Management of the Febrile Young Infant in 2019 Paul L. Aronson, MD Associate Professor of Pediatrics and of Emergency Medicine Section of Pediatric Emergency Medicine Yale School of Medicine

Disclosures I have no conflicts of interest or relevant financial relationships to disclose My research supported by: NCATS/NIH CTSA grant number KL2 TR001862 AHRQ grant number 1K08HS026006-01A1

Objectives Compare the modified Philadelphia criteria, Step-by-Step approach, and PECARN prediction rule Interpret the evidence for routine vs. selective lumbar puncture in febrile infants ≤60 days of age

Definitions Fever Young infant Serious Bacterial Infection (SBI) Rectal temp ≥38.0 C (100.4 F) Young infant <90 days old (many use ≤60 days) Neonate: ≤28 days old Serious Bacterial Infection (SBI) UTI Bacteremia and/or bacterial meningitis (i.e., invasive bacterial infection [IBI]) Full “workup” Urine, Blood, CSF

Fever in the Young Infant ~ 160,000 febrile infants ≤60 days of age evaluated each year in an emergency department (ED) Wier LM et al. HCUP 2006; Baskin MN. Pediatr Ann 1993; Aronson PL et al. Pediatrics 2014 ~ 10% will have a bacterial infection Up to 20% in neonates ≤28 days old Huppler AR et al. Pediatrics 2010; Schwartz S et al. Arch Dis Child 2009 Most bacterial infections are Urinary Tract Infection (UTI) Vast majority identified by urinalysis (positive leukocyte esterase or nitrites, or >5 WBC/hpf) Risk of adverse outcome low Huppler AM et al. Pediatrics 2010; Tzimenatos L et al. Pediatrics 2018; Schnadower D et al. Pediatrics 2010

Invasive Bacterial Infection Bacteremia and/or Bacterial Meningitis E. Coli, GBS, S. aureus, Enterococcus, other gram+/gram- Powell EC et al. Ann Emerg Med 2018; Woll C et al. J Pediatr 2018 Prevalence ~ 2% among febrile infants Greenhow TL et al. Pediatrics 2012; Greenhow TL et al. Pediatr Infect Dis J 2014; Powell EC et al. Ann Emerg Med 2018 Risk of mortality and neurologic morbidity if untreated de Louvois J et al. Eur J Pediatr 2005; Tsai MH et al. Pediatr Infect Dis J 2014 Clinical appearance or individual laboratory tests not sensitive indicators for IBI Baker MD et al. Pediatrics 1990; Hui C et al. Evid Rep Technol Assess (Full Rep) 2012; Nigrovic LE et al. Pediatrics 2017

Newer Algorithms to Risk Stratify Febrile Infants Classify febrile infants as “low-risk” or “not low-risk” Do not include routine cerebrospinal fluid testing for risk stratification

Modified Philadelphia criteria   Low Risk Factors Age Cutoff 29-56 days Past Medical History Previously healthy Clinical Appearance Well-appearing Physical Examination No skin or soft tissue infection Laboratory Normal Urinalysis WBC ≥5,000 and ≤15,000 I:T Ratio <0.2 Low-risk All of the above present

Step-by-Step Approach   Low Risk Factors Age Cutoff >21 days Clinical Appearance Well-appearing Laboratory No leukocyturia PCT <0.5 ng/mL CRP ≤20mg/L ANC ≤10,000/mm3 Low-risk All of the above present

PECARN Prediction Rule   Low Risk Factors Age Cutoff None Past Medical History No chronic condition or prematurity Clinical Appearance Not Critically ill Physical Examination No skin or soft tissue infection Laboratory Normal Urinalysis ANC ≤4,090/mm3 PCT ≤1.71 ng/mL Low-risk All of the above present

Performance Characteristics of Risk Stratification Algorithms for IBI Overall Sensitivity (95% CI) Specificity Modified Philadelphia Criteria 29-56 days; Non-low risk if ≤28 days 91.9% (85.9-95.9) 34.5% (28.6-40.8) Step-by-Step Approach ≤90 days; Non-low risk if ≤21 days (? ≤28 days) 92.0% (84.3-96.0) 46.9% (44.8-49.0) PECARN Prediction Rule ≤60 days 96.7% (83.3-99.4) 61.5% (59.2-63.9) Infants who had an EV PCR test performed had a similar age distribution to infants without an EV PCR test. Gomez et al. Pediatrics 2016; Aronson et al. Pediatrics 2018; Kuppermann N et al. JAMA Pediatr 2019

Performance Characteristics of Risk Stratification Algorithms for IBI Overall Sensitivity (95% CI) Specificity Modified Philadelphia Criteria 29-56 days; Non-low risk if ≤28 days 91.9% (85.9-95.9) 34.5% (28.6-40.8) Step-by-Step Approach ≤90 days; Non-low risk if ≤21 days (? ≤28 days) 92.0% (84.3-96.0) 46.9% (44.8-49.0) PECARN Prediction Rule ≤60 days 96.7% (83.3-99.4) 61.5% (59.2-63.9) Infants who had an EV PCR test performed had a similar age distribution to infants without an EV PCR test. Gomez et al. Pediatrics 2016; Aronson et al. Pediatrics 2018; Kuppermann N et al. JAMA Pediatr 2019

Performance Characteristics of Risk Stratification Algorithms for IBI Overall Sensitivity (95% CI) Specificity Modified Philadelphia Criteria 29-56 days; Non-low risk if ≤28 days 91.9% (85.9-95.9) 34.5% (28.6-40.8) Step-by-Step Approach ≤90 days; Non-low risk if ≤21 days (? ≤28 days) 92.0% (84.3-96.0) 46.9% (44.8-49.0) PECARN Prediction Rule ≤60 days 96.7% (83.3-99.4) 61.5% (59.2-63.9) Infants who had an EV PCR test performed had a similar age distribution to infants without an EV PCR test. Gomez et al. Pediatrics 2016; Aronson et al. Pediatrics 2018; Kuppermann N et al. JAMA Pediatr 2019

Performance Characteristics of Risk Stratification Algorithms for IBI Overall Sensitivity (95% CI) Specificity Modified Philadelphia Criteria 29-56 days; Non-low risk if ≤28 days 91.9% (85.9-95.9) 34.5% (28.6-40.8) Step-by-Step Approach ≤90 days; Non-low risk if ≤21 days (? ≤28 days) 92.0% (84.3-96.0) 46.9% (44.8-49.0) PECARN Prediction Rule ≤60 days 96.7% (83.3-99.4) 61.5% (59.2-63.9) Infants who had an EV PCR test performed had a similar age distribution to infants without an EV PCR test. Gomez et al. Pediatrics 2016; Aronson et al. Pediatrics 2018; Kuppermann N et al. JAMA Pediatr 2019

Bottom Line No algorithm is 100% sensitive for IBI Be cautious in neonates ≤28 days of age If low-risk, need to ensure close PCP f/u within 24 hours and provide clear and detailed discharge instructions Yale: Most now use the Step-by-Step approach Procalcitonin results available in as little as 1 hour But….what about the lumbar puncture?

Prevalence of Meningitis in Low-risk Infants ? 0% But….this is an imprecise estimate Modified Philadelphia: 17 infants with meningitis (but 26 others who were ill-appearing) Step-by-Step: 10 infants with meningitis PECARN: 10 infants with meningitis Be very cautious in neonates ≤28 days

Decision on Lumbar Puncture is a Scale…. Low prevalence of bacterial meningitis Downsides of lumbar puncture Bacterial meningitis is bad Lumbar puncture is “safe”

Two viable management options for low-risk infants in the ED 1) Lumbar puncture +/- hospitalization 2) No lumbar puncture and discharge home (No lumbar puncture and hospitalize off antibiotics) Risk/benefit ratio uncertain Should incorporate parents’ values and preferences Shared-decision making process recommended by Institute of Medicine, American Academy of Pediatrics

The Big Caveat for General EM Providers Err on the side of caution If you are not comfortable with “well-appearance” for a young infant, do the lumbar puncture (or transfer to pediatric ED) If you cannot guarantee outpatient follow-up, have a low threshold to do the lumbar puncture and admit

Questions and Discussion