Fever in Infants and Toddlers

Richard J. Scarfone M.D.

October, 2014

This may take awhile….

Febrile Children Without a Source

Under testingUnder treating

Over testingOver 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 GrayFYI- 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: no infection and well-appearing– Labs: CSF < 8 wbc/hpf

CSF profile wnl and negative Gram stainWBC < 15,000Band/neutrophil < 0.2UA < 8 wbc/hpfCXR: 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 Old254 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

1Chiu C, Pediatr Infect Dis J 19942Baker MD, Arch Pediatr Adolesc Med 19993Schwartz S, Arch Dis Child 2008

Study 1 Study 2 Study 3

Low risk 134 109 226

SBI rate 6% 5% 6%

NPV 94% 95% 94%

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 antibiotics5-8 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 ProtocolsDefining Low Risk

Rochester 1994 Boston 1992 Philadelphia 1993

< 60 days 28-89 days 29-56 days

TermNo antibioticsNo chronic diseaseNo prolonged hospitalization

No recent immunizationsNo antibiotics

None specified

Well-appearingNormal PE

Well-appearingNormal PE

Well-appearingNormal PE

WBC >5,000 and <15,000Absolute band count <1500UA <10 WBC

WBC <20,000UA <10 WBCCSF <10 WBC

WBC <15,000Band/neutrophil <0.2UA <10 WBCCSF <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 ProtocolsPerformance

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 oldTo 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

RSV (–)

N = 979

Any SBI 7% 12.5%

UTI 5.4% 10%

Bacteremia 1.1% 2.3%

Meningitis 0 1%

RSV Infection and Age

0%

5%

10%

15%

20%

411 FYI < 28 days of age

RSV

No RSVSBI

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

0%

5%

10%

15%

20%

25%

844 FYI < 60 days of age

Flu positive Flu negative

SBI

All had UTI

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

MMWR 2010

Universal screening

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 4Is 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 20102Kimberlin DW, Pediatrics 2001

Neonatal HSV Suspecting the Diagnosis

0

5

10

15

20

25

Skin, eye, mouth

CNS

Disseminated

Days

Mean age therapy started (N = 79)

Kimberlin DW, Pediatrics 2001

CASE 4When 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, EnterococcusGram negsHSV

AmpicillinCefotaximeAcyclovir

**22-28 days GBS, EnterococcusGram negs

AmpicillinCefotaxime

**29-56 days Late GBSPneumococcus

Cefotaxime

* Add vancomycin if Gram + bug in CSF or septic **Select older infants should be tested and treated for HSV

ED Management of FYISummary

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 FYISummary

Consider for outpatient management, without antibiotics: Born at term and without chronic illnessesAge 28 days or greaterNot received antibiotics within 48 hrsNo dehydration, lethargy, irritability, or wheezingNo focal source of infection on physical exam (except OM)Laboratory tests:

WBC between 5-15,000 and band:poly <0.2UA < 8 WBC/hpfCXR without infiltrate (if obtained) Caretaker available by phone, can return in 24 hrs

Febrile Toddler

2-24 mo T > 39.0° No source

Viral syndrome Occult bacterial infection

– Occult bacteremia (OB)– Pyelonephritis

18 mo girlT = 39.8°

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 IPD8 Geographic Areas in U.S.

> 400,000 Children < 2y

0

50

100

150

200

250

1996 1997 1998 1999 2000 2001

<1 year old 12-23 months >2 year old

Vaccine licensed

Cases per100,000

Whitney CJ, N Engl J Med 2003

Incidence of Pneumococcal Meningitis8 Geographic Areas in U.S.

Children < 2 Years Old

0

2

4

6

8

10

12

1998-99 2000-01 2002-03 2004-05

Vaccine licensed

Cases per100,000

Hsu HE, N Engl J Med 2009

64% ↓

IPD in Children 0-90 Days Old Herd Immunity

0

2

4

6

8

10

12

14

1997-98 1998-99 1999-00 2000-01 2001-02 2002-03 2003-04

Vaccine licensed

Cases per100,000 live births

Poehling KA, JAMA 2006

CDC data

40%↓

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

0

50

100

150

200

1998-99 1999-00 2000-01 2001-02 2002-03

Contaminants All pathogens S. Pneumoniae

Vaccine licensed

Per10,000Cultures

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

ImmunizedUnimmunized

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– 3-36 mo, febrile– Previously healthy, no source– In ED, none hospitalized– Blood culture obtained – 2004-2007

Retrospective– 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)

1 Hsu K, Pediatr Infect Dis J 20052 Kaplan SL, Pediatrics 2004

Replacement DiseaseInfections with Non-Vaccine Serotypes

8 Regions in US

605

1542 69

0

100

200

300

400

500

600

Pre-HPV7 Post-HPV7

Vaccine serotype Non-vaccine serotype

IPD

case

s/y

< 2

4 m

o o

ld

(42 to 69: 64% increase)

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 BacteremiaInside 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 BacteremiaWhat 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 BacteremiaWhat 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 BacteremiaInside The Numbers

*Post-HPV7 Incidence Complication Rate

∽1% 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 SourceTo Culture/Treat or Not?

NOAntibiotic resistanceDecreased pneumococcal diseaseContamination ratesInvasiveCostsSide effects

YESPrevent SBI?

Old Habits are Hard to Break

1000

1500

2000

2500

3000

1998-99 1999-00 2000-01 2001-02 2002-03

Total ED Blood Cultures ( Kaiser Permanente)

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 EvaluationRecommendations

*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 factorsGorelick M, Arch Pediatr Adolesc Med

2000

18 mo girlT = 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 ChildrenKey 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 SourceKey Point

Fever is not a sign of antibiotic deficiency!!

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