SJRH ED RoundsDec 11 2018By: Robin Clouston

The Febrile Infant

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Objectives• Discuss the risk of serious bacterial infection (SBI) in the

neonate or young infant (<90d) with fever

• Review current suggestions for the work up, management, disposition, and follow up in the care of neonates and young infants with fever

• Discuss the role of decision tools (ex: Rochester, Boston, Philadelphia) to aid in decision making for the well-appearing infant with fever

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Introduction• The febrile neonate (<28d) and young infant (<90d) are

commonly encountered in the emergency dept.

• Many will have a self limited, viral illness

• A small but significant proportion (up to 15%1 in some series) will have a serious bacterial infection (SBI)

• How to best assess and manage such infants has long been a matter of debate.

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Local context• No SJRH EM Guideline exists for the management of

neonatal fever

• Local variation in practice regarding:• Work up• Empiric management• Disposition• Follow up

• Recent clinical cases have highlighted this issue

• Forthcoming SJRH EM Guideline

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Burning questions…

• What IS the full septic work up?

• Which kids >30 days need blood work?

• Which kids >30 days need the LP?

• Can I avoid antibiotics in any of these kids?

• Which kids can I send home?

• Are there any harms to over-investigating and over-treating?

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Definitions• Neonate: 0 to 28d• Young Infant <90d

• Fever = rectal temp >/= 38.0C

• Serious bacterial infections (SBI) include2:• Bacterial meningitis, bacteremia, UTI, pneumonia• Some series: enteritis, cellulitis, abscess, osteomyelitis, septic joint

• Invasive Bacterial Infect (IBI)2

• Bacterial meningitis and bacteremia

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Rates of SBI• Many infants with fever have a self-limited viral illness

• Rates of serious bacterial infection3:• 3 to 28d: 13%• 29 – 56d: 9%• 90 days and younger: 7%• *in pre-pneumococcal vaccine era

• Prevalence is highest <2wk (25%)• UTI most common SBI, with prevalence 3 to 11%

• 1 – 2 % will have IBI4

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Common pathogensIn neonates < 28d, most common pathogens are1:• E. coli• Group B streptococcus• S. pnuemoniae• S. aureus• L. monocytogenes

• Also:• Herpes simplex virus• Respiratory syncytial virus• Enterovirus

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Work up of the toxic infant• Good consensus on management

• For infants ill appearing / toxic appearing, including5:• Lethargy• Poor perfusion• Cyanosis• Hypo or hyperventilation• Significant abnormalities in vital signs

à Full septic work up

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Work up of toxic infant“Full septic work up” always includes1,:

• CBC• Metabolic panel (routines)• Blood culture• Urinalysis with report of HPF (catheter specimen)• Urine culture• CSF cell count, glucose, protein• CSF fluid culture

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Work up of toxic infant• CXR 2-view

• only if respiratory symptoms present (tachypnea, hypoxemia, focal findings on exam)t6

• Respiratory panel for RSV if cough, rhinorrhea• Stool cultures if diarrhea• ALT / AST if considering HSV

• HSV testing if at risk: • < 21d, maternal hx, seizure, vesicles• Elevated AST, ALT, thrombocytopenia, CSF pleocytosis

• CRP?• Procalcitonin?

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Does every kid need the kitchen sink?• In the 1970s and 1980s, guidelines recommended a full

septic work up for all infants <90d4,7

• In 1980’s various groups derived Low-Risk Criteria for Management of Febrile Young Infants:

• Rochester Criteria• Philadelphia Criteria• Boston Criteria

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Rochester Criteria8

• Includes 0 to 60 days of age

• Inclusion:• Full term• Normal prenatal and post natal history• No post natal antibiotics• Well appearing• No focal infection

• Laboratory parameters defining low risk:• WBC 5000 to 15000• Bands < 1500• UA: <10 WBC/HPF• Stool < 5 WBC/HPF on smear (of obtained based on sx)

• Modified Rochester includes normal CRP

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Rochester Criteria8

• Treatment for high risk:• Hospitalize• Empiric antibiotics

• Treatment if low risk:• Home• 24h follow up required• No empiric antibiotics

• NPV: 98.9% (97.2 – 99.6)• Did not perform as well on series including infants > 60 days

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Philadelphia Criteria9

• Includes 29 – 56 days of age

• Inclusion:• Well-appearing• No focal infection

• Lab parameters defining low risk:• WBC < 15 000• Band: total neutrophil (I:T) ratio < 0.2• UA < 10 WBC / HPF• CSF: gram stain neg• CXR: no infiltrate (if obtained)• Stool: no blood, few or no WBC on smear (if obtained)

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Philadelphia Criteria9

• Treatment for high risk:• Hospitalize • Empiric antibiotics

• Treatment for low risk:• Home, if patient lives within 30 min of hospital• 24h follow up required• No empiric antibiotics

• NPV: 99% (99 – 100)

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Boston Criteria10

• Includes 28 – 89 days of age

• Inclusion:• No antibiotics within preceding 48h• No immunizations within preceding 48h• Well appearing• No focal infection

• Laboratory parameters defining low risk:• WBC < 20 000• UA: < 10 WBC / HPF• CSF: < 10 WBC/mm3

• CXR: no infiltrate (if performed)

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Boston Criteria10

• Treatment for high risk patients:• Hospitalize• Empiric antibiotics

• Treatment for low risk patients• Home if caregiver available by telephone• Empiric IM ceftriaxone 50mg/kg• Return for 24h follow up for second dose of IM/IV ceftriaxone

• NPV: 94.6% (92.2 – 96.4)

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Comparing the criteria• All have high NPVs• All have high sensitivity (92 to 97 %)• All have low specificity (40 to 55%)

• à Low Risk Criteria allow approximately 30% of patients to be treated safely without empiric antibiotic therapy

• à Rochester less invasive but not validated > 60 days

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Don’t forget HSV!• Most acquired in peripartum period, 90% < 21d1

• mean age of 14d

• Three types• Skin / Eye Mouth (SEM) • Central Nervous System• Disseminated

• Risk factors:• Maternal history • Seizure at presentation• Vesicles• CSF with pleocytosis• For disseminated disease: transaminitis, DIC, acidosis

• Treatment: high dose acyclovir (20mg/kg/dose q8h)

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What about suspected viral infections?• Enterovirus positive infants have low rates of co-

contaminant bacterial infection7

• Management may consist of supportive care alone

• Well-appearing, febrile, RSV positive infants are at decreased risk of SBI (7% vs 12.5%)12

• Notable risk for UTI (5.5%)• Low risk bacteremia (1.5%)• No cases meningitis• à Do perform urinalysis and culture, ?may avoid Abx and CSF

• …how this applies to suspected viral infections before viral panel results is lest clear...

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Procalcitonin (PCT)• Protein prohormone of calcitonin released by liver and

mononuclear cells 4h after tissue injury, peaks 6h after tissue injury, with sustained peak for 8 to 24 h

• In studies < 90d, favorable test characteristics compared to WBC and CRP

• Biggest challenge is threshold to define positivity• 0.13ng/mL – high sensitivity, low specificity• 0.5ng/mL – high specificity, inadequate sensitivity for SBI detection

• Most consistent cut off value reported• Sensitivity of 60% for SBI and 85% for IBI, specificity 85% for both

• Up and coming “Step-By-Step” approach?17

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Step By Step• Validation of “Step by Step” Approach in Management of of

Young Febrile Infants17 (Pediatrics Aug 2016)

üSuperior sensitivity to Rochester (92% vs 81%)üUp to age 90 days

• Considered low risk if:• not ill appearing• age > 21d• no WBC in urine• Procalcitonin <0.5• CRP <20 • ANC <10 000

• If meeting low risk criteria, infants are admitted x 24h without antibiotics and then discharged if still well-appearing.

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Antibiotic treatment:If infant toxic or decision to treat:

Less than 28d1:• Consider common pathogens:

• E. coli, Group B streptococcus, S. pnuemoniae, S. aureus, L. monocytogenes

• Cefotaxime 50 mg/kg IV OR Gentamicin 4mg/kg IV• AND Ampicillin 50mg/kg IV (for L. monocytogenes)• Add vancomycin if CSF pleocytosis• Add acyclovir 20mg/kg/dose q8h if <21d, toxic or high risk

for HSV

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Antibiotic treatment

29 to 60 days1

• Cefotaxime 50mg/kg OR Ceftriaxone 100mg/kg• May defer ampicillin (very low risk of L monocytogenes)• Add vanco if CSF Pleocytosis• Add acyclovir if high risk for HSV

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Antibiotic treatment

61 to 90 days1

• Cefotaxime 50mg/kg OR Ceftriaxone 100mg/kg• May defer ampicillin (very low risk of L monocytogenes)• Add vanco if CSF Pleocytosis

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Current controversies

• Many studies done in 1980’s and early 1990s4

• Before HiB (1987) and Pneumococcal vaccine (2000)• Before routine GBS prophylaxis in labour• Before CRP and procalcitonin available• Higher rates of circumcision compared to today

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Current controversies

• Significant variation in literature recommendations regarding work up of well-appearing neonate older than > 28d

• Is CSF > 28 days really necessary?• What about suspected viral infections?

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Current controversies

• Iatrogenic harms of over testing and over treatment are not well studied7

• Traumatic lumbar puncture• Antibiotic pre-treated CSF culture• Unnecessary antibiotic exposure• Radiation from x-rays• Phlebitis due to venipuncture injury• Hospitalization during a critical period of family bonding• Vulnerable child syndrome

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Some suggested management• Less than 28 days1:

• All get full septic work up regardless of appearance 1,5,14,15, 16:• CBC• Metabolic panel (routines)

• Blood culture• Urinalysis with report of HPF (catheter specimen)• Urine culture

• CSF cell count, glucose, protein• CSF fluid culture

• + HSV testing (vesicles, serum, CSF) if <21d or high risk• +/- CXR, RSV panel, stool culture only if indicated per sx

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Some suggested management• Less than 28 days1:

• ALL get empiric antibiotics:• Ceftaxime or Gentamicin• AND Ampicillin

• AND Acyclovir if < 21d or high risk for HSV

• AND Vancomycin if CSF pleocytosis or suspect meningitis

• Admit for IV antibiotics x 48 - 72h pending culture results

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Some suggested management• 28 to 60 days:

• Full septic work up if toxic appearing• Use corrected age for premature infants14

• May use Rochester Criteria • If high risk per criteria àFull septic work up (add CSF)

• Admit on IV Cefotaxime or Ceftriaxone pending culture results• If low risk per criteria:

• May discharge home without Abx + Follow up in 24h

• If decision to tx with antibiotics, conensus1,3,5 to also do LP• If well appearing and suspect bronchiolitis, may consider UA

only, but many guidelines recommend5,14,15,16 or “strongly consider”1 CBC, routines, blood cultures, +/- CRP

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Rochester Criteria8

• Includes 0 to 60 days of age

• Inclusion:• Full term• Normal prenatal and post natal history• No post natal antibiotics• Well appearing• No focal infection

• Laboratory parameters defining low risk:• WBC 5000 to 15000• Bands < 1500• UA: <10 WBC/HPF• Stool < 5 WBC/HPF on smear (of obtained based on sx)

• Modified Rochester includes normal CRP

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Some suggested management• 61 to 90 days:

• Full septic work up if toxic appearing• Use corrected age for premature infants14

• Rochester Criteria not well validated• Many existing guidelines do not include CSF (ex: NICE)

• Per NICE13, perform for all infants < 90d:• CBC, CRP, blood culture, urinalysis + culture• CXR only if resp sx present• Stool culture only if diarrhea

• Add CSF if high WBC• ??Step-By-Step

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Some suggested management• 61 to 90 days:

• If sx suggestive of bronchiolitis, some guidelines1,14

suggest deferring bloods and still do UA• Original study endorsed this strategy only for confirmed RSV12

• Admit if work up positive, ex:• WBC> 15000• UA with >10 WBC / HPF• CRP > 20 mg/L (2mg/dL)

• Start Abx pending neg cultures (Cefotaxime or Ceftriaxone)• If starting Abx, most guidelines recommend lumbar puncture

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Conclusions

• Many febrile infants have a viral infection

• Significant minority (up to 15%) have serious bacterial infection

• Cannot determine risk for SBI and IBI with Hx & P alone

• All toxic appearing infants need full septic work up, empiric

antibiotics, and admission

• Several Low Risk Criteria exist to aid in decision making

• Low specificity, often include recommendation for invasive testing

• Much variation in existing guidelines for management

• In absence of an accepting national or society guideline, best

approach is a thoughtful departmental guideline for the

management of neonatal fever

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Questions?

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Resources1. Aronson, PL. Evaluation of the Febrile Young Infant: An Update. EB medicine: Pediatric Emergency Medicine Practice. February 2013. from www.ebmedicine.net2. C Woll et al. Management of the Febrile Young Infant: Update for the 21st

Century. Pediatric Emerg Care. 2017 Nov: 33 (11):748-753.3. ACEP Clinical Policy for Well-Appearing Infants and Children Younger than 2 Years of Age Presenting to the Emergency Dept with Fever. Annals of Emergency Medicine. Vol 67, No. 5. May 2016.4. Jhaveri R. et al. Management of the Non-Toxic Appearing Acutely Febrile Child: A 21st Cetury Approach. The Journal of Pediatrics. August 2011. www.jpeds.com.5. Clinical Practice Guidelines for Febrile Infants. University of Iowa Stead Family Children’s Hospital. Updated 06/06/2017. Retrieved fr www.trekk.ca on Dec 2 2018. 6. Mintegi S et al. Occult pneumonia in Infants with High Fever Without Source: A prospective multicentre study. Pediatric Emergency Care 2010;26: 470 – 474. 7. Deporre AG et al. Facing the ongoing challenge of the febrile young infant. Critical Care (2017) 21:68.8. Jaskiewicz JA et al. Febrile Infants at low risk for Serious Bacterial Infection – An Appraisal of the Rochester Criteria and Implications on Management. Pediatrics Vol94. NO 3. Sept 1994.9. Baker MD et al. Outpatient Management without antibiotics of fever in selected infants. New England Journal of Medicine. 1993; 329(20):1437-1441.

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Resources10. Baskin MN et al. Outpatient treatment of febrile infants 28 to 89 days of age with intramuscular administration of ceftriaxone, Journal of Pedicatrics 1992:120(1):22-27.11. Huppler et al. Performance of Low risk criteria in the evaluation of young infants with fever: review of the literature. Pediatrics 2010: 125(2):228-233. 12. Lavine DA et al. 2004 Risk of Serious Bacterial Infection in Young Febrile Infants with Respiratory Syncytial Virus Infections. Pediatrics Vol. 113. No 6. June 2004.13. NICE Guideline. Fever in under 5 Years: Asessment and Initial Management. Published 22 May 2013. nice.org.uk/guideance/cg160. 14. Smitherman Hf et al. UpToDate: Febrile Infant Younger than 90 days of age: Outpatient evaluation. Retrieved Dec 6 2018 from www.uptodate.com.15. BC Children’s Hospital Febrile Infant Guideline. Retrieved Dec 2 2018 from www.trekk.ca. 16. Fever in Infants Less than 60 days Algorithm.. Children’s Hospital of Colorado. Updated February 2018. Retreived Dec 2 2018 from www.trekk.ca17. Gomez B et al. Validation of the “Step By Step” Approach in the Management of Young Febrile Infants. Pediatrics. Vol 138. Number 2. August 2016.

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