Fever PALS April 24, 2017 Good afternoon and thank you for the opportunity to talk today about the management of febrile young infants. The further along in my career I am, the more I have come to appreciate the significant practice variation that still exists around this common clinical conundrum. Hopefully, a review of the literature might be useful, if not to decrease that variation, at least to assure that the decisions we make individually are based on a solid foundation of evidence.

Overview < 28 days and 28 to 60 days Bronchiolitis UTIs Pharyngitis AOM

Epidemiology 5-9% 2-3% 0-2.1% 8.7-13% 3-6% 1-2% 0.1-1% 6-10% 3-12% UTI Bacteremia Meningitis Any SBI To 1 month 5-9% 2-3% 0-2.1% 8.7-13% 1-3 months 3-6% 1-2% 0.1-1% 6-10% 3-36 months 3-12% 0.2-0.7% 0.06-0.1% 6-13% In order to develop an evidence based approach, we all need to be on the same page as to the scope of the problem. At the center of the challenge highlighted by the index cases, is this: in febrile young infants, what is the risk for serious bacterial illness, and how do we identify those with SBI vs. those with viral illness? This slide is a composition derived from a number of large studies and attempts to reflect the changing epidemiology. Starting on the far right column, you can see that the risk for any serious bacterial illness is nearly constant across age groups. Importantly, however, from birth through early childhood, the proportion of SBI that reflects meningitis and bacteremia decreases with advancing age, and the vast majority of SBI in infants beyond 3 months are located in the urinary tract, obviating the need for blood or CSF cultures. Looking more specifically at neonates now, the prevalence of SBI is approximately 12% among febrile, well appearing neonates without a focus on history or physical exam. Bacteremia occurs in 2-3%, and meningitis may occur in as many as 2.1% of this population depending on the study.

Epidemiology Evolving epidemiology with GBS prophylaxis - Escherichia coli 56% of positive Bcx - Group B Streptococcus 21% of positive Bcx - Staphylococcus aureus 8% of positive Bcx - Listeria monocytogenes 0% of positive Bcx Consider HSV Though the incidence of bacteremia and meningitis have decreased with the introduction of common immunizations such as HiB and pneumococcus, it has changed very little in the neonatal population, with bacteremia rates remaining at approximately 2.2%. The microbiology of bacteremia, however, has evolved as a result of GBS prophylaxis. In a retrospective study of 4255 neonates in California, this is the breakdown of true positive blood cultures: E. Coli comprised more than half, while GBS, which used to be the predominant organism, no represents only 21%. Staph aureus has emerged in a small proportion, and there were no cases of listeria. There was one case of enterococcus bacteremia. Greenhow TL, et al. Pediatrics (2012); 129:e590-6.

Neonates High(er) risk: Risk Stratification? Prevalence Pathogens Immunity Unreliable exam / tests Risk Stratification? Rochester, Philadelphia, Boston Not helpful < 28 days So how should we manage the febrile neonate? Neonates are clearly at higher risk than older infants for bacteremia and meningitis; the bacteriology includes more invasive pathogens, and the immature immune system allows for systemic infection. Physical exam and history are unreliable due to the limited reflexive repertoire of neonates and add little to our ability to make clinical determinations of SBI. So what about risk stratification rules? We will now review three algorithms that have excellent sensitivity and negative predictive value in identifying infants at low risk for SBI, the Rochester, Philadelphia, and Boston criteria. Do these strategies work for neonates?

Neonates Schwarz et al. Arch Dis Child. Oct, 2009 No. This study by Schwarz and colleagues took a week-by-week approach to risk stratification. The blue line shows the prevalence of SBI by week of life while the red line shows the rates of SBI among infants who would be classified as low risk. As you can see, across the entire neonatal period, LR stratification rules would miss a significant number of SBI. Schwarz et al. Arch Dis Child. Oct, 2009

Neonates Summary: Risk stratification inaccurate Full Septic Work-up Empiric antibiotics Ampicillin AND Gentamicin or Cefotaxime Consider Acyclovir As a result, the approach to febrile neonates, at least in academic centers and Eds, is a full “septic work up” including blood, urine, and CSF Along with admission and empiric antibiotics until cultures are final.

Infants 1-2 Months Lower risk of SBI compared to neonates (6% vs 12%) Battle of the East Coast: Rochester vs. Philadelphia vs. Boston Admit or Discharge? As shown previously, the risk of SBI in the 1 to 3 month age group is lower than in the less than 1 month group, however it is not negligible. As just reviewed, it is not possible to delineate the high risk from low risk infants in the under 1 month of age group. However we will review how physical examination and risk stratification rules fare in this older group

Rochester Criteria Rochester Low Risk Criteria (<60 days) Well appearing, term, no evidence of skin/skeletal/ear infection Blood WBC 5,000-15,000/mm3 band neutrophils < 1,500/mm3 Urine < 10 WBC/hpf Stool (if diarrhea present) < 5 WBC/hpf Caveats: Full term birth, no prior illness (hospitalizations, antibiotics, hyperbilirubinemia, chronic or underlying illness).

Philadelphia Criteria Philadelphia Low Risk Criteria (29-56 days) Well appearing Blood WBC < 15,000/mm3 and Band:neutrophils < 0.2 Urine < 10 WBC/hpf and few or no bacteria on U/A Stool (if diarrhea present) Few or no WBCs Chest x-ray No evidence of pneumonia CSF < 8 WBC/hpf and no bacteria on gram stain

Boston Criteria Boston Low Risk Criteria (1-3 months) Well appearing, no soft tissue/skeletal/ear infection Blood WBC < 20,000/mm3 Urine < 10 WBC/hpf or negative leukocyte esterase Chest x-ray (if performed) No evidence of pneumonia CSF < 10 WBC/hpf and no bacteria on gram stain Low Risk: IM Ceftriaxone (50mg/kg) and home.

Performance of Low Risk Criteria Infants 1-2 months with fever: Meningitis 0.4% serum WBC and blood culture not predictive: 41% have normal CBC Rochester Philadelphia Boston Rates of SBI in low-risk patients (%) 1.1 0 to 0.3 5.4 Rochester criteria: Prospectively enrolled patients, 437 classified as low risk. 5 cases of SBI missed (1.1%), 2 bacteremia, 3 UTI. Philly: 747 prospectively enrolled patients between 29-56 days. All 65 patients with SBI identified as high risk (one caught by Band:Neutrophil) and all 287 low risk identified as such. F/U study - 101 Low risk infants, no case of SBI. Boston: 476 low risk patients prospectively enrolled, 27 with SBI (5.4%, 8 bacteremia, 8 UTI, 1 B+U, 10 GE) Baker MD, et al. N Engl J Med 1993; 329(20):1437-41. Baskin MN, et al. J Pediatr 1992; 120(1): 22-7. Bonsu BM, Harper MB. Ann Emerg Med 2003; 41: 206-14. Jaskiewicz JA, et al. Pediatrics 1994; 94(3): 390-6.

Summary Febrile infants between 1 and 2 months (w/o source) UA, Ucx, CBC, BCx Strongly consider LP Low risk: discharge home with close follow-up (+/- Abx) High risk or identified source: Abx for all Inpatient <2 months, consider outpatient tx for UTI > 2 months Because both the Rochester and Philadelphia criteria demonstrated a NPV of 99% or greater, all infants should have urine and blood investigations performed. However the NPV of the Phiadelphia criteria approached an NPV of 100%, and therefore a LP should be strongly considered in infants that are between 1 and 2 months of age.

Febrile Infant with Viral Illness Does a confirmed viral infection change management? Neonates? 1 to 2 months? Now that we have reviewed the literature and controversy in management of the infants without a source, how does a clear viral source influcence our practice? Specifically does it alter the management of infants less than one month of age, and does it alter infants between 1 and 3 months of age?

Febrile Infant with RSV RSV + Bacteremia All were under 28 days of age (9, 10, and 19 do) None in 1 to 2 month age group 2 patients did not have URI or wheezing 1 patient had retractions Of the children who had clinical bronchiolitis (rather than a diagnosis of RSV via NPW), there were no cases of bacteremia or meningitis. All children with confirmed RSV and bacteremia were under 1 month of age. The only SBI in children over 1 age of months with RSV was urinatry tract infections.

Febrile Infant Viral Source SBI in febrile infants 1-90 days Source of Infection Virus + Virus - All SBI 4.2% 12.3% UTI 3.2% 8.9% Bacteremia 1% 2.7% Meningitis 0% 0.67% When the results of al viruses are combined, rates of meningitis are negligible, and the rate of bacteremia siginificantly decreases. Unfortunately the authors do not identify the ages of the patients who ended up having bacteremia.

Febrile Infant with Viral Source Neonates FSW (urine, bloodwork, LP) Antibiotics Admission (also for apnea monitoring if RSV+) Between 1 and 2 months Test urine If U/A abnormal, send BCx and initiate antibiotics Though there were no cases of meningitis, we have insufficient evidence to support not doing the LP in the under 1 month of age group, as in the Levine study there was no statistically significant difference between the two groups. This may change as we continue to research this topic further. In the 1 to 3 month age group, the rates of UTI are not negligible, and a urine should be performed. In addition to this, blood cultures should be considered as well, as the risk of bacteremia may be 1% or less.

Febrile Infant after Immunizations NRI (%) Bacteremia 0.9 UTI 2.8 5.7 Meningitis 0.2 Pneumonia 0.4 Overall SBI 7.1 Prevalence of fever after immunizations is 27%. Does this mean that every child post-2 month immunization requires an extensive work-up to evaluate for fever? In this retrospective review of febrile infants between 6 and 12 weeks, they compared the rates of SBI between those who had recent immunization in the last 72 hours to controls. They found that the rate of Sbi decreased from 7.1% to 0.6% if immunization had occurred in the last 24 hours. Bottom line recommendation is that one should consider a U/A and culture in the recently immunized child with a fever. Wolff and Bachur. Acad Emerg Med. 16(12): 1284-9 (2009)

Febrile Infant after Immunizations NRI (%) Bacteremia 0.9 UTI 2.8 5.7 Meningitis 0.2 Pneumonia 0.4 Overall SBI 7.1 Prevalence of fever after immunizations is 27%. Does this mean that every child post-2 month immunization requires an extensive work-up to evaluate for fever? In this retrospective review of febrile infants between 6 and 12 weeks, they compared the rates of SBI between those who had recent immunization in the last 72 hours to controls. They found that the rate of Sbi decreased from 7.1% to 0.6% if immunization had occurred in the last 24 hours. Bottom line recommendation is that one should consider a U/A and culture in the recently immunized child with a fever. Wolff and Bachur. Acad Emerg Med. 16(12): 1284-9 (2009)

Summary Age No source Viral Source Post-Immunization < 1 month Urine Blood LP Admit with IV Abx N/A 1 – 2 moths +/-LP Risk Stratify for admission & IV Abx If U/A positive: < 2 months CBC, BCx, Admit, IV Abx > 2 months IV or PO Abx IV or PO Abx if U/A positive

Bronchiolitis Fever less than 28 days: Fever between 28 and 60 days: FSW, IV Abx, admit Fever between 28 and 60 days: U/A (if positive BW, IV Abx, admit) Routine CXR/viral testing not recommended Routine cultures not recommended in those over age 2 months

Bronchiolitis Criteria for admission Signs of severe respiratory distress Supplemental O2 required for sats > 90% Dehydration Cyanosis or apnea High risk patient

Bronchiolitis *helpful in admitted patients Recommended Equivocal Not Recomended Oxygen Epinephrine neb Ventolin Hydration 3% Hypertonic Saline* Corticosteroids Nasal Suctioning Antivirals Epinephrine and Dex Cool mist *helpful in admitted patients

UTIs Age Who to Test How to Test Less than 3 months All with fever > 38 Catheter 3 to 6 months 2 or more RFs: Ill appearing Previous UTI or GU anomaly Fever > 38.5 for > 48 h Fever > 39 No other source 6 to 24 months Or Clean Catch

UTIs Treatment: < 2 months Admit and IV antibiotics > 2 months Oral Cephalexin 50mg/kg/d for 10 days if well appearing, toleraring PO fluids, well hydrated and follow-up cant be assured Otherwise inpatient IV antibiotics Arrange follow-up

Pharyngitis Very uncommon in those under age 3 Routine testing and treatment not recommended Swab those who are over age 3 and complain of sore throat Treatment: Standard dose Amoxil x 10 days If concerns for allergy: cephalosporins or macrolides

AOM Wait and watch unless under 6 months, severe otalgia, temperature > 39, recent AOM Amoxil 80 to 90mg/kd/d divided BID: < 2 years: 10 days 2 to 5 years: 7 days > 5 years: 5 days

Questions?