R' Dagan

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 lt2 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
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 gt15,000/mm3 no Rx
• WBC Blood culture only if gt15,000/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
High fever No apparent focus
"classical" approach
Is this approach reasonable?
The risk for bacteremia ? with ? WBC ? with ?
fever ? in males ? age 7-11 months
13
Occult Bacteremia in the Pre-Hib Vaccination Era

• FEAR
• Sepsis
• Meningitis
• Focal infections

14
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
Hib Invasive Cases In Israel 1989 - 2003
16
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 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 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
Effect in Target Age Group Invasive Pneumococcal
Disease Rates in Children lt 3 Years, ABCs,
1998-2003
1 yr
lt1 yr
2 yrs
2003 data are preliminary
Farely et al, ICP, Cancun, Mexico, August 2003
21
Effect in Target Age Group Invasive Pneumococcal
Disease Rates in Children lt 3 Years, ABCs,
1998-2003
? 80 in invasive pneumococcal disease in
children lt 3 yrs
2003 data are preliminary
Farely et al, ICP, Cancun, Mexico, August 2003
22
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 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
Post-PCV
Post-Hib vaccine
Pre-Hib Vaccine
PERIOD
1 - 2
1 - 4
1 - 6
Expected cases of meningitis
1,000 - 1,998
500 - 1,998
334 - 1,998
Number of cases treated to prevent 1 case of
meningitis
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 Childrens Hospital Emergency
Department and Urgent Care Center
Stoll Rubin Arch Pediatr Adolesc Med 158671-5,
2004
28
Comparison of Data Post Hib Vaccination, Pre and
Post PCV
Stoll Rubin Arch Pediatr Adolesc Med 158671-5,
2004
29
Comparison of Data Post Hib Vaccination, Pre and
Post PCV
Stoll Rubin Arch Pediatr Adolesc Med 158671-5,
2004
30
Comparison of Data Post Hib Vaccination, Pre and
Post PCV
Stoll Rubin Arch Pediatr Adolesc Med 158671-5,
2004
31
Rate Difference (ObservedExpected) of
PneumococcalRelated Diseases per 1000 Children
Aged Younger than 2 Years 2nd Year After Vaccine
Introduction
Tenn
NY
Tenn
NY
Tenn
NY
Rate difference / 1000 children lt 2yrs in 2001-2
Pneumonia invasive infections
AOM
Other ARIs
statistically significant
Poehling al, Pediatr, 114755761, 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
  gt390C gt20,000 WBCs

For a child with gt390C WBC and gt 20,000/mm3,
PCV will not decrease significantly the risk for
bacteremia
33
(No Transcript)
34
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
  gt390C gt20,000 WBCs

For a child with gt390C WBC and gt 20,000/mm3,
PCV will not decrease significantly the risk for
bacteremia
39
How Should a Highly Febrile Child Aged 2-36 mos
Without Apparent Focus Be Managed at the ER?

• Age 2-36 mos
• Temp. gt 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 all Temp.
• Risk is equal for all ages
• 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 gt ? WBC)
• Risk is equal for all Temp. (? Temp. gt ? Temp.)
• Risk is equal for all ages (? 6-11 months)
• Risk is equal for both sexes (M gt F)
• Risk is equal for well vs ill appearing (ill gt
  well)
• Treatment prevents all meningitis cases (only 1/2
  -1/3)
• PCV will prevent all S. pneumoniae cases
  (incorrect)