Fever Caused By Occult Infections In The 3-To-36-Month-Old Child

Table of Contents

 

1. Abstract
2. Critical Appraisal Of The Literature
3. Epidemiology, Etiology, And Pathophysiology
   1. Occult Bacteremia
   2. Occult Urinary Tract Infection (UTI)
   3. Occult Pneumonia
4. Differential Diagnosis
5. Prehospital Care
6. ED Evaluation
7. Diagnostic Studies
8. Treatment
   1. Occult Bacteremia
   2. Occult Urinary Tract Infection
   3. Occult Pneumonia
9. Special Circumstances
10. Controversies/Cutting Edge
    1. SBI In The Presence Of Viral Illnesses
    2. Advancing Diagnostic Technology
    3. Changing Epidemiology: Resistant Microbes
11. Disposition
12. Summary
13. Key Points
14. Risk Management
15. Cost-Effective Strategies
16. Clinical Pathway: Occult Bacteremia
17. Clinical Pathway: Occult UTI
18. Clinical Pathway: Occult Pneumonia
19. References

Abstract

Fever is a common presenting complaint among pediatric patients, accounting for approximately 20% of emergency department (ED) visits by children.^1,2 Hence, management of the febrile child is a challenge faced by emergency physicians on a daily basis. Despite the fact that the vast majority of children with fever have self-limited viral illnesses,³ there is a finite number who may harbor serious bacterial illnesses (SBIs), and, in many cases, these patients are clinically indistinguishable from the rest. The emergency physician's challenge is to identify and treat those children who have SBIs while avoiding overtreatment with antibiotics of those without SBIs, thereby limiting the propagation of antimicrobial resistance. Making this distinction is particularly difficult early in the course of a febrile illness. In addition, this decision process is often conducted in the setting of a family with "fever phobia." Many myths regarding fever exist among the general public, and these misconceptions are often reinforced by the mixed messages that we in the medical community provide. Assessing the risk of SBI to an individual patient, selectively making reasonable diagnostic and therapeutic interventions, and simultaneously reassuring and educating families regarding appropriate concern for fever can make what appears to be a routine common complaint an important and challenging encounter.

Some instances of fever in children require simple decision making. When a child with fever has an evident source of infection, such as acute otitis media or acute gastroenteritis, decisions are relatively straightforward: treat the source and manage the patient's condition appropriately. In the case of the febrile patient with an underlying medical condition (such as sickle-cell disease) or indwelling hardware (such as a central venous catheter), diagnostic investigations and empiric therapy are usually protocoldriven. These circumstances place the patient at greater risk for SBI, and more aggressive management is apropos. This conservative approach extends to the youngest infants (less than 2-3 months of age), who have yet to develop a fully competent immune response. Finally, any patient who appears "toxic" demands a comprehensive search for the source of fever and empiric broad-spectrum antibiotic coverage until the clinical picture clears. This is true whether the patient is 45 days or 45 years of age.

Like the child in our vignette, however, it is the febrile pediatric patient without a readily identifiable source of infection, an unremarkable medical history, and a nontoxic appearance who can be the most challenging. What is this patient's risk of SBI? Are there laboratory tests that can guide us in pinpointing those at risk? Who should receive antibiotics? And what is an appropriate disposition and followup plan for these patients?

Critical Appraisal Of The Literature

The story of occult infection in children is an evolving one, and practice has changed over the past 30 years. Much of the initial literature regarding fever in the 3-year-and-under age group focused primarily on the identification of clinically inapparent infection in the form of "occult bacteremia" and the effort to prevent the potentially serious sequelae of bacteremia, such as meningitis, osteomyelitis, or pneumonia. Early investigations predated the availability of broad-spectrum parenteral antibiotics such as ceftriaxone, technology enabling continuous monitoring and detection of microorganisms in culture media, and development and widespread implementation of immunizations against the more common pathogens. As the landscape of occult infection in children has changed, more recent literature has attempted to take these factors into account, modifying recommendations and expanding the focus to include newer resistant organisms and the identification of other "occult" infections, such as urinary tract infection (UTI) or pneumonia.

Many ED physicians predicate their approach to febrile children on the practice guidelines outlined in a landmark 1993 article that appeared simultaneously in both Pediatrics and the Annals of Emergency Medicine. Because of their prominent display in the journals published by the American Academy of Pediatrics and the American College of Emergency Physicians, these guidelines had a certain voice of authority and quickly became a de facto standard of practice. A panel of experts chosen by the primary author performed a review of the existing literature at that time and arrived at recommendations on how to approach children of various ages with fever. These guidelines included two recommended options in the pursuit of occult bacteremia for children 3 to 36 months of age with a fever of 39°C (102.2°F) or greater without an identifiable source of infection: 1) obtain a blood culture and administer empiric treatment with parenteral antibiotics (ceftriaxone) pending culture results in all children meeting the above criteria; or 2) selectively culture and treat those whose white blood cell count (WBC) exceeds 15,000 muL. In addition, urine culture obtained by catheterization or suprapubic aspiration was recommended for all boys less than 6 months of age and all girls younger than 24 months.^4-5

Historically, much of the medical literature that laid the groundwork for this approach to occult infection in children originated in the 1970s and ‘80s and was a patchwork of sometimes flawed and inconsistent data. Initial reports simply described bacteremia rates as they varied by patient age and height of fever and characterized the primary offending organisms in a variety of population samples.^6-19 Most were gathered from patients seen in emergency departments and outpatient clinics, not in private practitioners' offices, a fact that injected a healthy dose of selection bias. None of the studies that applied a temperature threshold for initiating a fever workup accounted for prior use of antipyretics or subjective parental reports of fever in assessing bacteremia risk. Thus initial estimates of occult bacteremia rates in children less than 36 months of age were likely overstated and did not represent true prevalence data.^20-22 Nonetheless, they laid the groundwork for subsequent efforts to find and stop bacteremia in its tracks.

Furthermore, the 1993 guidelines are the result of a meta-analysis of existing studies, so they are only as good as the studies upon which they are based. The inclusion criteria (age, height of fever, etc.), the laboratory tests performed, the degree of WBC elevation associated with bacteremia, and the use of empiric antibiotics varied from study to study, making comparative analysis problematic. Some investigations lumped patients who had an identifiable source of infection (such as otitis media or pneumonia) with those without an apparent source on exam, which inevitably confounds interpretation of the results. Patients with a presumed bacterial source of infection would be expected to have a greater rate of bacteremia, and they would likely receive antibiotic therapy regardless of their WBC. In fact, because most of these studies did not randomly treat or not treat children with antibiotics, the group of children who were treated often already had one of the outcomes of interest and thus had a lower probability of subsequently developing a new focus of infection, biasing the outcomes of these studies in favor of antibiotic treatment.²³

The other presumption of the guidelines is that therapy with antibiotics (oral or parenteral) is effective in preventing sequelae, particularly meningitis, and it is not clear that this has been proven.^24-33 After the guidelines appeared, editorials written by prominent pediatric infectious disease specialists warned against the blanket use of ceftriaxone as a panacea.^23,34-36 In some of the studies promoting expectant antibiotic treatment, for example, recommendations were based upon the outcomes of the subset of patients with positive blood cultures and not the population of febrile children at risk for bacteremia as a whole. Naturally, few would quibble about treating patients with demonstrated bacteremia; but the issue—particularly for the emergency physician—remains to reliably identify which patients have bacteremia and selectively treating those. Even in the best case scenario, blood culture results are not available for 12-24 hours after they are obtained and are, therefore, not helpful in front-end decision making. To date, no readily available laboratory test(s), including the WBC, has been discovered that consistently and accurately positively predicts the presence of bacteremia. So, for the physician confronting the child with fever in real time, the question remains: who, if anyone, do you treat expectantly?

After the 1993 guidelines appeared, several surveys of the practicing medical community were circulated to assess their impact. It rapidly became clear that many emergency physicians were either unaware of the guidelines or actively chose not to follow them.^37-38 This was true not only for pediatric emergency physicians, but for general emergency physicians and primary care practitioners as well.^39-40 Further, those who were aware of and invoked the guidelines did not always apply them consistently.⁴¹ The use of ceftriaxone became widespread, in many instances indiscriminate and not in accordance with the published guidelines—the proverbial hammer for every nail that presented itself. This may have stemmed from the option, suggested by the 1993 guidelines, to treat everyone at risk (i.e., with a fever greater than 102.2°F without an obvious source). But many physicians obtained screening laboratories on patients, disregarded the (normal) results, and administered ceftriaxone anyway. While this strategy may provide an immediate sense of security for the emergency physician, who may feel that s/he has limited his or her personal liability and protected the patient in giving ceftriaxone, s/he may simultaneously be tying the hands of his or her partners in primary care and painting us all into the corner of antibiotic resistance in the long run. As was pointed out by early critics of ceftriaxone use in the emergency department, once this long-acting, broad spectrum, blood-brain barrier-crossing antibiotic has been administered, the parents and the primary care physician providing follow-up evaluation are robbed of their abilities to assess the child's clinical condition or need for continuing therapy.^34-35 And even if we grant that one or two doses of parenteral ceftriaxone are effective in treating bacteremia, two doses of ceftriaxone would be inadequate to treat meningitis if the child had already seeded the meninges. Clearly there is no easy or right answer to the question, to treat or not to treat?

Complicating the picture is the falling prevalence of SBIs as immunizations against the more common offending organisms—Haemophilus influenzae type B (HIB) and Streptococcus pneumoniae—have been developed and implemented on a widespread basis.^42-44 As rates of bacteremia and invasive infections due to these agents decline and, concomitantly, as the levels of resistance to our current antibiotics rise (witness the prolific emergence of MRSA and drug-resistant S. pneumoniae), management strategies we learned during our training years have become outdated and may no longer apply. The landscape of fever in children is constantly evolving, and the emergency physician must adapt his or her approach accordingly. This is not always easy, as old habits die hard. A recent study by Cox et al. highlighted that physicians tend to adhere to published guidelines or algorithms they were exposed to during their residency training, despite the appearance of newer or contradictory findings in the medical literature.⁴⁵ Though it is difficult to reconsider what was once dispensed as gospel, it is incumbent upon practicing physicians to modify their approach to the febrile child as new data and therapies emerge.

Fortunately, the guidelines have been appropriately revisited and modified to reflect the current situation.^46-52 While some current investigators persist in the attempt to build a better mousetrap for predicting SBI than the WBC (the absolute neutrophil count [ANC], C-reactive protein [CRP], and various cytokines have been posited as more appropriate substitutes),^53-62 these newer laboratory indices are rapidly becoming weapons in search of a war. Vaccination effectiveness has led several commentators to suggest that the search for occult bacteremia may already have become the medical equivalent of tilting at windmills.^48,50-51 Hence, the emphasis in more recent literature on fever in this 3-to-36-month age group is on detecting other sources of occult infection, such as UTI.^63-69

Risk Management

1. "The girl's urine dipstick was nitrite- and leukocyte esterase-negative so I sent her home without antibiotics and canceled her urine culture."

2. "I know his white blood cell count was only 12,000/L, but with a fever of 103°F, I felt it best to give him a shot of ceftriaxone before discharging him."

3. "She's got minimal upper respiratory symptoms, but her RSV is positive, so I've got my source of infection."

4. "The child's white blood cell count came back from the lab at 18,500/L, but he looked great and Mom was anxious to go home, so I discharged him without antibiotics. I hope he's OK."

5. "Billy has a raging left otitis media, but I don't think that fully explains his fever of 104.2°F. I'm sending a CBC on him."

6. "Josè and his family just moved to the States and don't have a PCP yet. Despite his fever, he looked >pretty good, so I told them they need to find themselves a doctor and sent them on their way."

7. "I know Keisha has sickle-cell disease, but her temperature is only 101°F and everybody in her family has got a cold right now. I think we're safe calling this thing a virus and having her follow up on Monday."

8. "Two-year-old Joey was transferred here for fever, a WBC of 22,000/L, and belly pain, but his urine is clean and his abdominal CT was negative. He looks good now after IV fluids and some acetaminophen. I think he's just got a virus."

9. "Mom says 18-month-old Sandra's fever at home was 103°F and she looked just terrible, but here in the ED she's playful and afebrile. No way she has a bacterial infection."

10. "I'm waiting on the CBC. If his WBC is up, I'm going to tap this kid."

References

Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.

To help the reader judge the strength of each reference, pertinent information about the study, such as the type of study and the number of patients in the study, are included in bold type following the reference, where available.

1. Nelson DS, Walsh K, Fleisher GR. Spectrum and frequency of pediatric illness presenting to a general community hospital emergency department. Pediatrics 1992;90(1 Pt 1):5-10. (Retrospective; 874 patients from general ED)
2. Krauss BS, Harakal T, Fleisher GR. The spectrum and frequency of illness presenting to a pediatric emergency department. Pediatr Emerg Care 1991;7(2):67-71. (Retrospective; 3784 patients from pediatric ED)
3. Kramer MS, Tange SM, Mills EL, et al. Role of the complete blood count in detecting occult fecal bacterial infection in the young child. J Epidemiol Commun Health 1993;46:349-357. (Prospective; 2492 febrile children 3-24 months)
4. Baraff LJ, Bass JW, Fleisher GR, et al. Practice guideline for the management of infants and children 0 to 36 months of age with fever without source. Pediatrics 1993;92(1):1-12. (Practice guideline & literature review)
5. Baraff LJ, Bass JW, Fleisher GR, et al. Practice guideline for the management of infants and children 0 to 36 months of age with fever without source. Ann Emerg Med 1993;22(7):1198-1210. (Practice guideline & literature review)
6. Soman M. Characteristics and management of febrile young children seen in a university family practice. J Fam Pract 1985;21:117-122. (Prospective cohort study; 311 children)
7. McGowan JE, Bratton L, Klein JO, et al. Bacteremia in febrile children seen in a "walk-in" pediatric clinic. N Engl J Med 1973;288:1309-1312. (Prospective; 708 febrile children)
8. Teele DW, Pelton SI, Grant MJ, et al. Bacteremia in febrile children under 2 years of age: results of cultures of blood of 600 consecutive febrile children seen in a "walk-in" clinic. J Pediatr 1975;87:227-230. (Prospective; 600 febrile children 1-24 months)
9. Murray DL, Zonana J, Seidel JS, et al. Relative importance of bacteremia and viremia in the course of fevers of unknown origin in outpatient children. Pediatrics 1981;66:157-160. (Prospective; 80 febrile children > 3 months)
10. Schwartz RH, Wientzen RL. Occult bacteremia in toxicappearing, febrile infants: a prospective clinical study in an office setting. Clin Pediatr 1982;21:659-663. (Prospective; 83 febrile patients 2-24 months)
11. Carroll WL, Farrell MK, Singer JI, et al. Treatment of occult bacteremia: a prospective randomized clinical trial. Pediatrics 1983;72:608-612. (Prospective RCT; 96 febrile patients 6-24 months)
12. Bass JW, Steele RW, Wittler RR, et al. Antimicrobial treatment of occult bacteremia: a multicenter cooperative study. Pediatr Infect Dis 1993;12:466-473. (Prospective multicenter trial; 519 febrile children 3-36 months)
13. Rosenberg N, Cohen SN. Pneumococcal bacteremia in pediatric patients. Ann Emerg Med 1982;11:2-6. (Prospective; 79 patients with pneumococcal bacteremia)
14. Yamamoto LT, Wigder HN, Fligner DJ, et al. Relationship of bacteremia to antipyretic therapy in febrile children. Pediatr Emerg Care 1987;3:223-227. (Prospective; 233 children 3-24 months with fever of 104.0°F or greater)
15. McCarthy PL, Dolan TF. Hyperpyrexia in children: eight-year emergency room experience. Am J Dis Child 1976;130:849-851. (Retrospective; 100 children with fever > 41.1°C.)
16. McCarthy PL, Jekel JF, Dolan TF. Temperature greater than or equal to 40°C. in children less than 24 months of age: a prospective study. Pediatrics 1977;59:663-668. (Prospective; 330 children < 24 months)
17. McCarthy PL, Grundy GW, Spiesel SZ, et al. Bacteremia in children: an outpatient clinical review. Pediatrics 1976;57:861- 868. (Retrospective; 1783 febrile children)
18. Dershewitz RA, Wigder HN, Wigder CM, et al. A comparative study of the prevalence, outcome, and prediction of bacteremia in children. J Pediatr 1983;103:352-358. (Prospective; 786 febrile patients 3-24 months)
19. Baron MA, Fink HD. Bacteremia in private pediatric practice. Pediatrics 1980;66:171-175. (Prospective; 146 episodes in febrile children 3-24 months)
20. Givens TG, Walsh-Kelly C, Glaeser P, et al. Letter to the editor. Pediatr Emerg Care 1996;12(6):460-461.
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22. Falik HL. Practice guidelines for management of infants and children with fever without source (FWS). Pediatrics 1994;93:347. (Letter to editor)
23. Kramer MS, Shapiro ED. Management of the young febrile child: a commentary on recent practice guidelines. Pediatrics 1997;100(1):128-134. (Editorial)
24. Avner JR. Occult bacteremia: how great the risk? Contemp Pediatr 1997;14(6):53-65. (Review)
25. Lieu TA, Schwartz S, Jaffe DM, et al. Strategies for diagnosis and treatment of children at risk for occult bacteremia: clinical effectiveness and cost-effectiveness. J Pediatr 1991;118:21-29. (Decision analysis)
26. Woods ER, Merola JL, Bithoney WG, et al. Bacteremia in an ambulatory setting: improved outcomes in children treated with antibiotics. Am J Dis Child 1990;144:1195-1199. (Retrospective; 414 bacteremic patients, 1 month-19 years)
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28. Baraff LJ, Oslund S, Prather M. Effect of antibiotic therapy and etiologic microorganism on the risk of bacterial meningitis in children with occult bacteremia. Pediatrics 1993;92(1):140-143. (Meta-analysis)
29. Fleisher GR, Rosenberg N, Vinci R, et al. Intramuscular versus oral antibiotic therapy for the prevention of meningitis and other bacterial sequalae in young, febrile children at risk for occult bacteremia. J Pediatr 1994;124:504-12. (Prospective RCT; 6733 febrile patients 3-36 months)
30. Harper MB, Bachur R, Fleisher GR. Effect of antibiotic therapy on the outcome of outpatients with unsuspected bacteremia. Pediatr Infect Dis J 1995;14(9):760-767. (Retrospective; 559 patients with occult bacteremia)
31. Bulloch B, Craig WR, Klassen TP. The use of antibiotics to prevent serious sequelae in children at risk for occult bacteremia: a meta-analysis. Acad Emerg Med 1997;4(7):679-683. (Metaanalysis)
32. Rothrock SG, Harper MB, Green SM, et al. Do oral antibiotics prevent meningitis and serious bacterial infections in children with Streptococcus pneumoniae bacteremia? A meta-analysis. Pediatrics 1997;99(3):438-444.
33. Rothrock SG, Green SM, Harper MB, et al. Parenteral vs. oral antibiotics in the prevention of serious bacterial infections in children with Streptococcus pneumoniae occult bacteremia: a meta-analysis. Acad Emerg Med 1998;5(6):599-606.
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35. Wald ER, Dashefsky B. Cautionary note on the use of empiric ceftriaxone for suspected bacteremia. Am J Dis Child 1991;145:1359-1361. (Editorial)
36. Schriger DL. Clinical guidelines in the setting of incomplete evidence. Pediatrics 1997;100:136. (Editorial)
37. Ros SP, Herman BE, Beissel TJ. Occult bacteremia: is there a standard of care? Pediatr Emerg Care 1994;10(5):264-267. (Survey; 306 PEM physicians)
38. Isaacman DJ, Kaminer K, Veligeti H, et al. Comparative practice patterns of emergency medicine physicians and pediatric emergency physicians managing fever in young children. Pediatrics 2001;108(2):354-358. (Retrospective; 568 febrile patients 3-36 months)
39. Wittler RR, Cain KK, Bass JW. A survey about management of febrile children without source by primary care physicians. Pediatr Infect Dis J 1998;17(4):271-277. (Survey; 406 pediatricians, family practice physicians, and emergency physicians)
40. Young PC. The management of febrile infants by primary care pediatricians in Utah: comparison with published practice guidelines. Pediatrics 1995;95:623-627. (Survey; 94 primary care pediatricians)
41. Jain S, Sullivan K. Ceftriaxone use in the emergency department: are we doing it right? Pediatr Emerg Care 2002;18(4):259-264. (Retrospective; 229 patients)
42. Herz AM, Greenbow TL, Alcantara J, et al. Changing epidemiology of outpatient bacteremia in 3- to 36-month-old children after the introduction of the heptavalent-conjugated pneumococcal vaccine. Pediatr Infect Dis J 2006;25(4):293-300. (Retrospective; blood cultures over five years in children 3-36 months)
43. Alpern ER, Alessandrini EA, Bell LM, et al. Occult bacteremia from a pediatric emergency department: current prevalence, time to detection, and outcome. Pediatrics 2000;106:505-511. (Retrospective cohort study; 5901 febrile patients 2-24 months)
44. Black SB, Shinefield HR, Hansen J, et al. Postlicensure evaluation of the effectiveness of seven valent pneumococcal conjugate vaccine. Pediatr Infect Dis J 2001;20:1105-1107. (Surveillance study)
45. Cox ED, Smith MA, Bartell JM. Managing febrile infants: impact of literature recommendations published during a physician's residency. Eval Health Prof 2005;28(3):328-348. (Survey, >5000 primary care providers)
46. Baraff LJ. Management of fever without source in infants and children. Ann Emerg Med 2000;36(6):602-614. (Review)
47. Isaacman DJ. The occult bacteremia controversy. Clin Ped Emerg Med 2000;1:109-116. (Review)
48. Kuppermann N. The evaluation of young febrile children for occult bacteremia: time to reevaluate our approach? Arch Pediatr Adolesc Med 2002;156:855-856. (Editorial)
49. American College of Emergency Physicians. Clinical policy for children younger than three years presenting to the emergency department with fever. Ann Emerg Med 2003;42:530-545. (Clinical policy statement)
50. Baraff LJ. Editorial: Clinical policy for children younger than three years presenting to the emergency department with fever. Ann Emerg Med 2003;42:546-549. (Editorial)
51. Stoll ML, Rubin LG. Incidence of occult bacteremia among highly febrile young children in the era of the pneumococcal conjugate vaccine: a study from a children's hospital emergency department and urgent care center. Arch Pediatr Adolesc Med 2004;158(7):671-675. (Retrospective; 329 febrile patients 2-36 months)
52. Ishimine P. Fever without source in children 0 to 36 months of age. Pediatr Clin N Am 2006;53:167-194. (Review)
53. Saladino R, Erikson M, Levy N, et al. Utility of serum interleukin-6 for the diagnosis of invasive bacterial disease in children. Ann Emerg Med 1992;21:1413-1417. (Prospective w/retrospective controls; 20 cases, 50 controls)
54. Isaacman DJ, Zhang Y, Reynolds EA, et al. Accuracy of a polymerase chain reaction-based assay for the detection of pneumococcal bacteremia in children. Pediatrics 1998;101(5):813-816. (Prospective case control study; 583 patients 2 weeks-15 years)
55. Strait RT, Kelly KJ, Kurup VP. Tumor necrosis factor-α, interleukin-1β, and interleukin-6 levels in febrile, young children with and without occult bacteremia. Pediatrics 1999;104(6):1321-1326. (Prospective, case control study; 33 cases, 66 controls)
56. Pulliam PN, Attia MW, Cronan KM. C-reactive protein in febrile children 1 to 36 months of age with clinically undetectable serious bacterial infection. Pediatrics 2001;108(6):1275-1279. (Prospective cohort study; 77 febrile patients 1-36 months)
57. Isaacman DJ, Burke BL. Utility of the serum C-reactive protein for detection of occult bacterial infection in children. Arch Pediatr Adolesc Med 2002;156:905-909. (Prospective; 256 febrile patients 3-36 months)
58. Neuman MI, Harper MB. Evaluation of a rapid urine antigen assay for the detection of invasive pneumococcal disease in children. Pediatrics 2003;112(6):1279-1282. (Prospective; 346 febrile children 3 months-5 years)
59. Lopez AF, Cubells CL, Garcia JJ, et al. Procalcitonin in pediatric emergency departments for the early diagnosis of invasive bacterial infection in febrile infants: results of a multicenter study and utility of a rapid qualitative test for this marker. Pediatr Infect Dis J 2003;22(10):895-904. (Prospective multicenter study; 445 febrile children)
60. Herrera P, Duffau G. Usefulness of C-reactive protein for the diagnosis of bacterial infections in children. Rev Med Chil 2005;133(5):541-546. (Review)
61. Hsiao AL, Baker MD. Fever in the new millennium: a review of recent studies of markers of serious bacterial infection in febrile children. Current Opin Pediatr 2005;17(1):56-61. (Review)
62. Pratt A, Attia M. Duration of fever and markers of serious bacterial infection in young febrile children. Pediatr Int 2007;49:31-35. (Prospective; 119 febrile children 1-36 months)
63. Hoberman A, Chao HP, Keller DM, et al. Prevalence of urinary tract infection in febrile infants. J Pediatr 1993;123:17-23. (Cross-sectional prevalence study; 945 febrile infants)
64. American Academy of Pediatrics, Committee on Quality Improvement, Subcommittee on Urinary Tract Infection. Practice parameter: The diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children. Pediatrics 1999;103(4):843-852. (Clinical practice guideline and literature review)
65. Shaw KN, Gorelick M, McGowan KL, et al. Prevalence of urinary tract infection in febrile young children in the emergency department. Pediatrics 1998;102(2):e16. (Cross-sectional prevalence study; 2411 febrile infants)
66. Gorelick MH, Shaw KN. Clinical decision rule to identify febrile young girls at risk for urinary infection. Arch Pediatr Adolesc Med 2000;154(4):386-390. (Prospective cohort study; 1469 febrile girls < 2 years old)
67. Shaw KN, Gorelick MH. Fever as a sign of urinary tract infection. Clin Ped Emerg Med 2000;1:117-123. (Review)
68. Gorelick MH, Hoberman A, Kearney D, et al. Validation of a decision rule identifying febrile young girls at high risk for urinary tract infection. Pediatr Emerg Care 2003;19(3):162-164. (Retrospective case-control study; febrile girls < 2 years, 98 cases, 114 controls)
69. Zorc JJ, Kiddoo DA, Shaw KN. Diagnosis and management of pediatric urinary tract infections. Clin Microbiol Rev 2005;18(2):417-422. (Review)
70. Cimpello LB, Goldman DL, Khine H. Fever pathophysiology. Clin Ped Emerg Med 2000;1:84-93. (Review)
71. Corneli HM. Beyond the fear of fever. Clin Ped Emerg Med 2000;1:94-101. (Review)
72. Avner JR. Preface. Clin Ped Emerg Med 2000;1:81-83. (Editorial)
73. Marshall R, Teele DW, Klein JO. Unsuspected bacteremia due to Haemophilus influenzae: outcome in children not initially admitted to hospital. J Pediatr 1979;95:690-695. (Retrospective; 94 cases H. influenzae bacteremia)
74. Anderson AB, Ambrosino DM, Siber GR. Haemophilus influenzae type b unsuspected bacteremia. Pediatr Emerg Care 1987;3(2):82-85. (Retrospective; 322 HIB infections)
75. Lee GM, Harper MB. Risk of bacteremia for febrile young children in the post-Haemophilus influenzae type b era. Arch Pediatr Adolesc Med 1998;152:624-628. (Prospective cohort study; 8974 blood cultures from febrile children 3-36 months)
76. Bandyopadhyay S, Bergholte J, Blackwell CD, et al. Risk of serious bacterial infection in children with fever without a source in the post-Haemophilus influenzae era when antibiotics are reserved for culture-proven bacteremia. Arch Pediatr Adolesc Med 2002;156:512-517. (Retrospective; 1202 blood cultures from febrile children 2-36 months)
77. Dashefsky B, Teele DW, Klein JO. Unsuspected meningococcemia. J Pediatr 1983;102(1):69-72. (Retrospective case series)
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