Management of the Young Febrile Child: A Commentary on Recent Practice Guidelines

Recently published “practice guidelines”12 and randomized antibiotic trials34 reflect a climate of increased diagnostic testing, more frequent treatment, and more invasive (ie, parenteral rather than oral) treatment of febrile children 3 to 36 months of age. For children in this age group with a temperature ≥39.0°C, the guidelines12 suggest a white blood cell (WBC) count and provide two options with respect to obtaining a blood culture: all such children or those whose WBC count is ≥15 000/mm2. Culture of urine obtained by catheterization or suprapubic aspiration is recommended for all boys <6 months and all girls <24 months. The guidelines recommend empiric treatment with ceftriaxone, once again with two options: treat all such children or those whose WBC count is ≥15 000/mm2. These practice guidelines are based on a meta-analysis that pooled data from both randomized controlled trials and observational (nonexperimental) studies of clinical outcomes in young febrile children, and on the views of an expert panel chosen by the senior author.12 Although the guidelines have not been officially endorsed by any professional organization, they were developed by authors who are widely recognized in the field and thus could have an important impact on both clinical practice and health care policy.The clinical setting is that of a child with acute onset (≤4 days) of fever who does not appear “toxic” (ie, seriously ill) and has no apparent focus of bacterial infection (otitis media, pneumonia, osteomyelitis/septic arthritis, lymphadenitis, cellulitis, dysentery-like enteritis, or meningitis) after a history is obtained and a physical examination is performed. When confronted with such a child, the clinician must make a series of decisions:It is hardly surprising that, faced with these multiple complex decisions, the potential threat of litigation, and different policies for follow-up, physicians vary widely in their practice, particularly between those who work in private office settings vs those who work in hospital emergency departments.56 Although some practitioners may welcome practice guidelines that help them navigate the complexity of the clinical issues and reduce their uncertainty7 and their perception of liability, one recent study8 based on simulated case scenarios found little compliance with the recently published guidelines.12The diagnostic tests called for in the guidelines are difficult to obtain for many physicians who practice in private office settings. More important, we believe that both the testing and the treatment may do more harm than good to the young febrile children and their families who are subjected to it. In the remainder of this commentary, we critically review the evidence upon which the recent guidelines are based and propose instead an approach that involves far less testing and no empiric antibiotic treatment, ie, one much closer to that used by many office-based practitioners. We shall argue that such an approach is more than defensible; we maintain that it is actually preferable, not only for the private office but for the emergency department as well.The diagnostic tests recommended in the guidelines12 are the complete blood count (CBC), blood culture, and urine culture. Several of the recommendations are keyed to the results of the CBC, with recommendations to perform a blood culture and/or to begin empiric antibiotic treatment based on the presence of a WBC count ≥15 000/mm3. It has been repeatedly shown that high WBC counts are significantly more common (approximately two- or threefold) in children with bacterial infections than in those with viral infections.9-16But the value of a diagnostic test depends not on whether the association between the test result and the condition of interest (eg, bacteremia) is statistically significant in a group of children, but rather on the predictive value of the result in an individual child. In particular, if the test is positive (or negative), how likely is it that the child has an occult bacterial infection? Because viral infections are far more prevalent than bacterial infections, the positive predictive value of an elevated WBC count for an occult bacterial infection is rather low (8% to 15% in most studies). Tversky and Kahneman17 have documented the widespread failure to adequately consider prior probability (ie, prevalence) in weighing the evidence for and against an uncertain proposition. This common error in probability assessment prevents many clinicians from appreciating the fact that the vast majority of young febrile children with a high WBC count do not have an underlying bacterial infection as a cause of their fever.16 Even among the true positives, ie, those with a high WBC count who do have an occult bacterial infection, most will have an infection that is likely either to clear spontaneously (bacteremia) or to respond to treatment without serious sequelae even if the diagnosis is delayed (pneumonia, cellulitis, UTI). The positive predictive value for more serious infections (meningitis, osteomyelitis, septic arthritis) is at least several orders of magnitude lower.The value of the blood culture itself is questionable. The primary concern is not bacteremia per se, but rather those few bacteremic children who subsequently develop serious focal infections. Many children who develop meningitis or other serious sequelae of their bacteremia will already have done so by the time the blood culture is recognized as positive.18 Moreover, serious sequelae of occult bacteremia are increasingly uncommon. In the past, many of the bacteremic children who developed meningitis or other sequelae were those with Haemophilus influenzae type b (Hib) bacteremia,19-24 which has become rare in the era of routine immunization with Hib conjugate vaccines.25-27Unfortunately, a management strategy that includes obtaining a blood culture as part of the initial assessment can lead to unnecessary hospitalization. Observational studies and randomized trials of young febrile children indicate that the majority of initially bacteremic children who remain febrile do not have persistent bacteremia, even if they did not receive antibiotics at the initial visit.342829 Thus, if the physician decides to hospitalize and treat all initially bacteremic children who remain febrile at follow-up, most such children will be hospitalized and treated unnecessarily.2930 It is precisely the knowledge that such children were bacteremic at the initial assessment that results in excessive hospitalizations. Without such knowledge, few clinicians would hospitalize children who remain febrile but do not appear seriously ill. Hospitalization is considered far more undesirable by young children's parents than by physicians.31Apart from the CBC and blood culture, the recent guidelines recommend a culture of urine obtained by catheterization or suprapubic aspiration for all boys <6 months and all girls <24 months. Catheterization and suprapubic aspiration cause discomfort, however, and the culture results are not usually available for 24 to 48 hours. Although routine urinalysis may not be sufficiently sensitive or specific to make the diagnosis of urinary tract infection reliably,32-34 two recent studies (from the same group of investigators) suggest that “enhanced” urinalysis based on a trained technician's use of a hemocytometer and Gram stain to examine an unspun urine sample may improve both the sensitivity and specificity for diagnosing UTI in this age group.3536 Preliminary evidence suggests that children with positive urine cultures but without pyuria appear to be at little risk of pyelonephritis and may represent cases of asymptomatic bacteriuria rather than of true urinary tract infection.3537 If these data are confirmed in future studies based on routine urinalysis (as performed in most office and hospital laboratories), a negative urinalysis on a clean-voided (bag) specimen may prove sufficient to obviate the need for urine culture obtained by a more invasive technique. Moreover, although a urine culture of a bag specimen is associated with a high risk of either contamination or inconclusive result,38-43 a negative result is strong evidence against a UTI.In arguing against the routine performance of the CBC, blood culture, and bladder catheterization or suprapubic aspiration, we do not dispute that liberal blood and urine testing have occasionally led to earlier relief of symptoms and to prevention of complications, perhaps even of death. But at what price? Apart from the monetary cost of the diagnostic tests themselves, what are the risks to both the child and his or her family? These risks include the pain and discomfort of the diagnostic procedure, the waiting time before the procedure is performed and until the results are received, the need for repeat cultures of blood and urine due to transient (ie, already resolved) bacteremia or contaminated initial blood or urine specimens, and unnecessary hospitalization and treatment with intravenously administered antibiotics (due to false-positive urinalysis or to contaminated blood culture).7 These risks and inconveniences are hardly life-threatening and are unlikely to be associated with long-term morbidity. At the individual level, they pale before the potential benefits of the diagnostic tests. After all, what are the pain and waiting time associated with a venipuncture compared with the prevention of either death or serious morbidity?But risks and benefits cannot be compared directly against one another, because they do not occur with anything approaching similar frequencies. Every child who receives one or more of these tests will experience pain and discomfort, and every family will have to wait for the test to be performed and for the physician to receive the results. By contrast, prevention of either death or serious morbidity is extremely rare.Moreover, recent studies suggest that physicians and parents have considerably different values for both the risks and the benefits of testing.3144 Parents emphasize the short-term risks of tests (particularly the associated pain or discomfort) and the possibility of diagnostic error, whereas physicians give considerably greater weight to rarely-occurring serious morbidity and long-term adverse sequelae of infections. Thus, even if physicians were capable of adequately considering each of the risks and benefits of diagnostic testing, their decisions might well not be optimal for children and their parents because of the fundamentally different values they place on those risks and benefits. Physicians may also obtain diagnostic tests because they believe that testing may protect them against possible litigation, although we are aware of no evidence to support this belief. The same tests are also commonly ordered in Canada (where malpractice claims are far lower in frequency and magnitude than in the United States), and their use is influenced by practice background and experience and the presence or absence of a clinical trainee.45Can serious complications of bacteremia be prevented in outpatients by treating young febrile children with antibiotics (“expectant” therapy)? Investigators have attempted to answer this question using two approaches: observational studies that retrospectively compare outcomes of treated vs untreated children with occult bacteremia,18-24 and experimental studies (randomized controlled trials) of expectant treatment.342846 Both approaches have been fraught with difficulties in design, analysis, and interpretation.The observational studies report that bacteremic children who were initially treated with antibiotics developed fewer “new” foci of infection than did children who did not receive antibiotics. Observational study designs are inherently biased toward finding a positive effect of treatment, however, because at baseline the children in the two groups are not equally likely to develop the subsequent outcomes (new foci of infection). Children in these studies were not assigned randomly either to receive or not to receive antibiotic treatment. In particular, those who were treated often already had the outcomes of interest (eg, pneumonia or otitis media–which is why they were treated27), so the probability that theysubsequently would develop new foci of infection was substantially lower than that of the untreated children.Because most of the published studies in this area have come from tertiary-care emergency departments or walk-in clinics, almost all treated children had some identified focus of infection at the initial visit. Some of the untreated children, however, may well have had an unrecognized focal infection, such as pneumonia (a chest radiograph may not have been performed) or otitis media (the tympanic membranes may have been difficult to visualize or were thought to be erythematous from crying). It is therefore not surprising that children with undetected focal infections who were not treated with an antibiotic were more likely to remain symptomatic and to have the focal infection detected at follow-up than children who received an antibiotic. Moreover, some untreated patients with more serious focal infections (eg, epiglottitis, septic arthritis) who were not diagnosed at the initial visit were classified as having developed “new” foci of infection at follow-up.19 Finally, several observational studies grouped meningitis with much less serious outcomes such as otitis media and pneumonia; in fact, treated and untreated children showed little difference in risk of developing meningitis.Randomized clinical trials are more likely to yield a scientifically valid answer to the question of whether expectant antibiotic treatment is effective. Nonetheless, all of the published trials (see Table) have had methodologic problems.47 In particular, all four trials limited their statistical analyses to children who later proved to have had bacteremia at the time they were enrolled. Such analyses are simply incorrect; they violate the epidemiologic maxim to “analyze what you randomize.” The proper denominator for such comparisons is the number of febrile children randomized. The treatment of children known to be bacteremic is not controversial; all such children should receive antibiotics parenterally. The pertinent clinical question is whether the benefits of treating all young febrile children (most of whom have self-limited viral infections) outweigh the financial and human costs and the adverse side effects of such a strategy. As we shall see, the trial investigators were sometimes able to obtain statistically significant differences between the groups only by analyzing the subgroup with occult bacteremia (<3% of the study sample), despite the smaller sample size used in their statistical tests. Unlike sociodemographic or clinical characteristics that are identifiable a priori (eg, age, sex, or and and that as a for subgroup analysis, the presence or absence of bacteremia cannot be at the time the physician must whether to treat or not to Moreover, an to bacteremic children the outcomes in the of children who were randomized and issues a clinical will why the analyses should not be limited to the subgroup with febrile child is in an emergency has blood for culture, is treated with an and is Although the initial blood culture is the child subsequently bacterial is a because blood cultures are not bacteremia does not develop in a febrile and may be most clinicians have such If such a child had been in these clinical would not have been in the statistical even if developed and the results of a randomized trial of expectant administered by administered vs no treatment in children to 24 months of age with a temperature and of either the WBC count or the Although the investigators that the treatment was in complications of bacteremia, the data was based only on the bacteremic children in each of children who received were with negative follow-up 24 to 48 later vs of untreated Such an a value of by but the based on all randomized a value of Moreover, because no was the investigators the parents of the were to treatment of the untreated bacteremic children had but could have influenced the two in the 3 of the who were at otitis media or persistent Moreover, if the is based on the more of all new focal bacterial infections of presence or absence of bacteremia at the initial the of vs yield a risk of and an value of randomized children 3 to 36 months of age with to receive or in a statistically significant differences in were between the two although the of focal complications of bacteremia of patients in the group and of in the statistical to a of Although bacteremic children who received significantly in temperature at the time of follow-up, no temperature data were for the child in either group developed randomized children 3 to 36 months of age with (or a WBC count ≥15 to receive either or the children whose at 24 were those treated with were significantly less likely to be febrile than those treated with of vs of The case of meningitis (due to in a child who had received ceftriaxone, although the was from obtained before the and most recent which has been widely to support the use of expectant treatment of febrile children with ceftriaxone, children 3 to 36 months of age with and no apparent bacterial focus of infection (or with otitis were randomized to receive either a of or a of Unlike the no outcomes were to treatment among the majority of children without the of outcomes by the proper the difference in persistent fever among bacteremic children was statistically significant (as the authors as a of bacteremic children, but not as a of all treated Moreover, of the children treatment groups developed new focal bacterial infections, which is similar to the among the bacteremic children who received although of the children developed meningitis or other serious bacterial their results in of both and bacterial infections, based on a priori clinical and These however, an in of a positive blood or culture at follow-up was for and a positive culture or Gram stain from a specimen was for Because in the and other are far more likely to the for potential and to do so for much than treatment with is more likely to result in negative cultures in a child who a focal infection such as Children who received and developed a bacterial infection were therefore more likely to be classified in the But would any clinician consider the children in the group with Hib bacteremia with white per and a positive test for Hib in the the other with a white cell count of not to have If only bacterial infections were the children who received had a lower of than those treated with of a difference that on statistical The difference in of was far from statistically however, bacterial infections the two children with but meningitis after and bacterial infections were Moreover, one of the cases of meningitis in the group in a child whose obtained at the initial visit was already (ie, before positive for the or cases of meningitis that in this were to an infection that has been the of conjugate even if one the of the the data are because the of occult bacteremia has the study was the risk of meningitis (the of occult bacteremia that is of because most of the other such as or pneumonia, can be treated they become apparent and are associated with serious among children with occult bacteremia has because the majority of cases of bacterial meningitis that developed in such children had been to the recently published guidelines are based on a meta-analysis of all published data on the of empiric antibiotic treatment, ie, an of data from observational studies and randomized Such an approach the in observational studies toward finding an apparent of treatment. In the evidence from the four randomized trials does not a of either or administered antibiotics in the risk of meningitis or of other serious bacterial infections. treatment (particularly does appear to lead to more But we question whether a of fever is sufficient to expectant treatment, particularly unrecognized focal infection (eg, otitis media or at the initial visit might well how this apparent Finally, any of antibiotic treatment may not be for the conjugate are the risks of routine expectant treatment of young febrile children with In to the financial and human antibiotics have as well as adverse side In the trial by to occur more in the group than in the In the trial by were more likely than to develop a Although of the cases of or in these studies to have been two recent in children with serious underlying who had received a of In because it is more difficult to the results of analyses of children treated with an a at the time of follow-up is more likely to result in hospitalization and parenteral treatment of a child for meningitis it is not Moreover, use of antibiotics for and is an important risk for infection by such most routine expectant antibiotic treatment could and follow-up of the febrile among and and the practice of with to an on at the of the in management between practitioners who work in emergency departments and those in office experience similar differences in despite health and the frequent use of hospital emergency departments as by families from all Because is no evidence that young children private and emergency departments with respect to the of the risk of serious sequelae of the and positive and negative predictive values of the CBC and other diagnostic or the of it is difficult to such management the suggest that decisions are for some management in the emergency department is often by the of with the child and family and her the of and compliance with the to and respond to their child can and should the But many emergency departments have developed of follow-up by and/or physician that work well for the vast majority of parents and children, with repeat as testing and treatment are and could even time at the initial and if the fever or other symptoms or are likely to be more if obtaining a blood culture and treatment with are for children without a focus of infection, why are they not also for children with identifiable bacterial foci of infection such as otitis media or The of bacteremia is at least as high in children with otitis media or pneumonia as in those without a bacterial focus of the of what evidence can one this of testing and parenteral antibiotic treatment of infections vs no testing and treatment of known focal recommend that young febrile children be for bacterial foci of child who should receive cultures and diagnostic and antibiotic treatment. If no focus is found and the child diagnostic tests other than urinalysis are not and no antibiotic treatment should be follow-up should be which will subsequent clinical and and/or antibiotic treatment as by or of symptoms and of If the physician is the of follow-up, time in the office or emergency department is often and hospital may occasionally be recommendations are based on of the available future may yield that a in diagnostic or In particular, if conjugate prove their use to that of conjugate Hib should substantially reduce the young febrile risk of bacteremia and obviate the need for studies this on diagnosis and and for their and on of this