Fever without a source and

related concepts

Fever 20% of pediatric emergency dept visits35% of ambulatory visits10% percent of febrile children have fever

without an apparent source of infection after history and physical examination.

Physiology Hypothalamus is the thermoregulatory center for the

bodyFever 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

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

Fever without a source (FWS)Children with fever lasting one week or less

without adequate explanation after a careful history and physical examination.

Definitions

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)

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.

Occult bacteremiais 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.

Etiology of occult bacteremia

S. pneumoniae – 85%H. influenzae type b – 10%N. meningitidis – 3%Salmonella – 2%

Differential Diagnosis of Fever Without FocusCommon 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)

GBSGram negative (E. coli, Kebsiella, Enterobacter cloacae, Salmonella)Listeria

Strep pneumoniae, H.influenza, N. meningitidis, Salmonella

Differential Diagnosis of Fever Without FocusCommon 0-3 months 3-36 monthsBacterial(UTI)

Gram negative organisms (E. coli , Klebsiella)

same

(other) meningitis Unlikely without signs

Differential Diagnosis of Fever Without Focus

Less common 3m-36 monthsConnective Tissue Diseases

Rheumatic fever, SLE, sarcoidosis, JRA,kawasaki

Malignancies Leukemia, Lymphoma, neuroblastoma, Ewing sarcoma

Poisoning Atropine, salicylates, cocaine, anticholinergics

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.

Diagnostic ApproachA careful history and physical is the first

step in evaluating a patient with fever of unknown origin.

HistoryFever : 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?!

Associated symptoms and behaviorsMedicationsEnvironmental exposuresSimilar symptoms in siblingsBirth and nursery history (STD, TORCH,

GBS, ROM) in infantsDate of last immunizations (MMR-fever

and rash 7-10 days afterwards)

Physical ExaminationToxic appearance (irritability, poor perfusion,

lethargy)SpO2 – better predictor of pulmonary infectionSigns of infection (omphalitis, arthritis,

cellulitis, herpes lesions)Meningitis – change in sleep pattern,

decreased feeding ,paradoxical irritability, bulging fontanelle (late sign).

Laboratory Data And InterpretationWBCNeutrophils / Bands Acute-phase reactantsAntigen testingBlood culturesLumbar punctureUA/Urine cultureCXRStool Analysis and CultureOther tests (KFT , LFT, etc) as indicated

WBCThere is direct relationship between

the WBC count and the prevalence of bacteremia

Temperature curve – not usefulCombination of temperature curve and

WBC curve offered no advantage over the WBC curve alone

Jaffe et al. Pediatrics 1991; 87:670

WBCLimitations

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

Neutrophils, Bands, ESRHave value in identifying children at risk

for serious illnessHigher the values, the greater the risk of

bacteremia

C – Reactive ProteinAcute phase reactant released by the

liver following inflammation or tissue damage.

High sensitivity but low specificityIncrease 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.

Procalcitonincutoff 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.

Antigen Testing

Strep pneumoniaeH. influenzae type bPCR methods (VZV, enterovirus)

Blood culturesGold standardFalse negatives

Prior treatment with antibioticsMissing an episode of bacteremiaInoculation of too little blood (<1ml) into the

media; too much blood may yield false negative due to ongoing killing of bacteria by neutrophils

False positivesImproperly cleaning the skin, resulting in

contamination with skin flora

LPIndicated if the diagnosis of sepsis or

meningitis is considered

UA/Urine cultureBest method if not toilet trained are

bladder catheterization or supra-pubic aspirationNOT BAG COLLECTION

OBTAIN IN ALL CHILDREN ON EMPIRIC ANTIBIOTICS

CXRChildren > 3 monthsOxygen Saturation <95% Respiratory distress TachypneaRales on lung auscultation Fever 39.5 C (103.1 F) or higher Asymptomatic with WBC >20,000

Stool Analysis and CultureImportant if diarrhea presentCan be considered a focus of infection

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.

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.

Philadelphia Rochester BostonAge 29-60d <60days 28-89d

Temp >38.2C >38C >38C

History Not specified Term infantNo perinatal AbxNo underlying diseaseNot hospitalized longer than the mother

No immunizations < 48hNo antimicrobial < 48hNot dehydrated

Physical Exam

Well-appearingUnremarkable exam

Well-appearingNo ear, soft tissue or bone infection

Well-appearingNo ear, soft tissue, or bone infection

Labs (defineLower risk)

WBC<15,000Band-neutrophil ratio<0.2UA <10wbc/hpfUrine gm stain: negativeCSF<8wbcCSF gm stain: negativeCXR: no infiltrateStool: no RBC, no WBC

WBC 5,000-15,000Absolute band <1500/mm3UA<10wbc/hpfStool smeal <5WBC/hpf

WBC <20,000CSF<10/mm3UA<10wbc/hpfCXR: no infiltrate

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

HomeNo antibioticsFollow-up required

HomeNo antibioticsFollow-up required

HomeEmpiric antibioticsFollow-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 availableSpecificity 94.6%PPV-not availableNPV-not available

CriteriaIn 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.

CriteriaPhiladelphia 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 antibioticsFewer patients require admission.

Rochester Criteria

Indications Assessment of febrile child ages 60-90 days Reassures against serious infection

Jaskiewicz JA, Pediatrics 1994 Sep;94(3):390-6

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

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

Management: 0 months to 3 months

Baraff LJ. Ann Emerg Med. 2000;36(6):602-614

Management: 3m to 36m

Baraff LJ. Pediatr Ann. 1993; 22(8): 497-8.

Empiric TreatmentGenerally 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

Antibiotics0-1 month:

AmpicillinGentamicin or Cefotaxime

1-2 months:Ampicillin and Cefotaxime Ceftriaxone (100mg/kg/day)

2m-36 months:Ceftriaxone

AntiviralsAcyclovir

In patients 0-1 month20 mg/kg/dose three times dailyIll appearingMucocutaneous vesiclesSeizuresElevated LFT (disseminated infection)Send HSV antigen DFA (vesicles)HSV DNA PCR (CSF).

AntipyreticsAcetaminophen

15mg/kg/dose q4hours prn temperature > 39oC (102.2 F)

Ibuprofen10mg/kg/dose q6hours prn

temperature > 39oC (102.2 F)Use in children 6 months or older

AntipyreticsIn 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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