fever without a source in pediatrics
DESCRIPTION
Lecture on fever without a source in the newborn and the infant up to 3 months old.TRANSCRIPT
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Moises Auron, MD FAAPPediatric Residency Program Noon Conference
8/21/2009
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Fever 20% of pediatric emergency dept visits35% of ambulatory visits5%-10%-20% percent of febrile children have fever
without an apparent source of infection after history and physical examination.
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Fever 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
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FeverFever 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
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DefinitionsFever without focus is defined as the acute onset of fever
(rectal temp > 38C) in a child in whom no probable cause for the fever is evident after a careful history and physical examination
Other termsFever without sourceFever without localizing signs
Current Opinion in Pediatrics 2009, 21:139–144
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Fever Without Source Age under 36 months old Higher risk in younger infants Fever (38 C or 100.4 F) without localizing signs Acute onset of fever persisting <1 week Assess for occult bacteremia
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Occult bacteremiaPathogenic bacteria are present in blood culture No apparent focus of infection and no signs of sepsisCause serious bacterial illnesses (SBIs):
MeningitisSepsisBone and joint infectionsUrinary tract infectionsPneumoniaEnteritis
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Data CollectionHistory
Associated symptoms and behaviorsOnset and duration of feverDegree of temperature-method and anatomic siteMedicationsEnvironmental exposuresSimilar symptoms in siblingsBirth and nursery history (STD, TORCH, GBS, ROM)Date of last immunizations (MMR-fever and rash
7-10 days afterwards)
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Data collectionTemperature assessment- rectal temps best assess
core temperatureBundled infants- rectal temp >38C may not
attributable to bundlingFever by History at home who is afebrile on
presentation: manage as fever documented in acute care setting
General appearance-acute illness observation scaleResponse to antipyretics-may hinder ability to assess
the child
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Physical ExaminationSpO2 – better predictor of pulmonary infectionToxic appearance (irritability, poor perfusion, lethargy)Signs of infection (omphalitis, arthritis, cellulitis, herpes
lesions)Meningitis – change in sleep pattern, decreased po,
paradoxical irritability, bulging fontanelle (late sign). Use of Yale Observation Scale (McCarthy, 1980-1987).
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Yale Observation Scale Indications
Assessment of febrile child ages 3-36 months Predicts serious infection (Occult bacteremia) Quantifies "Toxic Appearance" in children
Interpretation Score = 10
Incidence of serious illness: 2.7% Score = 11-15
Incidence of serious illness: 26% Score >16
Incidence of serious illness: 92.3%
McCarthy. J Pediatrics. 1987. 110:36-30
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Yale Observation Scale
Bang A. Indian J Pediatr 2009; 76 (6) : 599-604.
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Yale Observation ScaleScoring
Quality of Cry Strong or No cry: 1 Whimper or Sob: 3 Weak cry, Moan, or high pitched cry: 5
Reaction to parents Brief Cry or Content: 1 Cries off and on: 3 Persistent cry: 5
State variation Awakens quickly: 1 Difficult to awaken: 3 No arousal or falls asleep: 5
McCarthy. J Pediatrics. 1987. 110:36-30
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Yale Observation ScaleColor
Pink: 1 Acrocyanosis: 3 Pale, Cyanotic, or Mottled: 5
Hydration Eyes, skin, and mucus membranes moist: 1 Mouth slightly dry: 3 Mucus Membranes dry, eyes sunken: 5
Social Response Alert or Smiles: 1 Alert or brief smile: 3 No smile, anxious, or dull: 5
McCarthy. J Pediatrics. 1987. 110:36-30
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Laboratory Data And InterpretationWBCNeutrophils / Bands / Acute-phase reactantsAntigen testingBlood culturesLumbar punctureUA/Urine cultureCXRStool Analysis and Culture
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WBCDirect relationship between the WBC count and the
prevalence of bacteremia3m to 36m
WBC >30,000 42.9% WBC 15,000-30,000 16.6% WBC 10,000-15,000 2.8% Below 10,000 no 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
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WBCLimitations
Up to 50% of children with Hib bacteremia will have WBC 5,000-15,000
Children with Neisseria meningitidis may be leukopenicNot predictive of bacteremia in infants < 8 weeks of age
Jaffe et al. Pediatrics 1991; 87:670
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Neutrophils, Bands, ESR, CRPHave value in identifying children at risk for serious
illnessHigher the values, the greater the risk of bacteremiaNo clearly demonstrated advantage over the WBC
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Antigen TestingStrep pneumoniaeH. influenzae type bPCR methods (HSZ, VZV, enterovirus)
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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
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LPIndicated if the diagnosis of sepsis or meningitis is
consideredSeizures upon presentationIf empiric antibiotics are administered
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UA/Urine culture20% of children with UTI have a normal UA based on a
negative reagent stripInfants < 8w with UTI – 50% will have normal UABest method if not toilet trained
Bladder catheterization or supra-pubic aspirationNOT BAG COLLECTION
OBTAIN IN ALL CHILDREN ON EMPIRIC ANTIBIOTICS
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CXRRespiratory signs or symptoms are good predictors of
clinically significant positive CXR findings in the group under 2 months of ageSensitivity 93%Specificity 73%
Crain et al. Pediatrics 1991; 88:821
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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
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Stool Analysis and CultureImportant if diarrhea presentCan be considered a focus of infectionIf parent or guardian unsure of bowel habits, obtain stool
sample for guaiac and proceed if positive
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C – Reactive ProteinAcute phase reactant released by the liver following
inflammation or tissue damage.Wide range of sensitivity and specificity that vary by
cutoff levels.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.
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Procalcitonin2 observational studies (N=505) cutoff value 0.12 ng/mL
to detect SBISensitivity 95-96% (95% CI 83-99 percent)Specificity 23-26% (95% CI 20-32 percent)NPV 96% (95% CI 85-99 percent)
Caveats: limited availabilityVariation in results by age, type of infection, and pathogen
Maniaci, et al. Pediatrics. 2008 Oct;122(4):701-10. Dauber, et al. Pediatrics. 2008 No5;122(4):e1119-22.
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Differential Diagnosis of Fever Without FocusCommon 3-36 months 0-3 months
Viral Enterovirus, parainflueza, adenovirus, RSV, CMV, roseola, PV, influenza
Same + HSV
Bacterial(occult bacteremia)
Strep pneumoniae, H.influenza, N. meningitidis, Salmonella
Same + GBSGram negative (E. coli, Kebsiella, Enterobacter cloacae, Salmonella)Listeria
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Differential Diagnosis of Fever Without FocusCommon 3-36 months 0-3 months
Bacterial(UTI)
Gram negative organisms (E. coli, Klebsiella)
Same
(other) Unlikely without signs meningitis
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Differential Diagnosis of Fever Without Focus
Rare 3m-36 months
Connective Tissue Diseases
Rheumatic fever, SLE, sarcoidosis, JRA
Malignancies Leukemia, Lymphoma, neuroblastoma, Ewing sarcoma
Poisoning Atropine, salicylates, cocaine, anticholinergics
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Etiology of occult bacteremiaS. pneumoniae – 85%H. influenzae type b – 10%N. meningitidis – 3%Salmonella – 2%
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Fever Without SourceThe 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.
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Fever Without SourceFebrile infants and young children have, by tradition,
been arbitrarily assigned to different management strategies by age group: neonates (birth to 28 days)young infants (29 to 90 days)older infants and young children (3 to 36 months).
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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.
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Philadelphia Rochester Boston
Age 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
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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
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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.
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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.
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Rochester Criteria
Indications Assessment of febrile child ages 60-90 days Reassures against serious infection
Jaskiewicz JA, Pediatrics 1994 Sep;94(3):390-6
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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
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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
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Management: 0 months to 3 months
Baraff LJ. Ann Emerg Med. 2000;36(6):602-614
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Management: 0 months to 3 months Age <1 month old Admit for assessment for Neonatal Sepsis
Age >1 month old Evaluate Rochester Criteria for Febrile Infants Rochester Criteria suggests low risk patient
Evaluation Blood Culture Urine Culture Consider Lumbar Puncture
Normal WBC Count does not rule-out Meningitis
Bonsu. Ann Emerg Med. 1993, 41:206-14
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Management: 0 months to 3 months Management Option 1
Ceftriaxone 50 mg/kg IM x1 dose Re-evaluate infant within 24 hours
Management Option 2 Observe inpatient without antibiotics
Rochester Criteria suggests high risk patient Admit for assessment for Neonatal Sepsis
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Management: 3m to 36m
Baraff LJ. Pediatr Ann. 1993; 22(8): 497-8.
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Management: 3m to 36mToxic appearing febrile child
See Yale Observation ScaleAdmit to hospital Full rule-out sepsis workup Parenteral antibiotics
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Non-toxic child with fever <39.0 C (<102.2 F) Avoid further diagnostic tests or antibiotics Fever Symptomatic TreatmentCareful examination to rule out serious infection
PneumoniaAbscess Cellulitis or ImpetigoAcute SinusitisOtitis MediaOsteomyelitisLymphadenitis Streptococcal Pharyngitis or Scarlet Fever
Re-evaluation criteria Fever persists longer than 48 hours Condition deteriorates
Management: 3m to 36m
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Non-toxic 3m-36m child with fever >38.9 C (>102.1 F)
Step 1: Evaluate Urine Obtain Urine LE and Nitrite or UrinalysisUrine Culture in all patients on empiric antibiotics
(2001)Urine screening positive (LE and nitrite on UA)
Outpatient oral 3rd generation Cephalosporin
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Step 2: Additional Studies Chest Roentgenogram Indications
Oxygen Saturation <95% Respiratory distress TachypneaRales on lung auscultation Fever 39.5 C (103.1 F) or higher Asymptomatic with WBC >20,000
Non-toxic 3m-36m child with fever >38.9 C (>102.1 F)
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Step 2: Additional Studies
Stool Culture Indications Stool blood or mucus present Fecal WBC > 5/hpf
Non-toxic 3m-36m child with fever >38.9 C (>102.1 F)
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Step 3: Consider Antibiotic Indications to skip to Step 4 below (no antibiotics)
Pneumococcal Conjugate Vaccine received Temperature under 39.5 C (103.1 F)
Obtain Complete Blood Count (and hold Blood Culture) Antibiotics
Indications White Blood Cell Count >15,000 Consider for White Blood Cell Count <5000 Absolute Neutrophil Count (ANC) > 10,600
Protocol Send Blood Culture Ceftriaxone 50 mg/kg/day (max: 1 g) Re-evaluate within 24 to 48 hours
Non-toxic 3m-36m child with fever >38.9 C (>102.1 F)
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Step 4: Instructions Follow-up
Return within 24 hours if antibiotics started Return in 48 hours indication
Fever persists Condition deteriorates
Home management Observe for toxic appearance Fever Symptomatic Treatment
Non-toxic 3m-36m child with fever >38.9 C (>102.1 F)
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Step 5: Blood Culture or Urine Culture positive Admit if child febrile or toxic appearance Outpatient antibiotics if afebrile and well-appearing
Non-toxic 3m-36m child with fever >38.9 C (>102.1 F)
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Antibiotics0-1 month:
AmpicillinGentamicin or Cefotaxime
1-2 months:Ampicillin and Cefotaxime Ceftriaxone (100mg/kg/day)
2m-36 months:Ceftriaxone
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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).
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AntipyreticsAcetaminophen
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
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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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Lumbar PunctureDoes my child really need a lumbar puncture?Could you wait and see if his WBC count is high?I really don’t want my child to have a LP.
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Logistic regression modeling and ROC analysis of peripheral blood WBC count and cerebrospinal fluid WBC count for results obtained from 3- to 89-day-old infants undergoing a full sepsis evaluation.
Methods:
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Results:
P < 0.001
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Results:Twenty-two of 5,353 (4.1 per 1,000) infants had acute
bacterial meningitis. For diagnosing acute bacterial meningitis, the peripheral
blood WBC count was poorly discriminating and significantly inferior to the cerebrospinal fluid WBC count.
This was true both when the odds of meningitis were modeled to vary linearly and as a U-shaped function of the peripheral blood WBC count.
When relying on single and interval-based high-risk thresholds of peripheral blood WBC counts alone, the majority of infants with acute bacterial meningitis would have been missed.
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Conclusions:
Decisions to perform or withhold lumbar puncture should not be based on prevailing interpretations of the total peripheral blood WBC counts to maximize detection of bacterial meningitis in young infants.
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QuestionIt is RSV seasonDo we really need to do these work-ups?
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Pediatrics. Aug 2003. 112(2): 282-284.
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ObjectiveNeonates with fever generally undergo a full, invasive
septic evaluation to exclude serious bacterial infection (SBI).
The risk of SBI in febrile older infants and children with documented respiratory syncytial virus (RSV) infection has been found to be negligible.
Pediatrics. Aug 2003. 112(2): 282-284.
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Objective:Investigate the prevalence of SBI in febrile infants < 8 wk
and had documented RSV infection and compare the risk of SBI with control subjects who were febrile and RSV-negative
Pediatrics. Aug 2003. 112(2): 282-284.
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MethodsRetrospective cohort study Infants < 8 wk Presented with documented fever to the EROctober - April x 4-year period. RSV-positive cases were gender- and age-matched to
febrile RSV-negative control subjects (N=174 each)Clinical characteristics and the rate of SBI were
compared between the 2 groups.
Pediatrics. Aug 2003. 112(2): 282-284.
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Pediatrics. Aug 2003. 112(2): 282-284.
RR 0.09 [95% CI 0.02–0.38] P<0.0001
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Conclusions:Full septic evaluations are not necessary in nontoxic-
appearing infants with a positive RSV test. It seems prudent to examine the urine in these
infants, as there is a clinically relevant rate of urinary tract infection.
Pediatrics. Aug 2003. 112(2): 282-284.