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Fever without a Focus
Sarah S. Long, M.D.Sarah S. Long, M.D.
Professor of PediatricsProfessor of PediatricsDrexel University College of Drexel University College of MedicineMedicine
Chief, Section of Infectious Chief, Section of Infectious DiseasesDiseasesSt. Christopher’s Hospital for St. Christopher’s Hospital for ChildrenChildrenPhiladelphia, Pennsylvania Philadelphia, Pennsylvania
Dr. Long has no conflict of interest to disclose
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FEVER, NO FOCUS OF INFECTIONWHAT IS NEW?
Case 1
A 17-day old white male has an 8-hour history of fussiness and poor intake. Mother took temperature, which was 101.6. She brings him for evaluation. Labor and delivery were uncomplicated. Pregnancy was uncomplicated except for urinary tract infection.
Physical examination reveals temperature 38.6, HR 180, RR 46, BP 96/56. The infant is fussy, does not make eye contact, and has good color and tone. Fontanelle is flat. There is no exanthem, enanthem or respiratory tract finding. Remainder of examination also is normal. There are no anomalies and the infant is circumcised.
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Case 1
17-day old with short duration fever and no clues or physical findings. Reassuring examination.
My management plan would be
A. Observe at home with follow-up < 24 hrs
B. Blood culture + observe at home …
C. Blood, urine and CSF tests/cultures + observe at home …
D. C above + Ceftriaxone (if C tests negative)
E. Blood, urine, CSF tests/cultures + admit + ampicillin/gentamicin
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Case 2
A 6-week old white male has the same history and findings as Case 1
My management plan would be
A. Observe at home with follow-up < 24 hrs
B. Blood culture + observe at home …
C. Blood, urine and CSF tests/cultures + observe
at home ...
D. C above + Ceftriaxone (if C tests negative)
E. Blood, urine, CSF tests/cultures + admit + ampicillin/gentamicin
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Case 1
17-day old with short duration fever and no clues or physical findings. Reassuring examination.
My management plan would be
A. Observe at home with follow-up < 24 hrs
B. Blood culture + observe at home …
C. Blood, urine and CSF tests/cultures + observe at home …
D. C above + Ceftriaxone (if C tests negative)
E. Blood, urine, CSF tests/cultures + admit + ampicillin/gentamicin
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Case 2
A 6-week old white male has the same history and findings as Case 1
My management plan would be
A. Observe at home with follow-up < 24 hrs
B. Blood culture + observe at home …
C. Blood, urine and CSF tests/cultures + observe
at home ...
D. C above + Ceftriaxone (if C tests negative)
E. Blood, urine, CSF tests/cultures + admit + ampicillin/gentamicin
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FEVER IN VERY YOUNG INFANTS
DIAGNOSIS ISOLATESBacterial meningitis E. coliUrinary tract inf Grp B streptococcusBloodstream infection S. aureusOtitis media EnterococcusGastroenteritis SalmonellaPneumonia ListeriaSyphilis Others
Viral meningitis Herpes simplex pneumonia Enterovirus
disseminated InfluenzaOthers
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HIGH RISK FOR SERIOUS INFECTION
Younger age
High/low temp
Ill appearing
High/low WBC
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IDENTIFYING LOW RISK FOR SBI
ROCHESTER APPROACH*Clinically well with no risk factorNo soft tissue/skeletal siteTotal WBC >5000 & < 15,000Urinalysis <10 WBCsStool <5 WBCs
PITTSBURGH APPROACH**Add negative CSFAdd neg Enhanced UA & Gm stain
*Neg Pred Value 95-99% for SBI**NPV 100%
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“PRACTICE GUIDELINES 1993”<90 DAYS, WELL, W/O SOURCE
< 28 DAYS > 28 DAYS & LOW-RISK
Consensus Option 1 Option 2
Evaluate* Evaluate* Urine culture
Hospitalize Ceftriaxone OPD Observe OPD
Abx (Y or N) Re-evaluate 24h
Baraff, Bass, Fleisher, et al. Pediatrics 1993*Includes blood, urine & CSF cultures
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RELATIVE RISK IN FEBRILE YOUNG INFANTS
Urban EDs ILL NOT ILL LOW RISK
Serious bacterial 17% 9% 2%
Bloodstream inf 11% 2% 1%
Meningitis 4% 1% 0.5%
Office (PROS)*
Serious bacterial 14% <10%
Bact/Meningitis 4% 1%
*Pantell et al JAMA, 2004
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MULTIVARIATE PREDICTORS BSI/MENINGITIS (PROS)
Factors Odds Ratio
Age < 30 days 5.5 31-60 days 3.0
Ill, very 9.0 moderately 1.8
Temp > 38.60 2.5
URI 0.2 (NS)
Ill family 0.5
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SUMMATIVE RISK BY PROS CLINICAL PREDICTORS
Well or minimally ill + Age > 25 days
+Temperature < 38.60
Total = 1/3 patients
Risk = 0.4%
__________________
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PROS PRACTITIONER ADHERENCE “GUIDELINES”
Age/Appear Recommendation Follow < 30 days Complete W/U 46%
+hosp+abx
31-90 days WBC/UA 42% Min ill
31-90 days Complete W/U 36% Mod/very ill +hosp+abx
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PERFORMANCE CLINICAL PREDICTION MODEL
Sensitivity SpecificityClinical 58% 68%Clinical+Abn WBC 84% 54%Clinical+Abn WBC+UA 87% 51%Guidelines model 95% 35%PROS model* 94% 27%PROS actual exp** 97% 35%
*Min ill + age > 25 days + Temp < 38.6**Initial Rx with Abx
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PREVALENCE HSV BSI HOSP NEONATES*
No SBI VirusAll hosp 5817 4.6% 8.4%
Fever 960 14.2% 17.2% (0.3% HSV)
Bact men HSVCSF pleo 204 5.4% 1.0%CSF poly pleo 80 14.9% --CSF mono pleo 124 0.8% 1.6%Age 8-14 days 1400 0.2% 0.6% Hypothermia 187 -- 1.1%
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32 cases perinatally acquired HSV32 cases perinatally acquired HSV
• 50% had only nonspecific S/S at 50% had only nonspecific S/S at presentation, which was fever in 75% presentation, which was fever in 75%•75% had CNS HSV 75% had CNS HSV (40% presented with mucocutaneous only, (40% presented with mucocutaneous only, 83% with seizures, 94% with nonspecific S/S only) 83% with seizures, 94% with nonspecific S/S only)
Age ≤ 21 days at onset S/S captured 90% of all cases and Age ≤ 21 days at onset S/S captured 90% of all cases and 94% with nonspecific S/S only 94% with nonspecific S/S only
2011;30:556
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Don’t forget to lookDon’t forget to look
Don’t forget to evaluate and treat Don’t forget to evaluate and treat empirically well appearing neonates with empirically well appearing neonates with
vesicular skin lesionsvesicular skin lesions
2012;161:134
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Journal Club…in Context…with Journal Club…in Context…with AttitudeAttitude
Pearls and Perils of PCR Testing Pearls and Perils of PCR Testing
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Study Retro 388 CSF specimens from children < 18 yrs who had EV testing performed, 2009 RT–PCR HPeV+ All were < 6 mo Compared clinical of all patients tested < 6 mo
Results HPeV+ (66) EV+ (47) Negative (66) Age (d) 41 31 43 PICU 12% 2% 0 T max >39 38.4 38 Days fever 2.7 2 1.6 CSF WBCs 2% 38% 12% Periph WBCs 5.8 9.2 10.1
HPeV3 is an emerging CNS pathogen & should be considered in young infants w or w/o CSF pleocytosis
CNS Human Parechovirus – Kansas CityCNS Human Parechovirus – Kansas City
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Study Retro 440 CSF specimens from children who had evaluation for infection
Compared HPeV+ vs EV+
Results HPeV+ (12) EV+ (43) Age < 6 mo 67% 67% Seizures 42% 14% CNS S/S 75% 30% URI 58% 16% Vomiting 25% 26% CSF WBCs 25% 82%
HPeV is a CNS pathogen and should be considered
CNS Human Parechovirus – Los AngelesCNS Human Parechovirus – Los Angeles
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FEVER IN YOUNG INFANTS: MY WAY
• “All” infants <30 days should be hospitalized
• Usual tests/cultures + CSF/Plasma for PCR HSV +
EV, HPeV
• Infants >60 days can be evaluated clinically
• Individualize management for ages between
- Clinical + temp + sex/circcumcision
- Selective use lab/hosp/abx
- Minimize W/U + Ceph3 @ home for low risk
• OPD blood culture + no Rx = Not allowed
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FDA/LABEL CHANGE RE CEFTRIAXONE
CONTRAINDICATION (Neonates < 28 days):
8/2007
Ceftriaxone must not be co-administered with calcium-containing IV solutions because of risk of precipitation of ceftriaxone–calcium salt
Fatal reactions w Cef-Ca precip in lungs/kidneys
2007
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Case 3
A 6-month old white male has the same history and findings as Case 1. Temperature is 38.6 and except for URI, he has no other abnormalities. He has received two doses of PCV13
My management plan would be
A. Observe at home with follow-up < 24 hrs B. Urinalysis with further management pending results
C. CBC with further management pending resultsD. CBC, urinalysis & culture, blood culture + ceftriaxone IM
and observation at homeE. Tests of D + CSF + admit to hospital
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Case 3
A 6-month old white male has the same history and findings as Case 1. Temperature is 38.6 and except for URI, he has no other abnormalities. He has received two doses of PCV13
My management plan would be
A. Observe at home with follow-up < 24 hrs B. Urinalysis with further management pending results
C. CBC with further management pending resultsD. CBC, urinalysis & culture, blood culture + ceftriaxone IM
and observation at homeE. Tests of D + CSF + admit to hospital
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“PRACTICE GUIDELINES 1993”3-36 MOS, WELL, W/O SOURCE
Temp >39C: Consider blood cultureConsider urine examPerform WBC (unless virus S/S)
WBC>15,000: Perform blood culturePerform urine culture(M < 6 mo;F < 2 yr)Give ceftriaxone
Baraff, Bass, Fleisher, et al. Pediatrics 1993
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GLITCHES IN “GUIDELINES”
• Risk bacteremia/meningitis variable
• No treatment stat meningitis
• Pneumococcal meningitis rapid onset
• >90% patients pursued + treated have no bacterial infection
• F/U is clouded, tests, contam cultures
• Practitioners didn’t/don’t subscribe
Then
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GLITCHES IN “GUIDELINES”
• Pneumococcal invasive disease
• White blood count no longer useful as
doesn’t predict other pathogens
• Invasion of non-vaccine serotypes
pneumococcus occurs in patients with
underlying conditions; not “occult” but
“obvious”
Now
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OCCULT BACTEREMIA & VACCINES
BacteriologyPneumococcusHaemophilus b
MeningococcusStrep/StaphSalmonella/Other
<1990 3% 80% 10%
Rare 10%
>1990* 2%
90% --
Rare
10% *Hib conj
>2000** <0.5%
40% --
Rare 60%
PCVs
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Journal Club…in Context…with Journal Club…in Context…with AttitudeAttitude
Pearls and Perils of PCR Testing Pearls and Perils of PCR Testing 2014; 130: e1455
2014; 133:e538
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Study >200 children 2 to 36 mos fever w/o source vs probable/definite bacterial infection vs well PCR respiratory specimen + blood
Results Fever w/o source 75% virus Fever w bacterial inf 40% virus Well 35% virus ( Adeno, HHV6, EV, HPeV esp febrile vs well)
Also 34% positive PCRs detected only in blood
51% patients w virus-only were given antibiotics
Conclusion Viral infections are frequent in ill, and in healthy
Journal Club…in Context…with Journal Club…in Context…with AttitudeAttitude
Pearls and Perils of PCR Testing Pearls and Perils of PCR Testing Respiratory Viruses – Saint LouisRespiratory Viruses – Saint Louis
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OUTPATIENT BACTEREMIA: MY WAY
PLAN A Careful clinical assessment No WBC No blood culture No antibiotic Reassess
1993 2000 2010 2014
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Journal Club…in Context…with Journal Club…in Context…with Attitude Attitude
Sept 11, 2014
2011;128:595
Journal Club…in Context…with Journal Club…in Context…with Attitude Attitude
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Question Does antibiotic pro prevent recurrent UTI in children w vesicoureteral reflux (VUR)?
Method 2 yr, 19-site, RD-BPCT 607 children 2-71 mos with VUR Gr I-IV after 1-2 febrile UTIs TMP-SMX 3 mg/kg TMP or placebo daily 10 Outcome = Recurrent febrile or sympt UTI 20 Outcome = Renal scarring,
Rx failure (recurrence or scarring) TMP resistance
Results Recurrent UTI 27% (P 15% (TMP) HR.55 Renal scarring 12% (P) 10% (TMP) Recur/TMP R org 25% (P) 68% (TMP)
The RIVUR StudyThe RIVUR Study
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Significant UTIs with prophylaxis*•Female•Gr I or II VUR•Index UTI = first UTI•Index UTI = febrile•Index UTI = TMPS
•Bowel/bladder dysfunction•Absent constipation
* Hazard ratio + 95% CI < 1
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AAP PRACTICE GUIDELINES
Risk and pursuit UTI in febrile 2 mo – 2 yr
Girl Uncirc Boy Circ Boy > 3 risks > 1 risk 4 UTI risks
3% - 17% UTI 10% - 25% UTI >3% UTI
Girls Girls & Boys Boys
White < 12 mos Fever > 2 d
Temp > 390CAbsence of source
Non blackFever > 1 d
Cath urine + AntibioticUA and if UA+, Cath urine + Abx
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Pediatrics 2013;132:e749-e755 Pediatrics 2013;132:437-444
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UTI : URINE TESTING IN OUTPATIENTS UTI : URINE TESTING IN OUTPATIENTS TREATED FOR UTITREATED FOR UTI
Objective: Objective: Characterize urine test use in ambulatory Characterize urine test use in ambulatory children treated for UTIchildren treated for UTI
Methods:Methods: Outpatients <18 yrs w dx UTI + Abx script ’02-’07Outpatients <18 yrs w dx UTI + Abx script ’02-’07 Claims database 50 states/39 million insured Claims database 50 states/39 million insured
Results: Results: >40,000 UTIs in ~29,000 children>40,000 UTIs in ~29,000 children UA performed in 76%UA performed in 76% Urine culture performed in 57%Urine culture performed in 57% Of children <2 yrs, 32% had no UAOf children <2 yrs, 32% had no UA Over time use of culture Over time use of culture ↓↓ Compared w <2 yrs, OR culture Compared w <2 yrs, OR culture ↑↑ w age & w age & ↓↓ w male w male Compared w Family/IM docs Odds Ratio cultureCompared w Family/IM docs Odds Ratio culture ↑↑ w Peds (2.6) w Peds (2.6) ↑↑ w EM (1.2) w EM (1.2) ↓↓ w Urology (.5) w Urology (.5)
Conclusion: Conclusion: Yikes!Yikes! Implications Rx w/o confirmationImplications Rx w/o confirmation
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MANAGEMENT FIRST UTI: AAP 2011 MANAGEMENT FIRST UTI: AAP 2011 GUIDELINESGUIDELINES
• Pursue febrile Pursue febrile according to risk UTIaccording to risk UTI• Pursue stepwise only if not ill / low risk / no antibioticPursue stepwise only if not ill / low risk / no antibiotic UA by clean catchUA by clean catch If UA pos, culture by clean catch vs cath If UA pos, culture by clean catch vs cath
• Treatment (IV or PO re degree illness)Treatment (IV or PO re degree illness) First UTI >95% First UTI >95% E. coliE. coli (Occas (Occas KlebKleb, , EnterococcusEnterococcus)) E. coliE. coli susc : Amox 47% susc : Amox 47% Cephalexin 90%Cephalexin 90% Amox/Cl 66% Cefuroxime 96% Amox/Cl 66% Cefuroxime 96% TMP-SMX 76%TMP-SMX 76%• Ultrasonography: Kidneys and bladderUltrasonography: Kidneys and bladder
• Alert family re: fever/recurrenceAlert family re: fever/recurrence
• No antibiotic before cath urine for cultureNo antibiotic before cath urine for culture
• VCUG only if abnormal USVCUG only if abnormal US• No prophylaxis unless Gr V VURNo prophylaxis unless Gr V VUR
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