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

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.

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

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

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

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

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

HIGH RISK FOR SERIOUS INFECTION

Younger age

High/low temp

Ill appearing

High/low WBC

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%

“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

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

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

SUMMATIVE RISK BY PROS CLINICAL PREDICTORS

Well or minimally ill + Age > 25 days

+Temperature < 38.60

Total = 1/3 patients

Risk = 0.4%

__________________

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

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

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%

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

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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Pearls and Perils of PCR Testing Pearls and Perils of PCR Testing

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

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

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

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

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

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

“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

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

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

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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Pearls and Perils of PCR Testing Pearls and Perils of PCR Testing 2014; 130: e1455

2014; 133:e538

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

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Pearls and Perils of PCR Testing Pearls and Perils of PCR Testing Respiratory Viruses – Saint LouisRespiratory Viruses – Saint Louis

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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Sept 11, 2014

2011;128:595

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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

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

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

Pediatrics 2013;132:e749-e755 Pediatrics 2013;132:437-444

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

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