella spp. Staphylococcus aureus is associated with bone and joint infections, and Escherichia coli, as well as other enteric Gram negative bacilli, are found in urinary tract infections.

    The rate of bacteraemia due to Haemophilus influenzae and S pneumoniae declined after the introduction of the H influenzae conjugated vaccines and the polysaccharide-protein, seven serotypes conjugate pneumococcal vaccine.4 5 The risk of occult bacteraemia and its sequelae is predicted to be substantially reduced in vaccinated children.

    Summary points

    The main bacterial causes of infections in children aged under 1 month are group B streptococcus, Escherichia coli (and other enteric Gram negative bacilli), Listeria monocytogenes, Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Neisseria meningitides, and Salmonella spp

    Most bacterial infections in children over 3 months are caused by S pneumoniae (in non-immunised children), N meningitidis, or Salmonella spp

    All febrile children under 3 years old who have toxic manifestations should be admitted to hospital, be fully investigated for sepsis and meningitis, and receive antimicrobial treatment

    The risk of bacterial infection is very low in children over 24 months old who seem well, and follow up without laboratory tests or treatment with antimicrobials is generally adequate

    In 3-24 month old children antimicrobial treatment is initiated if foci are found; if no identifiable source is found and the child seems well, no diagnostic tests or antibiotics are generally needed

    Most febrile infants under 1 month old and all those under 7 days should be admitted to hospital and treated with antimicrobials; however, observation in hospital without antimicrobials or outpatient management is an option in selected low risk cases

    Box 1: Causes of bacteraemia and meningitis in young children

    Under 1 month old

    • Group B streptococcus

    • Escherichia coli (and other enteric Gram negative bacilli)

    • Listeria monocytogenes

    • Streptococcus pneumoniae

    • Haemophilus influenzae

    • Staphylococcus aureus

    • Neisseria meningitides

    • Salmonella spp

    1-3 months old

    • Streptococcus pneumoniae

    • Group B streptococcus

    • Neisseria meningitides

    • Salmonella spp

    • Haemophilus influenzae

    • Listeria monocytogenes

    Over 3 months old

    • Streptococcus pneumoniae

    • Haemophilus influenzae

    • Neisseria meningitides

    • Salmonella spp

    Epidemiology

    Fever in children aged under 3 months

    The risk of serious bacterial infection is greatest from birth throughout the first month of life and is especially high in prematurely born infants.6 The factors associated with a low risk of serious bacterial infection in febrile infants under 3 months were established in several studies. The first of these studies, from the University of Rochester,7 and all those that followed810 found that children unlikely to have a serious bacterial infection fulfilled the following criteria:

    • No clinical evidence of infection of the ear, skin, bones, or joints

    • White blood cell count between 5 and 15 x 109/l

    • Fewer than 1.5 x 109 band cells/l

    • Normal urine analysis.

    The risk of a serious bacterial illness in the “low risk” children is minimal. In a meta-analysis of studies of febrile children under 3 months, the risks of serious bacterial illness, bacteraemia, and meningitis were 24.3%, 12.8%, and 3.9% in “high risk” infants and 2.6%, 1.3%, and 0.6% in “low risk” infants.6 Although the risk of serious bacterial infection can be high in this age group, those infants who are at very low risk can be identified by using the established criteria (box 2).

    Fever in children aged over 3 months

    Occult bacteraemia is most often due to S pneumoniae and is rarely caused by N meningitides or H influenzae type b; it occurs in 3-8% of non-toxic seeming children of this age group with fever and no focus of infection.1315 The presence of a temperature > 39°C alone is associated with a risk of bacteraemia of only 3%.16 However, this risk is higher when elevated temperature is associated with high total white blood cell count.14 One study found a risk of 16.7% with a white blood cell count above 15 x 109/l.17

    The infection is generally transient, and the patient recovers without antimicrobial treatment. A serious focal or systemic infection such as meningitis or septic shock can rarely develop in these children.18 The risk of meningitis is related to the causative bacteria; it is lowest with S pneumoniae bacteraemia (1.8%) and greater for H influenzae type b (13%) and N meningitides (56%).15 However, the risk of bacteraemia and meningitis due to S pneumoniae and H influenzae type b has declined substantially since the licensing of the polysaccharide-protein, seven serotypes conjugate pneumococcal vaccine and the H influenzae conjugated vaccine.4 5

    Mechanisms of infection

    Newborn infants are at a greater risk of systemic infection. Haematogenous spread of infection is very common in this age group and in immuno-compromised patients. However, most young children who develop bacteraemia are immunologically intact. The process is initiated by nasopharyngeal colonisation and followed by bacterial invasion of the blood and rare systemic dissemination.19 Both colonisation and bacteraemia are often associated with a preceding viral respiratory tract infection.19

    Diagnostic tests and clinical scales

    The risk of bacteraemia has been evaluated by multiple diagnostic tests and clinical scales.11 20 21 The diagnostic tests include white blood cell count and differential erythrocyte sedimentation rate, C reactive protein, morphological changes in peripheral neutrophils, microscopic examination of buffy coat, and quantitative blood cultures. Despite all the studies, no test has sufficient sensitivity and predictive value to be of individual clinical utility.17

    Box 2:Clinical and laboratory “low risk” criteria for children younger than 3 months with fever and no focus of infection

    Clinical criteria

    • Born at term (gestational age 37 weeks) with uncomplicated nursery stay

    • Previously healthy infants

    • No focal bacterial infection (except otitis media)

    Laboratory criteria

    • White blood cell count 5-15 x 109/l, <1.5 x 109 band cells/l, or band/neutrophil ratio < 2

    • Normal urine analysis results (negative Gram stain of unspun urine, negative leucocyte esterase and nitrite,fewer than five white blood cells per high power field)

    • When diarrhoea is present, no haem and fewer than five white blood cells per high power field

    • Fewer than 8 x 106 white blood cells/l in cerebrospinal fluid, if lumbar puncture is performed, and negativeGram stain findings in cerebrospinal fluid

    • No infiltrate on chest radiograph

    Management

    All febrile children under 3 years old who have toxic manifestations should be admitted to hospital, be evaluated for possible sepsis or meningitis, and receive antimicrobial treatment. “Toxic” is defined as a clinical appearance consistent with the sepsis syndrome (that is, lethargy, poor perfusion, marked hypoventilation or hyperventilation, or cyanosis).11 A full work up for sepsis includes

    • Full blood count with manual differential

    • Blood culture

    • Urine analysis and urine culture (using a transurethral catheter or suprapubic tap)

    • Lumbar puncture for analysis and culture of cerebrospinal fluid

    • Stool culture and faecal white blood cell count for diarrhoea

    • Chest radiography.

    Children younger than 3 months

    Most febrile infants under 1 month and all those under 7 days should be admitted to hospital and given antimicrobial treatment.22 However, observation in the hospital without antimicrobial treatment or outpatient management is an option in selected “low risk” cases (box 2) after assessment for sepsis. Before an infant is placed in the low risk group, the home environment should be considered (reliable caregiver, availability of transportation and telephone).

    Fever with no focus of infection in children under 3 months should be managed differently from that in older children, because accurate assessment of their degree of wellness is difficult and they are at a greater risk of serious infections. They should be treated conservatively and admitted to a hospital to receive broad spectrum antibiotic treatment pending the results of cultures (blood, urine, and cerebrospinal fluid). This is done after a complete assessment, including evaluation for occult sources of infection.23 Chest radiography is done if signs of pneumonia are present (oxygen saturation < 95%, respiratory distress, abnormal breath sounds, tachypnoea).

    Although this conservative approach may be prudent, it is expensive and exposes the patient and the family to hospital admission with potential untoward sequelae.24 Administration of antimicrobials carries adverse impacts and side effects. These include generation of antimicrobial resistance, loss of clinical improvement as a marker of follow up, inability to interpret mildly abnormal cerebrospinal fluid results, increased costs, and adverse side effects including catheter site infection and thrombophlebitis.

    Several alternative approaches have been offered for selected 2-3 month old infants with fever and no focus of infection who seem well and are at low risk of infection (box 2). These approaches include

    • Home observation and management without laboratory tests or hospital admission, only if careful follow up is possible

    • Home observation and management if laboratory criteria predict low risk

    • Close observation without administration of antimicrobial treatment

    • Antimicrobial treatment for two days, with a daily dose of parenteral ceftriaxone (50 mg/kg), while awaiting the results of the cultures.

    Home observation without antimicrobials avoids the adverse side effects of these agents and intravenous cannulation, and it saves money without significantly increasing the risk of complications.3 Outpatient management may not be appropriate if the parent-physician relationship has not been established or the availability of a follow up evaluation is not certain. Whenever an antimicrobial agent is given blood, cerebrospinal fluid, and urine (obtained by either urethral catheterisation or suprapubic bladder aspiration) cultures should be collected before treatment is started.

    The optimal empirical treatment is intravenous ampicillin (100-200 mg/kg/day) plus gentamicin (7.5 mg/kg/day) or a third generation cephalosporin (ceftriaxone, 50 mg/kg/day in a single dose; or cefotaxime, 150 mg/kg/day) (box 3). Vancomycin is added when meningitis is present, to provide coverage for penicillin resistant S pneumoniae. The initial treatment can be adjusted or discontinued according to results of culture.

    Box 3: Parenteral antimicrobials used to treat children with fever and no focus of infection

    Children younger than 3 months

    Ampicillin 100-200 mg/kg/day intravenously in divided doses every 6 hours plus gentamicin 7.5 mg/kg/day in divided doses every 8 hours Or ceftriaxone, 50 mg/kg/day in a single dose Or cefotaxime, 150 mg/kg/day in divided doses every 8 hours

    Children older than 3 months

    Ceftriaxone, 50 mg/kg/day in a single dose Or cefuroxime, 150-200 mg/kg/day in divided doses every 6-8 hours

    Children older than 3 months

    The risk of bacterial infection is very low in children over 24 months old with fever and no focus of infection who seem well. Follow up without laboratory tests or treatment with antimicrobials is generally adequate.

    Controversy exists about if and what diagnostic tests should be done and whether antimicrobials should be initiated for 3-24 month old children with fever and no focus of infection.11 A white blood cell count and differential may help in identifying those at increased risk of occult bacterial infection but have poor predictive value and no direct therapeutic impact. Furthermore, blood culture results have little impact on outcome and can lead to unnecessary hospital admission, as many bacteraemias clear spontaneously.25 The role of administration of antimicrobial treatment for fever with no focus of infection in the prevention of serious complications such as meningitis has not been established.16

    The most prudent approach for fever with no focus of infection in 3-24 months old children is as follows12:

    • Administer antipyretic treatment with either paracetamol (acetaminophen) (15 mg/kg/dose every 4 hours) or ibuprofen (10 mg/kg/dose every 6 hours)

    • If the child looks toxic, he or she is admitted to hospital, cultures and diagnostic tests are done, and antimicrobials are administered (parenteral ceftriaxone, 50 mg/kg daily; or cefuroxime, 150-200 mg/kg/day in divided doses every 6-8 hours) (box 3)

    • Non-toxic looking children are assessed for a focus of infection: If foci are found, treatment is started according to the likely pathogens

      If no identifiable source is found and the temperature is < 39°C (102.2°F), no diagnostic tests or antimicrobials are generally needed

      If the temperature is > 39°C, urine studies (urine analysis and culture or urine leucocyte esterase and nitrate) are done. If the urine screening is positive, an oral third generation cephalosporin is given. In children who did not receive the conjugated S pneumoniae vaccine, white blood cell count and blood culture are done. If the white blood cell count is > 15 x 109/l, the blood culture is sent and an antibiotic is given. Chest radiography is done if oxygen saturation is < 95%, respiratory distress or rales is present, and the white blood cell count is > 20 x 109/l.

    Parents and medical personnel should watch for signs of development of potential serious problems (for example, vomiting, irritability, lethargy, apathy) in all patients. Parents should be instructed to return, however, if the child's fever persists for more than two to three days or if the child's condition deteriorates.3

    Children who have received the conjugated S pneumoniae vaccine are at lower risk of occult bacteraemia, as the vaccine prevents 90% of invasive disease.5 However, they are still at risk of infection by other pathogens and S pneumoniae strains not included in the vaccine.

    Conclusion

    Febrile children younger than 3 years without a clear source of infection have a small but important risk of sepsis and meningitis. These infections are associated with potential morbidity and mortality, even with prompt recognition and appropriate treatment. Although the risk of serious bacterial infections has decreased in countries where vaccination for S pneumonia and H influenzae has been introduced, vigilance and thorough evaluation of each febrile child followed by proper antimicrobial treatment are indicated when appropriate (box 4). As more data accumulate on the efficacy of vaccination, new modalities of fever with no focus of infection will emerge.

    Box 4: Pointers to referral and admission to hospital

    • Febrile infants 7 days of age or less

    • High risk (see box 2) febrile infants 28-90 days of age

    • Toxic looking febrile children up to 36 months of age

    Additional educational resources

    Pickering LK, ed. Red Book 2003: Report of the Committee on Infectious Diseases. 26th ed. Chicago, IL: America Academy of Pediatrics, 2003

    Egland AG, Egland TK, Tolan RW. Fever without a focus. 2002. www.emedicine.com/PED/topic2700.htm

    Virtual Children's Hospital (www.vh.org/pediatric/index.html)

    Information for patients

    emedicine (www.emedicine.com) –online textbook with extensive chapters on paediatric topics, including fever in young children

    Virtual Children's Hospital (www.vh.org/pediatric/index.html)–gives information on many paediatric topics, including fever in young children

    Footnotes

    • Competing interests None declared.

    References

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