Advanced Cases in Pediatric Fever Without a Source

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 Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent conjugate pneumococcal vaccine in children. Pediatric Infect Dis Journal 2000; 19:187-195Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent conjugate pneumococcal vaccine in children. Pediatric Infect Dis Journal 2000; 19:187-195

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!