An Approach to Fever Without an Apparent Source In the Pneumococcal Conjugate Vaccine Era

1. An Approach to Fever Without an Apparent Source In the Pneumococcal Conjugate Vaccine Era R. Dagan The Pediatric Infectious Disease Unit Soroka University Medical Center Ben-Gurion University Beer-Sheva, Israel

2. Fever Without Apparent Source • Statement of the problem • Status before and after Hib vaccination • Pneumococcal conjugate vaccine (PCV) • Will we modify our approach after introduction of PCV?

3. Fever Without Apparent Source • Statement of the problem • Status before Hib vaccination • Pneumococcal conjugate vaccine (PCV) • Will we modify our approach after introduction of PCV?

4. Fever The single most common chief complaint made to physicians who evaluate ambulatory children 30% of outpatient visits to clinic 20% of ER encounters (USA)

5. Febrile Episodes are Usually • Short-lived • Responsive to antipyretics • Uneventful • Subside without specific Rx Most children presenting with fever are <2 years of age

6. Possibility of occult bacteremia

7. Outcome of Febrile Infants Aged 3-24 m with Occult Bacteremia 1 2 3 CURE FOCAL SYSTEMIC + (mild to moderate) SERIOUS FOCAL OM bacteremia (sepsis) LRI meningitis skeletal skin + soft tissues etc.

8. Sepsis  meningitis Possibility of occult bacteremia

9. What is the Best Approach for Febrile Children Aged 3-24 mos Without Apparent Focus? • Follow up only • Blood culture alone • Blood culture and Rx • WBC; Blood culture only if >15,000/mm3; no Rx • WBC; Blood culture only if >15,000/mm3; Rx • Rx only

10. Fever Without Apparent Source • Statement of the problem • Status before and after Hib vaccination • Pneumococcal conjugate vaccine (PCV) • Will we modify our approach after introduction of PCV?

11. Occult Bacteremia in the Pre-Hib Vaccination Era • ~5% of highly febrile non-toxic appearing children aged 2-36 months without apparent focus had bacteremia • The risk for bacteremia •  with  WBC •  with  fever •  in males •  age 7-11 months

12. WBC Blood Cx >15,000 /mm3 Antibiotics "classical" approach High fever No apparent focus Is this approach reasonable? • The risk for bacteremia •  with  WBC •  with  fever •  in males •  age 7-11 months

13. Organism % of all cases S. pneumoniae 50-90% H. influenzae b 3-25% Others (Salmonella, N. meningitidis etc) < 5% S. pneumoniae: 1-4% H. influenzae b: 7-13% N. meningitidis: > 50% Occult Bacteremia in the Pre-Hib Vaccination Era • FEAR • Sepsis • Meningitis • Focal infections

14. occult bacteremia: ~5% ~50 Bacteremia Meningitis 1 - 4% 7 - 13% > 50% 0 - 2 S. pneumoniae: 50-90% H. influenzae: 3-25% N. meningitidis: < 5% 25 - 45 0 - 2 1 - 13 1 - 2 1 - 2 Occult Bacteremia in the Pre-Hib Vaccination Era: What Is the Risk for Meningitis in Untreated Patients with Occult Bacteremia 1,000 children 3-36m high fever 1- 6/1,000 (0.1-0.6%)

15. Introduction of Hib vaccines Universal vaccination Hib Invasive Cases In Israel 1989 - 2003

16. occult bacteremia: ~5% ~50 Bacteremia Meningitis 1 - 4% 7 - 13% > 50% 0 - 2 S. pneumoniae: 50-90% H. influenzae: 3-25% N. meningitidis: < 5% 25 - 45 0 - 2 1 - 13 1 - 2 1 - 2 Occult Bacteremia in the Post-Hib Vaccination Era: What Is the Risk for Meningitis in Untreated Patients with Occult Bacteremia 1,000 children 3-36m high fever 1- 6/1,000 (0.1-0.6%)

17. occult bacteremia: ~5% ~50 Bacteremia Meningitis 1 - 4% 7 - 13% > 50% 0 - 2 S. pneumoniae: 50-90% H. influenzae: 3-25% N. meningitidis: < 5% 25 - 45 0 - 2 1 - 13 1 - 2 1 - 2 Occult Bacteremia in the Post-Hib Vaccination Era: What Is the Risk for Meningitis in Untreated Patients with Occult Bacteremia 1,000 children 3-36m high fever 1- 6/1,000 (0.1-0.9%)

18. occult bacteremia: ~4% ~40 Bacteremia Meningitis 1 - 4% 7 - 13% > 50% 0 - 2 S. pneumoniae: 50-90% H. influenzae: 3-25% N. meningitidis: < 5% 25 - 45 0 - 2 1 - 13 1 - 2 1 - 2 1- 4/1,000 (0.1-0.4%) Occult Bacteremia in the Post-Hib Vaccination Era: What Is the Risk for Meningitis in Untreated Patients with Occult Bacteremia 1,000 children 3-36m high fever

19. Fever Without Apparent Source • Statement of the problem • Status before and after Hib vaccination • Pneumococcal conjugate vaccine (PCV) • Will we modify our approach after introduction of PCV?

20. PCV7 2003 vs baseline  77% (<1 yr)  83% (1 yr)  64% (2 yr) Effect in Target Age Group Invasive Pneumococcal Disease Rates in Children < 3 Years, ABCs, 1998-2003 1 yr <1 yr 2 yrs 2003 data are preliminary Farely et al, ICP, Cancun, Mexico, August 2003

21. 2003 vs baseline  77% (<1 yr)  83% (1 yr)  64% (2 yr) Effect in Target Age Group Invasive Pneumococcal Disease Rates in Children < 3 Years, ABCs, 1998-2003 ~  80% in invasive pneumococcal disease in children < 3 yrs 2003 data are preliminary Farely et al, ICP, Cancun, Mexico, August 2003

22. Bacteremia Meningitis 1 - 4% 7 - 13% > 50% 0 - 2 S. pneumoniae: 50-90% H. influenzae: 3-25% N. meningitidis: < 5% 25 - 45 0 - 2 1 - 13 1 - 2 1 - 2 Occult Bacteremia in the Post-Hib + PCV Vaccination Era: What Is the Risk for Meningitis in Untreated Patients with Occult Bacteremia IF Pnc Vaccine is PERFECT 1,000 children 3-36m high fever occult bacteremia: ~4% ~40 1- 4/1,000 (0.1-0.4%)

23. occult bacteremia: ~1 ~10 Bacteremia Meningitis 1 - 4% 7 - 13% > 50% 0 - 2 S. pneumoniae: 50-90% H. influenzae: 3-25% N. meningitidis: < 5% 25 - 45 0 - 2 1 - 13 1 - 2 1 - 2 1- 2/1,000 (0.1-0.2%) Occult Bacteremia in the Post-Hib + PCV Vaccination Era: What Is the Risk for Meningitis in Untreated Patients with Occult Bacteremia IF Pnc Vaccine is PERFECT 1,000 children 2-36m high fever

24. How Many Children Aged 2-36 m with High Fever Do We Have to Treat to Prevent Meningitis?* Simplistic calculation *assuming all meningitis cases present BRFORE the penetration of organisms to meninges

25. How Many Children Aged 2-36 m with High Fever Do We Have to Treat to Prevent Meningitis?* Simplistic calculation In reality, antibiotic Rx reduces only by ~1/2 the risk for meningitis *assuming all meningitis cases present BRFORE the penetration of organisms to meninges

26. How Many Children Aged 2-36 m with High Fever Do We Have to Treat to Prevent Meningitis?* Simplistic calculation PERIOD Pre-Hib Vaccine Post-Hib vaccine Post-PCV Expected cases of meningitis 1 - 6 1 - 4 1 - 2 Number of cases treated to prevent 1 case of meningitis 334 - 1,998 500 - 1,998 1,000 - 1,998 *assuming all meningitis cases present BRFORE the penetration of organisms to meninges

27. Incidence of Occult Bacteremia Among Highly Febrile Young Children in the Era of the PCV A Study From a Children’s Hospital Emergency Department and Urgent Care Center Stoll & Rubin Arch Pediatr Adolesc Med 158:671-5, 2004

28. Comparison of Data Post Hib Vaccination, Pre and Post PCV Stoll & Rubin Arch Pediatr Adolesc Med 158:671-5, 2004

29. Comparison of Data Post Hib Vaccination, Pre and Post PCV Stoll & Rubin Arch Pediatr Adolesc Med 158:671-5, 2004

30. Comparison of Data Post Hib Vaccination, Pre and Post PCV Stoll & Rubin Arch Pediatr Adolesc Med 158:671-5, 2004

31. Rate Difference (Observed–Expected) of Pneumococcal–Related Diseases per 1000 Children Aged Younger than 2 Years 2nd Year After Vaccine Introduction Tenn NY Tenn NY Tenn NY Rate difference / 1000 children < 2yrs in 2001-2 Pneumonia + invasive infections AOM Other ARIs * statistically significant Poehling al, Pediatr, 114:755–761, 2004

32. After Introduction of PCV, Compared with the Pre-PCV Era, We Expect to See: •  of visits due to fever with no focus • Of those with fever without focus,  % with bacteremia • However, same risk for bacteremia as before if >390C & >20,000 WBCs For a child with >390C + WBC and > 20,000/mm3, PCV will not decrease significantly the risk for bacteremia

34. < 24 m (n = 178) Invasive Pnc Isolate - Israel 1998-2001 7-valent vaccine serotypes 24-47 m (n = 59)

35. Replacement phenomenon

36. Invasive Pneumococcal Disease in Atlanta 2 mo - 4 yrs 1997-9 vs. 2001-3 2003 data are preliminary Farely et al, ICP, Cancun, Mexico, August 2003

37. Fever Without Apparent Source • Statement of the problem • Status before and after Hib vaccination • Pneumococcal conjugate vaccine (PCV) • Will we modify our approach after introduction of PCV?

38. After Introduction of PCV, Compared with the Pre-PCV Era, We Expect to See: •  of visits due to fever with no focus • Of those with fever without focus,  % with bacteremia • However, same risk for bacteremia as before if >390C & >20,000 WBCs For a child with >390C + WBC and > 20,000/mm3, PCV will not decrease significantly the risk for bacteremia

39. No •  risk for bacteremia •  WBC •  fever • male • age 7-11 mos ? "ill" , "toxic", "lethargic" etc.... Yes >20,000 WBC/mm3 ? ? ? Yes Consider Yes Antibiotic Rx AMOX or specify why other How Should a Highly Febrile Child Aged 2-36 mos Without Apparent Focus Be Managed at the ER? • Age 2-36 mos • Temp. > 390C Regardless of PCV status

40. The consensus is that there is no consensus

41. For every complex problem there is a simple solution....... which is false

42. How Many Children Aged 2-36 m with High Fever Do We Have to Treat to Prevent Meningitis? • The simplistic calculation assumes that: • Risk is equal for all WBC counts • Risk is equal for allTemp. • Risk is equal for allages • Risk is equal for both sexes • Risk is equal for well vs ill appearing • Treatment prevents all cases of meningitis • PCV will prevent all S. pneumoniae cases

43. How Many Children Aged 2-36 m with High Fever Do We Have to Treat to Prevent Meningitis? • The simplistic calculation assumes that: • Risk is equal for all WBC counts ( WBC >  WBC) • Risk is equal for allTemp. ( Temp. >  Temp.) • Risk is equal for allages ( 6-11 months) • Risk is equal for both sexes (M > F) • Risk is equal for well vs ill appearing (ill > well) • Treatment prevents all meningitis cases (only 1/2 -1/3) • PCV will prevent all S. pneumoniae cases (incorrect)