Fever in Infants and Toddlers
Richard J. Scarfone M.D.
October, 2014
This may take awhile….
Febrile Children Without a Source
Under testing
Under treating
Over testing
Over treating
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
Shades of Gray
FYI- Special Circumstances
Does age matter?
 Who needs a lumbar puncture?
 Bronchiolitis?
 Presumptive antibiotics and role for
acyclovir?

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?
Philadelphia Criteria
 Population
– Age:
29-56 days
– Fever: > 38.2°
 Low-risk criteria
– PE:
– Labs:
no infection and well-appearing
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
FYI < 4 Weeks Old
 Population
– 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
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
FYI < 4 Weeks Old
Study 1
Study 2
Study 3
Low risk
134
109
226
SBI rate
6%
5%
6%
NPV
94%
95%
94%
1Chiu
C, Pediatr Infect Dis J 1994
2Baker MD, Arch Pediatr Adolesc Med 1999
3Schwartz S, Arch Dis Child 2008
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?
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
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.
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
No antibiotics
None specified
Well-appearing
Normal PE
Well-appearing
Normal PE
Well-appearing
Normal PE
WBC >5,000 and <15,000
Absolute band count <1500
UA <10 WBC
WBC <20,000
UA <10 WBC
CSF <10 WBC
WBC <15,000
Band/neutrophil <0.2
UA <10 WBC
CSF <8 WBC
Home, no antibiotics
Ceftriaxone, home
Home, no antibiotics
CSF not used to define low-risk
CSF used to define low-risk
CSF used to define low-risk
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%)
NPV of low risk criteria:
94.6%
NPV of low risk criteria:
99.7% (98%-100%)
Low risk with BM: 0
Low risk with BM: 0
Low risk with BM: 0
No cases of bacterial meningitis (BM) among 1227 low risk FYI
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
No LP
Philadelphia and Boston
LP
*National Institute for Health and Care Excellence
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 29-56 days old, 0 cases of bacterial
meningitis among those who were low risk
– Number of low-risk in this age range was not reported
Huppler AR, Pediatrics 2010
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 29-56 days old, 0 cases of bacterial
meningitis among those who were low risk
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.
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 29-56 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.
Bronchiolitis
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
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
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
RSV and the FYI
RSV (+)
N = 269
7%
RSV (–)
N = 979
12.5%
UTI
5.4%
10%
Bacteremia
1.1%
2.3%
Meningitis
0
1%
Any SBI
RSV Infection and Age
20%
15%
SBI
RSV
No RSV
10%
5%
0%
411 FYI < 28 days of age
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
RSV and FYI
Source
Infection rate
Urine
3.3%
Blood
0.3% (5 cases)
CSF
0
Similar Story for Influenza
Flu positive
Flu negative
25%
20%
SBI
15%
10%
5%
0%
All had UTI
844 FYI < 60 days of age
Krief WI, Pediatrics 2009
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
An Emerging Theme
Neonates can’t be trusted!
CASE 3
 For those <29 days old
– RSV infection doesn’t significantly alter the rate of SBI
 For those 29-60 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
Urinary Tract Infections
Multicenter, prospective ED study of 1025
infants < 60 days old with T > 38.0°
 9% had pyelonephritis

– *Uncircumcised males - 21%
– Circumcised males 2%
– Females 5%
– Highest fever > 39.0 16%
*Half the males were uncircumcised
Zorc JJ, Pediatrics 2005
UTI- Do You Need to Look Further?

Cohort of 1895 infants 29-60 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
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?

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
Bacterial Pathogens
Incidence of GBS
Cases
per
1,000
births
 Universal screening
MMWR 2010
HSV Infection
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
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
Neonatal HSV
Suspecting the Diagnosis
25
20
15
Skin, eye, mouth
CNS
Disseminated
Days
10
5
0
Mean age therapy started (N = 79)
Kimberlin DW, Pediatrics 2001
CASE 4
When should we consider HSV?
 History
– < 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
CASE 4
Which antimicrobials are appropriate?
Age
Bugs
*Antimicrobials
0-21 days
GBS, Enterococcus
Gram negs
HSV
Ampicillin
Cefotaxime
Acyclovir
**22-28 days
GBS, Enterococcus
Gram negs
Ampicillin
Cefotaxime
**29-56 days
Late GBS
Pneumococcus
Cefotaxime
* Add vancomycin if Gram + bug in CSF or septic
**Select older infants should be tested and treated for HSV
ED Management of FYI
Summary

Full evaluation for sepsis, including LP:
– All 0-28 days old
– Any 29-56 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
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
Febrile Toddler



2-24 mo
T > 39.0°
No source
18 mo girl
T = 39.8°


Viral syndrome
Occult bacterial infection
– Occult bacteremia (OB)
– Pyelonephritis
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
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
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
Heptavalent Pneumococcal Vaccine



Licensed February 2000 for protection
against IPD
2, 4, 6, and 12-15 months
7 serotypes that cause 85% of IPD in
children
–
Nearly all of the serotypes that are highly
penicillin resistant
Incidence of IPD
8 Geographic Areas in U.S.
> 400,000 Children < 2y
<1 year old
12-23 months
>2 year old
250
200
Cases per 150
100,000
100
50
0
1996
1997
1998
1999
2000
2001
 Vaccine licensed
Whitney CJ, N Engl J Med 2003
Incidence of Pneumococcal Meningitis
8 Geographic Areas in U.S.
Children < 2 Years Old
12
10
Cases per 8
100,000
6
64% ↓
4
2
0
1998-99
2000-01
2002-03
2004-05
 Vaccine licensed
Hsu HE, N Engl J Med 2009
IPD in Children 0-90 Days Old
Herd Immunity
CDC data
14
12
10
Cases per
8
100,000
live births
40%↓
6
4
2
0
1997-98
1998-99
1999-00
2000-01
2001-02
2002-03
2003-04
 Vaccine licensed
Poehling KA, JAMA 2006
Before and After HPV7
Incidence of Bacteremia

Study cohort
–
–
–
–
–
–


3-36 mo
Previously healthy
Outpatients
Blood culture obtained
1998-2003
HPV7 immunization status not reported
Goal: report OB rates before and after HPV7 licensed
Retrospective
–
Selection bias
Herz AM, Pediatr Infect Dis J 2006
67% Decline in Bacteremia Rates
Contaminants
All pathogens
S. Pneumoniae
200
150
Per
10,000
100
Cultures
50
0
1998-99
1999-00
2000-01
 Vaccine licensed
2001-02
2002-03
Before and After HPV7
Incidence of Bacteremia

By the end of the study (2002-03)
–
–
>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
With vs Without HPV7
Incidence of Bacteremia

Study cohort
–
–
–


<36 mo with fever in the ED
Blood culture obtained
2000-2002
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
Bacteremia Rates
Immunized Unimmunized
N
*833
550
Bacteremia
0
13 (2.4%)
Contaminants 15 (1.8%)
28 (5%)
*48% had received just 1 HPV7
1% (13/1383) were bacteremic
After HPV7
Incidence of Bacteremia

Study cohort
–
–
–
–
–

Retrospective
–

3-36 mo, febrile
Previously healthy, no source
In ED, none hospitalized
Blood culture obtained
2004-2007
Selection bias
Results
–
–
8,408 children
21 (0.25%) true positives

–
No differences by age groups
159 (1.9%) contaminants
Wilkinson M, Acad Emerg Med 2009
Breakthrough Infections

IPD in completely vaccinated children does
occur
–
–
–
–
Uncommon1,2
Underlying chronic diseases
Undiagnosed immunodeficiencies
Illness with non-vaccine serotypes (replacement
disease)
Hsu K, Pediatr Infect Dis J 2005
2 Kaplan SL, Pediatrics 2004
1
Replacement Disease
Infections with Non-Vaccine Serotypes
8 Regions in US
Vaccine serotype
Non-vaccine serotype
605
600
IPD cases/y
< 24 mo old
500
400
42
( to 69: 64% increase)
300
200
100
42
15
69
0
Pre-HPV7
Post-HPV7
Kyaw MH, New Engl J Med 2006
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
Occult Bacteremia
Inside The Numbers

When making management decisions
regarding OB, must consider
–
Likelihood of OB
Herz
2006: 0.7%
 Carstairs 2007: 1%
 Wilkinson 2009: 0.25%

–
Outcomes for those who are not treated
presumptively with parenteral antibiotics???
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
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
Occult Bacteremia
Inside The Numbers
*Post-HPV7
Incidence
∽1%
Complication Rate
X
∽ 17%
=
.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)
Febrile Children Without a Source
To Culture/Treat or Not?
NO
Antibiotic resistance
Decreased pneumococcal disease
Contamination rates
Invasive
Costs
Side effects
YES
Prevent SBI?
Old Habits are Hard to Break
Total ED Blood Cultures (Kaiser Permanente)
3000
2500
2000
1500
1000
1998-99
1999-00
2000-01
2001-02
2002-03
 Vaccine licensed
Herz AM, Pediatr Infect Dis J 2006
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
Pyelonephritis
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
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
18 mo girl
T = 39.8°
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
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
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
Febrile Children Without a Source
Key Point
Fever is not a sign of
antibiotic deficiency!!
References










Baker MD, Bell LM, Avner JR. Outpatient management without antibiotics of
fever in selected infants. New Engl J Med 1993;329:1437-1441.
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):524526.
Rosenberg NM, Altieri MF, Bothner J, Avner JR. To do or not to do. Pediatr
Emerg Care 1993;9(3):171-173.
Baker MD, Avner JR, Bell LM. Failure of infant observation scales in detecting
serious illness in febrile 4-8 week old infants. Pediatrics 1990;85:1040-1043.
Baskin MN, O’Rourke EJ, Fleisher GR. Management of febrile infants 15-28
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;297:1825-1826.
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;49:772-777.
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;153:508-511.
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;151:1207-1214.
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;347:233-239.
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