1. Fever in Children Jay Hescock M.D. Assistant Professor of Pediatrics
LSU Department of Pediatrics

2. Objectives
Review etiologies of fever without a localizing source in the pediatric population
Discuss appropriate evaluation and treatment of children presenting with fever without a localizing source
Discuss preliminary data and the possible implications of universal pneumococcal immunization on the work-up/treatment of fever without a localizing source

3. Measuring Fever Rectal - most reliable in infants under 3 mos
Oral - only reliable in cooperative children
Axillary - least invasive; less accurate
Tympanic - results variable. Generally 1.0 to 1.8 F lower than rectal temperature
Pacifier - requires 3 to 4 minutes. Generally 0.5 F lower than rectal temperature
Temperature of 38 C (100.4 F) or greater considered fever

4. Fever Without a Localizing Source
Refers to an acute febrile illness in which the etiology of the fever is not apparent after a thorough history and physical exam

5. Etiology of Acute Fever Without Localizing Source
Infants < 28 days
Serious Bacterial Illness (UTI, bacteremia/sepsis, meningitis, pneumonia, bone/joint), viral infections
Infants 1 to 3 months
SBI, viral infections
Children 3 to 36 months
Occult bacteremia, SBI, viral infections

6. Approach to the Toxic Child

7. Definition of Toxicity
Refers to the apparent severity of a child’s disease based on physical exam
Yale Observation Score (not always reliable in young infants)
Child’s cry, reaction to parents, state variation, response to social overtures, color, hydration status
Clinical picture consistent with sepsis syndrome (with or without fever!)
lethargy, poor perfusion, hyper/hypoventilation, or cyanosis

8. Evaluation of the Toxic Child
Complete blood count
Blood cultures from 2 sites
Urinalysis
Urine culture
CSF studies, including culture
Consider unique factors eg. central lines, indwelling catheters/hardware

9. Treatment of the Toxic Child
Neonates <3 months: Ampicillin (high dose) + an aminoglycoside (or 3rd generation cephalosporin). Consider anti-staphylococcal coverage if warranted on PE
Children > 3 month: Vancomycin + 3rd generation cephalosporin
**Antibiotic coverage should be narrowed as soon as susceptibilities are known**

10. Approach to the Nontoxic Child

11. Cases

12. 1993 Practice Guideline - Rochester Criteria - Fever Without Localizing Source
Infants < 28 days old
Hospitalize
Full sepsis work-up with blood/urine/CSF cultures
IV antibiotics with ampicillin and 3rd generation cephalosporin or gentamicin to cover common pathogens in this age group (GBS, E. coli, and Listeria)
antibiotic may be D/C at hours provided cx (-) and child remains well appearing

13. 1993 Practice Guideline - Rochester Criteria - Fever Without Localizing Source
Infants 28 to 90 days old
Low risk
Option 1: BCx, UCx, outpt observation without antibiotics, re-evaluate in 24 hours
Option 2: BCx, UCx, CSF cx, outpt observation with Ceftriaxone x 1, re-evaluate 18 to 24 hours
Non low risk
Hospitalize, blood/urine/CSF cultures, IV abx

14. Low Risk Criteria - Rochester 1993
Previously healthy
Non-toxic appearing
No focal bacterial infection on examination
Negative laboratory screening
WBC 5,000 to 15,000
Less than 1,500 absolute band count
Normal urinalysis
Less than 5 WBC/hpf in stool if diarrhea present

15. Results - Rochester Infants < 90 days Sensitivity 83-97%
1.1% low risk had bacteremia
1.4% low risk had serious bacterial infection
0.5% low risk had meningitis
Sensitivity 83-97%
Specificity 47-53%
PPV 10-16%
NPV %

16. Summary – Infants < 3 months old
Infants < 28 days should be fully evaluated and treated for possible SBI, since clinical and laboratory criteria are not reliable indicators of SBI
Infants 29 to 90 days should have laboratory evaluation and treatment according to protocols. LP should be done if antibiotics are given. Low risk infants may be safely managed as outpatients if parents are reliable

17. 1993 Practice Guideline - Rochester Criteria - Fever Without Localizing Source
Children 3 to 36 months old (nontoxic)
Fever < 39.0 C (102.2 F)
No laboratory tests or antibiotics
Return if fever persists >48 hour or clinical picture deterioration

18. 1993 Practice Guideline - Rochester Criteria - Fever Without Localizing Source
Children 3 to 36 months old (nontoxic)
Fever > 39.0 C (102.2 F)
WBC < 15,000 and UA normal – no additional tests, supportive treatment
return if fever persists >48 hours or clinical picture deteriorates
WBC > 15,000
Blood culture, stool culture if bloody diarrhea
Urine culture for boys < 6 months, girls < 2 years
Ceftriaxone pending culture results
Re-evaluation 24 to 48 hours

19. Occult Bacteremia
Definition: Positive blood culture in a well-appearing febrile child (clinically indistinguishable from those without bacteremia)
Most cases occur between 6 and 24 months; may occur as early as 3 months
Can occur with common bacterial illnesses such as otitis media

20. Incidence of Occult Bacteremia in Children with FWLS
Before routine H. influenzae vaccination
3 to 11%
85% S. pneumoniae
10% H. influenzae
3% N. meningitidis

21. Incidence of Occult Bacteremia in Children with FWLS
After routine H. influenzae vaccination
1 to 5%
>90% S. pneumoniae
remainder: N. meningitidis, Salmonella species, group A streptococci, and S. Aureus

22. 1993 Practice Guideline - Recommendation for Treatment
Children 3 to 36 months with positive BCx
H. influenzae or N. meningitidis - hospitalize, repeat BCx, lumbar puncture, IV antibiotics
S. pneumoniae
Afebrile and well appearing - 2nd dose Ceftriaxone, then 10 days oral penicillin
Febrile or ill appearing - hospitalize, lumbar puncture, IV antibiotics pending sensitivities

23. Rochester Criteria - Results Using Practice Guideline 1993
Guidelines do not totally eliminate all risk as the NPV of a WBC <15, 000 is 97%
Children 3 to 36 months
Without outpatient antibiotics 20% with occult bacteremia will have persistent bacteremia
9.2% developed meningitis (3-4/1000)
With outpatient antibiotics 4% with occult bacteremia will have persistent bacteremia
4.5 % developed meningitis (2/1000)
Highlights the need for appropriate F/U

24. Occult Bacteremia in Children with FWLS
The Current Era - After S. pneumoniae vaccination

25. Pneumococcal Vaccine Licensed in 2000
Protein-polysaccharide conjugate vaccine
Targets 7 serotypes commonly associated with invasive pneumococcal disease (causing 80% IPD)
When started as infant, involves 4 shot regimen

26. Impact of Pneumococcal Vaccine
Black et al. (PIDJ 2000)
94% effective in reducing disease caused by vaccine serotypes
89% reduction in invasive pneumococcal disease regardless of serotype
Whitney et al. (NEJM 2003)
78% reduction in disease caused by vaccine related serotypes
overall 69 % reduction in invasive disease regardless of serotype

27. Impact of Pneumococcal Vaccine
Fireman et al. (PIDJ 2003)
11% decrease in pneumonia
7.8% reduction in visits for OM and 5.7% reduction in antibiotic prescriptions
Kaplan et al. (Pediatrics 2004)
77% reduction in disease caused by vaccine related serotypes
66% reduction in invasive disease overall

28. Impact of Pneumococcal Vaccine
Stoll and Rubin (APAM 2004)
incidence of occult bacteremia in children 2-36 months old with temp >39C was 0.91%
neither elevated total WBC >15,000 or elevated ANC was highly predictive of occult bacteremia
Hsu et al. (PIDJ 2005)
69% reduction in IPD since introduction of PCV7

29. Summary - Children 3 to 36 months old
Increasing evidence that routine CBC and empiric antibiotic treatment is not necessary
UA/UCx all girls < 2y, uncircumcised boys < 2y, circumcised boys < 6 mo -1 yr (See AAP practice parameter Pediatrics 1999)
Lee et al (Pediatrics 2001) - with current rate of pneumococcal bacteremia, most cost effective method is CBC with BCx and empiric antibiotics if WBC > 15,000

30. Summary - Children 3 to 36 months old
Pneumococcal vaccine will decrease the incidence of bacteremia (and therefore IPD)
Full impact of vaccine on need for evaluation and empiric treatment for children with FWLS has yet to be determined
Many experts recommend continuing to use previous guidelines until full impact is assessed

31. Unanswered Questions
What additional effect will the new Pneumococcal vaccine have on rates of IPD
If the incidence of occult bacteremia continues to fall, will the risks associated with empiric Abx (i.e. anaphylaxis) outweigh the benefits
Are other screening tests now necessary to assess risk of SBI (i.e. procalcitonin levels) and minimize unnecessary ABX exposure

32. Bibliography
Alpern et al. Occult bacteremia from a pediatric emergency department: Current prevalence, time to detection, and outcome. Pediatr. 2000;106:
Bandyopadhyay 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 Adol Med. 2002;156:

33. Bibliography
Baraff et al. Practice guideline for the management of infants and children 0 to 36 months of age with fever without source. Ann Emerg Med ;22:
Baskin et al. Outpatient treatment of febrile infants 28 to 89 days of age with intramuscular administration of ceftriaxone. J Pediatr ;120:22-27.

34. Bibliography
Black et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J. 2000; 19:
Fireman et al. Impact of the pneumococcal conjugate vaccine on otitis media. Pediatr Infect Dis J ;22:10-16.

35. Bibliography
Hsu et al. Population-Based Surveillance for Childhood Invasive Pneumococcal Disease in the Era of Conjugate Vaccine. Pediatr Inf Dis J ;24(1):
AAP Practice Parameter: The diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children. Pediatr ;103:

36. Bibliography
Kadish et al. Applying outpatient protocols in febrile infants 1-28 days of age: Can the threshold be lowered? Clin Pediatr. 2000; 39(2):81-8.
Kaplan et al. Decrease of Invasive Pneumococcal Infections in Children Among 8 Children’s Hospials in the United States After the Introduction of the 7-Valent Pneumococcal Conjugate Vaccine. Pediatrics. 2004; 113(3):

37. Bibliography
Lee GM, Harper MB. Risk of bacteremia for febrile young children in the post-Haemophilus influenzae type b era. Arch Pediatr Adolesc Med ;152(7):
Lee et al. Management of febrile children in the age of the conjugate pneumococcal vaccine: A cost-effectiveness analysis. Pediatr. 2001;108:

38. Bibliography
Stoll and Rubin. Incidence of Occult Bacteremia Among Highly Febrile Youn Children in the Era of the Pneumococcal Conjugate Vaccine. Arch Pediatric Adolesc Med ;158:
Whitney et al. Decline in Invasive Pneumococcal Disease after the Introduction of Protein-Polysaccharide Conjugate Vaccine. NEJM. 2003;348(18):