Each recommendation is followed by evidence grades (A-X) identifying the type of supporting evidence. Definitions of the evidence grades are presented at the end of the "Major Recommendations" field.
Clinical Assessments
Temperature and Fever
Fever is defined as a temperature of at least 38.0 degrees C (100.4 degrees F) rectally (see Table 2 in the original guideline document). Although rectal temperatures are more accurate, it is recommended that a practitioner give credence to a parent’s verbal report of a child’s fever measured by any method, including when detected only by touch.
Note: A parental report of fever detected only by touch is likely to be accurate (sensitivity 82 to 89%, specificity 76 to 86%) (Graneto & Soglin, 1996 [C]; Hooker, 1993 [C]; Singhi & Sood, 1990 [C])
History and Physical Examination
- In the history and the physical examination it is important to recognize signs and symptoms of ill-appearance or toxicity (see Table 1 in the original guideline document).
Note 1: The sicker a febrile child appears, the more likely the fever is associated with a serious bacterial infection (SBI) (Teach & Fleisher, 1995 [A]; McCarthy et al., 1985[C])
Well-appearing |
<3% chance of SBI |
Ill-appearing |
26 % chance of SBI |
Toxic |
92% chance of SBI |
(McCarthy et al., 1982) [C]
Note 2: Response to antipyretics is not a reliable predictor of illness severity (Kuppermann, 1999) [S, E].
- It is recommended that history be targeted to determine the child’s immunization status and exposures to known infectious agents. Specifically, history of heptavalent conjugate pneumococcal vaccine (PCV7) significantly lowers risk for invasive pneumococcal disease (Whitney et al., 2003) [D].
- It is recommended that history also be targeted to determine if symptoms associated with some focal infections have been observed. These include, but are not limited to, the ear pulling of otitis media, coughing of pneumonia, vomiting of gastroenteritis, or crying with voiding associated with some urinary tract infections.
Note 1: The following are clinical signs and symptoms of urinary tract infections for this age group as adapted from the Cincinnati Children's Hospital Medical Center (CCHMC) Evidence Based Guideline for First Time Urinary Tract Infections©.
- Diarrhea
- Vomiting
- Strong-smelling urine
- Abdominal or flank pain
- New onset urinary incontinence
- Failure to thrive
- Fever
Note 2: Gastroenteritis due to any cause is rarely occult and almost always signaled by some combination of diarrhea and vomiting.
Note 3: Rotavirus is the most common cause of acute gastroenteritis in children ("Practice parameter," 1996) [S, E]. A prevalence of only 6% was shown in fever of uncertain source (FUS) patients aged 15 days to 4 years presenting without diarrhea or vomiting, though these patients developed these symptoms soon thereafter (Staat et al., 2002) [C].
Note 4: Bacterial gastroenteritis is usually associated with bloody or mucoid stools. There is also increased likelihood if there is a history of foreign travel or occurrence during a specific pathogen community outbreak (Kuppermann, 1999 [S, E]; Limbos & Lieberman, 1995 [S]).
Synthesis after Clinical Assessment
Both subjective and objective measures are recommended to estimate the degree of illness (Bleeker et al., 2001) [D]. The classification of the child as well-appearing, ill-appearing, or toxic is extremely important in determining the course of action. Towards this classification, input from the caregiver is essential.
Because bacteremia can occur with focal infections, it is recommended that when a source of infection is identified on physical examination, further evaluations be considered whenever the practitioner judges that focal findings are insufficient to explain the degree of the child’s fever and illness (Local Expert Consensus) [E].
Laboratory and Radiologic Studies
General
Viral infections are the most common etiology for FUS in this age group. Therefore, most children with FUS do not need testing.
If elected, the options for testing include:
- Complete blood count (CBC) with differential and blood culture
- Urinalysis and urine culture
- Viral studies
When indicated, testing options may also include:
- Chest x-ray
- Lumbar puncture
- Stool culture
See algorithm in original guideline document.
Special Note about 2 to 3 Month Age Group
Many FUS studies group infants age 2 to 3 months in a 0 to 90 day study population and most other studies on FUS are conducted on a 3 to 36 month group. Therefore, there is less known about the risks for and complications of bacteremia and SBI in the infant 2 to 3 months of age.
Testing Recommendations
- It is recommended that a well-appearing child, in the clinician’s judgment, with an unremarkable history, be considered a candidate for observation at home without initial laboratory testing. This assumes the presence of all of the following:
- Available reliable follow-up as needed
- Health-care provider(s) confident that caregiver will use appropriate observational and follow-up skills
- Primary care physician (PCP) and family agree with plan of care
It is recommended for select children, depending on season and clinical presentation, that the following be considered: rapid diagnostic tests and/or culture for influenza, respiratory syncytial virus (RSV), or enteroviruses. If a viral etiology is identified, SBI is unlikely, and it is recommended that management be modified accordingly.
- Note 1: Pre-PCV7data showed bacteremia present in 0.2% (95% CI: 0.01, 0.8) of children age 3 to 36 months with viral infections (croup, varicella, bronchiolitis stomatitis) (Greenes & Harper, 1999) [D]. Of 156 bronchiolitis patients age 0 to 24 months, there were no bacteremia cases and urinary tract infection was diagnosed in 1.9% of the 106 patients who were cultured (Kuppermann et al., 1997) [C].
- Note 2: As many as 55% of children hospitalized for an acute febrile illness in the summer and fall seasons were subsequently found, by polymerase chain reaction (PCR) testing, to have enteroviral infection. Therefore, early identification of enteroviral infection could decrease hospitalization rates during these seasons (Rotbart et al., 1999) [C].
- Note 3: Rapid flu testing of young children in the Emergency Department (ED) decreases use of diagnostic tests and antibiotics and decreases time in the ED (see table in original guideline document).
- It is recommended that a practitioner have a low threshold for obtaining both a urinalysis and a urine culture. Urinary tract infection (UTI) is the most common SBI for children age 2 to 36 months of age at the time of this guideline review. Overall prevalence of UTI in this age group is 4.2 to 5.4% (Downs, 1999) [S, E].
Risk factors for UTI include:
- Male
- Female: <2 years
- Caucasian race
- Fever >39 degrees C
(Shaw et al., 1998 [C]; Hoberman et al., 1993 [C]; Bachur & Harper, 2001 "Reliability of the urinalysis" [D] & "Predictive model" [D])
Absence of high fever or other specific risk factors does not preclude the presence of UTI (see Appendix 1 in the original guideline document).
It is recommended that urine samples be collected by catheter, as they are less likely to be contaminated than "clean catch" samples (Weinberg & Gan, 1991) [D].
It is recommended that any positive urinalysis result, while pending results of culture, be considered consistent with a presumptive diagnosis of UTI and an indication to initiate antibiotic therapies and other measures fully described in the Cincinnati Children's Hospital Medical Center (CCHMC) Evidence Based Clinical Practice Guideline for First Time Urinary Tract Infections©.
Note: A positive culture on urine collected using sterile technique remains the only standard for diagnosing a definite UTI (Hoberman et al., 1994) [C]. Any one of the following study results defines a positive urinalysis (Gorelick & Shaw, 1999) [M]:
- Positive nitrite screen
- Positive leukocyte esterase
- Positive microscopic exam: the definition of abnormal microscopic exam is dependent on patient or provider-specific determinants (see table in the original guideline document)
If all of the above three tests are performed and any one is abnormal (using >5/high power field [hpf] as the abnormal value for white blood cells [WBC]), the aggregate sensitivity is 100% (95% CI; 96.4, 100) and aggregate specificity is 60.1% (95% CI; 56.1, 64.1) (Lohr et al., 1993) [D].
- Routine CBC and blood culture of well-appearing children with FUS are not recommended (Lee, Fleisher & Harper, 2001 [Q]; Kuppermann, 2002 [X]).
- It is recommended that a CBC with differential and a blood culture be performed on any child who is ill-appearing or if the practitioner determines the child to be at high risk for occult SBI.
- Note: It is preferred that the blood culture sample be collected from a separate site from the insertion of an intravenous line, as this has been shown to lower blood culture contamination rates by 69% (Norberg et al., 2003)[C].
In the post-PCV7 era, the predictive values of individual diagnostic tests have not been studied. The factors influencing the decision to perform the tests include:
- PCV7 series incomplete for age (see Appendix 2 in original guideline document)
- Age, more likely less than 24 months
- Clinical appearance
- Lack of viral symptoms or exposure
- Duration of illness
- High fever (such as >40.0 degrees C)
- Inadequate access to follow-up care
- Family’s tolerance for risk
- Meningococcal contact
(Finkelstein, Christiansen & Platt, 2000 [D]; Kuppermann, Fleisher & Jaffe, 1998 [A])
The following notes are based on pre-PCV7 data.
- Note 1: An absolute neutrophil count (ANC) is more sensitive and specific than a WBC or absolute band count (ABC) for occult pneumococcal bacteremia detection (Kuppermann, 1999 [C]; Isaacman et al., 2000 [D]; Kuppermann, Fleisher & Jaffe, 1998 [A]).
- An ANC of >10,000/mm3 increases risk, to 8 to 10% (Kuppermann, Fleisher & Jaffe, 1998) [A].
- Note 2: A WBC of >15,000/mm3 raises risk for bacteremia to 3 to 4%; if >20,000/mm3, the risk is 8 to 10% (Bachur, Perry & Harper, 1999 [C]; Lee & Harper, 1998 [C]).
- Note 3: A CBC is not routinely helpful in identifying unsuspected meningococcal bacteremia in febrile children (Kuppermann, 1999) [D].
- There is no published evidence demonstrating that chest x-rays, stool cultures, or lumbar punctures are helpful as routine studies. No specific recommendations are made other than to consider these studies when there are specific indications that the child is likely to have occult or complicated pneumonia, gastroenteritis, or meningitis (Kuppermann, 1999) [D].
Note 1: Pneumonia is seldom occult, but may be. Pre-PCV7 evidence suggests that a chest x-ray be considered when a fever exceeds 39 degrees C and WBC exceeds 20,000/mm3 (Bachur, Perry & Harper, 1999) [C]. However, chest x-rays do not often help in the choice of appropriate pneumonia therapy (McCarthy et al., 1981) [C].
Note 2: In children with lower temperatures and WBC counts, the absence of respiratory distress, tachypnea, rales (crackles), or decreased breath sounds reduces the likelihood of pneumonia (Jadavji et al., 1997) [S, E].
Medications and Management
General
Routine empiric antibiotic therapy in febrile patients results in the treatment of many children unlikely to benefit (Bulloch, Craig & Klassen, 1997 [M]; Lee, Fleisher & Harper, 2001 [Q]; Kuppermann, 2002 [X]) . Moreover, the decision to use antibiotics and the specific choice of antibiotic must be balanced against the increasing emergence of bacterial resistance.
Note: Although complications are rare, and up to 75% of occult pneumococcal bacteremia resolve spontaneously, children with occult bacteremia and treated with antibiotics clinically improve earlier and are less likely to be bacteremic at follow-up. Also, in spite of a prevalent practice of starting empiric oral or parenteral antibiotics in febrile patients to try to prevent complications, the efficacy for this practice has never been documented in a randomized controlled fashion (Rothrock et al., 1998 [M]; Bulloch, Craig & Klassen, 1997 [M]; Harper, Bachur & Fleisher, 1995 [D]; Kuppermann, 1999 [S, E]).
Treatment Recommendations
- It is recommended that well-appearing children with FUS who are judged to be at sufficiently low risk to preclude the need for diagnostic studies, and also have the likelihood of excellent follow-up, can be considered for outpatient observation without starting antibiotic therapy (Local Expert Consensus [E]).
- It is recommended that well-appearing children with FUS with positive laboratory evaluation for viral illnesses, such as influenza, RSV, and enteroviruses, and who also have the likelihood of excellent follow-up, be observed as outpatients without starting antibiotic therapy. Instructions for caregivers are important regarding careful observation of clinical course and appropriate follow-up with primary care provider (PCP) (Local Expert Consensus [E]).
- It is recommended that well-appearing children with FUS who have normal laboratory studies, and also have the likelihood of excellent follow-up, can be considered for outpatient observation without starting antibiotic therapy (Local Expert Consensus [E]).
- It is recommended that well-appearing children with FUS who have positive diagnostic studies consistent with the diagnosis of UTI, community acquired pneumonia, or gastroenteritis are treated according to the CCHMC Evidence Based Clinical Practice Guideline specific for that condition (Local Expert Consensus [E]).
- It is recommended that well-appearing children with FUS who have risk factors for and positive diagnostic studies consistent with bacteremia, and also have the likelihood of excellent follow-up, be considered for treatment as outpatients with antibiotics after obtaining appropriate samples for culture (Local Expert Consensus [E]).
In the era preceding the availability of a conjugated pneumococcal vaccine, empiric antibiotic therapy was based on the observation that 83 to 85% of the episodes of occult bacteremia in this age group were due to Streptococcus pneumoniae (Fleisher et al., 1994 [A]; Segal & Chamberlain, 2000 [D]). Therefore, amoxicillin, ceftriaxone, or a combination of both was recommended. There was no consistent evidence of the superiority of one regimen over the others, of the optimal dose of amoxicillin, or of the alternative drug of choice for patients unable to tolerate amoxicillin or ceftriaxone (Rothrock et al., 1998 [M]; Fleisher et al., 1994 [A]). Conjugated pneumococcal vaccine has dramatically reduced the incidence of occult pneumococcal bacteremia and there are no longer clear epidemiological data upon which the recommendations for empiric therapy can be based (Whitney et al., 2003 [D]; Black et al., 2001 [O]) .
- It is recommended that ill-appearing children with history, physical examination, and diagnostic evaluation most consistent with SBI be treated with antibiotics after obtaining appropriate samples for culture (Local Expert Consensus [E]).
The most effective dose of amoxicillin is still uncertain. There is increasing emergence of amoxicillin resistant strains of S. pneumoniae nationally. To address the issue of resistance, "high dose" amoxicillin, 80 to 100 mg/kg/day, divided into 2 or 3 daily doses, has been advocated for some indications. In pediatrics, the efficacy of this higher dosing has primarily been demonstrated as therapy for acute otitis media (Seikel, Shelton & McCracken, 1997 [C]; McCracken, 1998 [S]). Although there are no confirmed demonstrations of high-dose amoxicillin efficacy for S. pneumoniae in the bloodstream, the dose is still included here because it is locally considered a reasonable option pending the publication of contrary evidence (Local Expert Consensus [E]).
See Table 3 in the original guideline document for dosage information.
- It is recommended that antibiotic therapy be discontinued if bacterial cultures are negative and the course of illness is consistent with a viral infection (Local Expert Consensus [E]).
- It is recommended that, if a blood culture is positive, the patient be reexamined to assess for clinical improvement or whether bacteremia was due to a previously undetected focal infection such as meningitis, UTI, or bacteremia (Finkelstein, Christiansen & Platt, 2000 [D]; Kuppermann et al., 1999 [D]).
Education
It is recommended that the family be educated regarding careful observation of the febrile child and the importance of follow-up with the primary care provider (PCP), as unsuspected sepsis or meningitis may not be determined early in the course of a febrile illness (Kuppermann et al., 1999 [D]).
Family education and review is recommended on the following topics.
- Fever:
- Observing for signs, including taking an accurate temperature measurement
- Causes
- Comfort measures
(O’Neill-Murphy, Liebman & Barnsteiner, 2001 [O]; Crocetti, Moghbeli & Serwint, 2001[O])
- Indications to call their physician
- Anticipated course of the illness
Refer to the "Patient Resources" field for on-line information on Fever.
Definitions:
Evidence Based Grading Scale:
A: Randomized controlled trial: large sample
B: Randomized controlled trial: small sample
C: Prospective trial or large case series
D: Retrospective analysis
E: Expert opinion or consensus
F: Basic laboratory research
S: Review article
M: Meta-analysis
Q: Decision analysis
L: Legal requirement
O: Other evidence
X: No evidence