1. Advanced Cases in Pediatric
Fever Without a Source
Andi Marmor
June, 2004

2. Key Questions
 What are the risk factors for SBI and UTI
in febrile infants?
 How effective is the pneumococcal
vaccine?
 Partial vaccination
 Technical difficulties: when the best laid
plans go awry
 How do you collect urine?
 Do viruses count as a fever source?

3. Fever Without a Source – A Quick
Review
 For nearly 20% of febrile children, no source of
infection can be identified after thorough history
and physical exam
 A small proportion of these children, although
well-appearing, will have a serious bacterial
infection (SBI) or occult urinary tract infection
(UTI)
 Guidelines have been developed to help
physicians identify and treat those children at
high risk for these conditions

4. Age Groups for Estimating Risk of SBI in
Well-Appearing Infants
 Guidelines for management of infants with
fever without a source are based on
groupings of infants into 3 age groups
based on both their risk of SBI/UTI and the
most likely bacterial causes of SBI
 Neonate (0-28 days)
 Infant 1-3 mo
 Infant 3-36 mo

5. Neonates (<28 days)
 Causes of SBI/UTI:
 E. Coli, GBS, Listeria, Salmonella
 What counts as a fever source?
 Clinical exam is unreliable, and even infants with viral
symptoms may be at risk for SBI
 Prevalence of SBI in well-appearing infants <28
days with T>38
 4-12%
 UTI
 Prevalance of UTI is high for boys and girls
 Associated with a 15-20% risk of bacteremia

6. Recommendations:
Neonates, T >38
 CBC, blood cultures
 Cath UA and urine culture
 LP
 Antibiotics
 Ampicillin
and gentamicin IV, or ampicillin and
cefotaxime IM
 Admission

7. Infants 1-3 months of age
 Causes of SBI/UTI
 E. Coli (UTI), GBS, S. pneumonia, N. meningitidis,
Hib
 What counts as a fever source?
 Named viral syndrome
 Otitis media
 Other viruses?
 Prevalence of UTI in this age group is about 9%
overall, (highest in uncirc boys, but only 2% in
circumcised boys)

8. Infants 1-3 months of age:
Predictors of SBI
 Studies in the early 90’s established
criteria for dividing well-appearing febrile
infants this age into groups at high or low
risk for SBI based on WBC count
 WBC 5-15: Risk of SBI (NOT including UTI) is
~1-3%
 High risk: ~10-20%

9. Recommendations: 1-3 months, T>38
 Cath urinalysis and urine culture on all infants
 If UA is positive, begin treatment for pyelonephritis and
consider admission
 CBC and blood culture
 If WBC>15K, antibiotics (ceftriaxone IM/IV)
 Lumbar puncture
 If signs of CNS irritability, and strongly consider if giving
antibiotics
 Follow up
 The next day (2nd dose if antibiotics were given)
 Admit if unable to follow up

10. Infants 3-36 months, T>38.5
 Causes of SBI:
 S. pneumonia>>>N. meningitidis, Hib
 Causes of UTI:
 E. Coli>>>Klebsiella, Proteus, Strep spp
 Risk highest in girls and in uncirc boys up to 6-12 mo
 Risk for SBI…before pneumococcal vax
 Overall risk of SBI in these infants estimated 2-6%
 WBC count useful to stratify infants into “high risk”
(~10%) and “low risk” (~1%)

11. Hooray for the pneumococcal vaccine!
 7-valent polysaccharide conjugate vaccine
 Approximately 97% of pneumococcal
isolates that cause IPD are represented in
PCV-7
 Recommended since August, 2000
 2,4 and 6 months with booster at 12-15 mo

12. Vaccine Efficacy
 PCV-7 tested in a large NC Kaiser-based
randomized controlled trial of 37,868 children
 Efficacy against IPD from vaccine serotypes
 Fully vaccinated children (4 doses): 97.4%
 Those receiving one or more dose of vaccine: 94%.
 Efficacy against IPD from any pneumococcal
serotype,
 Those receiving one or more doses: 89.1%

13. Vaccine Efficacy – Post-licensure
 Multiple post-licensure studies have
supported the expected reduction in
invasive pneumococcal disease (IPD)
 78-85% drop in rates of IPD in children <2
years of age.
 Rates of disease from non-vaccine
serotypes have not increased
 However, IPD and SBI are still possible,
even in vaccinated children.

14. How should vaccine change our
management?
 Since IPD is responsible for the majority of
SBI in infants >3 months of age
 And the vaccine is at least 90% effective
against IPD
 The risk of SBI in vaccinated children is
<1%, regardless of WBC count.
 Therefore, a CBC is unlikely to
significantly impact the assessment or
management of vaccinated children.

15. Is this change in management cost-
effective?
 Lee et al (2001) conducted a cost-
effectiveness analysis of various
management strategies for infants with
FWS
 Conclusion: empiric CBC/blood cx NOT
cost effective if rates of SBI <0.5%
 Costs >300,000$ per life saved
 Rates of SBI <0.5% in vaccinated infants,
based on current data

16. Recommendations for vaccinated
children 3-36 mo of age
 Is the child effectively immunized?
 At least two doses (3 is better!)
 2 weeks from 2nd dose
 Screen for UTI as for the unvaccinated
child
 Well-appearing, vaccinated children are
low risk, so blood tests not likely to change
management!

17. Case 1
 Rutabaga is a 9 week old male infant with fever
at home to 103, parents gave Tylenol.
 In clinic, T is 37.6, vitals otherwise normal for
age, baby is well-appearing
 Exam/hx: hint of a cough, mild papular rash
onchest, feeding well, older sibs with colds
 Received 1st dose of Prevnar 3 weeks ago
 Uncircumcised

18. What are the key parts of Rutabaga’s Hx/
PE in estimating his risk of SBI/UTI?
 Age: 1-3 mo
 Appearance: Non-toxic
 Fever source:
 Possible viral source? Sick contacts?
 Uncircumcised
 Immunization status:
 *One dose of PCV-7 – is he protected?

19. Partial Vaccination – Evidence
 Efficacy of the vaccine after < 3 doses is unclear
at the moment due to lack of sufficient data.
 Kaiser study results suggest that immunity
against invasive disease is good in partially
immunized infants
 Herd immunity protective
 Two recent studies have demonstrated good
serotype-specific antibody responses after 2
doses of the vaccine (Goldblatt, 2006; Huebner 2002)
 Vaccination against pneumococcus DOES NOT
protect against UTI, primarily caused by E. Coli

20. What’s your plan?
 Cath U/A
 Negative for LE, nitrites, + small blood
 CBC
 WBC 18.7, 75% lymphs
 Blood culture
 Can’t obtain blood culture after multiple sticks
 What are your options?
 Try again for blood cultures
 Treat without cx: commit to full course of antibiotics
 No antibiotics, admit for obs
 No antibiotics, home for obs

21. Another version…
 In a similar case, you obtain blood cultures, but
are unable to obtain spinal fluid after 3 tries…
 What are your options?
 Treat without tap:
 Commit to full course for presumed meningitis
 Try again tomorrow for cell count
 Don’t treat:
 Admit for obs without tap (plan to tap and treat if ill-
appearing)

22. Case 2
 Cheyote is 6 month old girl who just
received 3rd dose of PCV-7 2 days ago
 She has had a fever for 3 days, has a
temp of 39.8 in clinic, no source for fever
on exam or history, and is well-appearing
 What studies, if any, would you do on this
infant?
 How do you obtain urine?

23. Bag vs Cath
 Catheter specimens
 Current gold standard
 For culture: Sens 95%,
spec 99%
 Bag
 Less invasive (?)
 BUT results difficult to
interpret
 Culture: Sens/spec
~85%

24. Can a bag specimen be used for UA?
 Bottom line: No published data compares
sensitivity and specificity of UA on bag
specimens to other types of specimens!
 UA from bag may have slightly decreased
specificity compared to cath specimen
 False positives may result from contamination
from distal urethra, diaper
 Avoid in patients in whom false positives are
unacceptable

25. Predictive value of UA
 “Predictive value” refers to the posterior
probability of disease, given a positive or
negative test
 Depends on sensitivity, specificity, and prior
probability
 Example: For a UA positive for LE only:
Prior prob PPV NPV
5% 20% <1%
10% 33% 1%
20% 53% 3%
 Which patient is most likely to be impacted?

26. Predictive value of UA
 “Predictive value” refers to the posterior
probability of disease, given a positive or
negative test
 Depends on sensitivity, specificity, and prior
probability
 Example: For a UA positive for LE only:
Prior prob PPV NPV
5% 20% <1%
10% 33% 1%
20% 53% 3%
 Which patient is most likely to be impacted?

27. Predictive Value: The Bottom Line
 PPV is maximized when PP is high
 NPV is maximized when PP is low
 Best use of UA for
 Low prior prob patient: Rule OUT UTI
 High prior prob patient: start empiric treatment

28. Can a bag specimen be sent for culture?
 False positives are the major concern:
 Contamination rate depends on the population,
technique, and positive threshold
 Very low in circ boys
 As high as 20% in other populations
 However, false negatives also occur,
depending on the threshold chosen for
positive test…
 For >100,000 org, sens and spec ~85%

29. Predictive value of bag culture
 NPV of bag cx best in low prior prob patient,
PPV best in high prior prob pt
 Example:
Prior prob PPV NPV
5% 23% 1%
10% 40% 2%
20% 60% 4%
 The only clinically meaningful use of the bag
culture is to rule OUT UTI in the low prior
probability patient

30. Predictive value of bag culture
 NPV of bag cx best in low prior prob patient,
PPV best in high prior prob pt
 Example:
Prior prob PPV NPV
5% 23% 1%
10% 40% 2%
20% 60% 4%
 The only clinically meaningful use of the bag
culture is to rule OUT UTI in the low prior
probability patient

31. Summary: Bag specimen
 Characteristics of UA from bag specimen make
it most useful to rule out UTI in low probability
patients
 Can also be used to start treatment in high risk
patient
 Bag culture
 False positive/negative results are a significant risk
 Neg results helpful in low-prob patients
 Must weigh the implications of false pos/false neg for
the patient, against the discomfort of a cath

32. Recommendations: Collection of Urine
Specimen
 High risk infants, or a child who looks sick
enough to require IV antibiotics/admission:
 Obtain a catheter specimen for UA and culture
 Positive UA: empiric treatment, confirm with culture
 Lower risk patients:
 If desired, collect bag specimen for screening UA:
 Negative UA: UTI is unlikely
 Positive UA: consider empiric treatment, but confirm
with a culture
 If you send the bag for culture – consider the clinical
implications before you send the test!

33. Case Three
 Daikon is a 6 week old boy, temp of 101 at
home, 38.7 in clinic
 It’s winter, influenza and RSV are rampant
 He is well-appearing, without any URI
symptoms on exam or history, mom says
she has had the “flu” and is wondering if
he might have the same thing
 No immunizations yet

34. Key Question:
 Would viral testing change your
management?

35. Viral Testing - Evidence
 The advent of rapid viral testing has added
a new option for identifying infants at low
risk for SBI
 Rapid tests exist for RSV, adeno, paraflu,
influenza, entero and rotaviruses
 In general, these tests are more specific
than they are sensitive, which makes false
positives extremely rare

36. Viral Testing - Evidence
 A number of recent studies, mostly retrospective, have
evaluated the risk of SBI in infants found to have a
positive viral test
 Example: recent prospective trial (Byington, et al 2004)
of 1385 febrile infants <90 days, tested for multiple
viruses
 Stratified infants into HR/LR by Rochester criteria
 Among LR infants, risk of SBI low (1-3%) regardless of viral test
 Among HR infants, those with + viral tests had a significantly
reduced chance of SBI (16.7% -> 5.5)
 Risk of UTI still clinically significant in HR+ infants (4%), while
bacteremia occurred in <1%, and none had meningitis

37. Recommendations
 Bottom Line:The negative predictive value of a
rapid viral test is best in low probability patients!
 Therefore, viral testing is most likely to change
management in those infants with a low-mod
prior probability of SBI
 In very young infants or those at high risk, an
appreciable risk of UTI remains
 Consider testing for UTI in infants at high risk of UTI,
regardless of viral diagnosis

38. Case 3 - Continued
 You decide to get a CBC and blood
culture, a cath UA and a rapid viral test for
RSV and influenza
 Results:
 WBC 18, with 67% lymphs
 Rapid viral test positive for influenza
 Cath U/A negative
 What do you want to do?
 Treat with antibiotics? Admit? Tap?

39. Summary of Recommendations
5 questions to ask about child with FWS
1. Is this child toxic?
2. Is there a source for the fever?
3. Has this child been vaccinated against
pneumococcus?
4. If it’s a boy, is he circumcised?
5. Will this child come back if he/she gets
sick?

40. My Silly Mnemonic…
 If the baby’s smiling at me
 And has had Prevnar X 3
 Skip the CBC
 But don’t forget to collect the pee!