a pediatric healthcare network a 21st century approach to fever in infants and young children james...

A pediatric healthcare network

A 21st Century Approach to Fever in Infants and Young Children

James M Callahan, MDDivision of Emergency Medicine

Department of PediatricsThe Children’s Hospital of Philadelphia

University of PennsylvaniaSchool of Medicine

DisclosuresDisclosures

• James M Callahan, MD

I have no relevant financial relationships to disclose or conflicts of interest to resolve.

This presentation will not involve discussion of unapproved or off-label, experimental or investigational use medications or devices.

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ObjectivesObjectives

• After this session, participants will be able to:– Discuss the bacteriology of serious infections in

children less than three months of age.

– Discuss the bacteriology of bacteremia in children 3 – 36 months of age.

– Discuss an approach to management of febrile infants less than 3 months of age.

– Discuss an approach to children 3 – 36 months of age with fever without a source in an era of widespread pneumococcal vaccination.

– Discuss the importance of urinary tract infections as a source of fever in young children.

Fever in Infants and Young ChildrenFever in Infants and Young Children

• Introduction• Fever in the First Three Months of Life• Fever in Children 3 – 36 Months of Age

– Occult Bacteremia– Urinary Tract Infections– Febrile Seizures

• Summary

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FeverScope of the ProblemFeverScope of the Problem

• Common presenting complaint in children

• 20% of pediatric visits to ED’s are for a chief complaint of fever; common “sick visit” complaint in offices

• The majority of these children are less than three years old

• Fever accompanies both minor and life – threatening infections

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Definition of FeverDefinition of Fever

• A rectal temperature of > 38°C in an appropriately dressed child at rest for 30 minutes.

• Life – threatening, infectious disease may be present in young infants without fever.

• Hypothermia in young infants is an ominous sign.

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Fever PhobiaFever Phobia

• The public, especially parents fear fever.• Rarely does fever itself cause problems.• Extreme fevers (T > 41.1°C or 106°F) are

more likely to result from environmental heat excess.

• Fever has an evolutionary role.• Fever’s significance and possible

beneficial role need to be explained.• It alerts us to an underlying illness to

diagnose and treat, if necessary.

Fever and antipyretic useFever and antipyretic use

• AAP Technical Report – 2011– Appropriate counseling for parents– Fever is not dangerous in healthy children– Fever may be a benefit– Fever is not the same as hyperthermia

– Sullivan JE, et al. Pediatrics 2011

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Fever and antipyretic useFever and antipyretic use

• AAP Technical Report – 2011– Goal of antipyretics – comfort

• Not normalizing temperature

• Acetaminophen and ibuprofen both safe and effective in appropriate doses

• Combination therapy not shown to be beneficial – may increase dosing errors

– Health care provider role: • Minimize “fever phobia”

• Emphasize monitoring for signs and symptoms of serious disease

– Sullivan JE, et al. Pediatrics 2011

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Fever:Management and ApproachFever:Management and Approach

• The management of fever depends on:– Severity of illness

– Age of the patient

– Focus of infection, if any

– Height of the fever

– Immune status of the patient

– Practice setting

Fever in the First Three Months: Usual PathogensFever in the First Three Months: Usual Pathogens

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• E. coli• Other gram negative

enterics• Group B

streptococcus• Lysteria

monocytogenes• H. influenzae type B

Fever in the First Three Months: EpidemiologyFever in the First Three Months: Epidemiology

• Infants have:– Higher rates of bacteremia and SBI.– Are less immunocompetent.– Unreliable physical examinations.

• 3 – 15% of febrile infants < 3 mo will have a SBI.• Academic standard of care has been a sepsis

work – up.• A septic appearing infant should prompt a broad

differential diagnosis.

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Fever in the First Three Months: History of FeverFever in the First Three Months: History of Fever

• An infant presents with a history of tactile or rectal fever at home and without antipyretics is now afebrile:– 0/26 of infants with a history of tactile

fever were febrile during hospitalization.

– 8/40 infants with history of rectal fever were febrile.

– 19/19 infants with SBI had an abnormal exam or abnormal lab values.

• Bonadio, et al. Pediatr Infect Dis J 1990.

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Management:Infants 0 – 28 Days OldManagement:Infants 0 – 28 Days Old

• All children < 29 d old should have a full sepsis workup with LP, be admitted to the hospital and receive parenteral antibiotics pending cultures.

• Labs and exam not good predictors (negative predictive value of only 88% at best)

• The LP is necessary.

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• Baskin, O’Rourke, Fleisher:– J Pediatr 1992

– Age 29 – 89 d; T > 38°c– Normal PE– Normal labs:

• CSF < 10 wbc• UA – negative L.E.• Normal CXR• WBC < 20k

– All given 50 mg/kg CTX IM and discharged.– Repeat exam and CTX in 24 h if culture

negative.

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• Baskin, O’Rourke, Fleisher:– J Pediatr 1992

• Results:– 503 patients

• 27 (5%) with SBI– 8 bacteremia– 1 UTI/bacteremia– 8 UTI– 10 bacterial gastroenteritis

– All subsequently treated and did well

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• Baker, Bell, Avner: – New Engl J Med 1993

– Age 29 – 56 days; T > 38.2°C.– Normal PE (I.O.S.).– Normal labs:

• WBC 5 – 15K; BNR < 0.2• UA < 10 wbc/hpf; < few bacteria• CSF < 7 wbc; normal GS, glc, pro• Normal CXR

– Randomized management.– Re – examined at 24 and 48 hours.

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• Baker, Bell, Avner:– New Engl J Med 1993

• Results:– 747 infants

• 1/65 with SBI had a negative screen• NPV 99% (95% C.I. 98 – 100)• $3300 – 5500 vs. $785

• Follow – up studies:– 420 infants – 0/43 with negative screen with SBI

– Baker, et al. Pediatrics 1999

• Reliable in a different population – Garra, et al. Acad Emerg Med 2005


• Baraff, et al.:– Ann Emerg Med 1993

• Meta – analysis and consensus guidelines• Low risk criteria:

– Previously healthy– No focal infection– WBC 5 – 15K– Bands < 1500– Normal UA– In children with diarrhea: stool wbc < 5/hpf

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• Baraff, et al.:– Ann Emerg Med 1993

• Option 1 – Low Risk Infants– Blood culture

– Urine culture

– LP

– CTX 50 mg/kg IM and recheck in 24 h

• Option 2 – Low Risk Infants– Urine Culture

– Careful observation

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Rochester: More than a city in Upstate New YorkRochester: More than a city in Upstate New York

• Criteria– No focal infection– 5,000 < WBC < 15,000– Absolute bands < 1,500– U/A < 10 wbc/hpf; stool < 5 wbc/hpf if diarrhea

• Results– NPV ~ 98% - original study and follow-up by same group

• Criticism – Pro and Con– No LP– 13 of 27 patients with SBI in another study missed– Recent report – new population NPV 97.3%

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Management:Young Infants with RSVManagement:Young Infants with RSV

• Titus, Wright. Pediatrics 2003– Retrospective, cohort– 174 infants < 8 w with RSV: 2 with SBI (UTI)– 174 infants < 8 w without RSV: 22 with SBI

• Conclusions– Risk of SBI in febrile infants with RSV seems

very low– Full sepsis evaluations probably not needed– Urine should be examined

Management:Young Infants with RSVManagement:Young Infants with RSV

• Levine, et al. Pediatrics 2004– 3 year, multicenter, prospective cross –

sectional study– T >38°C, age < 60d– RSV from nasal swabs, urine, blood,

CSF, stool culture– Yale Observation Score– Looked for signs and symptoms of

bronchiolitis

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Management:Young Infants with RSVManagement:Young Infants with RSV• Results

– 1248 patients• 269 (22%) with RSV• SBI 11.4% overall

– Rate of SBI: • RSV negative 12.5%• RSV positive 7.0%

– Bacteremia if RSV (+) 1.1%– No patient with RSV had meningitis

• RSV negative UTI 10.1% • RSV positive UTI 5.4%

– Prevalence of SBI is less in infants with RSV but SBIs are present, especially UTI

– Levine, et al. 2004

Management:Young Infants with InfluenzaManagement:Young Infants with Influenza

• Krief WI, et al. Pediatrics 2009– 3 year, multicenter, prospective cross –

sectional study– T >38°C, age < 60d– Influenza by rapid antigen detection and

urine, blood, CSF, stool culture– Yale Observation Score

• Results– Lower prevalence of SBI (2.5% vs.

13.8%) and UTI (2.4% vs. 10.8%) in children with influenza

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Fever in Children 3 – 36 Months of AgeFever in Children 3 – 36 Months of Age

• Cause usually found with a thorough history and physical.

• Most common diagnosis: viral URI.

• Other common causes: other viral illness, otitis, UTI, streptococcal pharyngitis, adenitis, cellulitis, pneumonia

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ToxicityToxicity

• Clinical picture consistent with sepsis syndrome (lethargy, poor perfusion, hypo- or hyperventilation, marked irritability or cyanosis).

• Lethargy – poor or absent eye contact, failure to recognize parents or interact with the environment.

• ALL febrile children who are toxic appearing should be hospitalized for evaluation and treatment of possible sepsis and/or meningitis with parenteral antibiotics.

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Fever in Children 2 – 6 months old (57 – 180d)Fever in Children 2 – 6 months old (57 – 180d)

• Hsiao, HL. Pediatrics 2006– Prospective study of patients 57 – 180 d, T > 37.9°C;

faculty member performed YOS– CBC, CRP, Blood culture, U/A, urine culture,

respiratory pathogens; CXR and LP at MD discretion

• Results– 429/448 (96%) eligible patients enrolled– 44/429 (10.3%) with SBI:

• 41 bacteruria• 4 bacteremia (1 with E. coli and bacteruria) • 3/4 normal YOS

– 0/58 LP positive for bacterial meningitis (7 pleocytosis)– SBI in 4.9% of patients with confirmed viral infection– WBC, ANC and CRP increased in patients with SBI– SBI common in this age group but mostly UTI

Occult BacteremiaOccult Bacteremia

• 4% of children brought to an urban, “walk – in” clinic with a T of > 38.3°C and no source of infection had unsuspected bacteremia.

– McGowan, et al. New Engl J Med 1973

• Similar rates found in other settings.• These children were well appearing.• Definition: a positive blood culture in a well

appearing febrile child.• This informed the approach to febrile infants

and toddlers for the last 30+ years

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Occult Bacteremia:Bacteriology - TraditionalOccult Bacteremia:Bacteriology - Traditional

Bacteria % of Bacteremia patients

% that develop invasive infection

S. Pneumoniae 50 – 60 4 – 5

H. Influenzae type B 20 – 30 20 – 50

N. meningitidis 10 – 20 25

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Occult Bacteremia – Epidemiology: Height of FeverOccult Bacteremia – Epidemiology: Height of Fever

Height of Fever % with bacteremia

> 39.4 3

> 40.0 6

> 40.5 13

> 41.1 26*

*Avner, Contemp Pediatr 1997

Occult Bacteremia:Effect of otitis mediaOccult Bacteremia:Effect of otitis media

• There is no difference in the prevalence of bacteremia based on the presence or absence of otitis media.

• Schutzman, et al. Pediatrics 1991

• There may be a decreased risk of invasive disease.

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Occult Bacteremia Bacteriology:That was then, this is now…Occult Bacteremia Bacteriology:That was then, this is now…

• > 90% S. pneumoniae– 149 pathogens:100 contaminants

• Rate of bacteremia 1.5%

• No H. influenzae type B– Lee, et al. Arch Pediatr Adol Med 1998

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Occult Bacteremia Bacteriology:That was then, this is now…Occult Bacteremia Bacteriology:That was then, this is now…• 1.9% bacteremia

• Approximately equal numbers of contaminants and pathogens

• No H. influenzae type B• Time to positive culture

– Pathogens 14.9h– Contaminants 31.1h– Culture that is positive in < 18h is thirteen

times more likely to be a true pathogen

» Alpern, et al. Pediatrics 2000.

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Occult Bacteremia Bacteriology:That was then, this is now…Occult Bacteremia Bacteriology:That was then, this is now…

• Widespread conjugate pneumococcal vaccine – rate of occult pneumococcal bacteremia < 1%

• Stoll, et al. 2004• Herz, et al. 2006• Carstairs, et al. 2007

• Marked decrease in invasive disease• Kaplan, et al. 2004• Kyaw, et al. 2006• Peters, et al. 2007

Patients at increased risk:ImmunodeficiencyPatients at increased risk:Immunodeficiency

• Sickle cell disease• Splenectomy (ITP, Hodgkin’s, hereditary

red cell defects, trauma)• HIV• Congenital immunodeficiencies• In – dwelling devices• Chemotherapy

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Occult Bacteremia:LaboratoryOccult Bacteremia:Laboratory

• WBC of < 10K has a NPV of 99.2%• WBC of > 15K increases the prevalence of

bacteremia to 10%• ANC of > 10K is the best single predictor

• Kupperman, et al. Ann Emerg Med 1997

• ESR and CRP are roughly equivalent and less available

• However, with such low prevalence, PPV of WBC > 15K is only 1.5 – 3.2%

• Stoll, 2004 and Herz, 2006

Occult Bacteremia:OutcomeOccult Bacteremia:Outcome

• Before 1990:– Untreated, 7% of patients could be

expected to acquire meningitis in older studies.

– Up to 20% of patients would acquire some invasive disease.

• Pathogen dependent!• H. influenzae type B was the real

problem

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Occult Bacteremia:Presumptive TherapyOccult Bacteremia:Presumptive Therapy

• Oral amoxicillin no better than placebo at preventing complications of occult bacteremia

– Jaffe, et al. N Engl J Med 1987

• Similar results with several other agents

• Meta – analysis suggests slight benefit for invasive complications except meningitis

– Rothrock, et al. Pediatrics 2000

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• Fleisher, et al. J Pediatr 1994– 6,733 patients

• 192 with positive blood culture

– Age 3 – 36 months– T > 39°C– Otitis media or no focal findings– All had blood cultures– Randomized to receive oral amoxicillin or IM

ceftriaxone

• 101 with positive blood culture received CTX

• 91 with positive blood culture received amoxicillin

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Invasive Infections in Children FollowingBacteremia – Interpretation 1

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Infection Ceftriaxone Amoxicillin

Meningitis 2* 3+

Pneumonia --- 1

Sepsis --- 1

Osteomyelitis 1 ---

Arthritis --- 1

Total 3 6


Invasive Infections in Children Following

Bacteremia – Interpretation 2

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Infection Ceftriaxone Amoxicillin

Meningitis* 4 2

Pneumonia --- 1

Sepsis --- 1

Osteomyelitis 1 ---

Arthritis --- 1

Sinusitis* 1 ---

Preseptal cellulitis* 1 ---

Total 7 5

Occult Bacteremia:Proposed ApproachOccult Bacteremia:Proposed Approach

• Meta – analysis and expert panel

• Included Fleisher’s results

• T > 39°C, nontoxic appearance– Urine culture: males < 6 mo; females < 2 y– CXR and stool culture if indicated– Option 1: Blood culture and CTX all children– Option 2: Blood culture and CTX if WBC > 15K

– Baraff LJ, et al. Ann Emerg Med, 1993

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Occult Bacteremia:Problems with Presumptive TherapyOccult Bacteremia:Problems with Presumptive Therapy

• Less thoughtful approach to febrile patients

• Potential adverse reactions• Treating large numbers of nonbacteremic

patients• Problems with contaminated cultures • Decreases reliability of subsequent

studies• Loss of clinical tools at reassessment• Antibiotic resistance!

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Occult Bacteremia:Positive Blood CulturesOccult Bacteremia:Positive Blood Cultures

• Recheck all patients

• Management depends on:– Organism

– Treatment at original visit

– Age of patient

– Persistence of fever

– Clinical appearance

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Occult Bacteremia:Pneumococcal VaccineOccult Bacteremia:Pneumococcal Vaccine

• Impact of heptavalent conjugate pneumococcal vaccine:– 97% of OB isolates covered; decreased OB at

least 90%– Children presenting with fever and no source:

• 0.3% will develop significant sequelae• Only 0.03% will develop meningitis

– Cost – effectiveness of approach depends on rate of bacteremia:

• 1.5 – 2.0% - CBC and selectively sending a blood culture/treating is the most cost – effective strategy

• 0.5% (about where we are), observation alone clearly becomes the most cost – effective

– New vaccine covering 13 serotypes now licensed and in use – what effect will this have?

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Warning Signs Recently SeenWarning Signs Recently Seen

• Rates of pneumococcal meningitis decreasing but increasing number of cases caused by serotypes not in the heptavalent vaccine.

• Hsu HE, et al. N Engl J Med 2009

• Recent outbreaks of invasive H. influenzae Type B disease.

• Rainbow J, et al. MMWR 2009

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Fever Without a Source:Urinary Tract InfectionsFever Without a Source:Urinary Tract Infections

• High rate of urinary tract abnormalities in young children with UTI.

• Fever and UTI in young children indicates the presence of upper tract disease.

• Case fatality rate of febrile UTI in young children in 1930: 33%.

• Renal scarring increases by 33% for every day of fever before antibiotics are started in children with UTI.

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• Shaw, et al. Pediatrics 1998:– 1560 patients with T > 38°C

• 82% of all children < 1 y• 82% of all females < 2 y

– Bladder catherization for urine culture

– Blood culture in all patients < 3 mo and all patients 6 – 24 mo with T > 39°C

– Positive urine culture defined > 104 CFU/ml

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Urinary Tract InfectionsResults – Shaw, 1998Urinary Tract InfectionsResults – Shaw, 1998

% (with 95% CI)

UTI – all patients 3.1 (2.3, 4.1)

UTI – Caucasian females 17.9 (10.6, 25.2)

Males 1.5 (0.7, 2.8)

Age 6 – 24 mo, T > 39°C 2.5 (1.6, 3,8)

Bacteremia 0.3 (0, 1.0)

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• Hoberman had similar results in an office – based study.

• Hoberman A, et al. Pediatr Infect Dis J 1997

• Prevalence of UTI not affected by diagnosis of OM

• Possible biologic explanation for high rates in Caucasian females.

• Best diagnostic tool a combination of the UA and urine Gram’s stain.

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Febrile SeizuresFebrile Seizures

• Children with simple febrile convulsions have rates of bacteremia similar to those with only fever.

• A simple, self – limited, febrile seizure alone is not indicative of meningitis, even in young children (6 – 18 mo.)

– Green SM, et al. Pediatrics 1993– Kimia AA, et al. Pediatrics 2009

• Lethargy is a better predictor of meningitis than seizure.

• Even isolated complex seizures rarely associated with acute bacterial meningitis

– Kimia A, et al. Pediatrics 2010

• AAP Guideline for Evaluation of SFS– Subcomm. of Febrile Seizures, Pediatrics 2011

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The Febrile Child 3 – 36 Months of Age: A 21st Century ApproachThe Febrile Child 3 – 36 Months of Age: A 21st Century Approach

• T > 39°C, no source or otitis media:– UA, GS and urine culture all females and all

males < 6 months (1 y ?)– CBC and CXR based on clinical judgment– Blood culture if T > 40° (in the ED)?– Treat only known, focal infections

• Role of practice setting• Good follow – up is the most important part of

management

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Fever in Infants and Young Children: SummaryFever in Infants and Young Children: Summary

• “Unfortunately, many practitioners have become reluctant to rely on clinical judgment, preferring diagnostic tests and frequent use of antibiotics…. We should resist the urge to use antibiotics empirically, especially in a patient who looks well, for whom antibiotics have not been shown clearly to be beneficial.”

– Stamos JK, Shulman ST. Lancet 1997

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Fever in Infants and Young Children: SummaryFever in Infants and Young Children: Summary

“Antibiotics are not antipyretics.”

Krug SE. SAEM 2002

Thank you!55

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