1. Fever in Infants and Toddlers
Richard J. Scarfone M.D.
October, 2014

2. Outpt peds, we earn our stripes in evaluating the young child with fever. Trying to strike the right balance between ordering appropriate tests, yet not over-testing or over-using abx.
This may take awhile….

3. Febrile Children Without a Source
Under testing
Under treating
Over testing
Over treating
Outpt peds, we earn our stripes in evaluating the young child with fever. Trying to strike the right balance between ordering appropriate tests, yet not over-testing or over-using abx.

4. The FYI (< 56 days old) Recipe
Do full sepsis work-up
Sprinkle with equal parts ampicillin and gentamicin
Simmer for 48 hours
Stir occasionally
Serve when cool

5. Shades of Gray FYI- Special Circumstances
Does age matter?
Who needs a lumbar puncture?
Bronchiolitis?
Presumptive antibiotics and role for acyclovir?

6. CASE 1- Age Matter?
A previously healthy 22 day old girl presents with a chief complaint of “feeling warm”. No vomiting, diarrhea, cough, or irritability.
Alert, well-appearing, 38.6º
How should the patient’s age impact the management and disposition decisions?

7. Philadelphia Criteria
Population
Age: days
Fever: > 38.2°
Low-risk criteria
PE: no infection and well-appearing
Labs: CSF < 8 wbc/hpf
CSF profile wnl and negative Gram stain
WBC < 15,000
Band/neutrophil < 0.2
UA < 8 wbc/hpf
CXR: no infiltrate
Social: Good observer and car and phone
Baker MD, N Engl J Med 1993

8. FYI < 4 Weeks Old Population Protocol
Age 3-28 days
Temp >38.0º
Protocol
Full sepsis work-up
Hospitalized
Treated with empiric antibiotics
Retrospective application of the Philadelphia criteria
Baker MD, Arch Pediatr Adolesc Med 1999

9. FYI < 4 Weeks Old 254 FYI 109 (43%) Low Risk
Serious Bacterial Infection (SBI): 5/109 (4.6%)
NPV for Low-Risk Group: 95%
(95% CI = 90-99%)
Baker MD, Arch Pediatr Adolesc Med 1999

10. FYI < 4 Weeks Old Study 1 Study 2 Study 3 Low risk 134 109 226
SBI rate 6% 5%
NPV
94%
95%
1Chiu C, Pediatr Infect Dis J 1994
2Baker MD, Arch Pediatr Adolesc Med 1999
3Schwartz S, Arch Dis Child 2008 10

11. CASE 1
A previously healthy 22 day old girl presents with a chief complaint of “feeling warm”. No vomiting, diarrhea, cough, or irritability.
Alert, well-appearing, 38.6º
How should the patient’s age impact the management and disposition decisions?

12. CASE 1
A previously healthy 22 day old girl presents with a chief complaint of “feeling warm”. No vomiting, diarrhea, cough, or irritability.
Alert, well-appearing, 38.6º
How should the patient’s age impact the management and disposition decisions?
< 4 weeks old: admit, presumptive antibiotics
5-8 weeks old: may consider outpatient therapy without antibiotics, if low risk criteria are met

13. CASE 2- LP or Not? A 47 day old presents with fever
On PE, T = 38.6°. She is slightly fussy but consoles easily and has a normal exam.
You wish to perform a complete sepsis workup. The parents are reluctant to consent for the lumbar puncture (LP). You speculate that the LP may be omitted if the peripheral WBC count and UA are normal.

14. Background: Dueling Protocols Defining Low Risk
Rochester 1994
Boston 1992
Philadelphia 1993
< 60 days
28-89 days
29-56 days
Term
No antibiotics
No chronic disease
No prolonged hospitalization
No recent immunizations
None specified
Well-appearing
Normal PE
WBC >5,000 and <15,000
Absolute band count <1500
UA <10 WBC
WBC <20,000
CSF <10 WBC
WBC <15,000
Band/neutrophil <0.2
CSF <8 WBC
Home, no antibiotics
Ceftriaxone, home
CSF not used to define low-risk
CSF used to define low-risk
No universally accepted defn for low-risk or approach.
What your practice is is largely a function of where you trained and where you work

15. Background: Dueling Protocols Performance
Rochester 1994
Boston 1992
Philadelphia 1993
Total FYI: 1,057
Total FYI: not reported
Total FYI: 747
Low risk: 437 (41%)
Low risk: 503
Low risk: 287 (38%)
Low risk with SBI: 5
Low risk with SBI: 27
Low risk with SBI: 1
NPV of low risk criteria:
98.9% (97.2%-99.6%)
94.6%
99.7% (98%-100%)
Low risk with BM: 0
No universally accepted defn for low-risk or approach
No cases of bacterial meningitis (BM) among 1227 low risk FYI

16. Low Risk 29-56 days old To LP or not to LP
Region
Recommendations/Practice
United States National Guidelines
None!
2013 Great Britain National Guidelines (NICE)*
No LP
Rochester
Philadelphia and Boston LP
No proven role for corticosteroids in meningitis in this age group
*National Institute for Health and Care Excellence 16

17. Outcomes for Low Risk 22 Studies 1985-2010
3984 FYI 0-56 days old who met low risk criteria
2 (0.05%) had bacterial meningitis
Patient #1: 8-day-old
Patient #2: <29 days old
Among days old, 0 cases of bacterial meningitis among those who were low risk
Number of low-risk in this age range was not reported
Neonates were included- only 4 studies restricted to older FYI (would presumably increase incidence of SBI/BM among low-risk pts)
Authors don’t report number who are days old
Huppler AR, Pediatrics 2010

18. CHOP Data 2007-2014 FYI 29-56 days old (low and high risk)
1475 LPs performed in ED
2 patients with bacterial meningitis
Salmonella, critically ill
GBS, “crying/inconsolable”, “very fussy”, 8 bands/60 polys
Among days old, 0 cases of bacterial meningitis among those who were low risk
Neonates were included- only 4 studies restricted to older FYI (would presumably increase incidence of SBI/BM among low-risk pts)
Authors don’t report number who are days old

19. CASE 2- LP or Not? A 47 day old presents with fever
On PE, T = 38.6°. She is slightly fussy but consoles easily and has a normal exam.
You wish to perform a complete sepsis workup. The parents are reluctant to consent for the lumbar puncture (LP). You speculate that the LP may be omitted if the peripheral WBC count and UA are normal.

20. CASE 2- LP or Not? A 47 day old presents with fever
On PE, T = 38.6°. She is slightly fussy but consoles easily and has a normal exam.
You wish to perform a complete sepsis workup. The parents are reluctant to consent for the lumbar puncture (LP). You speculate that the LP may be omitted if the peripheral WBC count and UA are normal.
FYI days old who meet all other low risk criteria are highly unlikely to have bacterial meningitis. It is reasonable to omit the LP in this setting.

21. Bronchiolitis

22. CASE 3- Bronchiolitis?
A 38 day old presents with coughing and “trouble breathing”
On PE, T = 38.3º. He is well-appearing and noted to be wheezing.
You wonder if a full sepsis workup may be omitted, since there is a probable source for the fever

23. Background Office-based practitioners
3066 febrile infants < 3 months old
218 (7%) had clinical bronchiolitis
Full sepsis evaluation was performed half as often for infants with clinical bronchiolitis
Luginbuhl LM, Pediatrics 2008

24. RSV and the FYI Multicenter, prospective
1258 FYI < 60d old (1/3 < 30d old)
Nearly all had blood, urine, and CSF cultures and RSV antigen testing
Goal: compare SBI rates for those with and without RSV
Levine DA Pediatrics 2004

25. RSV and the FYI RSV (+) N = 269 RSV (–) N = 979 Any SBI 7% 12.5% UTI
5.4%
10%
Bacteremia
1.1%
2.3%
Meningitis 1%

26. RSV Infection and Age
SBI

27. RSV and the FYI Review of 1749 FYI < 90 days, in 11 studies
FYI with clinical bronchiolitis or documented RSV infection
Ralston S, Arch Pediatr Adolesc Med 2011

28. RSV and FYI Source Infection rate Urine 3.3% Blood 0.3% (5 cases) CSF
UTI 100X more likely

29. Similar Story for Influenza
SBI
All had UTI
Krief WI, Pediatrics 2009 29

30. CASE 3 A 38 day old presents with coughing and “trouble breathing”
On PE, T = 38.3º. He is well-appearing and noted to be wheezing.
You wonder if a full sepsis workup may be omitted, since there is a probable source for the fever

31. An Emerging Theme
Neonates can’t be trusted!

32. CASE 3 For those <29 days old For those 29-60 days old
RSV infection doesn’t significantly alter the rate of SBI
For those days old
Those with clinical bronchiolitis (with or without documented RSV infection) are at significantly lower risk for SBI compared to others
There is a clinically important rate of UTI among FYI with RSV and/or bronchiolitis

33. Urinary Tract Infections
Multicenter, prospective ED study of 1025 infants < 60 days old with T > 38.0°
9% had pyelonephritis
*Uncircumcised males %
Circumcised males %
Females %
Highest fever > %
*Half the males were uncircumcised Zorc JJ, Pediatrics 2005
- I, the copyright holder of this work, hereby release it into the public domain. This applies worldwide. In case this is not legally possible: I grant anyone the right to use this work for any purpose, without any conditions, unless such conditions are required by law. 33

34. UTI- Do You Need to Look Further?
Cohort of 1895 infants days old with fever and pyelonephritis
63% males
44% WBC > 15,000
6.5% bacteremia
88% E. coli
5 bacterial meningitis
Schnadower D, Pediatrics 2010
- I, the copyright holder of this work, hereby release it into the public domain. This applies worldwide. In case this is not legally possible: I grant anyone the right to use this work for any purpose, without any conditions, unless such conditions are required by law. 34

35. CASE 4
An 11 day old presents with poor feeding, fussiness, and a tactile fever
On PE, T = 38.7º. He is irritable and slightly dehydrated
You plan to perform a full sepsis work-up, initiate antibiotics, and hospitalize
Which antibiotics are appropriate?
Is there a role for acyclovir?

36. Bacterial Pathogens Retrospective, 2005-2009 Ages 1 week – 3 months
4255 had blood cultures in ED, clinic, or first 24 hr of hospitalization
340 positive blood cultures
247 contaminants
93 (2%) had bacteremia
Greenhow TL, Pediatrics 2012

37. Bacterial Pathogens
56% e coli, 21% GBS, 8% s aureus

38. Incidence of GBS Cases per 1,000 births  Universal screening
Late= horizontal transmission (so risks are hospitalization, abx early in life)
 Universal screening
MMWR 2010

39. HSV Infection

40. Neonatal HSV SEM (1/3): localized to skin, eye, and/or mouth
CNS (1/3): central nervous system disease, with or without skin vesicles
Disseminated (1/3): multiple organs, especially lungs and liver, with or without skin vesicles 40

41. CASE 4
Is there a role for routinely screening for HSV or using acyclovir?
< 1000 cases/yr of neonatal HSV infections in US
CSF HSV screening leads to prolonged hospital stays and increased costs1
Acyclovir side effects include nephrotoxicity and neutropenia
Acyclovir should not be used routinely for FYI2
1Shah SS, J Pediatr 2010
2Kimberlin DW, Pediatrics 2001

42. Neonatal HSV Suspecting the Diagnosis
Days
Mean age therapy started (N = 79)
Kimberlin DW, Pediatrics 2001

43. CASE 4 When should we consider HSV? History Examination Lab studies
< 21 days old
Mom had active primary HSV at delivery
Examination
Vesicles
Seizure (27%)
Lab studies
CSF pleocytosis (especially if CSF RBCs also)
Increased liver enzymes
Consider empiric testing and treating with acyclovir (60 mg/kg/day tid) for any one of these criteria

44. CASE 4 Which antimicrobials are appropriate? Age Bugs *Antimicrobials
0-21 days
GBS, Enterococcus
Gram negs
HSV
Ampicillin
Cefotaxime
Acyclovir
**22-28 days
**29-56 days
Late GBS
Pneumococcus
No proven role for corticosteroids in meningitis in this age group
* Add vancomycin if Gram + bug in CSF or septic
**Select older infants should be tested and treated for HSV

45. ED Management of FYI Summary
Full evaluation for sepsis, including LP:
All 0-28 days old
Any day old who fails to meet any of the low risk criteria
CBC with differential, blood culture, enhanced urinalysis and urine culture:
29-56 days old who meet all low risk criteria
CXR only if respiratory signs or symptoms

46. ED Management of FYI Summary
Consider for outpatient management, without antibiotics:
Born at term and without chronic illnesses
Age 28 days or greater
Not received antibiotics within 48 hrs
No dehydration, lethargy, irritability, or wheezing
No focal source of infection on physical exam (except OM)
Laboratory tests:
WBC between 5-15,000 and band:poly <0.2
UA < 8 WBC/hpf
CXR without infiltrate (if obtained)
Caretaker available by phone, can return in 24 hrs

47. Febrile Toddler 2-24 mo T > 39.0° No source Viral syndrome
Occult bacterial infection
Occult bacteremia (OB)
Pyelonephritis

50. Occult Bacteremia The Evolution
1980s- Standard Practice
H. influenzae type b, S. pneumoniae
H. influenzae type b highly virulent, causing invasive disease
Standard practice
Blood culture
Presumptive antibiotics

52. Occult Bacteremia The Evolution
1990s- Confused Practice
H. influenzae type b disappears
S. pneumoniae is considerably less virulent
Guidelines recommend blood culture and presumptive antibiotics
Confused practice
Blood culture and presumptive antibiotics for all or
Selective testing and treating or
No testing or treating

53. Occult Bacteremia The Evolution
21st Century- Informed Practice
Heptavalent pneumoccocal vaccine (HPV7) 2000
Incidence of invasive pneumoccocal disease (IPD = CSF, blood, pleural or peritoneal fluid) and OB has dropped dramatically
Incidence of IPD and OB caused by resistant serotypes has dropped dramatically
Informed practice
Goal of this talk

54. Heptavalent Pneumococcal Vaccine
Licensed February 2000 for protection against IPD
2, 4, 6, and months
7 serotypes that cause 85% of IPD in children
Nearly all of the serotypes that are highly penicillin resistant

55. Incidence of IPD 8 Geographic Areas in U. S
Incidence of IPD 8 Geographic Areas in U.S. > 400,000 Children < 2y
Cases per
100,000
 Vaccine licensed
Whitney CJ, N Engl J Med 2003

56. Incidence of Pneumococcal Meningitis 8 Geographic Areas in U. S
Incidence of Pneumococcal Meningitis 8 Geographic Areas in U.S. Children < 2 Years Old
Cases per
100,000
64% ↓
 Vaccine licensed
Hsu HE, N Engl J Med 2009

57. IPD in Children 0-90 Days Old Herd Immunity
CDC data
Cases per
100,000 live births
40%↓
 Vaccine licensed
Poehling KA, JAMA 2006

58. Before and After HPV7 Incidence of Bacteremia
Study cohort
3-36 mo
Previously healthy
Outpatients
Blood culture obtained
HPV7 immunization status not reported
Goal: report OB rates before and after HPV7 licensed
Retrospective
Selection bias
Herz AM, Pediatr Infect Dis J 2006

59. 67% Decline in Bacteremia Rates
Per
10,000
Cultures
 Vaccine licensed

60. Before and After HPV7 Incidence of Bacteremia
By the end of the study ( )
>70% of positive cultures were contaminants
Among the 6216 tested
44 (0.7%) had bacteremia
15 (0.2%) S. pneumoniae
15 (0.2%) E. coli
All had UTIs
95% had abnormal UAs

61. With vs Without HPV7 Incidence of Bacteremia
Study cohort
<36 mo with fever in the ED
Blood culture obtained
Goal: compare OB rates for immunized (at least 1 HPV7) vs unimmunized
Limitations
Retrospective
Selection bias (60% of eligible did not have a blood culture)
Infants <2 mos old were included
Carstairs KL, Ann Emerg Med 2007

62. Bacteremia Rates N *833 550 Bacteremia 0 13 (2.4%)
Immunized Unimmunized
N *
Bacteremia (2.4%)
Contaminants 15 (1.8%) (5%)
*48% had received just 1 HPV7
1% (13/1383) were bacteremic

63. After HPV7 Incidence of Bacteremia
Study cohort
3-36 mo, febrile
Previously healthy, no source
In ED, none hospitalized
Blood culture obtained
Retrospective
Selection bias
Results
8,408 children
21 (0.25%) true positives
No differences by age groups
159 (1.9%) contaminants
Immunization rates not reported
1 in 400 had OB (outcomes not discussed)
7.6 contaminants for each true positive
Stoll study replaced with this one, but include Stoll in a review article
Wilkinson M, Acad Emerg Med 2009

64. Breakthrough Infections
IPD in completely vaccinated children does occur
Uncommon1,2
Underlying chronic diseases
Undiagnosed immunodeficiencies
Illness with non-vaccine serotypes (replacement disease)
1 Hsu K, Pediatr Infect Dis J 2005
2 Kaplan SL, Pediatrics 2004

65. Replacement Disease Infections with Non-Vaccine Serotypes 8 Regions in US
IPD cases/y
< 24 mo old
(42 to 69: 64% increase)
Both 10 and 13 valent vaccines are undergoing phase 3 clinical trials
Kyaw MH, New Engl J Med 2006

66. The News Just Got Better
Feb 2010: a 13-valent pneumococcal conjugate vaccine was licensed by the FDA
Replaces HPV-7
4 doses between 2-59 months

67. Occult Bacteremia Inside The Numbers
When making management decisions regarding OB, must consider
Likelihood of OB
Herz : 0.7%
Carstairs 2007: 1%
Wilkinson 2009: 0.25%
Outcomes for those who are not treated presumptively with parenteral antibiotics???

68. Occult Bacteremia What are the Outcomes?
Retrospective (selection bias)
2-24 mo, T > 39.0°
Pre-HPV7
½: oral antibiotics, ½: no antibiotics
All treated as outpatients
5901 blood cultures
111 bacteremia
103 (93%) had negative repeat cultures
19 (17% of those with bacteremia) complications:
12 had pneumonia or cellulitis
Alpern ER, Pediatrics 2000

69. Occult Bacteremia What are the Outcomes?
Retrospective (selection bias)
2-36 mo, T > 39.0°, no source
Pre-HPV7
None treated with antibiotics
1202 blood cultures
37 bacteremia
2 (5.4% of those with bacteremia) complications
Bandyopadhyay S, Arch Pediatr Adolesc Med 2002

70. Occult Bacteremia Inside The Numbers
*Post-HPV7
Incidence Complication Rate
∽1% X ∽ 17% = %
Should 10,000 febrile children be cultured and treated in an attempt to impact 17 cases of pneumococcal bacteremia?
(*Incidence among all febrile children will be much less)

71. Febrile Children Without a Source To Culture/Treat or Not?
Antibiotic resistance
Decreased pneumococcal disease
Contamination rates
Invasive
Costs
Side effects
YES
Prevent SBI?

72. Old Habits are Hard to Break
 Vaccine licensed
Herz AM, Pediatr Infect Dis J 2006

73. Times Have Changed
“Children 3-36 months of age with fever of 39.0º or more and whose WBC count is 15,000/mm3 or more should have a blood culture and be treated with antibiotics…’’
.…Baraff LJ, 1993
“The widespread use of this vaccine will make the use of WBC counts, blood cultures, and antibiotic treatment of children with fever without source who have received this vaccine obsolete” ….Baraff LJ, 2000
“In the absence of signs of sepsis, fever alone in a young immunocompetent child should no longer be considered an indication for a blood culture” ….Me, 2014
Some clinicians may choose to be more conservative in managing those who have not red’d HPV7 (as per Carstairs data)

74. Pyelonephritis

75. Pyelonephritis Females < 24 mos and males < 12 mos
Temp > 38.5° with no definite source
URI, otitis, gastroenteritis were enrolled
80/2411 (3%) had pyelonephritis
4% females vs 2% males
8% uncircumcised males vs 1% circumcised
16% white females vs 2.7% black females
Shaw K, J Pediatr 1998

76. Pyelonephritis Evaluation Recommendations
*Females
Age < 12 mo
White
T > 39.0
Fever > 2 days
No other source
Males
Age < 6 mo
Uncircumcised
*Consider screening if 2 or more risk factors
Gorelick M, Arch Pediatr Adolesc Med 2000

77. 18 mo girl
T = 39.8°

78. Febrile Young Children
Risk for pyelonephritis, all females
4% = 400 per 10,000
Risk for pyelonephritis, white females
16% = 1600 per 10,000
Risk for adverse outcome with OB
.17% = 17 per 10,000

79. Febrile Young Children Key Points
Dramatic declines in IPD and bacteremia, post-HPV7
1 dose of HPV7 is effective, especially if given after age 12 mos
Herd immunity
Continue to monitor impact of replacement disease
The prevalence of pyelonephritis, especially among infant girls and uncircumcised boys, is high

80. Suggested Approach to Febrile Young Children
Perform a careful H and P
Assess for UTI, if risk factors
For non-toxic children, other diagnostic tests are not routinely indicated
Avoid empiric antibiotic therapy
Detailed discharge instructions
Arrange follow-up

81. Febrile Children Without a Source
Key Point
Fever is not a sign of antibiotic deficiency!!

82. References
Baker MD, Bell LM, Avner JR. Outpatient management without antibiotics of fever in selected infants. New Engl J Med 1993;329:
Baskin MN, O’Rourke EJ, and Fleischer GR. Outpatient treatment of febrile infants 28 to 89 with intramuscular administration of ceftriaxone. J Pediatr 1992;120:22-27.
Avner JR, Crain EF, Shelov SP. The febrile infant less than 60 days of age in the emergency department. Sem Pediatr Infect Dis 1993;4(1):18-23.
Crain EF, Bulas D, Bijur PE, Goldman HS. Is a chest radiograph necessary in the evaluation of every febrile infant less than 8 weeks of age? Pediatrics 1991;88(4):821-4.
Bramson RT, Meyer TL, Silbiger ML, et al. The futility of the chest radiography in the febrile infant without respiratory symptoms. Pediatrics 1993;92(4):
Rosenberg NM, Altieri MF, Bothner J, Avner JR. To do or not to do. Pediatr Emerg Care 1993;9(3):
Baker MD, Avner JR, Bell LM. Failure of infant observation scales in detecting serious illness in febrile 4-8 week old infants. Pediatrics 1990;85:
Baskin MN, O’Rourke EJ, Fleisher GR. Management of febrile infants days of age with parenteral ceftriaxone and 24 hours of inpatient observation. Arch Pediatr Adolesc Med 1994;148:49 (Abstract).
Peters TR, et al. Invasive pneumococcal disease- the target is moving. JAMA 2007;297:
Cartstairs KL, et al. Pneumococcal bacteremia in febrile infants presenting to the ED before and after the introduction of the heptavalent pneumococcal vaccine. Ann Emerg Med 2007;49:

83. References
Baker MD, Bell LM. Unpredictability of serious bacterial illness in febrile infants from birth to 1 month of age. Arch Pediatr Adolesc Med 1999;153:
Kuppermann N, Bank DE, Walton EA, Senac MO, McCaslin I. Risks for bacteremia and urinary tract infections in young febrile children with bronchiolitis. Arch Pediatr Adolesc Med 1997;151:
Schrag SJ, et al. A population-based comparison of strategies to prevent early-onset group B streptococcal disease in neonates. New Engl J Med 2002;347:
Kimberlin DW, et al. Natural history of neonatal herpes simplex virus infections in the acyclovir era. Pediatrics 2001;108:
Prevention of perinatal group B streptococcal disease. MMWR 2002;51 (RR-11):1-22.
Titus MO, Wright SW. Prevalence of serious bacterial infections in febrile infants with respiratory syncytial infection. Pediatr 2003;112:
Newman TB, et al. Urine testing and urinary tract infections in febrile infants seen in office settings. Arch Pediatr Adolesc Med 2002;156:44-54.
Levine DA, et al. Risk of serious bacterial infection in young febrile infants with respiratory syncytial virus infections. Pediatrics 2004;113:
Singleton RJ, et al. Invasive pneumococcal disease caused by nonvaccine serotypes among Alaska native children. JAMA 2007;297:
Gorelick MH, Shaw KN. Clinical decision rule to identify febrile young girls at risk for urinary tract infection. Arch Pediatr Adolesc Med 2000;154:

84. References
Pantell RH, et al. Management and outcomes of care of fever in early infancy. JAMA 2004;291:
Zorc JJ, et al. Clinical and demographic factors associated with urinary tract infection in young febrile infants. Pediatrics 2005;116:
Byington CL, et al. Serious bacterial infection in febrile infants younger than 90 days of age: importance of ampicillin-resistant pathogens. Pediatrics 2003;111:
Herr SM, et al. Enhanced urinalysis improves identification of febrile infants ages 60 days and younger at low risk for serious bacterial infection. Pediatrics 2001;108:
Whitney CG, Farley MM, Hadler J, et al. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med 2003;348:
Herz AM, Greenhow TL, Alcantara J, et al. Changing epidemiology of outpatient bacteremia in 3- to 36-month-old children after the introduction of the heptavalent-conjugated pneumococcal vaccine. Pediatr Infect Dis J 2006;25:
Stoll ML, Rubin LG. Incidence of occult bacteremia among highly febrile young children in the era of the pneumococcal conjugate vaccine. Arch Pediatr Adolesc Med 2004;158:
Poehling KA, Talbot TR, Griffin MR, et al. Invasive pneumococcal disease among infants before and after introduction of pneumococcal conjugate vaccine. JAMA 2006;295:

85. References
Kaplan SL, Mason EO, Wald ER, et al. Decrease of invasive pneumococcal infections in children among 8 children’s hospitals in the US after the introduction of the 7-valent pneumococcal conjugate vaccine. Pediatrics 2004;113:
Hsu K, Pelton S, Karumuri S, et al. Population-based surveillance for childhood invasive pneumococcal disease in the era of conjugate vaccine. Pediatr Infect Dis J 2005;24:17-23.
Kyaw MH, Lynfield R, Schaffner W, et al. Effect of introduction of the pneumococcal conjugate vaccine on drug-resistant Streptococcus pneumoniae. N Engl J Med 2006;354:
Alpern ER, Alessandrini EA, Bell LM, Shaw KN, McGowan KL. Occult bacteremia from a pediatric emergency department: current prevalence, time to detection, and outcome. Pediatrics 2000;106:
Shaw KN, et al. Prevalence of urinary tract infection in febrile young children in the emergency department. Pediatrics 1998;102:e16.
Bandyopadhyay S, et al. Risk of serious bacterial infection in children with fever without a source in the post-Haemophilus influenza era when antibiotics are reserved for culture-proven bacteremia. Arch Pediatr Adolesc Med 2002;156:
Perinatal Group B streptococcal disease after universal screening recommendations- U.S MMWR July 20, 2007;56(28),
King RL, et al. Routine cerebrospinal fluid enterovirus polymerase chain reaction testing reduces hospitalization and antibiotic use for infants 90 days of age or younger. Pediatrics 2007;120:

86. References
Hsu HE, et al. Effect of pneumococcal conjugate vaccine on pneumococcal meningitis. NEJM 2009;360:
Wilkinson M, et al. Prevalence of occult bacteremia in children aged 3-36 months presenting to the emergency department with fever in the postpneumococcal conjugate vaccine era. Acad Emerg Med Jan 2009 (online view in advance of publication)