Fever is an abnormal elevation in body temperature (≥38.0°C or 100°F) and is a sign of infection. It is one of the most common problems in infants and toddlers.
Fever may indicate a mild, self-limiting viral infection or a severe, life-threatening bacterial infection. Serious bacterial infection (SBI) implies bacteremia, bacterial meningitis, and bacterial urinary tract infection. An invasive bacterial infection (IBI) implies bacteremia and bacterial meningitis. The prognosis depends upon the cause and severity of the infection. Fever in infants and toddlers poses a challenge for pediatricians and often requires a workup, especially in situations of a fever without any other focus of infection.
This article addresses the most common etiologies of fever in these age groups and the appropriate clinical prediction rules for identifying infants and toddlers at the lowest risk for SBIs. Recommendations from the latest clinical practice guidelines on the evaluation of well-appearing febrile infants 8-60 days of age are included. (See also Fever Without a Focus and Emergent Management of Pediatric Patients With Fever.)
The infectious causes of fever depend on age, immune system maturity, and exposure. This article categorizes the cause of fever, its workup, and management into age groups: neonates 0 to 21 days, neonates 22 to 28 days, young infants 29 to 90 days, and infants and children 3 months to 3 years.
A fever of concern generally is defined by a temperature ≥38.0°C (100.4°F). Regarding the site for temperature measurement, the Bright Futures Guidelines for health supervision suggest rectal thermometer use for patients younger than 4 years of age. The National Institutes of Health recommends axillary measurement for neonates less than 4 weeks old and axillary or tympanic for infants and children from 4 weeks to 5 years of age. The axillary thermometer is easy to use, more acceptable to parents, and provides quicker results in neonates younger than 4 weeks. Similarly, an axillary or infrared tympanic membrane thermometer conveniently provides temperature measurement in infants older than 4 weeks and children younger than 5 years of age.
Neonates (aged ≤28 days) with fever may have few clues on history taking and physical examination. Therefore, the decision to conduct a workup and the extent of the investigation are primarily based on the risk of infection determined by neontal age and prenatal testing results.
The risk of invasive bacterial infection (IBI) such as bacteremia and bacterial meningtis is age dependent. The risk of IBI is highest in febrile neonates aged < 21 days: it is estimated at 3-5% for bacteremia and 1.1-2.7% for meningitis.[1] The risk of IBI in neonates aged 22-28 days is relatively lower at 0.2-0.7%.[2, 3] Typically, infections that occur in the first 7 days of life are secondary to vertical transmission, and those infections occurring after the first 7 days are usually community acquired or hospital acquired.
Obtaining the pertinent medical history regarding the pregnancy, delivery, and early neonatal life of the febrile neonate is essential. Note the following:
Definitive identification of a serious bacterial infection requires laboratory investigation; a full sepsis evaluation; and a positive result in blood culture, cerebrospinal fluid (CSF), and/or urine. Bacterial meningitis is more common in the first month of life than at any other time. An estimated 5-10% of neonates with early-onset GBS sepsis have concurrent meningitis.[4] The incidence of Staphylococcus aureus bacteremia in infants aged < 1 year has consistently been higher than in older children. The incidence in infants has been reported as high as 16.7 per 100,000 population and in neonates as high as 124.8 per 100,000.[5, 6]
The general approach to fever in a febrile infant aged 29-60 days includes maintaining a high index of suspicion because they often lack clues on physical examination. The prevalence of a serious bacterial infection in infants younger than 3 months is approximately 6-10%, most often urinary tract infections (UTIs). Interestingly, infants aged 3 months or younger with a confirmed viral infection are at lower risk for a serious bacterial infection when compared with those in whom a viral infection is not identified[7] ; however, a UTI is still a significant concurrent infection (3.3%) in infants with bronchiolitis.[8]
According to guidelines from the Agency of Health Care Policy and Research published in 2012, in infants younger than 3 months with rectal temperatures 38ºC (100.4°F) or higher, the prevalence of serious bacterial infection reported in studies conducted in North American emergency departments or primary care practices ranged from 4.1% to 25.1%.[9, 10]
Historically, children aged 3 months to 3 years with rectal temperatures of 38.5ºC (101.3ºF) or higher had a risk of 2-4% for occult bacteremia.[11] The leading cause of bloodstream infection was Streptococcus pneumoniae, followed by Haemophilus influenzae type b. With the introduction of effective vaccines for these pathogens, the incidence and epidemiology of childhood bacteremia in the immunologically normal host has changed considerably; only 1 in 200 (0.5%) febrile children are now found to be bacteremic.[12, 13]
The incidence of occult bacteremia in this population now ranges from 0.25% to 0.7%; moreover, 2 of every 3 blood isolates from these children represent a contamination and not a true pathogen.[12, 14, 15]
S pneumoniae and Escherichia coli are the most common pathogens, accounting for two thirds of cases. Invasive pneumococcal disease is most common in children younger than 5 years. In infants with S pneumoniae, many isolates are strains not covered by the currently available 15- and 20-valent pneumococcal conjugate vaccines. Children with pneumococcal bacteremia may present with a focus, such as acute otitis media, pneumonia, symptoms of sinusitis, meningitis, or cellulitis (including orbital or facial cellulitis), or nonspecific febrile illnesses without a focus. E coli bacteremia is most common in children aged younger than 1 year and is usually associated with a UTI. Staphylococcus aureus may be associated with skin, soft tissues, or musculoskeletal infections. Salmonella species, Neisseria meningitidis, and Streptococcus pyogenes account for most of the remaining infections. After the COVID-19 pandemic, invasive group A streptococcal infections increased in children in the United States and in several European countries.[16, 17]
The approach to the febrile child aged 3 months to 3 years consists of a targeted medical history, a complete physical examination, and the judicious use of the laboratory tests.
Fever is a centrally mediated rise of body temperature higher than the normal daily variation in response to a stimulus such as a pathogen. Tissue damage and pathogens result in the release of cytokines (interleukin-1 [IL-1], IL-6, tumor necrosis factor, and interferon alpha) by the reticuloendothelial system, macrophages, and endothelium. These cytokines reach the optic area of the hypothalamus via systemic circulation and release primarily prostaglandin E2 (PGE2) by the hypothalamic endothelium. PGE2 raises the temperature set point to an elevated temperature, resulting in increased metabolic rate and decreased heat loss from the body.[18]
A study estimated the extent to which Canadian expectant parents would seek medical care in a febrile neonate (aged 30 days or younger). The study also evaluated expectant parents' knowledge of signs and symptoms of fever in a neonate and the actions Canadian expectant parents would take to optimize the health of their child. Despite universal access to high quality health care in Canada, the study highlighted concerning gaps in the knowledge of the care of the febrile infant in one fifth of expectant parents. Physicians and health providers should strive to provide early education to expectant parents about how to recognize signs of fever in the neonate and how best to seek medical care.[19]
A thorough history is essential for all neonates with fever. Associated symptoms may be system specific (eg, cough, diarrhea) or nonspecific (eg, poor feeding, irritability, lethargy). Seizures have been reported in neonates with meningitis; for example, 13% of infants with Escherichia coli meningitis had seizures in a national survey study in France.[20] Exposures to sick contacts in the household or childcare should be ascertained, as well as recent history of a previous illness, or antibiotic use while in the birth hospital or since discharge.
A review of the prenatal history, including maternal history of sexually transmitted infections (human immunodeficiency virus [HIV], hepatitis B and hepatitis C, syphilis, gonorrhea, chlamydia, herpes simplex), maternal group B Streptococcus (GBS) status and prophylaxis, mode of delivery, prolonged rupture of membranes, and history of maternal fever should be noted.
Determine maternal vaccination history during pregnancy, such as receipt of the tetanus diphtheria and pertussis (Tdap) and respiratory syncytial virus (RSV) vaccines.
A history of febrile illness in pregnancy with gastroenteritis should prompt inquiry on risk factors for Listeria infection, such as consumption of unpasteurized milk, soft cheeses, and ready-to-eat meats. Listeria infections have declined significantly over the past two decades, since the institution of stricter food industry regulations.
A birth weight of less than 2500 g, rupture of membranes before the onset of labor, septic or traumatic delivery, fetal hypoxia, maternal peripartum infection, and galactosemia are all risk factors for a serious bacterial infection in the neonate. Gestational age should be determined, because premature infants are at increased risk for serious bacterial infections. See the Gestational Age from Estimated Date of Delivery (EDD) calculator.
The neonate’s nursery course should be noted, including the age at which the patient went home from the nursery, whether or not a male neonate has been circumcised, and the use of peripartum or antepartum antibiotics. Any underlying diseases or conditions, as well as the use of medications that may increase the risk of infection, should be ascertained. Diet (ie, quantity and description of milk consumed; breast milk vs formula; and, if pertinent, the method the caregiver uses for preparing and storing the formula) and sleep histories should be obtained, because decreased oral intake or an acute change in sleep patterns may be clues to an invasive infection.
Any ill contacts in the household should also be noted. Exposure to any animals should be determined (eg, because of risk of invasive Pasteurella infection in neonates from exposure to cats' or dogs' saliva). A history of maternal fetal loss or death due to an infectious disease in a previous infant increases the suspicion of congenital anomalies and primary immunodeficiencies.
Identifying who is in the neonate’s household, who is the primary caregiver, contact with recent immigrants, and exposure to homelessness and poverty all impact the care the neonate receives (eg, exposure to tuberculosis).
A thorough review of systems must be obtained to identify any other symptoms associated with the fever. A complete physical examination is necessary, including vital signs of temperature, respiratory rate, heart rate, blood pressure, pulse oximetry, and growth parameters with percentiles. General appearance should be noted for activity level, color, tone, and irritability. Signs of localized infection should be identified via a thorough examination of the skin (vesicles, maculopapular rash, etc), mucous membranes (conjunctival injection, oral lesions, etc), ears (bulging tympanic membrane, etc), lungs (crackles, decreased air entry, etc), and extremities (redness, swelling, etc).
The presence of an umbilical stump after age 4 weeks should be noted, because it is a potential clue to leukocyte adhesion deficiency, and the lack of a circumcision in males should be noted, because it increases the risk for a urinary tract infection (UTI). In addition to fever, the most common clinical features of a UTI in a neonate include failure to thrive, jaundice (typically secondary to conjugated hyperbilirubinemia from cholestasis), and vomiting. Irritability, inconsolability, poor perfusion, poor tone, decreased activity, and lethargy can be signs of a serious infection in this age group.
Most neonates with bacterial meningitis have a full fontanelle with normal neck flexion at the time of presentation. Neonates with significant bacterial infections can appear to be at low risk when analyzing history, physical examination findings, and laboratory values; thus, a high index of suspicion must be maintained.
As is the case in neonates, a febrile infant aged 29-60 days may have symptoms that are nonspecific (eg, poor feeding, irritability, lethargy) or specific symptoms (eg, diarrhea, cough). History of exposure to sick contacts in the household or childcare should be obtained, as well as a recent history of a previous illness, immunization, and recent antibiotic use.
The past medical history needed is essentially the same as in neonates. A prenatal, perinatal, and neonatal history should be obtained. Underlying diseases or conditions and the use of medications that may increase the risk of infection should be determined. In addition, as with neonates, feeding and sleep histories should be obtained, because decreased oral intake or an acute change in sleep patterns may be clues to an invasive infection.
Determine maternal vaccination history during pregnancy, such as receipt of the Tdap and RSV vaccines. The vaccination status of household members should also be determined.
As with neonates: (1) a family history of a previous death in a young infant from an infectious disease increases the suspicion of congenital anomalies and primary immunodeficiencies, and (2) identifying who lives in the household, who is the primary caregiver, exposure to any recent immigrants, and exposure to homelessness and poverty helps establish risk for infection (eg, tuberculosis) and how to manage the infant.
A thorough review of systems must be obtained to identify any other symptoms associated with the fever. A complete physical examination including vital signs (temperature, respiratory rate, heart rate and blood pressure), pulse oximetry, and growth parameters with percentiles is necessary.
As with a neonate, irritability, inconsolability, poor perfusion, poor tone, decreased activity, and lethargy can be signs of a serious infection. Similarly, signs of localized infection should be identified by a thorough examination of the skin, mucous membranes, ears, and extremities. Lack of a circumcision in males should be noted (because of risk of UTI).
Bacterial meningitis is often associated with minimal signs and symptoms in this group, and a bulging fontanelle is a late sign. Nuchal rigidity is present in only 27% of infants younger than 6 months.
The medical history should focus on factors that would predispose the infant or toddler to serious bacterial infection.
Documentation of the child’s temperature and how it was measured is essential. In addition to identifying when the fever started and how long it has lasted, a detailed search should be made for other symptoms, including but not limited to diarrhea, vomiting, rhinorrhea, cough, rash, limp, and changes in weight or feeding habits.
Underlying chronic diseases, previous surgery, hospital admission, history of urinary tract infections (UTIs), and incomplete immunization to Streptococcus pneumoniae or Haemophilus influenzae type b must be specifically delineated. In infants younger than 9 months, neonatal and perinatal history is also important.
Episodes of recurrent infections among siblings and first cousins or a history of maternal fetal loss raises suspicion of primary immunodeficiencies. Parental HIV status is essential information. A history of chronic infections (eg, hepatitis B, hepatitis C, tuberculosis) in the immediate or extended family is also important to obtain. The presence of acute illness in the family, such as a respiratory tract infection, is useful information in determing the cause of fever in older infants and toddlers.
Animal and insect (tick, mosquito) exposure; exposure to contaminated potable water and sewage; recent travel (particularly international travel); and attendance at childcare provide epidemiologic and environmental clues to the etiology of fever.
A detailed review of systems helps to identify other symptoms associated with fever. Important associations include rash, conjunctivitis, ear pain or drainage, lymphadenopathy, respiratory symptoms, changes in appetite, weight loss, diarrhea, vomiting, changes in frequency of voiding, pain with voiding, failure to bear weight, pain on passive motion of an extremity, and overt neurologic symptoms.
A careful and thorough physical examination is essential in the evaluation of the febrile child. Vital signs, including length and weight with percentiles, should be part of the evaluation. The child’s general state of nutrition, level of activity, and level of arousal should be noted.
Physical examination findings that suggest serious bacterial infections in febrile children (aged 3-36 months) include ill appearance, fever, vomiting, tachypnea with retractions, and delayed capillary refill. These findings are associated with bacterial infection in more than 39.5% of febrile children aged 24-36 months and in more than 39% of children aged 3-24 months.
Careful examination of the skin, eyes, ears, nose, and throat is necessary, because many febrile infants have viral infections with associated rashes or associated respiratory symptoms. Inspection and auscultation of the chest should be included in all evaluations. The abdomen should be inspected for signs of distention. Auscultation may reveal signs of ileus or hyperactivity. The extremities should be evaluated for capillary refill; range of motion, swelling, and local tenderness should be evaluated. Neurologic and developmental examinations appropriate for age should be performed.
The extent of evaluation in a febile infant or toddler depends on the age at presentation, risk factors, underlying medical problems, immunization history, and severity of illness.
Note the following:
Additionally, the workup should be designed based on the history and physical examination and should consider the following:
A full sepsis evaluation is often recommended in febrile neonates and young infants. This includes laboratory tests for the following:
1 - Screening studies:
2 - Source studies:
Pending the results of these cultures, febrile neonates should be hospitalized and receive intravenous antibiotics.
For well-appearing febrile infants aged 8-21 days, clinical practice guidelines from the American Academy of Pediatrics (AAP) recommend a complete evaluation for invasive bacterial infection that includes urine, blood, and CSF for culture.[21, 22] This approach considers all infants in this age cohort as high risk. Urine samples for culture from these young infants should be obtained by catheterization or suprapubic aspiration.(See Guidelines for more detail.)
According to the AAP guidelines, well-appearing febrile infants aged 22-28 days are at intermediate risk.[21, 22] The recommendation for these infants is to obtain a urine specimen by catheterization or suprapubic aspiration for both urine analysis and culture. Blood culture, as well as inflammatory marker levels, should also be obtained from all infants in this age group. The AAP recommends considering a procalcitonin value of 0.5 ng/mL or higher as positive, which indicates that the infant is at greater risk for invasive bacterial infection and possibly should undergo an extensive workup with CSF studies.
Complete blood cell count: A study by Cruz et al analyzed the accuracy of individual CBC count parameters to identify febrile infants with invasive bacterial infections. The study included 4313 infants; 1340 (31%) were aged 0-28 days, of whom 97 (2.2%) had an invasive bacterial infection. The study reported low sensitivities for common CBC parameter thresholds. A white blood cell (WBC) count of < 5000/µL was detected 10% of the time; a WBC count of ≥15,000/µL, 27%; an absolute neutrophil count of ≥10 000/µL, 18%; and a platelet count of < 100 × 103/µL, 7%.[23]
C-reactive protein level: A marker released from the liver is commonly used as a sign of underlying infection or inflammation and has a high negative predictive value of 97%.[24] A value of >20 mg/L is considered abnormal. It is not specific, and the rise can be associated with noninfectious conditions: for example, respiratory distress syndrome in a premature neonate. It is beneficial in trending responses to treatment.
Procalcitonin level: It is expressed mainly by thyroid C cells and is produced rapidly in response to tissue injury or infection. A value of >0.5 ng/mL is considered abnormal. Compared with other markers such as CRP level or absolute neutrophil count, it is more specific for bacterial infection and is preferred when available.[25]
Detection of a viral pathogen on antigen and PCR panel may provide the etiology of fever in a neonate. Many PCR assays are commercially available either in the form of rapid detection of individual viruses, a combination of viruses (RSV, influenza, SARS-CoV-2), or multiplex PCR assays capable of identifying 20 common viruses and atypical bacteria. The presence of a virus does not preclude investigation for a bacterial pathogen.[26] Additionally, CSF PCR panels can detect viruses such as enterovirus and parechovirus as a cause of fever in a neonate.
Blood cultures are fundamental in testing for infections and are of the highest yield when obtained before antibiotic administration. Pediatric blood culture bottles are preferred (< 12.7 kg). Ideal blood volume is based on the weight to maximize yield (1 mL in a neonate of < 1 kg, 2 mL in a neonate of 1.1-2 kg, and 3 mL in a neonate of 2.1-12.7 kg). Many hospital laboratories use the Vitek System to identify bacteria and report antibiotic susceptibilities.
A lumbar puncture for CSF examination is recommended in all neonates younger than 21 days and may be considered in neonates 22-28 days if the screening inflammatory markers are elevated, or empiric antibiotics are to be given or if the neonate had a seizure. CSF should be assessed for WBC count and differential, glucose level, protein level, Gram staining, and routine culture. CSF should be tested for herpes simplex virus (HSV) using PCR in all neonates and infants with skin vesicles, seizures, hypothermia, CSF pleocytosis in the absence of a positive Gram stain result, leukopenia, thrombocytopenia, or elevated alanine aminotransferase levels
Enterovirus PCR analysis should be performed on the CSF during the summer enteroviral season. Additionally, meningitis/encephalitis pathogen PCR panels can identify common neonatal bacterial and viral causes and provide results within 2 to 3 hours. In a retrospective review, their use did not affect the length of stay or antibiotic or acyclovir use duration.[27]
Because the incidence of urinary tract infections (UTIs) is high in this age group, a urine specimen should be obtained for urinalysis and urine culture. A urine culture should be obtained through urethral catheterization, because bag urine specimens may reflect contamination. Urine testing in neonates includes both urinalysis and urine culture; pyuria may or may not be present, and a UTI may occur, especially early in the course.[28]
A study by Tzimenatos et al that included an analysis of data from 4147 febrile infants ≤60 days old reported that for the 289 infants with a UTI and colony counts of ≥50,000 colony-forming units (CFUs)/mL, a positive urinalysis regardless of bacteremia showed sensitivities of 0.94; 1.00 with bacteremia; and 0.94 without bacteremia. Specificity in all groups was 0.91.[29]
A stool culture or a gastrointestinal (GI) PCR panel is recommended when a neonate has diarrhea and blood, mucus, or both in the stool. An advantage of a GI PCR panel is the identification of common viruses, such as norovirus or sapovirus, in addition to the common bacterial pathogens responsible for gastroenteritis, such as diarrheagenic E coli, Salmonella, and Shigella. A drawback of GI PCR panels is the frequent detection of multiple pathogens, making it difficult to separate true diarrhea-causing pathogens from colonization.
A chest radiograph should be considered for neonates with signs of respiratory illness, such as cough, coryza, tachypnea, rales, rhonchi, retractions, grunting, nasal flaring, or wheezing.
In infants older than 29 days, low-risk criteria are well defined. The reference range white blood cell (WBC) count is 5000-15,000 cells/μL. However, the WBC count alone has poor sensitivity and specificity for identifying young infants with bacteremia and meningitis; thus, the decision to perform a sepsis workup should not be based on the WBC count alone.
Because urinary tract infections (UTIs) are still common in this age group, a urine specimen for urinalysis and urine culture must be obtained. Urinalysis and urine culture should be obtained in infants 29 days to 2 months of age. In infants older than 2 months of age, urinalysis with a reflex to urine culture should be sent, which implies that only if there is pyuria of more than 5 WBCs in a high-power field (HPF) and/or bacteriuria on automated urinalysis or more than 10 WBCs in an HPF (enhanced urinalysis) will a urine culture be done. A UTI is defined in infants aged 2 to 24 months as the presence of pyuria and/or bacteriuria plus growth of 50,000 CFUs/mL on urine culture.[30]
Chest radiography should be considered for infants with signs of respiratory illness, such as cough, coryza, tachypnea, rales, rhonchi, retractions, grunting, nasal flaring, or wheezing. During respiratory virus season, an attempt should be made to identify a respiratory viral etiology using PCR tests. Various PCR tests are now available for individual viruses, a combination of 2 or 3 viruses, or multiplex PCR panels that can detect 20 common viruses and atypical bacteria responsible for respiratory tract infections.
For well-appearing, febrile infants aged 29-60 days, a urine evaluation is recommended. The AAP suggests a two-step approach may be used: (1) obtaining a urine analysis by a noninvasive method and (2) obtaining a culture only if the urinalysis results are positive. However, only catheter or suprapubic specimens are appropriate for urine culture.[21, 22]
The AAP recommends that clinicians obtain blood cultures for all infants aged 29-60 days without a focus of infection. Inflammatory markers should also be assessed, because lumbar puncture for CSF culture may be avoided in these infants if the tests for inflammatory markers are negative. If CSF is obtained, enterovirus testing is recommended. Meningitis/encephalitis pathogen PCR panels can identify common bacterial and viral causes.
Although some experts consider a lumbar puncture optional in well-appearing infants with low-grade fever who are older than 28 days, a diagnosis of meningitis carries a significant risk of morbidity and mortality, and acceptable risk must be determined for each individual patient.
Various criteria have been developed in an attempt to identify the infant older than 28 days at low risk for a serious bacterial infection. The incidence of a serious bacterial infection in infants categorized as low risk after a full evaluation is small (0.5% in studies that included a lumbar puncture and 1.1% in studies without a lumbar puncture).
These studies have led to the development of the Rochester, Boston, and Philadelphia protocols, all of which were conducted in urban emergency departments. The Rochester and Boston criteria exclude patients with ear infections from low-risk groups, and the Philadelphia criteria considers low-risk infants those with an "unremarkable physical examination."
However, subsequent studies have shown that, when these criteria are applied to the neonatal population (age, 1-28 d), an increased number of infants with serious bacterial illnesses are misidentified as low risk when compared with infants aged 1-3 months. Neonates should be considered high risk, and a complete sepsis evaluation should be performed. All febrile neonates should be hospitalized and should receive empiric antibiotic therapy.
The importance of reliable follow-up cannot be overstressed if the decision is made not to perform invasive studies in a febrile, well-appearing infant; no guidelines for the minimal evaluation of a febrile, well-appearing infant are recognized. If empiric antibiotics are given, a lumbar puncture should always be performed.
Rochester criteria
The Rochester criteria are used to assess febrile (temperature > 38°C) infants aged 28-60 days.[31] The risk for occult bacteremia in well-appearing febrile infants is 7-9%; if all Rochester criteria are present, the risk is less than 1%. Infants at high risk were hospitalized with empiric antibiotics, and infants at low risk were discharged with follow-up in 24 hours.[31]
The Rochester low-risk criteria for occult bacteremia include the following[31] :
Boston criteria
The Boston criteria are used to assess febrile (temperature > 38°C) infants aged 28-89 days.[32] Infants who met these criteria were managed as outpatients with 50 mg/kg ceftriaxone intramuscularly at the time of discharge. The scheduled follow-up visit was in 24 hours; 5.4% of patients had a serious bacterial infection at follow-up.
The Boston low-risk criteria for occult bacteremia are as follows[32] :
Philadelphia criteria
The Philadelphia criteria were used to assess febrile infants aged 29-60 days with fever (> 38.2°C). All high-risk patients were hospitalized and treated with empiric antibiotics. Low-risk patients were not treated with antibiotics, with follow-up in 24 hours. Sensitivity for identifying patients with a serious bacterial infection was 98%, specificity was 42%, positive predictive value was 14%, and the negative predictive value was 99.7%.
The Philadelphia low-risk criteria for occult bacteremia included the following:
The laboratory evaluation of children aged 3 months to 3 years consists of two parts.
The first part is dictated by epidemiologic and focal findings uncovered by the history and physical examination. Children with cough and respiratory distress should undergo chest radiography as part of their evaluation; children with limp or evidence of focal infection should undergo appropriate imaging studies (a hip ultrasound scan, bone MRI scan, etc).
The second part of the evaluation is designed to identify patients at low risk for serious bacterial infections. Children who appear clinically ill, have a history of vomiting, have chest wall retractions with tachypnea, or have delayed capillary refill times are at increased risk for bacterial infection. Increasing fever also increases the risk of bacterial infection. Children aged 3-24 months with fever exceeding 39ºC and children aged 24-36 months with fever exceeding 39.5ºC have a higher risk of bacteremia than children with lower temperatures.[34]
Occult UTI is the most common cause of unexplained fever and bacteremia in females and uncircumcised males in this age group; thus, all of such children should undergo a urine culture. This is the only routine laboratory study recommended by most experts. Circumcised males should have a urinalysis and if abnormal, culture of the urine.
Catheterized, unspun urine samples with more than 10 WBCs per HPF or bacteria found in any of 10 oil immersion fields of a Gram-stained sample is highly suggestive of infection. The presence of leukocyte esterase or nitrites by dipstick of unspun samples also suggests infection. Febrile children with suspicious urinalysis findings require cultures of both urine and blood. Urine cultures that yield more than 50,000 CFUs/mL are diagnostic of infection.[35] Many children's hospitals use automated urinalysis systems (spun urine sample, with criteria of more than 5 WBCs).
WBC counts, absolute neutrophil counts (ANC) (see the Absolute Neutrophil Count calculator), serum C-reactive protein (CRP) concentration, and serum procalcitonin concentration are additional metrics that help to distinguish further children at low risk for serious bacterial infection.
Total WBC counts below 15,000 cells/μL, ANCs below 10,000 neutrophils/μL, CRP concentrations less than 40 mg/L, and serum procalcitonin levels less than 0.5 ng/mL identify children at low risk for serious bacterial infection.[13, 36, 37, 38]
Laboratory findings suggestive of serious bacterial infections include the following:
- Enhanced (unspun): More than 10 WBCs/HPF, bacteria in any of 10 HPFs, or positive leukocyte esterase and nitrite findings
- Automated (spun): More than 5 WBCs/HPF, presence of bacteria, positive leukocyte esterase and/or nitrite
The clinical management of infants and toddlers with fever is based on their age group.
Management should be individualized based on host factors (age, immunization status, immune status), risk factors (exposure to sick contacts, recent antibiotic use, recent hospital stay), clinical appearance, and clinical judgment.
Ill-appearing children with poor capillary refill and lethargy and children who have clinical signs and symptoms suggestive of meningitis need workup, timely antibiotics, and hospitalization. Children with focal infections such as otitis media and pneumonia need to be managed with appropriate antimicrobial therapy. Infants and children without a focus of infection should be tested for UTI, occult bacteremia, and viral infections.
For any well-appearing febrile infant considered at higher risk for invasive bacterial infection (young age, ill appearance, prematurity < 37 weeks, technology-dependent [tracheostomy, ventriculoperitoneal shunt, G-tube], immune deficiency, congenital chromosomal abnormality, maternal risk factors for sepsis in a neonate [peripartum maternal fever, prolonged rupture of membrane, vaginal culture positive for GBS]), the American Academy of Pediatrics recommends a 24- to 36-hour rule-out period with empiric antimicrobial treatment and active monitoring in the hospital. Presumptive treatment can be discontinued if bacterial cultures are sterile after 24-36 hours of incubation.[21, 22] With the widespread use of pneumococcal vaccine in young children, the incidence of occult bacteremia in febrile children aged 3 months to 3 years has fallen from 4.6% to less than 1%.[12, 39]
Fever management includes ensuring adequate hydration, decreasing activity, and considering antipyretics.
Treating fevers with antipyretics should be based on shared decision-making with the parents. Potential benefits of antipyretic therapy include relief from discomfort, analgesia, and reducing the risk of dehydration. Antipyretics should be used based on weight in children, not age. The choice of antipyretics depends upon underlying liver issues (avoid acetaminophen) and interaction with other medications (avoid selective serotonin inhibitor use with ibuprofen, which can enhance the antiplatelet effect). Acetaminophen should not be administered to infants younger than 3 months, and ibuprofen should not be administered to infants younger than 6 months without evaluation by a pediatrician.[40]
Acetaminophen is preferred in infants less than 6 months of age based on the safety profile, as ibuprofen can be associated with renal toxicity because of limited renal reserve compared with older infants and young children. Ibuprofen is slightly more effective and lasts longer than acetaminophen. Ibuprofen has an anti-inflammatory effect in addition to an antipyretic effect. Alternating acetaminophen and ibuprofen is discouraged, as it can lead to confusion and toxicity. Switching is reasonable if the discomfort is not relieved by an antipyretic after 3 to 4 hours.
Intravenous (IV) acetaminophen is approved by the US Food and Drug Administration (FDA) to treat fever in children of all ages, including premature neonates, neonates, and infants. Rectal acetaminophen is also an option in children at home who cannot tolerate oral acetaminophen .
Ampicillin and gentamicin, or ampicillin and cefotaxime for the neonate, covers GBS, E coli, Listeria, and most S pneumoniae and N meningitidis. For infants aged 1-2 months, recommended empiric coverage includes ampicillin, cefotaxime, and vancomycin to provide adequate coverage for community-acquired pathogens. All antibiotic dosages should be adequate to treat meningitis. For infants older than 2 months, vancomycin and cefotaxime are the empiric antibiotic choices. Vancomycin is especially important if the patient has evidence of soft-tissue infection, given the increasing prevalence of methicillin-resistant S aureus (MRSA), or a CSF profile consistent with bacterial meningitis to cover for antibiotic-resistant S pneumoniae.
Well-appearing and relatively well-appearing infants
Relatively well-appearing febrile infants younger than 28 days who are diagnosed with a viral respiratory tract illness should have a septic workup that includes cultures of blood, urine, and CSF. These infants should receive empiric antibacterial therapy in the hospital until culture results are known.
Infants older than 28 days who look well and whose history, physical examination, and laboratory evaluation findings classify them as low risk can be treated as outpatients with ceftriaxone (50 mg/kg in a single intramuscular dose), as long as 24-hour follow-up can be ensured.
Infants older than 28 days who are diagnosed with bronchiolitis or influenza and are relatively well-appearing should undergo a limited laboratory evaluation, including CBC count with differential, blood culture, urinalysis, and urine culture. If the CBC count and urinalysis findings are benign, these patients can be initially managed without antibacterial therapy.
Ill-appearing neonates
In addition to empiric antibiotics, acyclovir (60 mg/kg/d divided every 8 h) is recommended for febrile neonates who appear ill, have mucocutaneous vesicles, experience seizures, or have a CSF pleocytosis.[33] In addition, herpes simplex virus (HSV) polymerase chain reaction (PCR) or viral culture should be performed on skin vesicles and conjunctival, nasopharyngeal, and rectal mucous membranes. CSF should be assessed for HSV PCR.
Empiric antimicrobial therapy in non–toxic-appearing children aged 3 months to 3 years is not recommended. For those requiring hospitalization, antimicrobial therapy must provide coverage against the suspected pathogens and must achieve high and sustained serum concentrations.[41] In this setting, a single intramuscular (IM) dose of ceftriaxone has been shown to prevent sustained bacteremia in children whose initial blood culture has yielded Streptococcus pneumoniae. In vitro, ceftriaxone is also effective against most strains of E coli, thus supporting the empiric use of this agent until bacterial culture results are known (see Workup).
A retrospective study by Shaikh et al that included 482 children aged younger than 6 years with a first or second UTI found that renal scarring was associated with a delay in the initiation of antimicrobial therapy. Thirty-five children (7.2%) developed new renal scarring, and the median duration of fever before initiation of antibiotic therapy in the group with renal scarring was 72 hours compared with 48 hours in children with no renal scarring.[42]
Children at risk for Staphylococcus aureus infections (ill-appearing; device [ventriculoperitoneal shunt, central lines, etc]; cancer, bone, or joint focus; or history of skin infections) should receive vancomycin (methicillin-resistant) or cefazolin/nafcillin (methicillin sensitive). Children with suspected toxic shock syndrome or necrotizing skin and soft tissue infections should also be started on either clindamycin or linezolid for an anti-toxin effect.
Clinical practice guidelines on the evaluation and management of febrile infants were published in August 2021 by the American Academy of Pediatrics (AAP).[21, 22] The guidelines cover the assessment and treatment of well-appearing term infants aged 8-60 days who have a fever of at least 100.4°F (38°C).
Infants Aged 8-21 Days
Urinalysis, blood culture, and analysis of cerebrospinal fluid (CSF) are strongly recommended for infants in this age group. Parenteral antimicrobial therapy and active monitoring by nurses and hospital staff with experience in neonatal care are also strongly recommended. Infants with positive results of urine, blood, or CSF testing for bacterial pathogens should receive targeted antimicrobial therapy. Parenteral antibiotics can be discontinued and patients can be discharged when culture results have been negative for 24-36 hours and the infant appears clinically well or is improving.
Infants Aged 22-28 Days
Urinalysis, blood culture, and assessment of inflammatory markers are strongly recommended for infants in this age group. If more than one inflammatory marker level is abnormal, CSF analysis and bacterial culture are recommended. When CSF analysis has not been performed or the results are uninterpretable, the infant should be hospitalized. Antimicrobial agents can be discontinued and patients can be discharged when culture results have been negative for 24-36 hours, the infant appears clinically well or is improving, and no other infection requiring treatment is present.
Infants may be managed at home if they have negative CSF analysis and urinalysis results and no abnormal inflammatory marker levels. Infants who will be treated at home should receive parenteral antimicrobial therapy. In addition, home care should involve verbal and written instructions for caregivers, plans for re-evaluation in 24 hours, and plans for access to emergency care if the patient’s clinical status changes.
Infants Aged 29-60 Days
Urinalysis, blood culture, and assessment of inflammatory markers are recommended for infants in this age group. If all inflammatory marker levels are normal, CSF analysis and culture are not necessary. However, CSF testing may be performed if any inflammatory marker level is abnormal. If CSF analysis suggests bacterial meningitis, parenteral antimicrobial therapy is strongly recommended. Antimicrobial therapy is not required for patients with normal CSF analysis results, negative urinalysis results, and normal results of testing for inflammatory markers.
Antibiotics are used to treat occult bacterial infection. Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens for the patient's age range and in the clinical setting. Whenever feasible, select antibiotics based upon blood culture sensitivity.
Clinical Context: Ampicillin is a beta-lactam antibiotic that is bactericidal for susceptible organisms, such as group B Streptococcus (GBS), Listeria, non–penicillinase-producing Staphylococcus, some strains of Haemophilus influenzae, and meningococci. Reports have indicated ampicillin (in combination with gentamicin) is the first-line therapy for suspected sepsis in the newborn.
Clinical Context: Gentamicin is an aminoglycoside that is bactericidal for susceptible gram-negative organisms, such as Escherichia coli and Pseudomonas, Proteus, and Serratia species. This agent is effective in combination with ampicillin for group B Streptococcus (GBS) and Enterococcus. Reports have indicated gentamicin (in combination with ampicillin) is the first-line therapy for suspected sepsis in the newborn.
Clinical Context: Cefotaxime is a third-generation cephalosporin with excellent in vitro activity against group B Streptococcus (GBS) and Escherichia coli and other gram-negative enteric bacilli. This agent has good serum and cerebrospinal fluid (CSF) concentrations. However, concern exists about the emergence of drug-resistant gram-negative bacteria at a more rapid rate than with traditional penicillin and aminoglycoside coverage. In addition, cefotaxime is ineffective against Listeria and enterococci; use in combination with ampicillin. In more recent publications, this drug is not a first-line agent for neonatal sepsis because of its association with increased mortality.
Clinical Context: Vancomycin is a bactericidal agent against most aerobic and anaerobic gram-positive cocci and bacilli; this is especially important in the treatment of methicillin-resistant Staphylococcus aureus (MRSA). Vancomycin is recommended therapy when coagulase-negative staphylococcal sepsis is suspected. Therapy with rifampin and/or gentamicin may be required with endocarditis or cerebrospinal fluid (CSF) shunt infection by coagulase-negative Staphylococcus.
Clinical Context: Ceftriaxone is a third-generation cephalosporin with broad-spectrum, gram-negative activity; lower efficacy against gram-positive organisms; and higher efficacy against resistant organisms. The bactericidal activity of this drug results from inhibiting cell wall synthesis by binding to one or more penicillin binding proteins; ceftriaxone exerts antimicrobial effect by interfering with the synthesis of peptidoglycan, a major structural component of bacterial cell wall. Bacteria eventually lyse due to the ongoing activity of cell wall autolytic enzymes while cell wall assembly is arrested.
Ceftriaxone is highly stable in the presence of beta-lactamases, both penicillinase and cephalosporinase, of gram-negative and gram-positive bacteria. Approximately 33-67% of the drug dose is excreted unchanged in urine, and the remainder is secreted in bile and ultimately in feces as microbiologically inactive compounds. Ceftriaxone reversibly binds to human plasma proteins, and binding has been reported to decrease from 95% bound at plasma concentrations < 25 mcg/mL to 85% bound at 300 mcg/mL.
Clinical Context: Clindamycin is a semisynthetic antibiotic produced by the 7(S)-chloro-substitution of the 7(R)-hydroxyl group of the parent compound lincomycin. This agent inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Clindamycin widely distributes in the body without penetration of the central nervous system (CNS); this drug is protein bound and excreted by the liver and kidneys.
Clindamycin is used for treatment of serious skin and soft tissue staphylococcal infections. It is also effective against aerobic and anaerobic streptococci (except enterococci).
Clinical Context: An oxazolidinone that inhibits bacterial protein synthesis by binding to bacterial 23S ribosomal RNA of the 50S subunit. Linezolid demonstrate activity in vitro against a variety of gram-positive bacteria including streptococci, enterococci (including vancomycin-resistant enterococci), coagulase-negative staphylococci, methicillin-sensitive Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), Bacillus species, Corynebacterium species, and Listeria monocytogenes
Empiric antimicrobial therapy must provide coverage against the suspected pathogens for a given age group, and treatment must achieve high and sustained serum concentrations (see Treatment).
Clinical Context: Acyclovir is a prodrug activated by phosphorylation by virus-specific thymidine kinase that inhibits viral replication. The Herpes virus thymidine kinase (TK), but not host cells TK, uses acyclovir as a purine nucleoside, converting it into acyclovir monophosphate, a nucleotide analogue. Guanylate kinase converts the monophosphate form into diphosphate and triphosphate analogues that inhibit viral DNA replication.
Acyclovir has affinity for viral TK and, once phosphorylated, causes DNA chain termination when acted on by DNA polymerase. This drug inhibits the activity of both Herpes simplex virus type 1 (HSV-1) and HSV-2. Patients experience less pain and faster resolution of cutaneous lesions when acyclovir is used within 48 hours from rash onset. This agent may prevent recurrent outbreaks. Early initiation of therapy is imperative.
Nucleoside analogs are initially phosphorylated by viral thymidine kinase to eventually form a nucleoside triphosphate. These molecules inhibit HSV polymerase with 30-50 times the potency of human alpha-DNA polymerase.
Clinical Context: NSAID that is indicated for reduction of fever.
Clinical Context: Indicated for management of mild-to-moderate pain, management of moderate-to-severe pain as an adjunct to opioid analgesics, and fever reduction in patients aged 3 months and older.
Clinical Context: Indicated for reduction of fever. Caution when administering as the various oral liquid products are available in a variety of dosage concentrations. Carefully calculate dosage and volume of dose according to specific product.
Clinical Context: Indicated for reduction of fever in children, infants, and neonates, including premature neonates born at ≥32 weeks gestational age.