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INTRODUCTION — Fever is a common symptom among children seeking medical care. Most children undergo evaluation for a febrile illness before their third birthday, and nearly one-third of pediatric outpatient visits are for fever [1-3].
When the history and physical examination cannot identify a specific source of fever in an acutely ill, nontoxic-appearing child less than three years of age, the illness is often called fever without a source (FWS). Alternative terms are fever without localizing signs (FWLS) or fever without a focus.
This topic will review the etiology, evaluation, and management of the child 3 to 36 months of age with fever of less than seven days duration. Fever in newborns, infants younger than three months, and fever of unknown origin (≥7 days) are reviewed separately. (See "Evaluation and management of fever in the neonate and young infant (less than three months of age)" and "Approach to the child with fever of unknown origin" and "Etiologies of fever of unknown origin in children".)
Fever of concern — In children 3 to 36 months of age, the diagnosis of fever is based upon core temperature, which is measured most accurately rectally. The history of an elevated temperature recorded at home should be considered equivalent to that taken in a medical facility. Fever 39ºC (102.2ºF) or higher is the threshold above which evaluation for a source of occult infection, including urinary tract infection (UTI), may be warranted . (See 'Occult sources of infection' below.)
The majority of children with fever have either a self-limited viral infection or a recognizable source of bacterial infection. However, research in the 1970s identified a population of well-appearing febrile young children who had occult bacteremia [5,6]. Subsequent studies demonstrated that some of these children went on to develop serious focal bacterial infections, such as pneumonia and meningitis [7,8]. Although laboratory testing identified a group of children at an increased risk for occult bacteremia, many who were not bacteremic received presumptive treatment with broad spectrum antibiotics while awaiting definitive blood culture results.
The introduction of vaccines to prevent Haemophilus influenzae type b (Hib) and pneumococcal disease has dramatically lowered the incidence of occult bacteremia and, as a result, changed the issues facing the clinician who is evaluating a young child with fever. (See 'Impact of vaccines' below.)
Population of interest — This topic will focus on the evaluation and management of well-appearing, immunocompetent children 3 to 36 months of age with fever ≥39ºC (102.2ºF) of less than seven days duration and no focus of infection identified by a complete physical examination. The evaluation of the febrile infant younger than three months is discussed separately. (See "Evaluation and management of fever in the neonate and young infant (less than three months of age)".)
Immunization status — The approach to the child who has fever without a source is greatly determined by immunization status.
Complete immunization — In the discussion that follows, a completely immunized child has received the primary booster series of three immunizations with conjugate vaccines Streptococcus pneumoniae (PCV7 or PCV13), at least two doses of Haemophilus influenzae, type b (Hib), and remains on schedule. However, some experts consider two doses of PCV7 or PCV13 sufficient to prevent invasive Streptococcus pneumoniae infection. Patients who have not received the booster 12 to 15 months after the third Hib and either PCV7 or PCV13 are also considered to be at much lower risk of bacteremia. (See "Pneumococcal (Streptococcus pneumoniae) conjugate vaccines in children", section on 'Alternative or abbreviated schedule'.)
Incomplete immunization — In the discussion that follows, an incompletely immunized child has not received the primary booster series of three vaccinations with both Hib and either PCV7 or PCV13. Based on these criteria, any child under six months of age is incompletely immunized.
CAUSES OF FEVER — Fever can be caused by infectious and noninfectious processes. The vast majority of young children with fever have an infectious etiology. Noninfectious etiologies include drug fever, immunization reactions, central nervous system dysfunction, malignancy (eg, leukemia), and chronic inflammatory conditions (ie, inflammatory bowel disease and juvenile idiopathic arthritis).
Although caretakers may sometimes attribute fever to teething, fever >38.5ºC is unlikely to be caused by teething . (See "Anatomy and development of the teeth", section on 'Primary teeth eruption'.)
The source of fever may be a recognizable bacterial or viral illness. In a study of a large cohort of children 3 to 36 months of age presenting to a primary care provider with a febrile illness, a readily identifiable presumed bacterial illness was diagnosed at the initial encounter in 56 percent of children, almost 90 percent of whom had otitis media . A specific viral infection (eg, croup, bronchiolitis, varicella, roseola) was identified in an additional 4 percent of children . Similarly, 6 percent of 21,216 children 3 to 36 months of age with fever ≥39ºC seen in the emergency department of an urban tertiary care children's hospital had a recognizable viral syndrome, 47 percent had FWS, and 47 percent had a specific bacterial infection requiring antibiotics or chronic illness (eg, immunocompromised state, central line) that affected the fever evaluation .
Serious bacterial infectious syndromes that occur in children 3 to 36 months of age include meningitis, pneumonia, and cellulitis. In one series (prior to the introduction of Hib and pneumococcal conjugate vaccines) of 996 febrile children less than 36 months of age, <1 percent had meningitis, 10 percent had focal soft tissue infections, and 30 percent had pneumonia . These diagnoses are discussed in detail elsewhere. (See "Bacterial meningitis in children older than one month: Clinical features and diagnosis" and "Cellulitis and erysipelas" and "Community-acquired pneumonia in children: Clinical features and diagnosis", section on 'Clinical presentation'.)
OCCULT SOURCES OF INFECTION — The goal of the evaluation of a young child with fever is to identify sources of infection that require further evaluation and definitive treatment. Such infections are usually bacterial, although the majority of children who are well-appearing and have no identifiable source of infection have a nonspecific self-limited viral illness [1,12]. The remainder of this discussion will focus on occult bacterial infections.
Pneumonia — Most children with fever and pneumonia have some abnormality on physical examination: usually tachypnea, abnormal auscultation, low pulse oximetry, retractions, or nasal flaring, suggesting respiratory tract disease [13-16]. However, a reliable physical examination in a young child can be a challenge. In an observational study, radiographic pneumonia was found in 20 to 30 percent of highly febrile young children (<5 years) without clinical evidence of pneumonia, but with a white blood cell count (WBC) ≥20,000/mm3 . Similarly, another observational study demonstrated that 41 percent of children between 3 and 36 months of age with a WBC >25,000/mm3 had lobar or segmental pneumonia on chest radiograph . This association between leukocytosis and pneumonia remains strong, even in the post-conjugate pneumococcal vaccine era . (See "Community-acquired pneumonia in children: Clinical features and diagnosis", section on 'Clinical presentation'.)
Urinary tract infection — The urinary tract is the most common site of bacterial infection among febrile infants and young children. This finding was demonstrated in two large prospective studies [20,21]. The prevalence of UTI in these reports was significantly influenced by demographic factors, such as sex, age, race, and circumcision status (table 1). (See "Urinary tract infections in children: Epidemiology and risk factors", section on 'Host factors'.)
Bacteremia — Bacteremia that occurs in a seriously ill patient with a focal infection, such as 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 apparent. This discussion will focus on the young febrile child who looks well and may have unsuspected, or occult, bacteremia.
Before routine immunization with Hib and either PCV7 or PCV13, the prevalence of occult bacteremia was 5 percent in well-appearing febrile children [5,6]. The predominant pathogens were S. pneumoniae (80 percent) and Hib (20 percent). Neisseria meningitidis represented a small number of cases.
Predictors — Factors associated with an increased the risk of occult bacteremia in unimmunized children to over 10 percent included [23-25]:
Neither response to antipyretics nor clinical appearance predicted bacteremia [26-28].
Some children with bacteremia went on to have serious bacterial infections (SBI), including meningitis [7,29]. When children at risk for bacteremia were treated empirically with antibiotics until the results of blood cultures were known, they were less likely to develop these complications [23,24,30].
Impact of vaccines — The initiation of routine immunization of infants with the conjugate vaccines for Hib and S. pneumoniae has dramatically altered the prevalence of invasive disease due to these organisms. The incidence of occult bacteremia in well-appearing febrile children has fallen from 5 to below 1 percent, while the rate of isolation of a contaminant from blood cultures has remained constant at 1.8 to 3.0 percent [15,31-38]. (See "Pneumococcal (Streptococcus pneumoniae) conjugate vaccines in children", section on 'Invasive disease' and "Prevention of Haemophilus influenzae infection", section on 'Efficacy/effectiveness'.)
Since the routine immunization of children with PCV7 or PCV13 vaccine, pathogens other than S. pneumoniae are the cause of the majority of cases of unsuspected bacteremia . E. coli and Staphylococcus aureus are frequently isolated organisms. Most reports of occult bacteremia also include cases caused by N. meningitidis, Group A streptococcus, and Salmonella species [33,39]. Laboratory parameters (ie, WBC >15,000/microL) may be less reliable predictors of bacteremia with these pathogens. (See 'WBC and ANC counts' below.)
In addition, the impact of PCV7 or PCV13 on variables, such as the role of nonvaccine serotypes in invasive pneumococcal disease and the duration and durability of protection after vaccination, continues to evolve. (See "Pneumococcal (Streptococcus pneumoniae) conjugate vaccines in children", section on 'Invasive disease' and "Impact of universal infant immunization with pneumococcal (Streptococcus pneumoniae) conjugate vaccines in the United States", section on 'Invasive disease caused by non-vaccine serotypes'.)
Given the decreased prevalence of occult bacteremia in the post-conjugate vaccine era, a less aggressive approach to the management of completely immunized, well-appearing, febrile (≥39ºC) children 3 to 36 months of age who do not have a focal source of infection appears reasonable [35,40,41]. (See 'Initial approach' below.)
A cost-effectiveness decision analysis of evaluation and management strategies for FWS in the post-conjugate vaccine era considered negative aspects of diagnostic testing and treatment and used cases of meningitis and lives saved as outcome measures . The management strategies evaluated were no work-up, clinical judgment, blood culture, blood culture plus antibiotics, WBC plus blood culture and antibiotics, and WBC plus selective blood culture and antibiotics. The following observations were noted:
EVALUATION — The goal of the evaluation of the young, well-appearing, febrile child without an apparent source of infection is to identify a subtle bacterial infection and/or the risk of a more serious occult bacterial infection, both of which require further investigation and antibiotic therapy.
History — Historical features of a febrile illness that suggest an occult source of infection may be subtle and not immediately obvious to the caretakers. Therefore, a thorough history must include information about the child's functional status, including oral intake, presence of irritability or lethargy, and associated symptoms. The duration of fever appears to be a poor predictor of unsuspected bacteremia .
Specific questions regarding cough, vomiting, or change in activity should be included. As an example, children with pneumonia may have cough or tachypnea noted by a caretaker. Signs or symptoms of UTI (eg, dysuria, frequency, abdominal pain, back pain, new onset incontinence), should be specifically sought. Likewise, vomiting, with or without diarrhea, can occur in young children with UTI, and caretakers occasionally note that the urine is foul-smelling, although these symptoms are nonspecific. Finally, a young child with a deep soft tissue or bone infection may protect the affected area.
A careful history must identify any known underlying medical condition that increases the child's risk for serious infection, such as sickle cell disease or urinary tract reflux. In addition, the immunization history will greatly influence the subsequent evaluation, since the child who is incompletely immunized is at greater risk for occult bacteremia than the one who is completely immunized. (See 'Immunization status' above and 'Incomplete immunization' above.)
Physical examination — The child who is being evaluated for a subtle infection or fever without a source should be well-appearing. Febrile children who are acutely ill with symptoms, such as lethargy, poor perfusion, hypoventilation or hyperventilation, and cyanosis are said to appear toxic or septic. They are considered to have a significant bacterial infection until proven otherwise. Cultures of blood, urine, and CSF, when meningitis is suspected, should be obtained, intravenous fluid provided, antibiotic therapy initiated, and admission to the hospital arranged. (See 'Ill-appearing' below.)
Attention to abnormal vital signs and a thorough physical examination may identify a source of infection. Specific features to note include the following:
Laboratory testing — Testing in febrile children 3 to 36 months of age has been used to screen for the risk of bacterial infection as well as to diagnose specific infections. The decision to perform laboratory tests depends upon a variety of factors including age, immunization status, and obvious findings of infection (eg, otitis media, bronchiolitis, croup).
Recommendations regarding when to obtain specific tests are provided below. (See 'Initial approach' below.)
WBC and ANC counts — Several studies have identified an increased risk of occult pneumococcal bacteremia among unimmunized children with WBC ≥15,000/microL and absolute neutrophil count (ANC) ≥10,000/microL [33,44-46]:
Taken together, these studies suggest that a WBC >15,000/microL, while not ideal in screening for occult bacteremia, is helpful in determining which incompletely immunized children deserve blood culture and treatment in the post-conjugate vaccine era. However, these reports and others also have demonstrated that an elevated WBC, by itself, has both limited sensitivity and specificity as an indicator of SBI, particularly as other pathogens, such as S. aureus become more prominent isolates in children with bacteremia [33,47].
Urine tests — Multiple studies and two meta-analyses have evaluated screening tests for UTI [48,49]. In general, urine screening tests markedly improve the ability to detect UTI, but a urine culture should be sent in all young children in whom catheterized urine is obtained. The usefulness of various urine screening tests (dipstick, Gram stain, and microscopy) is summarized in the table and discussed elsewhere (table 2). (See "Urinary tract infections in infants and children older than one month: Clinical features and diagnosis", section on 'Rapidly available tests'.)
Cultures — The diagnosis of a SBI 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.
Chest radiograph — A chest radiograph should be obtained 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.)
Inflammatory mediators — Preliminary evidence suggests that elevations in levels of inflammatory mediators (ie, C-reactive protein and procalcitonin) may be better markers of SBI than WBC and ANC in children at significant risk for bacterial infection, although the usefulness of these tests in practice is uncertain .
Taken together, the evidence suggests that CRP and PCT are equivalent with respect to diagnostic accuracy. However, CRP is much more widely available than PCT and is thus more useful in clinical practice.
INITIAL APPROACH — The evaluation and management of the febrile child 3 to 36 months of age without a source of infection must balance the consequences of not diagnosing a SBI with the decreasing prevalence of occult infection and the potential adverse effects of excessive testing and treatment . Burdens of testing and expectant antibiotic therapy include false-positive results, adverse reactions to antibiotics, and, possibly, the effect of widespread antibiotic use on patterns of antibiotic resistance. The likelihood of SBI varies significantly by clinical appearance, age, and immunization status. (See 'Occult sources of infection' above.)
Well-appearing children 3 to 36 months of age, with fever ≥39ºC (102.2ºF), who have no underlying medical condition that would alter susceptibility to infection, and no focus of infection identified by a complete physical examination, are hereafter referred to as children with FWS.
Ill-appearing — Children who are ill-appearing or have unstable vital signs should be fully evaluated for serious infection with cultures of blood, urine, and, when meningitis is suspected, CSF. Those with tachypnea or leukocytosis (>20,000/microL) should have a chest radiograph. These patients should receive parenteral antibiotic therapy targeting the likely pathogens in this age group (S. pneumoniae, S. aureus, N. meningitidis, H. influenzae type b) and be admitted to the hospital.
Immunization incomplete — The risk of occult bacteremia in incompletely immunized children is estimated to be as high as 5 percent (ie, what it was during the preconjugate vaccine era); the actual risk is probably somewhat lower because of "herd immunity." (See 'Immunization status' above and 'Impact of vaccines' above.)
Strategies for the evaluation and management of these children reflect the increased risk of bacteremia compared with completely immunized children and are drawn from experience and guidelines developed during the preconjugate vaccine era [4,30,31,33,44,50,63,64].
We suggest the following approach to evaluation of these children:
Children with an abnormal urinalysis should be treated for a urinary tract infection, although in questionable cases awaiting results of urine culture represents a reasonable alternative. (See "Urinary tract infections in infants and children older than one month: Acute management, imaging, and prognosis", section on 'Overview'.)
We recommend that children with FWS who are incompletely immunized who have a WBC ≥15,000/microL receive parenteral antibiotic therapy pending blood and urine cultures [4,42]. Ceftriaxone (50 mg/kg, intramuscularly) is preferred because of its antimicrobial spectrum and prolonged duration of action. Clindamycin (10 mg/kg, intravenously followed by oral clindamycin eight hours later) is one alternative for patients allergic to cephalosporins. Outpatient follow-up should occur within 24 hours. Patients in whom outpatient follow-up is uncertain should be admitted.
This strategy of selective treatment of high-risk children with FWS and WBC ≥15,000/microL is in agreement with the practice guidelines of the American Academy of Pediatrics and the American College of Emergency Physicians for children with FWS [4,65,66].
Support for treating patients 3 to 36 months of age with FWS and significant risk of bacteremia with empiric parenteral antibiotics is derived from meta-analyses and randomized trials performed before the routine availability of Hib, PCV7, and PCV13 conjugate vaccines [23,24,30].
Possible dermatologic adverse reactions were more commonly seen in the ceftriaxone group (8.7 versus 4.9 percent), but gastrointestinal complaints, such as diarrhea, were not different (14.5 versus 15.0 percent). No anaphylaxis was seen in either group.
Taken together, these studies indicate that unimmunized children with FWS avoid progression of bacteremia to focal infections, especially meningitis, when treated with parenteral antibiotics. Given the increasing prevalence of penicillin resistant S. pneumoniae, intramuscular ceftriaxone remains a preferred parenteral agent.
Immunization complete — A child with FWS who is completely immunized has a risk of bacteremia that is <1 percent. Decision analysis suggests that at this low risk, laboratory evaluation and empiric antibiotic therapy do not significantly alter the likelihood of progression to focal bacterial infection and are not indicated [42,68]. (See 'Immunization status' above and 'Impact of vaccines' above.)
However, the risk of UTI as an occult source of infection remains substantial in fully immunized children, depending on age, gender, and circumcision status . This risk guides recommendations for evaluation and treatment in these patients .
Despite the high risk for UTI and low risk for bacteremia among fully immunized children, evidence suggests that some emergency department (ED) clinicians may not utilize laboratory testing and antibiotic therapy appropriately when caring for these patients. As an example, between 2006 and 2008, estimates regarding laboratory testing and antibiotic treatment extrapolated from 1600 ED visits by fully immunized febrile children 6 to 36 months of age in the United States were as follows :
These estimates suggest that urine testing may be underutilized while measurement of complete blood count and antibiotic treatment may be overutilized in these patients.
FOLLOW-UP — Follow-up should be arranged within 24 hours for those children with FWS who have received parenteral antibiotics. Patients who are not treated with antibiotics should be instructed to seek medical attention within 48 hours if they have persistent fever.
Careful instructions should be given to caretakers to return immediately if fever becomes higher, the patient looks sicker, or local symptoms or signs develop (eg, cough, diarrhea, cellulitis).
Positive blood cultures — An organism may not be identified definitively for 24 to 48 hours after the blood culture becomes positive, making management decisions difficult. The clinical appearance of the child and the Gram stain of the organism can be useful in deciding whether or not the child should be admitted to the hospital. 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 pathogen. Patients with a positive culture that is felt to be a pathogen should be reevaluated and managed according to appearance, persistence of fever, and specific isolate (algorithm 2).
The main goal is to identify and avoid progression to serious bacterial infection, especially meningitis:
Other pathogens — The limited data for bacteremia caused by organisms other than S. pneumoniae suggests 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, hospital admission and parenteral antibiotic therapy is suggested for children with a blood culture that is positive for N. meningitidis, H. influenzae type b, S. aureus, gram negative rods, or other pathogens. A lumbar puncture should be performed if meningitis is clinically suspected. CSF 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 contaminant — With the decline in the prevalence of occult bacteremia, it is now more likely that a blood culture will be positive for a contaminant than for a pathogen [31-33,50]. Microbiologic features, such as Gram stain, showing gram-positive rods, gram-positive cocci that are coagulase negative, and slow growth suggest a contaminant. Consultation with the microbiology laboratory and/or an infectious disease specialist may be useful when preliminary results are unclear.
The child who is well on follow-up, afebrile, and has an isolate from blood culture that is a likely contaminant can be followed without antibiotic treatment, pending the final identification of the organism.
Children who are not well on follow-up or continue to have fever should be reevaluated and the assumption that the positive blood culture represents a contaminant should be reevaluated (algorithm 2). (See 'Positive blood cultures' above.)
Positive urine culture — Children with a positive urine culture should be treated for UTI. (See "Urinary tract infections in infants and children older than one month: Acute management, imaging, and prognosis", section on 'Overview'.)
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