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Fever without a source in children 3 to 36 months of age: Evaluation and management

Fever without a source in children 3 to 36 months of age: Evaluation and management
Author:
Coburn H Allen, MD
Section Editors:
Sheldon L Kaplan, MD
Mark I Neuman, MD, MPH
Deputy Editor:
James F Wiley, II, MD, MPH
Literature review current through: Dec 2022. | This topic last updated: Oct 06, 2022.

INTRODUCTION — This topic will review the etiology, evaluation, and management of the otherwise healthy child 3 to 36 months of age with fever less than five days in duration. Fever in newborns and infants younger than three months, fever in immunocompromised patients, atypical Kawasaki disease (which may present with fever of five days or longer), and fever of unknown origin (fever lasting seven days or longer) are reviewed separately:

(See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates" and "Management of neonates at risk for early-onset group B streptococcal infection".)

(See "The febrile infant (29 to 90 days of age): Outpatient evaluation".)

(See "Fever in children with chemotherapy-induced neutropenia" and "Management of children with non-chemotherapy-induced neutropenia and fever".)

(See "Evaluation and management of fever in children and adults with sickle cell disease".)

(See "Fever of unknown origin in children: Evaluation" and "Fever of unknown origin in children: Etiology".)

(See "Incomplete (atypical) Kawasaki disease".)

DEFINITIONS

Fever of concern — Fever of ≥39°C (102.2°F) taken rectally is the threshold above which evaluation for a source of occult infection, including urinary tract infection (UTI), may be warranted in children 3 to 36 months of age with no identified infectious source on physical examination [1]. A temperature of 39°C or greater by methods other than rectal measurement should be regarded as a fever of concern. Temperatures measured by other, non-rectal methods that are near 39°C should be interpreted on a case-by-case basis using the overall clinical assessment. (See "Fever in infants and children: Pathophysiology and management", section on 'Site and method of measurement'.)

The history of an elevated temperature recorded at home should be considered equivalent to that taken in a medical facility, especially if antipyretic medications have been given prior to evaluation. Although a temperature ≥39°C (102.2°F) may require additional evaluation, febrile children with temperatures lower than this threshold can also have a serious bacterial infection and warrant careful assessment of all clinical findings to determine further care. Furthermore, in addition to occult infection, prolonged fevers may warrant additional workup for atypical Kawasaki disease (duration ≥5 days) or fever of unknown origin (duration ≥7 days). (See "Incomplete (atypical) Kawasaki disease" and "Fever of unknown origin in children: Evaluation".)

In some settings, the diagnosis and height of fever are obtained by measurement at other sites (eg, axillary or tympanic membrane). However, investigations for risk of serious bacterial illness have typically relied on rectal temperatures [1]. For this reason, we advise the use of rectal temperatures to guide decision-making in this age group. If rectal temperatures are not available in a setting, then measurements from other sites need to use the range of normal values for that device to determine if a fever is present. Furthermore, the clinician should recognize that these devices may provide contradictory results when compared with rectal temperatures. (See "Fever in infants and children: Pathophysiology and management", section on 'Site and method of measurement'.)

Fever with a source — Among children with fever presenting to a primary care provider or emergency department, approximately 55 to 60 percent will have an identified bacterial or viral infection on physical examination [2,3]. Causes include:

Acute otitis media – The majority of these patients with bacterial infection have acute otitis media, although unimmunized or incompletely immunized children with acute otitis media and a temperature ≥39°C (102.2°F) are still at risk for occult bacteremia [2] (see 'Risk by immunization status' below).

Recognizable or rapidly diagnosed viral illness – A recognizable or rapidly diagnosed viral illness (eg, enterovirus and parechovirus, influenza, COVID-19, croup, bronchiolitis) accounts for up to 6 percent of young children presenting with fever [2,3].

Enterovirus and parechovirus infection (hand, foot, and mouth, disease) – During the summer months, infants and young children with non-polio enterovirus infection may demonstrate fever and an oral enanthem (picture 1 and picture 2) or herpangina (picture 3) as well as a cutaneous exanthem (picture 4 and picture 5). (See "Hand, foot, and mouth disease and herpangina" and "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention".)

Seasonal influenza – Influenza occurs in distinct outbreaks every year, mainly during the winter months in temperate climates, although the specific timing and duration of the influenza season vary from country to country and year to year. Clinical features of uncomplicated influenza in children consist of fever, cough, and rhinitis. For children <5 years of age and especially <2 years of age, confirmation by laboratory testing is recommended due to the high risk of complications (table 1). (See "Seasonal influenza in children: Clinical features and diagnosis" and "Seasonal influenza in children: Management".)

COVID-19 – Infants >3 months of age and young children with COVID-19 frequently have fever, sore throat, nasal congestion, and cough. Vomiting and diarrhea have also been described. Testing is necessary to confirm infection, although there is geographic variability in the criteria for testing. (See "COVID-19: Clinical manifestations and diagnosis in children", section on 'Approach to diagnosis'.)

Croup – Croup typically occurs in children six months to three years of age. Symptoms usually begin with nasal discharge, congestion, and coryza and progress over 12 to 48 hours to include fever, hoarseness, barking cough, and stridor. (See "Croup: Clinical features, evaluation, and diagnosis".)

Bronchiolitis – Bronchiolitis is a clinical syndrome of respiratory distress that occurs primarily in children younger than two years of age and generally presents with fever (usually ≤38.3°C [101°F]), cough, and respiratory distress (eg, increased respiratory rate, retractions, wheezing, crackles). It often is preceded by a one- to three-day history of upper respiratory tract symptoms (eg, nasal congestion and/or discharge). (See "Bronchiolitis in infants and children: Clinical features and diagnosis".)

Serious bacterial infections – Serious bacterial infectious syndromes that occur in children 3 to 36 months of age include meningitis, sepsis, pneumonia, septic arthritis, and cellulitis. In one series of 996 febrile children younger than 36 months of age performed prior to the availability of Streptococcus pneumoniae (PCV7 or PCV13) or Haemophilus influenzae, type b (Hib) conjugate vaccines, <1 percent had meningitis, 10 percent had focal soft tissue infections, and 30 percent had pneumonia [4]. These diagnoses are discussed in detail elsewhere. (See "Bacterial meningitis in children older than one month: Clinical features and diagnosis" and "Community-acquired pneumonia in children: Clinical features and diagnosis", section on 'Clinical presentation' and "Cellulitis and skin abscess: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

Noninfectious fever – Immunization reactions are the most frequent source of noninfectious fever in children 3 to 36 months of age.

Other noninfectious etiologies for fever are uncommon and include Kawasaki disease, drug fever, central nervous system dysfunction, malignancy (eg, leukemia), and chronic inflammatory conditions (eg, inflammatory bowel disease and juvenile idiopathic arthritis).

Although tooth eruption may be associated with an increase in body temperature, it should not be considered a source of fever (ie, temperature >38°C [100.4°F]). (See "Anatomy and development of the teeth", section on 'Teething symptoms'.)

Fever without a source — When a complete history and physical examination cannot identify a specific source of fever ≥39°C (102.2°F) in previously healthy, otherwise well-appearing child between three months and three years of age, the illness is called fever without a source [1]. Alternative terms are fever without localizing signs or fever without a focus. Previously healthy children 3 to 36 months of age with fever ≥39°C (102.2°F) and no infectious source identified on physical examination are at risk for occult infections such as UTI, occult bacteremia, and clinically occult pneumonia. (See 'Occult bacterial infection' below.)

Fever without a source has been described in febrile young infants with COVID-19 but has not been commonly reported in young children with SARS-CoV-2 infection. Nevertheless, it is an important consideration in children with a known exposure to COVID-19 or those who develop other manifestations of the infection. (See "COVID-19: Clinical manifestations and diagnosis in children", section on 'Clinical manifestations'.)

OCCULT BACTERIAL INFECTION — The majority of children who are well-appearing and have no identifiable source of infection have a self-limited viral illness [2,5]. Bacterial infections that may not be clinically apparent despite a careful physical examination primarily consist of urinary tract infections (UTIs), bacteremia, and pneumonia.

Urinary tract infection — With a prevalence of about 8 to 10 percent in young children with a fever ≥39°C (102.2°F), UTI is the most common occult bacterial infection among febrile infants and young children [6,7]. The prevalence of UTI is significantly influenced by demographic factors such as sex, age, and circumcision status (table 2). Furthermore, the presence of another potential source of fever (eg, upper respiratory tract infection, acute otitis media, or acute gastroenteritis) does not rule out the possibility of UTI, and patients with high fever and known urologic abnormalities. (See "Urinary tract infections in children: Epidemiology and risk factors", section on 'Host factors' and "Urinary tract infections in infants and children older than one month: Clinical features and diagnosis", section on 'Clinical evaluation'.)

In children younger than two years, UTI may present with nonspecific symptoms; fever may be the sole manifestation. UTICalc can be used to estimate the probability of UTI in febrile children ages 2 through 23 months according to clinical characteristics. We obtain a urine sample in febrile children <2 years of age with a pretest probability of UTI ≥2 percent (ie, approximately 10 children need to be tested for every UTI detected). For children ≥2 years old, potential indications for urine testing are provided in the table (table 3) and as follows (see "Urinary tract infections in infants and children older than one month: Clinical features and diagnosis", section on 'Laboratory evaluation and diagnosis'):

Females – Based on UTICalc, the probability of UTI is approximately 5 to 17 percent among females age 3 to 24 months old with high fever (≥39°C [102.2°F]) and no source regardless of duration and warrants urine testing.

Males – Among highly febrile males (≥39°C [102.2°F]) who are 3 to 24 months of age, uncircumcised, and with no source of infection, urine testing is also warranted because UTICalc estimates the probability of UTI as similar to febrile females with these characteristics.

By contrast, circumcised males with high fever have a probability of UTI that is <1 percent and urine testing is not indicated unless the patient has a prior history of UTI or known genitourinary anomaly.

The recommended method for obtaining a urine sample depends upon whether or not the child is toilet-trained, and interpretation of dipstick and microscopic urinalysis are discussed separately. (See "Urinary tract infections in infants and children older than one month: Clinical features and diagnosis", section on 'Laboratory evaluation and diagnosis'.)

Bacteremia — Occult bacteremia is defined as the isolation of a bacterial pathogen in a blood culture taken from an otherwise well-appearing febrile child. The risk of occult bacteremia in these patients depends upon their immunization status. (See 'Risk by immunization status' below.)

By contrast, bacteremia that occurs in a seriously ill patient with a focal infection (eg, meningitis, septic arthritis, or cellulitis) is usually readily identified. The risk of sepsis in a child who is ill appearing, febrile, and without an obvious source of infection is also high. The recognition and treatment of sepsis and septic shock in children are discussed separately. (See "Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis" and "Septic shock in children: Rapid recognition and initial resuscitation (first hour)".)

Risk by immunization status — The risk of occult bacteremia in the child who has fever without a source is largely determined by immunization status:

Completely immunized – The incidence of occult bacteremia in completely immunized children who have fever without a source is <1 percent [8-18]. This degree of protection has generally occurred in children who have received the primary series of three immunizations with conjugate vaccines against S. pneumoniae (PCV7 or PCV13) and at least two or three doses, depending upon vaccine formulation, of H. influenzae, type b (Hib). Using these criteria, any child under six months of age is incompletely immunized. However, some experts consider two doses of PCV7 or PCV13 sufficient to prevent invasive S. pneumoniae infection [19]. (See "Standard immunizations for children and adolescents: Overview", section on 'Routine schedule'.)

Although evidence is limited, the risk of bacterial infection does not appear to be increased in completely immunized febrile children who are highly febrile (ie, ≥40°C [104°F]). For example, in a single-center cohort study performed after wide availability of conjugated vaccines, occult pneumococcal bacteremia occurred in 3 of 363 (0.8 percent [95% CI 0-1.8 percent]) previously healthy, well-appearing, immunized children 3 to 24 months of age who had a fever ≥40.5°C (104.9°F) and no focus of infection on examination [20]. Furthermore, in a large prospective observational study published since wide availability of conjugate vaccines, body temperature was not an accurate marker for the presence of serious bacterial illness in children [21]. However, the patient population in this study included infants younger than three months of age, children older than 36 months of age, and patients with a focus of infection on physical examination. Thus, this study may be less applicable to infants and young children 3 to 36 months of age with fever without a source.

Given the decreased prevalence of occult bacteremia in the post-conjugate vaccine era, a less aggressive approach to the evaluation and management of completely immunized, well-appearing, febrile (≥39°C [102.2°F]) children 3 to 36 months of age who do not have a focus of infection on examination is recommended [13,22-24]. (See 'Completely immunized' below.)

Unimmunized or incompletely immunized — The frequency of occult bacteremia in well-appearing 3- to 36-month-old children with temperatures >39°C (102.2°F) prior to the availability of PCV7 or PCV13 and Hib conjugate vaccines was 3 to 11 percent [25]. If left untreated, occult bacteremia progressed to invasive bacterial infection, including meningitis, in approximately 5 percent of these patients depending upon the specific pathogen [25,26]. A shorter duration of fever (<2 days) was associated with occult bacteremia [27]. In the post-conjugate vaccine era, herd immunity has decreased the risk for invasive bacterial illness in unvaccinated children and adults, although the risk is still higher than in vaccinated patients.

Since routine immunization with conjugate vaccines has become established, herd immunity provides some protection for unimmunized or incompletely immunized children (ie, received fewer than three immunizations with PCV7 or PCV13 and two or three doses, depending upon vaccine formulation, of Hib). However, similar to young children in the pre-conjugate vaccine era, these patients still have a substantial risk for occult bacteremia and subsequent invasive bacterial infections [25,26,28,29]. Furthermore, response to antipyretic therapy, well appearance, or presence of either an acute otitis media or nonspecific upper respiratory tract infection on examination does not lower this risk [30-33]. Factors that increase the risk of pneumococcal occult bacteremia include younger age, higher fever, and elevations of the white blood cell or absolute neutrophil count [34,35]. (See 'Utility of diagnostic studies' below.)

Microbiology — Before routine availability of pneumococcal and Hib conjugate vaccines, the predominant pathogens were S. pneumoniae (80 percent) and Hib (20 percent). Neisseria meningitidis and other pathogens (Staphylococcus aureus, group A beta-hemolytic Streptococcus [GABHS], group B Streptococcus, Salmonella species, Escherichia coli) represented a small number of cases. In the post-conjugate vaccine era, pathogens other than S. pneumoniae cause the majority of cases of unsuspected bacteremia and, based upon blood cultures in one large health care system, the annual rate of bacteremia for all organisms has fallen from 97 to 21 cases per 100,000 children [11,17,36]. E. coli and S. aureus are frequently isolated organisms [17]. Most reports of occult bacteremia also include cases caused by Neisseria meningitidis, group A streptococcus, and Salmonella species [11,36,37]. With these pathogens, less evidence is available to guide the use of laboratory parameters (ie, white blood cell [WBC] count >15,000/microL) to predict the risk for bacteremia. (See 'White blood cell and absolute neutrophil counts' below.)

Pneumonia — Most children with fever and pneumonia have some abnormality on physical examination: usually cough, tachypnea, abnormal auscultation, low pulse oximetry, retractions, and/or nasal flaring suggesting respiratory tract disease. (See "Community-acquired pneumonia in children: Clinical features and diagnosis".)

However, a reliable physical examination in a young child can be a challenge, and pneumonia may not be apparent. In an observational study conducted prior to widespread pneumococcal immunization, radiographic pneumonia was found in 20 to 30 percent of over 270 young children (<5 years) with temperature ≥39oC, no clinical evidence of pneumonia, but with WBC ≥20,000/microL [38]. Similarly, another observational study demonstrated that 41 percent of children between 3 and 36 months of age with WBC >25,000/microL had lobar or segmental pneumonia on chest radiograph [39]. This association between leukocytosis and pneumonia remains strong, even in the post-conjugate pneumococcal vaccine era [40]. Clinical features, indications for chest radiographs, and diagnosis of community-acquired pneumonia in children are discussed in greater detail separately. (See "Community-acquired pneumonia in children: Clinical features and diagnosis".)

ILL-APPEARING PATIENTS — Previously healthy febrile children who are ill appearing or have unstable vital signs should be managed for presumed sepsis or septic shock (ie, rapid stabilization, evaluation for serious infection, and empiric treatment with intravenous antibiotics as discussed in detail separately). (See "Septic shock in children: Rapid recognition and initial resuscitation (first hour)" and "Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis".)

In addition, children with clinical findings of the pediatric multisystem inflammatory disease reported with COVID-19 warrant evaluation for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure or infection (table 4). (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis".)

WELL-APPEARING PATIENTS

Evaluation — The goal of the evaluation of the young, well-appearing, febrile child without an apparent source of infection on examination is to determine the risk of a clinically occult bacterial infection and the need for further investigation and/or antibiotic therapy.

This approach differs in important ways from the evaluation of fever in newborns and infants younger than three months, fever in immunocompromised patients, atypical Kawasaki disease (which may present with fever of five days or longer), and fever of unknown origin (fever lasting seven days or longer), all of which are discussed separately:

(See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates" and "Management of neonates at risk for early-onset group B streptococcal infection".)

(See "The febrile infant (29 to 90 days of age): Outpatient evaluation".)

(See "Fever in children with chemotherapy-induced neutropenia" and "Management of children with non-chemotherapy-induced neutropenia and fever".)

(See "Evaluation and management of fever in children and adults with sickle cell disease".)

(See "Incomplete (atypical) Kawasaki disease".)

(See "Fever of unknown origin in children: Evaluation" and "Fever of unknown origin in children: Etiology".)

History — The immunization history largely determines the subsequent evaluation in children with fever without a source because the child who is unimmunized or incompletely immunized is at a much greater risk for occult bacteremia. (See 'Risk by immunization status' above.)

Regardless of immunization status, children with a fever ≥7 days and no source warrant a different evaluation as discussed separately. (See "Fever of unknown origin in children: Evaluation".)

Historical findings that suggest an occult source of infection may be subtle. The provider should ask about the child's functional status, including oral intake, presence of irritability or lethargy, change in activity, and associated symptoms. Cough with symptoms of respiratory distress suggests pneumonia. In older, more verbal children, dysuria, frequency, abdominal pain, back pain, or new-onset incontinence may point to a urinary tract infection (UTI). Decreased walking, crawling, or movement of an extremity may indicate a deep soft tissue or bone infection.

The clinician should also identify any underlying medical condition that increases the child's risk for serious infection, such as sickle cell disease, underlying immunodeficiency, drug-induced immunocompromise, or anatomic abnormality (eg, ureteral reflux or chronic lung disease).

Physical examination — Typical sources of fever in well-appearing children are described above (see 'Fever with a source' above). For unimmunized or incompletely immunized children 3 to 36 months of age with a fever ≥39°C (102.2°F), acute otitis media or an upper respiratory tract infection other than a recognizable viral illness such as croup, bronchiolitis, or influenza should not be considered a source that decreases the risk of occult infection.

On careful evaluation, some children initially felt to have fever without a source may demonstrate subtle findings that suggest an infectious focus. Specific features to note include:

Unexplained tachycardia

Lesions in the oropharynx that may identify a recognizable viral illness, such as herpes gingivostomatitis (anterior ulcers) or Coxsackie virus (pharyngeal vesicles) (see "Soft tissue lesions of the oral cavity in children", section on 'Infections' and "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention" and "Herpetic gingivostomatitis in young children", section on 'Clinical features')

Tachypnea, pulse oximetry ≤95 percent, increased work of breathing indicated by nasal flaring, retractions or use of accessory muscle in children with pneumonia

Suprapubic or costovertebral angle tenderness

Pain with bone palpation or passive joint range of motion

Skin findings, such as petechiae, cellulitis, or viral exanthem

Ancillary studies — The approach to diagnostic testing in children 3 to 36 months of age who have fever without a source varies according to immunization status.

Unimmunized or incompletely immunized — We suggest the following studies in unimmunized or incompletely immunized children who have a fever ≥39°C (102.2°F) and no focus for infection on examination (algorithm 1):

Serum procalcitonin (PCT).

Complete blood count (CBC) with differential.

Blood culture should also be sent for patients with a procalcitonin ≥0.5 ng/mL, white blood cell (WBC) count ≥15,000/microL, or absolute neutrophil count (ANC) ≥10,000/microL. To avoid multiple blood draws, we typically obtain the blood culture with the initial blood tests and hold it until the results are available. Recognizing that either a WBC or ANC is not an ideal screening test, some clinicians may prefer to always send a blood culture in these patients [11,24,37].

Urine dipstick or microscopic urinalysis and a urine culture in selected patients as described below. (See 'Completely immunized' below.)

Chest radiograph in children with WBC ≥20,000/microL.

Serum PCT has better diagnostic accuracy for invasive bacterial illness (bacteremia or meningitis) in children with fever without a source compared with WBC or ANC, although only a small number of studies have been performed in unimmunized or incompletely immunized children 3 to 36 months of age [41]. If performed, PCT >0.5 ng/mL has high specificity for invasive bacterial illness and may be a useful test where results are rapidly available (turnaround time of one hour or less). (See 'Procalcitonin and other biomarkers' below.)

The recommended studies for these children reflect the increased risk of bacteremia compared with completely immunized children and are drawn from experience and guidelines developed during the pre-conjugate vaccine era [1,9,11,33,34,42-44]. (See 'Risk by immunization status' above.)

Completely immunized — Given the low risk for occult bacteremia, blood studies such as CBC, PCT, or C-reactive protein are not recommended (see 'Risk by immunization status' above). However, the risk of a UTI remains substantial in some fully immunized children and supports rapid testing by urine dipstick or microscopic urinalysis and a urine culture in selected patients (see 'Urinary tract infection' above) (algorithm 2):

Girls younger than 24 months of age

Uncircumcised boys younger than 12 months of age

Circumcised boys younger than six months or age

Children with a prior history of UTI, urogenital anomalies, or prolonged fever (>48 hours)

Patients with signs or symptoms of UTI, which must be specifically sought (eg, dysuria, frequency, abdominal pain, back pain, or new-onset incontinence)

In children who are not toilet-trained, urine should be collected by catheterization or, in exceptional cases (eg, tight phimosis or severe labial adhesions), suprapubic aspiration. Bag specimens should not be sent for culture because they are frequently contaminated. An acceptable alternative to catheterization of every child for urine culture is to collect a bagged specimen and rely on the results of the urinalysis only if completely negative. A positive result mandates subsequent catheterization for a repeat urinalysis and culture. A clean-voided urine specimen is preferred in toilet-trained children. (See "Urine collection techniques in infants and children with suspected urinary tract infection".)

The accuracy and interpretation of urine dipstick results compared with standard or enhanced urinalysis is discussed separately. (See "Urinary tract infections in infants and children older than one month: Clinical features and diagnosis", section on 'Rapidly available tests'.)

Some experts suggest that the decision to obtain a urine culture be based upon a calculated probability of UTI that is >2 percent [45]. However, this approach has not undergone prospective validation in an unselected population of infants and young children who have fever without a source. Furthermore, the calculated post-test probability is based upon the results of an enhanced (unspun) urinalysis, which is frequently not available. (See "Urinary tract infections in infants and children older than one month: Clinical features and diagnosis", section on 'Decision to obtain urine sample'.)

Management — The algorithms provide the management for children who have fever without a source by immunization status (algorithm 1 and algorithm 2).

Unimmunized or incompletely immunized — Management of unimmunized or incompletely immunized children 3 to 36 months of age who have fever without a source is determined by the results of ancillary studies (algorithm 1):

Elevated markers for occult bacteremia – We recommend that previously healthy children with fever without a source who are incompletely immunized and who have procalcitonin >0.5 ng/mL, WBC ≥15,000/microL, and/or ANC ≥10,000/microL receive parenteral antibiotic therapy pending blood and urine cultures [1,24,41]. Ceftriaxone (50 mg/kg intramuscularly) is preferred because of its antimicrobial spectrum and prolonged duration of action. It is also an appropriate option to cover E. coli in children with abnormal rapid urine testing while awaiting results of urine culture. (See "Urinary tract infections in infants older than one month and young children: Acute management, imaging, and prognosis", section on 'Choice of regimen'.)

For patients allergic to cephalosporins, clindamycin (10 mg/kg intravenously followed by oral clindamycin eight hours later) is one alternative to provide empiric therapy for occult bacteremia, although it lacks coverage for Gram-negative organisms. Thus, patients with in whom a UTI is suspected should receive additional antibiotic treatment as described separately. (See "Urinary tract infections in infants older than one month and young children: Acute management, imaging, and prognosis", section on 'Antibiotic therapy'.)

Once these patients receive parenteral antibiotics, they may be discharged with assured follow-up within 24 hours and again at 48 hours to reevaluate for progression of illness and to adjust treatment based upon blood and urine culture results. Patients in whom outpatient follow-up is uncertain should be admitted.

Patients with a positive blood culture that is felt to be a pathogen should be reevaluated and receive further treatment according to appearance, persistence of fever, and specific isolate (algorithm 3). Most blood cultures that turn positive within 24 hours represent true pathogens [42]. (See 'Culture follow-up' below.)

Support for this approach is based upon meta-analyses and randomized trials performed before the routine availability of H. influenzae, type b (Hib), PCV7, and PCV13 conjugate vaccines, which indicate a risk of occult bacteremia that ranges from 3 to 11 percent in untreated and unvaccinated children and a substantial risk for subsequent invasive bacterial illness, including meningitis. (See 'Risk by immunization status' above.)

Occult bacterial pneumonia – Patients who have WBC ≥20,000 and radiographic findings of pneumonia on chest radiograph merit empiric antibiotic treatment for bacterial pneumonia. Hospitalization for community-acquired pneumonia may also be warranted in selected children based upon age, underlying medical problems, and clinical factors, including clinical severity of illness (table 5). (See "Pneumonia in children: Inpatient treatment".)

For well-appearing children 3 to 36 months of age with fever >39°C and leukocytosis, treatment consists of oral high-dose amoxicillin (90 to 100 mg/kg per day divided into two or three doses; maximum dose 4 g/day). Alternative regimens for patients with a history of a reaction to penicillin or who are unable to tolerate oral therapy are provided separately. (See "Community-acquired pneumonia in children: Outpatient treatment", section on 'Suspected bacterial etiology'.)

Positive urine dipstick or urinalysis and normal blood studies – Results with reasonable sensitivity and high specificity for a UTI include positive nitrites or leukocyte esterase on urine dipstick or microscopic analysis that demonstrates pyuria or bacteriuria (table 6). Children with these findings but normal blood studies should receive empiric treatment for a UTI and follow-up in 24 to 48 hours to assess the patient and to review the urine culture results. (See "Urinary tract infections in infants older than one month and young children: Acute management, imaging, and prognosis", section on 'Oral therapy'.)

Normal blood and urine studies – Children with normal ancillary studies should not receive antibiotics and may be followed as outpatients. Their caregivers should be instructed to seek medical attention promptly if:

The child looks sicker (eg, difficult to arouse, gray or cyanotic appearance)

The child develops signs of dehydration (eg, no tears with crying, tacky or dry mucous membranes, or decreased urine output)

Signs of localized or systemic bacterial infection appear (eg, cough with tachypnea or difficulty breathing, cellulitis, or petechial rash)

Temperature ≥40.5oC (104.9°F) occurs

Fever is still present after 48 hours

Completely immunized — Further care of completely immunized children is as follows (algorithm 2):

Positive urine dipstick or urinalysis – Children with an abnormal urinalysis (positive nitrites or leukocyte esterase on urine dipstick, pyuria, or bacteriuria (table 6)) should receive empiric treatment for a UTI. (See "Urinary tract infections in infants older than one month and young children: Acute management, imaging, and prognosis".)

Urine dipstick or urinalysis normal or not performed – Completely immunized children with normal urine testing or in whom urine testing is not indicated should be discharged home. Their caregivers should be instructed to seek medical attention promptly if:

The child looks sicker (eg, difficult to arouse, gray or cyanotic appearance)

The child develops signs of dehydration (eg, no tears with crying, tacky, or dry mucous membranes, or decreased urine output)

Signs of localized or systemic bacterial infection appear (eg, cough with tachypnea or difficulty breathing, cellulitis, or petechial rash)

Fever is still present after 48 hours

Culture follow-up — Careful instructions should be given to caretakers to seek medical attention promptly if fever becomes higher, the patient looks sicker, or local symptoms or signs such as cough, cellulitis, or diarrhea develop.

Positive blood culture — A positive blood culture requires prompt reevaluation and treatment based upon the results, presence of fever, and patient assessment (algorithm 3).

Ill-appearing – Ill-appearing children should receive evaluation and treatment as described separately for children with sepsis or septic shock. (See "Septic shock in children: Rapid recognition and initial resuscitation (first hour)" and "Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis".)

Positive Gram stain – An organism may not be identified definitively for 24 to 48 hours after a blood culture becomes positive, which can make management decisions difficult. As discussed below, certain microbiologic features, such as a Gram stain showing either gram-positive rods or gram-positive cocci that are coagulase negative or slow growth, suggest contamination, especially if the child is well-appearing and afebrile at reevaluation. (See "Detection of bacteremia: Blood cultures and other diagnostic tests", section on 'Assessing clinical significance'.)

Children who are not well or continue to have fever on revisit should undergo evaluation, receive empiric antibiotic therapy appropriate for the presumed pathogen, and be admitted to the hospital, as described in the algorithm (algorithm 3). Consultation with the microbiology laboratory personnel and/or an infectious disease consultant may be helpful in narrowing the list of potential organisms and the likelihood that the findings represent a true pathogen. Blood cultures that become positive within 24 hours are more likely to represent a true pathogen [42].

Probable pathogen Patients with a positive blood culture that is felt to be a pathogen should be reevaluated and managed according to appearance, persistence of fever, and specific isolate (algorithm 3):

S. pneumoniae Further evaluation and treatment of well-appearing children with blood cultures showing growth of S. pneumoniae are determined by the presence of fever and the child's appearance at reevaluation:

-Febrile – Children who are well but febrile and whose blood culture is positive for S. pneumoniae at reevaluation have up to a 40 percent chance of continued bacterial infection (most commonly persistent bacteremia) and over a 4 percent chance of meningitis [44]. Because of this high risk of serious bacterial infections, patients with a blood culture positive for S. pneumoniae who are febrile on revisit should undergo a full sepsis evaluation (including lumbar puncture). They should also receive parenteral antibiotics tailored to the isolate's susceptibility or to the community susceptibility pattern for S. pneumoniae if the culture susceptibility is not yet available.

If cerebrospinal fluid findings show no evidence of meningitis, these children may receive parenteral ceftriaxone, especially if they have a history of poor oral intake or vomiting, followed by continued antibiotic therapy as an outpatient for 7 to 10 days with close follow-up. Antibiotic regimens should provide coverage for resistant S. pneumoniae. Possibilities include high-dose oral amoxicillin (30 mg/kg per dose, three times daily; maximum dose: 3 g daily), oral amoxicillin (45 mg/kg per dose, twice daily; maximum dose: 3 g daily), or, in penicillin-allergic patients, clindamycin (10 mg/kg per dose, three times daily).

-Afebrile – Prior to widespread availability of conjugate vaccines, well-appearing, afebrile children who did not receive antibiotics at the initial visit and who had a blood culture positive for S. pneumoniae had a risk of persistent bacteremia of approximately 9 percent, which likely remains similar for unimmunized patients [44]. They can be managed with antibiotics as an outpatient with close follow-up. Another blood culture should be drawn before further antibiotic therapy is initiated. Antibiotic regimens should provide coverage for resistant S. pneumoniae. Possibilities include high-dose oral amoxicillin (30 mg/kg per dose, three times daily; maximum dose: 3 g daily), oral amoxicillin (45 mg/kg per dose, twice daily; maximum dose: 3 g daily), or, in penicillin-allergic patients, clindamycin (10 mg/kg per dose, three times daily).

Other pathogens – The limited data for bacteremia caused by organisms other than S. pneumoniae suggest that outpatient therapy with oral antibiotics does not prevent serious bacterial infection, even in well-appearing, afebrile children. In addition, the risk of meningitis is presumed to be high for patients with N. meningitidis bacteremia.

For these reasons, lumbar puncture, hospital admission, and parenteral antibiotic therapy is suggested for children with a blood culture that is positive for N. meningitidis, Hib, Gram-negative rods, or other pathogens. Cerebrospinal fluid evaluation is also recommended for patients with blood culture positive for N. meningitidis and for young infants (three to six months of age) with group B Streptococcus bacteremia. Well children over three months of age with a blood culture positive for E. coli or S. aureus do not need a lumbar puncture.

Probable blood culture contamination – With the decline in the prevalence of occult bacteremia, it is now more likely that a blood culture taken from a completely immunized child will be positive for a contaminant than for a pathogen [9-11,42].

Certain microbiologic features, such as slow growth or Gram stain showing either gram-positive rods or gram-positive cocci that are coagulase negative, suggest a contaminant. Consultation with the microbiology laboratory and/or an infectious disease specialist may be useful when preliminary results are unclear. Molecular assays can help rapidly detect S. aureus, including methicillin-resistant strains, coagulase-negative Staphylococcus species, in blood cultures positive for gram-positive cocci in clusters and Streptococcus species (including S. pneumoniae, S. pyogenes, Enterococcus spp. and alpha Streptococcus species) in blood cultures positive for gram-positive cocci in chains. (See "Rapid detection of methicillin-resistant Staphylococcus aureus", section on 'Blood cultures'.)

The child who is well on follow-up, afebrile, and has an isolate from blood culture that is a likely contaminant can continue to be followed without antibiotic treatment, pending the final identification of the organism.

Positive urine culture — Children with positive urine cultures should be treated for UTI based upon the sensitivity of the isolate. Depending upon the patient's age, past medical history, or family history, renal imaging may also be indicated as discussed separately. (See "Urinary tract infections in infants older than one month and young children: Acute management, imaging, and prognosis", section on 'Overview'.)

UTILITY OF DIAGNOSTIC STUDIES

White blood cell and absolute neutrophil counts — Based upon studies performed in the pre-conjugate vaccine era, children 3 to 36 months of age who have fever >39°C (102.2°F) without a source and a white blood cell (WBC) count ≥15,000/microL have a greater than 5 percent risk for occult bacteremia [30-32]. Observational studies performed after the introduction of conjugate vaccines against H. influenzae, type b (Hib) but not S. pneumoniae (PCV7 or PCV13) found an absolute neutrophil count (ANC) ≥10,000/microL to be a better predictor of occult bacteremia than WBC, although sensitivity and specificity for either test is not optimal [11,34,35,46]. Thus, ANC may be a better predictor of occult bacteremia in incompletely immunized children.

Among a population of children with high rates of immunization, an elevated WBC, by itself, has both limited sensitivity and specificity as an indicator of serious bacterial infections, particularly as other pathogens such as S. aureus become more common isolates in children with bacteremia [11,47]. For example, in a multicenter, retrospective observational study of almost 42,000 children 3 to 36 months of age who had blood cultures performed after introduction of Hib and PCV7, a WBC ≥15,000/microL had a sensitivity and specificity of 72 and 55 percent, respectively, for bacteremia [11]. In this study, the frequency of bacteremia (1.6 percent) was lower than the rate of blood culture contamination (1.8 percent).

Procalcitonin and other biomarkers — When the prevalence of invasive bacterial illness (IBI), such as bacteremia, sepsis, and/or bacterial meningitis, is >1 percent, inflammatory markers, particularly procalcitonin (PCT), show promise for the detection of IBI in young children who have fever without a source [41,48]. In a meta-analysis of 12 studies (almost 7300 children, the majority younger than three months of age), PCT at a threshold of 0.5 ng/mL identified IBI with a sensitivity of 82 percent and specificity of 86 percent (positive likelihood ratio [LR] 6, summary area under the curve 0.88) [41]. In the study included in this meta-analysis that was performed in children younger than 36 months, procalcitonin showed similar diagnostic accuracy for IBI [49]. Thus, measurement of PCT in unimmunized or incompletely immunized children 3 to 36 months of age is a reasonable approach, although more study in this population is warranted to determine the optimal threshold value. PCT levels rise in response to bacterial infections more rapidly than other markers, such as C-reactive protein [50] and ANC, and PCT is more specific than WBC count for IBI [51].

Preliminary research has also identified and validated candidate proteins, specifically tumor necrosis factor (TNF)-related apoptosis-inducing ligand and interferon gamma-induced protein that, when combined with C-reactive protein in an experimental assay, distinguished bacterial from viral infections in febrile children (3 months to 18 years of age) with significantly higher sensitivity than C-reactive protein or PCT, but this assay has not been widely implemented [52-54].

Rapid urine tests — Urine screening tests such as urine dipstick for leukocyte esterase and nitrites, urine Gram stain, and urine microscopy are useful to identify children with increased probability of a urinary tract infection (UTI). However, a urine culture should be sent in all young children in whom catheterized urine is obtained. The test characteristics of these studies is summarized in the table (table 6) and discussed in detail separately. (See "Urinary tract infections in infants and children older than one month: Clinical features and diagnosis", section on 'Rapidly available tests'.)

Chest radiograph — A chest radiograph is an appropriate study in patients with tachypnea, respiratory distress, or oxygen saturation ≤95 percent. In addition, chest radiograph is suggested in children with WBC >20,000/microL even in the absence of these findings (see 'Pneumonia' above). An infiltrate on chest radiograph confirms the diagnosis of pneumonia in children with compatible clinical findings. A radiograph cannot reliably identify whether a pneumonia is bacterial or viral (table 7). We recommend antibiotic treatment when an infiltrate is associated with this degree of leukocytosis. (See "Community-acquired pneumonia in children: Clinical features and diagnosis", section on 'Diagnosis'.)

Cultures — The diagnosis of a serious bacterial infection is often made with cultures, although the inherent delay between the initial evaluation of the patient and the availability of culture results complicates decisions regarding empiric antibiotic therapy.

Blood – Continuously monitored blood culture systems have decreased the length of time for a blood culture to turn positive. For example, in a retrospective review of over 1300 positive blood cultures obtained from children, the time to positivity was a median of 13 hours for definitive pathogens and 23 hours for contaminating or opportunistic organisms; only three definitive pathogens were identified after 24 hours in well-appearing children [55].

Urine – For the diapered child, urine for culture should be collected by catheterization or, in exceptional cases (eg, tight phimosis), suprapubic aspiration. Bag urine specimens should not ordinarily be sent for urine culture because they are frequently contaminated. A clean catch is the preferred method of urine collection for culture in the child who is toilet-trained. The culture definition of UTI is discussed elsewhere. (See "Urine collection techniques in infants and children with suspected urinary tract infection" and "Urinary tract infections in infants and children older than one month: Clinical features and diagnosis", section on 'Diagnostic criteria'.)

Cerebrospinal fluid – Children who are being evaluated for fever without a source should be well appearing and therefore not require lumbar puncture. That being said, cerebrospinal fluid should be obtained from any patient with suspected meningitis. (See "Bacterial meningitis in children older than one month: Clinical features and diagnosis", section on 'Course'.)

Molecular assays — Molecular methods to identify bacterial infection include polymerase chain reaction (PCR) and detection of bacterial 16S ribosomal RNA genes or host RNA signatures.

Molecular assays based upon PCR, detection of bacterial 16S ribosomal RNA genes, or identification of host RNA signatures have shown potential in the rapid diagnosis of sepsis. However, these tests are not routinely available and require further validation before broad clinical implementation. (See "The febrile infant (29 to 90 days of age): Outpatient evaluation", section on 'Host RNA biosignatures' and "Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis", section on 'Laboratory studies'.)

The use of PCR for the detection of meningococcal disease is discussed in greater detail separately. (See "Diagnosis of meningococcal infection", section on 'Polymerase chain reaction'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fever in children".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Fever in children (The Basics)")

Beyond the Basics topic (see "Patient education: Fever in children (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Definition – The following guidance applies to well-appearing children 3 to 36 months of age, with fever ≥39°C (102.2°F), who have no underlying medical condition that would alter susceptibility to infection and no focus of infection identified by a complete physical examination, referred to below as children who have fever without a source. A thorough history, including immunization status and complete physical examination, should be performed in all febrile children to identify obvious and subtle focuses of infection. (See 'Definitions' above and 'Well-appearing patients' above.)

Potential causes – The majority of children with fever have either a self-limited viral infection or a recognizable source of bacterial infection (see 'Fever with a source' above). Relatively common occult sources of infection include pneumonia and urinary tract infections (UTIs), with occasional cases of bacteremia. (See 'Occult bacterial infection' above.)

In addition to occult infection, prolonged fevers may warrant additional workup for multisystem inflammatory syndrome in children (MIS-C, duration 3 to 5 days), typical or atypical Kawasaki disease (duration ≥5 days) or fever of unknown origin (duration ≥7 days). (See "Kawasaki disease: Clinical features and diagnosis" and "Incomplete (atypical) Kawasaki disease" and "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis" and "Fever of unknown origin in children: Evaluation".)

Ill-appearing – Children who are ill appearing or have unstable vital signs should be stabilized, evaluated, and managed for presumed sepsis or septic shock, including rapid stabilization, evaluation for serious infection, and empiric treatment with intravenous antibiotics as discuss in detail separately. (See "Septic shock in children: Rapid recognition and initial resuscitation (first hour)" and "Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis".)

Well-appearing – Evaluation and management is determined by immunization status:

Unimmunized or incompletely immunized – For well-appearing children who are unimmunized or incompletely immunized, we suggest the following tests and management (algorithm 1) (see 'Unimmunized or incompletely immunized' above):

-If rapidly available (eg, within one hour), we suggest procalcitonin (PCT), although evidence is limited regarding its utility in these patients. A blood culture is also suggested for patients with PCT ≥0.5 ng/mL.

-Complete blood count (CBC) with differential; a blood culture should also be sent for patients with a white blood cell (WBC) count ≥15,000/microL or absolute neutrophil count (ANC) ≥10,000/microL. Some clinicians may choose to send a blood culture for all patients.

-Urinalysis and urine culture by bladder catheterization or, in exceptional cases (eg, tight phimosis or severe labial adhesions), suprapubic aspiration for girls <24 months of age, uncircumcised boys <12 months of age, and circumcised boys <6 months of age. (See "Urinary tract infections in infants and children older than one month: Clinical features and diagnosis", section on 'Laboratory evaluation and diagnosis'.)

-Chest radiograph for patients with WBC ≥20,000/microL.

Management of well-appearing children who are unimmunized or incompletely immunized is determined by results of testing:

-Abnormal blood inflammatory markers – For children who have PCT >0.5 ng/mL, WBC ≥15,000/microL, or ANC ≥10,000/microL, we recommend parenteral antibiotic therapy pending culture results (Grade 1B). When not contraindicated by allergy, a single dose of intramuscular ceftriaxone (50 mg/kg) is preferred because of its antimicrobial spectrum and duration of action.

Once these patients receive parenteral antibiotics, they may be discharged to home with assured follow-up within 24 hours and again at 48 hours to reevaluate for progression of illness and to adjust treatment based upon blood and urine culture results. Patients in whom outpatient follow-up is uncertain should be admitted. (See 'Unimmunized or incompletely immunized' above.)

-Abnormal urinalysis – Well-appearing, incompletely or unimmunized children with a urinalysis indicative of a likely UTI (eg, positive leukocyte esterase or nitrite on dipstick, positive Gram stain, or >5 white blood cells per high-powered field) should be treated for a UTI. Patients who subsequently have a positive urine culture require additional treatment tailored to the identified organism and their clinical status and warrant renal imaging as described separately. (See "Urinary tract infections in infants older than one month and young children: Acute management, imaging, and prognosis", section on 'Antibiotic therapy' and "Urinary tract infections in infants older than one month and young children: Acute management, imaging, and prognosis", section on 'Imaging'.)

-Normal blood and urine testing – Well-appearing, incompletely or unimmunized children with normal blood and urine studies may be followed as outpatients, but their caregivers should be instructed to promptly seek medical attention if they child becomes ill appearing, develops dehydration, has signs of a localized bacterial infection, has fever ≥40.5°C (104.9°F), or has a fever that persists for >48 hours. (See 'Unimmunized or incompletely immunized' above.)

-Positive blood culture – Discharged patients with a positive blood culture result require prompt reevaluation and treatment based upon the culture findings, presence of fever, and patient assessment (algorithm 3). We suggest that the child who is well on follow-up, afebrile, and has an isolate from a preliminary report of a blood culture that is a likely contaminant be followed on a daily basis as an outpatient without antibiotic treatment, pending the final identification of the organism (Grade 2C). (See 'Positive blood culture' above.)

Completely immunized – For completely immunized children who have fever without a source, blood studies such as a CBC, PCT, or blood culture are not necessary (algorithm 2). (See 'Completely immunized' above.)

Children at increased risk for UTI should undergo urine testing, including a urine culture. Urine for culture should be collected by catheterization or, in exceptional cases (eg, tight phimosis or severe labial adhesions), suprapubic aspiration. The use of bag urine specimens for culture should be discouraged because they are frequently contaminated. Patients with abnormal urinalysis require empiric treatment for a urinary tract infection. (See "Urinary tract infections in infants and children older than one month: Clinical features and diagnosis", section on 'Laboratory evaluation and diagnosis' and "Urinary tract infections in infants older than one month and young children: Acute management, imaging, and prognosis", section on 'Antibiotic therapy'.)

Completely immunized children with fever without a source may be followed as outpatients, but their caregivers should be instructed to promptly seek medical attention if the child becomes ill appearing, develops dehydration, has signs of a localized bacterial infection, or has a fever that persists for >48 hours. (See 'Culture follow-up' above.)

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References