approach

2. Fever
 20% of pediatric emergency dept visits
 35% of ambulatory visits
 10% percent of febrile children have fever
without an apparent source of infection after
history and physical examination.

3. Physiology
 Hypothalamus is the thermoregulatory center for the
body
 Fever results when a shift in the hypothalamic set point
causes a controlled elevation of body temperature above
the normal range
 Normal set point for humans has a daily circadian rhythm
ranging 36C-37.8C with peak occurring in the afternoon
Current Opinion in Pediatrics 2009, 21:139–144

4.  Fever production begins when an infectious agent, toxin,
immune complex, or other inflammatory agent
stimulates macrophages or endothelial cells to produce
endogenous pyrogens, such as interlukin-1 and tumor
necrosis factor
 Pyrogens hypothalamus  PGE2 and AA metabolites
 raise thermostat set point (thermoregulatory neurons)
Current Opinion in Pediatrics 2009, 21:139–144
Pathophysiology

5. Fever without a source (FWS)
 Children with fever lasting one week or less
without adequate explanation after a careful
history and physical examination.
Definitions

6.  Fever of 38.3 or greater of at least eight days
duration, with no apparent diagnosis after initial
outpatient or hospital evaluation that includes a
careful history and physical exam and initial
laboratory assessment.
(This definition is useful for clinical purposes, but there
is much variability in published studies of fever of
unknown origin with required duration of fever
ranging between 1 to 3 weeks.)
Fever of unknown origin (FUO)

7. The vast majority of children who present acutely with
fever without source (or fever of unclear source) have
underlying infections, typically requiring urgent
evaluation and empirical treatment (especially in young
children). In contrast, fever of unknown origin is not well
defined in children. It has been historically used to
describe a subacute presentation of a single illness of at
least 2 weeks duration during which a fever >38.3°C
(100.9°F) is present for most days and the diagnosis is
unclear after 1 week of intense investigation. [1] The
most common causes are infections,
inflammatory/vasculitic disorders, and malignancies.
These children require a more deliberate, comprehensive,
and prolonged evaluation, and frequently do not need
urgent empirical therapy.

8. Occult bacteremia
 is defined as the presence of bacteria in the
bloodstream of a febrile child who has no apparent
focus of infection and clinically does not appear to be
ill.
 Some experts include in this definition children who have ottitis
media at their initial presentation and are subsequently found
to have positive blood cultures.

9. Etiology of occult bacteremia
S. pneumoniae – 85%
H. influenzae type b – 10%
 N. meningitidis – 3%
 Salmonella – 2%

10. Differential Diagnosis of Fever Without
Focus
Common 0-3 months 3-36 months
Viral HSV + Enterovirus,
parainflueza, adenovirus,
RSV, CMV, roseola, PV,
influenza
Enterovirus, parainflueza,
adenovirus, RSV, CMV,
roseola, PV, influenza
Bacterial
(occult
bacteremia)
GBS
Gram negative (E. coli,
Kebsiella, Enterobacter
cloacae, Salmonella)
Listeria
Strep pneumoniae,
H.influenza, N. meningitidis,
Salmonella

11. Differential Diagnosis of Fever Without
Focus
Common 0-3 months 3-36 months
Bacterial
(UTI)
Gram negative
organisms (E. coli
, Klebsiella)
same
(other) meningitis Unlikely without
signs

12. Differential Diagnosis of Fever Without
Focus
Less common 3m-36 months
Connective
Tissue Diseases
Rheumatic fever, SLE, sarcoidosis,
JRA,kawasaki
Malignancies Leukemia, Lymphoma,
neuroblastoma, Ewing sarcoma
Poisoning Atropine, salicylates, cocaine,
anticholinergics

13. Usually caused by common disorders
which may have an atypical presentation
rather than by uncommon disorders with
typical presentations.
Most common categories are infectious
disease
A diagnosis is sometimes never
established.

14. Diagnostic Approach
A careful history and physical is the first
step in evaluating a patient with fever of
unknown origin.

15. History
Fever : Duration, height and pattern,
measurement technique
Whether or not the fever responds to
antipyretic drugs Lack of response to
NSAIDs may indicate a non-inflammatory
condition as the cause of the fever
Fever pattern?!

16. Associated symptoms and behaviors
Medications
Environmental exposures
Similar symptoms in siblings
Birth and nursery history (STD, TORCH,
GBS, ROM) in infants
Date of last immunizations (MMR-fever
and rash 7-10 days afterwards)

17. Physical Examination
 Toxic appearance (irritability, poor perfusion,
lethargy)
 SpO2 – better predictor of pulmonary infection
 Signs of infection (omphalitis, arthritis,
cellulitis, herpes lesions)
 Meningitis – change in sleep pattern,
decreased feeding ,paradoxical irritability,
bulging fontanelle (late sign).

18. Laboratory Data And Interpretation
 WBC
 Neutrophils / Bands
 Acute-phase reactants
 Antigen testing
 Blood cultures
 Lumbar puncture
 UA/Urine culture
 CXR
 Stool Analysis and Culture
 Other tests (KFT , LFT, etc) as indicated

19. WBC
There is direct relationship between
the WBC count and the prevalence of
bacteremia
 Temperature curve – not useful
 Combination of temperature curve and WBC
curve offered no advantage over the WBC
curve alone
Jaffe et al. Pediatrics 1991; 87:670

20. WBC
Limitations
Up to 50% of children with Hib
bacteremia will have WBC 5,000-15,000
Children with Neisseria meningitidis
may be leukopenic
Not predictive of bacteremia in infants
< 8 weeks of age
Jaffe et al. Pediatrics 1991; 87:670

21. Neutrophils, Bands, ESR
Have value in identifying children at risk
for serious illness
Higher the values, the greater the risk of
bacteremia

22. C – Reactive Protein
Acute phase reactant released by the
liver following inflammation or tissue
damage.
High sensitivity but low specificity
Increase until 12 hours after the onset of
fever and can rise in both viral and
bacterial infections.
Pulliam PN. Pediatrics. 2001 Dec; 108(6):1275-9.

23. Procalcitonin
 cutoff value 0.12 ng/mL to detect SBI
 Sensitivity 95-96% (95% CI 83-99 percent)
 Specificity 23-26% (95% CI 20-32 percent)
 NPV 96% (95% CI 85-99 percent)
Maniaci, et al. Pediatrics. 2008 Oct;122(4):701-10.
Dauber, et al. Pediatrics. 2008 No5;122(4):e1119-22.

24. Antigen Testing
Strep pneumoniae
H. influenzae type b
PCR methods (VZV, enterovirus)

25. Blood cultures
 Gold standard
 False negatives
 Prior treatment with antibiotics
 Missing an episode of bacteremia
 Inoculation of too little blood (<1ml) into the
media; too much blood may yield false negative
due to ongoing killing of bacteria by neutrophils
 False positives
 Improperly cleaning the skin, resulting in
contamination with skin flora

26. LP
 Indicated if the diagnosis of sepsis or
meningitis is considered

27. UA/Urine culture
Best method if not toilet trained are
bladder catheterization or supra-pubic
aspiration
NOT BAG COLLECTION
OBTAIN IN ALL CHILDREN ON EMPIRIC
ANTIBIOTICS

28. CXR
Children > 3 months
Oxygen Saturation <95%
Respiratory distress
Tachypnea
Rales on lung auscultation
Fever 39.5 C (103.1 F) or higher
Asymptomatic with WBC >20,000

29. Stool Analysis and Culture
Important if diarrhea present
Can be considered a focus of infection

30. Criteria
 Rochester - Jaskiewicz JA, et al. Febrile infants at low risk for
serious bacterial infection - an appraisal of the Rochester
criteria and implications for management. Febrile Infant
Collaborative Study Group. Pediatrics 1994 Sep;94(3):390-6
 Philadelphia - Baker MD, et al. Outpatient management
without antibiotics of fever in selected infants. N Engl J Med
1993 Nov 11;329(20):1437-41.
 Boston - Baskin MN, et al. Outpatient treatment of febrile
infants 28 to 89 days of age with intramuscular administration
of ceftriaxone. J Pediatr 1992 Jan; 120(1): 22-7.

31. The purpose of these criteria is to reduce
the number of infants hospitalized
unnecessarily and to identify infants who
may be managed as outpatients by using
clinical and laboratory criteria.

32. Philadelphia Rochester Boston
Age 29-60d <60days 28-89d
Temp >38.2C >38C >38C
History Not specified Term infant
No perinatal Abx
No underlying disease
Not hospitalized longer than
the mother
No immunizations < 48h
No antimicrobial < 48h
Not dehydrated
Physical
Exam
Well-appearing
Unremarkable exam
Well-appearing
No ear, soft tissue or bone
infection
Well-appearing
No ear, soft tissue, or
bone infection
Labs
(define
Lower
risk)
WBC<15,000
Band-neutrophil ratio<0.2
UA <10wbc/hpf
Urine gm stain: negative
CSF<8wbc
CSF gm stain: negative
CXR: no infiltrate
Stool: no RBC, no WBC
WBC 5,000-15,000
Absolute band <1500/mm3
UA<10wbc/hpf
Stool smeal <5WBC/hpf
WBC <20,000
CSF<10/mm3
UA<10wbc/hpf
CXR: no infiltrate

33. Three Most Common Strategies for
Managing Febrile Infants
Philadelphia Rochester Boston
Higher Risk
patients
Hospitalize +
Empiric antibiotics
Hospitalize+
Empiric antibiotics
Hospitalize+
Empiric antibiotics
Lower risk
patients
Home
No antibiotics
Follow-up required
Home
No antibiotics
Follow-up required
Home
Empiric antibiotics
Follow-up required
Reported
Stats
Sensitivity 98%
Specificity 42%
PPV 14%
NPV 99.7%
Sensitivity 92%
Specificity 50%
PPV 12.3%
NPV 98.9%
Sensitivity-not available
Specificity 94.6%
PPV-not available
NPV-not available

34. Criteria
In the first 2 strategies, the lower risk patients are
selected for outpatient therapy without antibiotics,
whereas the Boston strategy treats all patients with
empiric antibiotics but selects a smaller high-risk
population for hospitalization.

35. Criteria
 Philadelphia protocol and Rochester criteria:
 High NPV - 99.7% and 98.9%, respectively.
 Low PPV - 14% and 12% - large numbers of patients considered
higher risk and therefore hospitalized for antibiotics.
 Boston criteria - more cost-effective strategy
 Treating all with antibiotics
 Fewer patients require admission.

36. Rochester Criteria
 Indications
 Assessment of febrile child ages 60-90 days
 Reassures against serious infection
Jaskiewicz JA, Pediatrics 1994 Sep;94(3):390-6

37. Rochester Criteria
 Reassuring if all criteria are present
 Well appearing infant
 No skeletal, soft tissue, skin or ear infections
 Full term birth
 No prior illness
 No prior hospitalizations
 Not hospitalized longer than mother after delivery
 No prior antibiotics
 No Hyperbilirubinemia
 No chronic or underlying illness
 CBC normal
 WBC normal (5000 to 15,000/mm3)
 Band Neutrophils < 1,500/mm3
 Other Lab Findings
 If Diarrhea is present, Fecal WBC <5 per hpf
 Urine WBC <10 per hpf
Jaskiewicz JA, Pediatrics 1994 Sep;94(3):390-6

38. Rochester Criteria
 Occult bacteremia risk
Well-appearing febrile infant risk: 7-9%
All Rochester criteria present: <1%
Jaskiewicz JA, Pediatrics 1994 Sep;94(3):390-6

39. Management: 0 months to 3 months

40. Management: 3m to 36m

41. Empiric Treatment
 Generally avoid empiric treatment with anti-inflammatory
medications or antibiotics as an effort to diagnose the
patient’s condition.
 Empiric antibiotics can mask or delay diagnosis of
infections .
 Exceptions:
Nonsteroidal agents in children with presumed JIA
Patients who are clinically deteriorating
in whom bacteremia or sepsis is strongly suspected
Patients who are immunocompromised

42. Antibiotics
0-1 month:
Ampicillin
Gentamicin or Cefotaxime
1-2 months:
Ampicillin and Cefotaxime
Ceftriaxone (100mg/kg/day)
2m-36 months:
Ceftriaxone

43. Antivirals
 Acyclovir
 In patients 0-1 month
 20 mg/kg/dose three times daily
 Ill appearing
 Mucocutaneous vesicles
 Seizures
 Elevated LFT (disseminated infection)
 Send HSV antigen DFA (vesicles)
 HSV DNA PCR (CSF).

44. Antipyretics
Acetaminophen
15mg/kg/dose q4hours prn
temperature > 39oC (102.2 F)
Ibuprofen
10mg/kg/dose q6hours prn
temperature > 39oC (102.2 F)
Use in children 6 months or older

45. Antipyretics
 In children with baseline temperatures < 102.2°F -
both ibuprofen doses and acetaminophen are equally
effective.
 In those children with temperatures > 102.2°F, the
ibuprofen 10 mg/kg dose is more effective.
 It is superior in efficacy and length of anti-pyretic
effect that 5 mg/kg dose.
 Infants: Safety and efficacy of ibuprofen in < 6 months
has not been established

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