Fever without a Focus

Sarah S. Long, M.D.

Professor of Pediatrics
Drexel University College of
Medicine
Chief, Section of Infectious
Diseases
St. Christophers Hospital for
Dr. Long has no
conflict of interest to disclose
Children
Philadelphia, Pennsylvania

FEVER, NO FOCUS OF INFECTION

WHAT 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
D. C above + Ceftriaxone (if C tests negative)
E. Blood, urine, CSF tests/cultures + admit +
ampicillin/gentamicin

at home

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
D. C above + Ceftriaxone (if C tests negative)
E. Blood, urine, CSF tests/cultures + admit +
ampicillin/gentamicin

at home

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
ISOLATES
Bacterial meningitis
E. coli
Urinary tract inf
Grp B streptococcus
Bloodstream infection
S. aureus
Otitis media
Enterococcus
Gastroenteritis
Salmonella
Pneumonia
Listeria
Syphilis
Others
Viral meningitis
Herpes simplex
pneumoniaEnterovirus
disseminated
Influenza
Others

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 factor
No soft tissue/skeletal site
Total WBC >5000 & < 15,000
Urinalysis <10 WBCs
Stool <5 WBCs
PITTSBURGH APPROACH**
Add negative CSF
Add 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
Consensus
Evaluate*
Hospitalize
Abx (Y or N)

> 28 DAYS & LOW-RISK

Option 1
Option 2
Evaluate*
Urine culture
Ceftriaxone OPD Observe OPD
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%
Bact/Meningitis
4%

<10%
1%

*Pantell et al JAMA, 2004

MULTIVARIATE PREDICTORS
BSI/MENINGITIS (PROS)
Factors
Age < 30 days
31-60 days

Odds Ratio
5.5
3.0

Ill, very
moderately

9.0
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
< 30 days
Complete W/U
+hosp+abx
31-90 days
Min ill

WBC/UA

Follow
46%

42%

31-90 days Complete W/U

Mod/very ill
+hosp+abx

36%

PERFORMANCE CLINICAL PREDICTION MODEL

Sensitivity
Clinical
58%
Clinical+Abn WBC
84%
Clinical+Abn WBC+UA
87%
Guidelines model
95%
PROS model*
94%
PROS actual exp**
97%
*Min ill + age > 25 days + Temp < 38.6
**Initial Rx with Abx

Specificity
68%
54%
51%
35%
27%
35%

PREVALENCE HSV BSI HOSP NEONATES*

No
SBI
Virus
All hosp
5817
4.6%
8.4%
Fever
960
14.2%
17.2%
(0.3% HSV)
Bact men HSV
CSF 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%

2011;30:556

32 cases perinatally acquired HSV

50% had only nonspecific S/S at
presentation, which was fever in 75%
75% had CNS HSV

(40% presented with mucocutaneous only,

83% with seizures, 94% with nonspecific S/S
only)

Age 21 days at onset S/S captured 90%

of all cases and 94% with nonspecific S/S
only

Dont forget to look

Dont forget to evaluate and treat
empirically well appearing neonates with
vesicular skin lesions
2012;161:134

Journal Clubin Contextwith

Attitude
Pearls and Perils of PCR Testing

CNS Human Parechovirus Kansas City

Study

Retro 388 CSF specimens from children < 18 yrs

who had EV testing performed, 2009
RTPCR HPeV+ All were < 6 mo
Compared clinical of all patients tested < 6 mo

Results
Age (d)
PICU
T max
Days fever
CSF WBCs
Periph WBCs

HPeV+ (66)
41
12%
>39
2.7
2%
5.8

EV+ (47)
31
2%
38.4
2
38%
9.2

Negative (66)
43
0
38
1.6
12%
10.1

HPeV3 is an emerging CNS pathogen & should be considered

in young infants w or w/o CSF pleocytosis

CNS Human Parechovirus Los Angeles

Study Retro 440 CSF specimens from children
who had evaluation for infection
Compared HPeV+ vs EV+
Results
Age < 6 mo
Seizures
CNS S/S
URI
Vomiting
CSF WBCs

HPeV+ (12)
67%
42%
75%
58%
25%
25%

EV+ (43)
67%
14%
30%
16%
26%
82%

HPeV is a CNS pathogen and should be considered

FEVER IN YOUNG INFANTS: MY WAY

All infants <30 days should be hospitalized
Usual tests/cultures + CSF/Plasma for PCR
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

HSV +

FDA/LABEL CHANGE RE CEFTRIAXONE

CONTRAINDICATION (Neonates < 28 days):

Ceftriaxone must not be co-administered
with calcium-containing IV solutions
because of risk of precipitation of
ceftriaxonecalcium salt
8/2007

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.
B.
C.
D.

Observe at home with follow-up < 24 hrs

Urinalysis with further management pending results
CBC with further management pending results
CBC, urinalysis & culture, blood culture + ceftriaxone IM
and observation at home
E. 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.
B.
C.
D.

Observe at home with follow-up < 24 hrs

Urinalysis with further management pending results
CBC with further management pending results
CBC, urinalysis & culture, blood culture + ceftriaxone IM
and observation at home
E. Tests of D + CSF + admit to hospital

PRACTICE GUIDELINES 1993

3-36 MOS, WELL, W/O SOURCE
Temp >39C:

Consider blood culture

Consider urine exam
Perform WBC (unless virus S/S)

WBC>15,000: Perform blood culture

Perform urine culture
(M < 6 mo;F < 2 yr)
Give ceftriaxone
Baraff, Bass, Fleisher, et al. Pediatrics 1993

GLITCHES IN GUIDELINES

Then
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 didnt/dont subscribe

GLITCHES IN GUIDELINES

Now
Pneumococcal invasive disease
White blood count no longer useful as
doesnt predict other pathogens
Invasion of non-vaccine serotypes
pneumococcus occurs in patients with
underlying conditions; not occult but
obvious

OCCULT BACTEREMIA & VACCINES

<1990
3%

>1990*
2%

80%
10%

90%
--

40%
--

Meningococcus Rare
Strep/Staph
10%
Salmonella/Other

Rare
10%

Rare
60%

*Hib conj

PCVs

Bacteriology
Pneumococcus
Haemophilus b

>2000**
<0.5%

Journal Clubin Contextwith

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

2014; 133:e538

Journal Clubin Contextwith

Attitude
Pearls and Perils of PCR Testing
Respiratory Viruses Saint Louis
Respiratory Viruses Saint Louis

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
healthy

Viral infections are frequent in ill, and in

OUTPATIENT BACTEREMIA: MY WAY

1993

200
0

2010

PLAN A
Careful clinical assessment
No WBC
No blood culture
No antibiotic
Reassess

2014

Journal Clubin Contextwith

Attitude

2011;128:595

Sept 11, 2014

The RIVUR Study

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)

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
> 3 risks

3% - 17% UTI

Uncirc Boy
> 1 risk

10% - 25% UTI

Circ Boy
4 UTI risks

>3% UTI

Cath urine + Antibiotic

UA and if UA+, Cath urine + Abx
Girls
White
< 12 mos
Fever > 2 d

Girls & Boys

Temp > 390C
Absence of source

Boys
Non black
Fever > 1 d

Pediatrics 2013;132:e749-e755

Pediatrics 2013;132:437-4

UTI : URINE TESTING IN OUTPATIENTS

TREATED FOR UTI
Objective:

Characterize urine test use in ambulatory

children treated for UTI

Methods:

Outpatients <18 yrs w dx UTI + Abx script 02-07

Claims database 50 states/39 million insured

Results:

>40,000 UTIs in ~29,000 children

UA performed in 76%
Urine culture performed in 57%
Of children <2 yrs, 32% had no UA
Over time use of culture
Compared w <2 yrs, OR culture w age & w male
Compared w Family/IM docs Odds Ratio culture
w Peds (2.6) w EM (1.2) w Urology (.5)

Conclusion:

Yikes!
Implications Rx w/o confirmation

MANAGEMENT FIRST UTI: AAP 2011

GUIDELINES
Pursue febrile according to risk UTI
Pursue stepwise only if not ill / low risk / no antibiotic

UA by clean catch
If UA pos, culture by clean catch vs cath

No antibiotic before cath urine for culture

Treatment (IV or PO re degree illness)

First UTI >95% E. coli (Occas Kleb, Enterococcus)

E. coli susc : Amox
47%
Cephalexin
90%
Amox/Cl 66%
Cefuroxime
96%
TMP-SMX 76%

Ultrasonography: Kidneys and bladder

VCUG only if abnormal US
No prophylaxis unless Gr V VUR
Alert family re: fever/recurrence