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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.
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 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
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
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
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
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
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
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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.
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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):524-526.
Rosenberg NM, Altieri MF, Bothner J, Avner JR. To do or not to do. Pediatr Emerg Care 1993;9(3):171-173.
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ReferencesReferences Hsu HE, et al. Effect of pneumococcal conjugate vaccine on pneumococcal
meningitis. NEJM 2009;360:244-56. 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)