Fever in the newborn and infant

Moises Auron, MD FAAPPediatric Residency Program Noon Conference

8/21/2009

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.

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

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)


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


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

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

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)

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

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).

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

Yale Observation Scale

Bang A. Indian J Pediatr 2009; 76 (6) : 599-604.

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


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


Laboratory Data And InterpretationWBCNeutrophils / Bands / Acute-phase reactantsAntigen testingBlood culturesLumbar punctureUA/Urine cultureCXRStool Analysis and Culture

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

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

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

Antigen TestingStrep pneumoniaeH. influenzae type bPCR methods (HSZ, 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

consideredSeizures upon presentationIf empiric antibiotics are administered

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

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

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 infectionIf parent or guardian unsure of bowel habits, obtain stool

sample for guaiac and proceed if positive

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.

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.

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

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

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

Etiology of occult bacteremiaS. pneumoniae – 85%H. influenzae type b – 10%N. meningitidis – 3%Salmonella – 2%

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.

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).

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.

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

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


Rochester Criteria Occult bacteremia risk

Well-appearing febrile infant risk: 7-9%

All Rochester criteria present: <1%


Management: 0 months to 3 months

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

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

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

Management: 3m to 36m

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

Management: 3m to 36mToxic appearing febrile child

See Yale Observation ScaleAdmit to hospital Full rule-out sepsis workup Parenteral antibiotics

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

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

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


Step 2: Additional Studies

Stool Culture Indications Stool blood or mucus present Fecal WBC > 5/hpf


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


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


Step 5: Blood Culture or Urine Culture positive Admit if child febrile or toxic appearance Outpatient antibiotics if afebrile and well-appearing


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)Ibuprofen

10mg/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

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.

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:

Results:

P < 0.001

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.

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.

QuestionIt is RSV seasonDo we really need to do these work-ups?

Pediatrics. Aug 2003. 112(2): 282-284.

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.

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.

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.

Pediatrics. Aug 2003. 112(2): 282-284.

RR 0.09 [95% CI 0.02–0.38] P<0.0001

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.

Fever in the newborn and infant

Documents

y children

antibiotics y

y acrocyanosis

y mouth

y reaction

leukopenic y

y weak

y strong