Pediatric fever of uncertain source

Background

• Fever accounts for 30% of pediatric visits
• Children <3 months are immunocompromised (e.g. poor opsonization, poor IgG response to encapsulated bacteria, macrophage and neutrophil dysfunction, bone marrow insufficiency)
• Concern is for missing a serious bacterial infection (SBI)

Epidemiology and Risk

Age	0-14 days	14-28 days	28-60 days (pre vaccine)	28-60 days (post vaccine)	60-90 days	> 90 days
Meningitis/SBI Prevalence	1/10	1/20	1/100	1/1000	1/1000-10,000	> 1/10,000

• Serious bacterial illness (SBI) includes UTI, meningitis, pneumonia, bacteremia
• 7% of patients <2 years old with fever have pneumonia, however the etiology (viral/bacterial) or even the presence of pneumonia has low inter-observer reliability even among pediatric radiologists
• 4% Prevalence of UTI with common other sources of fever (OM, viral URI, etc)
• 0.3% of previously well children aged 3-36 months who have a fever without a source will develop significant sequelae, 0.03% will develop sepsis or meningitis

Concomitant Respiratory Viral Infection

• Relatively high coincidence of RSV, enterovirus, and paraflu with bacteremia (and UTIs), so positive lab test for these viruses should not change testing and management plan
  • RSV+ neonates aged 0-28 days, 3.7% were bactremic (and 6.1% had UTIs)
  • RSV+ infants aged 29-60 days, (5.5% had UTIs)
• There is a low coincidence of influenza with SBI, so postivie lab test for this virus may change testing and management plan (i.e. lower risk of concurrent bacterial illness)

Clinical Features

• Febrile
  • Defined as temperature ≥38°C (100.4°F).
  • Peripheral temperature is not clinically accurate and central measurements are the preferred means of determining fever.
  • Parental report of confirmed fever at home (i.e. via thermometer), even with no fever in ED, has rates of SBIs high as 4.7% (0-28 day range)

Differential Diagnosis

Pediatric fever

• Upper respiratory infection (URI)
• UTI
• Sepsis
• Meningitis
• Febrile seizure
• Juvenile rheumatoid arthritis
• Pneumonia
• Acute otitis media
• Whooping cough
• Unclear source
• Kawasaki disease
• Neonatal HSV
• Specific virus
  • COVID-19 (peds)
    • MIS-C

Evaluation & Management

• Preemies: Count age by estimated postconception date (not by actual delivery date) for 1st-90d

0-7 Days

For all infants (toxic and well-appearing)

Child Appearance	Work Up	Treatment	Disposition & Follow-up	Comments
Temperature ≥38° Toxic or Well	CBC Blood cultures Urinalysis, Urine culture LP-CSF CXR +/- Stool studies (if diarrhea)	If <14 days, Ampicillin 50mg/kg/dose AND (Gentamicin 4mg/kg/dose or Cefepime 30mg/kg/dose) If >14 days, Ampicillin 50mg/kg/dose AND Ceftriaxone 50-100mg/kg/dose Acyclovir 20mg/kg/dose	Admit	SBI incidence Ill appearing: 13%–21% Not ill appearing: <5%

^Acyclovir if:

• HSV infection in baby or mother
• CSF pleocytoisis
• Concerning skin lesions
• Seizures
• Abnormal LFTs

Note:

• CXR is optional if no resp sx and another source identified
• LP is necessary even if another source identified due to immature blood-brain barrier
• Do not give ceftriaxone to children <28d as may cause hyperbilirubinemia

8-21 Days

• For toxic infants, treat for sepsis and admit
• For well-appearing infants:

8-21 day algorithm

Child Appearance	Work Up	Treatment	Disposition & Follow-up	Comments
Temperature ≥38°C Well-appearing No evident source of infection Increased HSV risk	Urinalysis, Urine culture Blood culture Inflammatory markers (IMs) - may obtain LP-CSF HSV studies	Initiate parenteral antimicrobial(s), including Acyclovir	Observe in hospital If pathogen or source identified → Treat infection If all culture results negative at 24-36 hours AND HSV PCR negative → Discontinue antimicrobials; may discharge. Manage for duration of illness.	Consider HSV if: Maternal h/o genital HSV lesions or fever 48 hrs before to 48 hrs after delivery Vesicles, mucous membrane ulcers Seizures Hypothermia CSF pleocytosis + negative gram stain Leukopenia Thrombocytopenia Elevated ALT
Temperature ≥38°C Well-appearing No evident source of infection No increased HSV risk	Urinalysis, Urine culture Blood culture Inflammatory markers (IMs) - may obtain LP-CSF	Initiate parenteral antimicrobial(s)	Observe in hospital If pathogen or source identified → Treat infection If all culture results negative at 24-36 hours → Discontinue antimicrobials; may discharge. Manage for duration of illness.

22-28 Days

• For toxic infants, treat for sepsis and admit
• For well-appearing infants:

Child Appearance	Work Up	Treatment	Disposition & Follow-up	Comments
Temperature ≥38°C Well-appearing No source of infection Abnormal IMs CSF pleocytosis or uninterpretable	Urinalysis, Urine culture (bladder catheterization or SPA if UA positive) Blood culture Inflammatory markers (IMs) Perform LP(11b) - CSF	Administer IV antibiotics	Observe in hospital If pathogen or source identified → Treat infection If all cultures negative at 24-36 hours and HSV PCR negative (if sent) → Discontinue IV antibiotics; may discharge. Follow for duration of illness.	Abnormal Inflammatory Markers: Temp > 38.5 Procalcitonin > 0.5 ng/mL CRP ≥ 20 mg/L ANC > 4500 or 5200
Temperature ≥38°C Well-appearing No evident source of infection Abnormal IMs No CSF pleocytosis (or CSF not obtained)	Urinalysis, Urine culture (bladder catheterization or SPA if UA positive) Blood culture Inflammatory markers (IMs) Perform LP - CSF (may not be obtained)	If observation at home: Administer IV antibiotics If observation in hospital: May administer IV antibiotics	If observation at home: Observe at home. Reassess in 24 hours. If observation in hospital: Observe in hospital). If pathogen or source identified → Treat infection If all cultures negative at 24-36 hours and HSV PCR negative (if sent) → Discontinue IV antibiotics; may discharge. Follow for duration of illness.
Temperature ≥38°C Well-appearing No evident source of infection Normal IMs LP performed, CSF obtained, CSF pleocytosis or traumatic	Urinalysis, Urine culture (bladder catheterization or SPA if UA positive) Blood culture Inflammatory markers (IMs) May perform LP - CSF	May administer IV antibiotics	Observe in hospital If pathogen or source identified → Treat infection If all cultures negative at 24-36 hours and HSV PCR negative (if sent) → Discontinue IV antibiotics; may discharge. Follow for duration of illness.
Temperature ≥38°C Well-appearing No evident source of infection Normal IMs LP performed, CSF obtained, no CSF pleocytosis/not traumatic OR CSF not obtained OR LP not performed	Urinalysis, Urine culture (bladder catheterization or SPA if UA positive) Blood culture Inflammatory markers (IMs) May perform LP	If observation at home: Administer IV antibiotics If observation in hospital: May administer IV antibiotics If LP performed but CSF not obtained, or LP not performed: May administer IV antibiotics); Observe in hospital	If observation at home: Observe at home. Reassess in 24 hours. If observation in hospital: Observe in hospital. If pathogen or source identified → Treat infection If all cultures negative at 24-36 hours and HSV PCR negative (if sent) → Discontinue IV antibiotics; may discharge. Follow for duration of illness.

29-60 Days

• For toxic infants, treat for sepsis and admit
• For well-appearing infants:

29-60 day algorithm

Child Appearance	Work Up	Treatment	Disposition & Follow-up	Comments
Temperature ≥38°C Well-appearing No evident source of infection Abnormal IMs	Urinalysis (obtain for all) Blood culture (obtain for all) Inflammatory markers (IMs) (obtain for all) Send bladder catheterization or SPA urine culture if positive urinalysis (15) May perform LP (18a)	If CSF result is positive: Administer parenteral antimicrobial(s) (19a) If CSF result is negative and either urinalysis negative or positive: May administer parenteral or oral antimicrobial(s) (19b) If CSF not available or uninterpretable: Administer parenteral antimicrobial(s) (19a)	If CSF result is positive: Observe closely in hospital (20a) If CSF result is negative and either urinalysis negative or positive: May observe closely in hospital or at home (20b,d) If CSF not available or uninterpretable: May observe closely in hospital or at home (20b)	Abnormal Inflammatory Markers: Temp > 38.5 Procalcitonin > 0.5 ng/mL CRP ≥ 20 mg/L ANC > 4500 or 5200
Temperature ≥38°C Well-appearing No evident source of infection Normal IMs Positive urinalysis result	Urinalysis (obtain for all) Blood culture (obtain for all) Inflammatory markers (IMs) (obtain for all) Send bladder catheterization or SPA urine culture (15) Need not perform LP (18b)	Administer oral antimicrobial(s) (19c)	May observe closely at home Follow-up in 12 to 24 hours (20d)
Temperature ≥38°C Well-appearing No evident source of infection Normal IMs Negative urinalysis result	Urinalysis (obtain for all) Blood culture (obtain for all) Inflammatory markers (IMs) (obtain for all) Need not perform LP (18b)	Need not administer antimicrobial(s) (19d)	Observe closely at home (20c) Follow-up within 24-36 hours (20c)

At 24 to 36 hours follow-up:

• If pathogen or source identified at 24-36 hours AND source limited to urine → Complete treatment with oral antimicrobials (21c); Discharge hospitalized infants (21b); Manage for duration of illness
• If pathogen or source identified at 24-36 hours AND source NOT limited to urine → Treat infection (21d)
• If NO pathogen or source identified at 24-36 hours → Discontinue antimicrobials if administered (21a); Discharge hospitalized infants (21b); Manage for duration of illness

60 Days - 36 Months

Appearance	Work Up	Treatment	Disposition & Follow-Up
T≥38° + Toxic	CBC Blood cultures Urinalysis, urine culture LP-CSF CXR^	Ceftriaxone 50-100mg/kg/dose AND Consider Vancomycin 15mg/kg	Admit
T≥39°C + Well + Non-complete Prevnar (No Prevnar or <4 weeks post 1st Prevnar dose)	Urinalysis, Urine culture CBC +/- CXR	If WBC(+): Ceftriaxone 50mg-100mg/kg (also then consider blood culture and LP, especially in <6mo old)	Outpatient (24 hour follow-up)
T≥39°C + Well + Prevnar (2 Prevnar or ≥4 weeks post 1st Prevnar dose)	Urine workup (UA, urine culture) for: Circumcised males <6 months Uncircumcised males <12 months All females +/- CXR	Treat cystitis or pneumonia if postitive	Outpatient (48hour follow up)
T≥38-38.9°C + Well	Consider UA, CXR based on symptoms, etc	Treat cystitis or pneumonia if positive	Outpatient (48-72 hour follow-up)

• Consider CXR for:
  • Respiratory symptoms
  • Fever >48 hrs
  • Tachypnea
  • Hypoxia

• Non-UTI SBI incidence of <.4% in children >6 mo

Low Risk Lab Criteria

If low-risk criteria below not met, then perform the LP (if not done) and admit for inpatient antibiotics

CBC

• WBC 5-15 /mm³
• Absolute Band count <1500 /mm³
• Procalcitonin ≤0.5 ng/mL
• ANC ≤4000/mm³

Urinalysis

• Clear
• Neg Nitrate and Leukocyte esterase
• WBC <10/high powered field

CSF

• Studies should include WBC, protein, glucose, Gram stain, and culture for bacteria. Consider viral studies (HSV).

0-28 days

• WBC: 0-22/mm³
• Protein: <100mg/dL

>29 days

• WBC 0-7/mm³
• Protein: 15-25mg/dL

Additional Management

Neonatal Antibiotics by Source

Suspected Infection Source	8-21 Days Old	22-28 Days Old	29-60 Days Old
UTI	Ampicillin IV or IM (150 mg/kg per day divided q8) AND either: Ceftazidime IV or IM (150 mg/kg per day divided q8) or Gentamicin IV or IM (4 mg/kg per dose q24)	Ceftriaxone IV or IM (50 mg/kg per dose q24)	Ceftriaxone IV or IM (50 mg/kg per dose q24) Oral options: Cephalexin 50-100 mg/kg per day QID or Cefixime 8 mg/kg QD
No source identified	Ampicillin IV or IM (150 mg/kg per day divided q8) AND either: Ceftazidime IV or IM (150 mg/kg per day divided q8) or Gentamicin IV or IM (4 mg/kg per dose q24)	Ceftriaxone IV or IM (50 mg/kg per dose q24)	Ceftriaxone IV or IM (50 mg/kg per dose q24)
Bacterial meningitis	Ampicillin IV or IM (300 mg/kg per day divided q6) AND Ceftazidime IV or IM (150 mg/kg per day divided q8)	Ampicillin IV or IM (300 mg/kg per day divided q6) AND Ceftazidime IV or IM (150 mg/kg per day divided q8)	Cephalosporin Ceftriaxone IV (100 mg/kg QD) or Ceftazidime IV (150 mg/kg QD) AND Vancomycin IV (60 mg/kg QD)

Acetaminophen Pediatric Dosing Chart

Weight (kg)	Weight (lbs)	Age	Dosage (mg)
3-4	6-11	0-3 mo	40
5-7	12-17	4-11 mo	80
8-10	18-23	1-2 y	120
11-15	24-35	2-3 y	160
16-21	36-47	4-5 y	240
22-26	48-59	6-8 y	320
27-32	60-71	9-10 y	400
33-43	72-95	11 y	480

Dosage can be given q6 hours

See Also

• Acute fever
• Fever of unknown origin (peds)
• Urinary tract infection (peds)
• Sepsis (peds)
• Meningitis (peds)
• Febrile seizure
• PECARN Febrile Infant

External Links

• PEM ED Algorithm for Pediatric Fever
• DDxOf: Pediatric Fever