2. Fever Without Localizing Signs in 2013 Coburn Allen, MD Pediatric Infectious Diseases Pediatric Emergency Medicine Dell Children’s Hospital

3. Objectives  Discuss the epidemiology of serious bacterial infections in febrile young children.  Review recent research that is relevant to this population.  Present evidence based recommendations (when available) for the evaluation and treatment of these processes.

4. Definitions  Fever = 38°C (100.4°F), 39°C (102.2°F) often used after 2-3 months  Hypothermia < 36°Celsius (96.8°F)  Hyperpyrexia > 105.5 or 106° F  SBI = Serious Bacterial Infections  Neonate = 0-28 days  Young Infant = 0-60 (or up to 90) days  FWLS = 0-36m old child with fever < 7d and no recognized source after H/P, “non-toxic”  Fever of Unknown Origin (prolonged, all ages)

5. Toxic Criteria  “Toxic” appearance (A.K.A. septic)  Lethargy  Poor perfusion  Marked hypo/hyperventilation  Cyanosis  “Toxic” patients = full evaluation  20% of “toxic” 0-90 day old children have and SBI

6. SBI Epidemiology in FWLS  UTI (most common)  High risk populations (6-8+%)  Girls 0-24m  Boys 0-6m, uncirc’d to 12m  VUR, anatomic issues, recurrent UTIs  E. coli >> other GNRs, enterococcus  Occult bacteremia (OB)+/- meningitis  0-2 months: GBS, E. Coli, Listeria  2-36 months  Pneumococcus #1, decreased 85% if PCV

7. SBI Epidemiology  H. flu era (before1990)  Pneumococcus #1  H. flu type B  Meningococcus  Post H. flu era (1990s)  Pneumococcus #1  Salmonella  Meningococcus  Pneumococcal vaccine(s) era (2000s)

8. Post-HiB SBI Epidemiology  Occult bacteremia  Lee and Harper, 1998; 3-36m, T > 102.2 F  1.6% occult bacteremia  92% pneumococcus, 5% Salmonella  Alpern et al, 1999; 2-24m, T > 102.2 F  1.9% occult bacteremia  83% pneumococcus, 5% Salmonella, 5% GABHS  0.03% meningitis/death  UTI  Boys (< 1 year) 2-3%, 8% if uncircumcised  Girls (0-2 years) 6-8%, 20-30% white infants

9. Pneumococcal Conjugate Vaccine (PCV), “Prevnar”  FDA, February 2000  7 serotypes (4, 6b, 9v, 14, 18c, 19f & 23f)  Black, et al., PIDJ 2000  Double blind, Prevnar or meningococcus C  37,868, randomized 1:1, 4 year follow-up  40 cases invasive pneumococcus (fully vaccinated)  39 of 40 in meningococcal group  97.4% efficacy for vaccine serotypes, 89.1% all serotypes  7% less OM, 20% less PETs, 20% less pneumonia  Alpern, et al., 2001  FWLS, occult bacteremia  97% pneumoccus serotypes covered (83% expected)  Suggests the serotypes selected for vaccine focused on OB

10. Post-PCV Era FWLS Epidemiology Stoll et al., Arch Pediatr Adolesc Med, 2004  Retrospective, 12/2001-3/2003, NY Pedi EC  329 2-36m FWLS (T>39C)  3 (0.9%) occult bacteremia (all pneumococcus)  One child twice, no Prevnar  Other child had serotype not in vaccine  4 (1.2%) contaminants  Only 28% at 7m and 66% at 12m “UTD”  CBC poor screening test

11. Post-PCV Era Occult Pneumococcal BCx +  Carstairs et al., Ann Emerg Med, June 2007  San Diego  2000-2002,  T > 100.4,  BCx done  Compared any Prevnar to none

12. Post-PCV Era Occult Pneumococcal BCx +  Unvaccinated  13 of 550 (2.4%) pneumococcal +  All over 28d  Half had pneumonia and bacteremia  Vaccinated (any)  NO pneumococcal cases  15 contaminants (1.8%)  2 had E. coli + BCx with UTIs Carstairs et al., Ann Emerg Med, June 2007

13. Other Post-Prevnar Data  MMWR, 2/08  77% reduction in “invasive Pneumococcal disease”  Herd immunity for unvaccinated  Arch Dis Child, 6/2008  Compared occult bacteremia rates (Duke)  Post Prevnar era FWLS BCx +  14 contaminants, 1 pathogen (no S. pneumo)  95% reduction in OB rates pre/post Prevnar  50% of FWLS pts. received abx  Eur J Emerg Med, 8/2009  Spain, Retrospective, 3-36 m with FWLS  OB 0.23% if 2 Prevnar, 0.82% if < 2 doses

14. TCH Experience: Pneumococcal Bacteremia

15. TCH Experience: Pneumococcal Meningitis

16. Typical SBI Pathogens in Young Infants  Prospective Cohort: 1-90 d/o with fever (38°C) presenting to EC 1999-2002  N =1298 febrile infants  105 (8%) SBI  UTI in 77 (73%) = 6% of cohort  63 of 77 were E. coli  6 of 77 had + BCx (all E. coli)  1 of 77 had + CSF (Serratia marcesens)  Bacteremia in 28 (26%) = 2% of cohort  Meningitis in 9 (8%) = 0. 7% of cohort  53% of pathogens resistant to ampicillin Byington CL, Pediatrics 2003

17. Resistance Concerns 1-90d Byington CL, Pediatrics 2003

18. What is Causing Occult Bacteremia Now? Herz et al., PIDJ 4/06

19. EBM Approach to FWLS  Understand/assign risk (high vs. low)  Look for a source  Tests, if needed  Treat, if needed  Good anticipatory guidance and follow-up

20. Low Risk SBI Criteria in Young infants with FWLS Clinical Criteria 1. Previously healthy, term infant 2. Non-toxic 3. No focal bacterial infection (except OM) Laboratory Criteria 1. WBC 5-15K, <1.5K bands, or b/n ratio <0.2 2. Gram stain un-spun urine negative (preferred), or neg LE and nitrite, or <5 WBC/hpf 3. If diarrhea, <5 WBC/hpf in stool 4. If CSF done, <8 WBC/mm 3 and NOS

21. “Low Risk Young Infants”  Review of literature: Baraff, 2000  Total = 3,161, 1420 “low risk”  Total SBI rate 0.9% in low risk  0.4% UTI  0.4% Occult Bacteremia  0.2% Bacterial Enteritis  NO Bacterial Meningitis in any of the low risk 0-90 day olds from any of the studies

22. What is a viral source?

23. Viral Sources: Young Infants  RSV +  Vanderbilt, retrospective cohort (Titus and Wright)  0-8 weeks, fever (38C), full eval in EC  174 RSV+  2 with SBI (UTIs)  Corpus Christi, retro cohort (Purcell and Fergie)  0-90 d/o with RSV+ bronchiolitis  No bacteremia/meningitis  1.1% UTI  Influenza  Krief WI, et. al., Pediatrics, July 2009  0-60d, fever (100.4), rapid flu + vs –  Flu +, 2.5% with SBI, (2.4% UTI)  Flu -, 13.3% with SBI, (10.8% UTI, 2.2% bacteremia, 0.9% mening)  Recommend urine in Flu +

24. Viral Sources: Older Kids Greenes and Harper, PIDJ 1999  3-36m, T > 102.2 F, blood culture done  Viral syndrome, 2 of 876 (0.2%) bacteremia  Bronchiolitis, 1 of 411 (0.2%)  Croup, 0 of 249  Stomatitis, 0 of 123  Varicella, 1 of 93 (1.1%)  1.4% BCx = contaminants Kuppermann, Arch Ped Adol Med 1997  156 < 2y/o w/ bronchiolitis; 0 Bcx +, 2% UTI

25. Is Diarrhea a Source?  Prospective, Texas Children’s  3-24 m/o, FWLS, w/ or w/o diarrhea  Cath Ucx if at risk for UTI  Boys 0-6m (circ), 0-12 (uncirc)  Girls 3m-24m  Results (N = 231)  No diarrhea: 12.4% had UTI  Diarrhea: 8.5 % had UTI Cardone G, Allen CH, Caviness C, AAP 2009 NCE, Washington, D.C.

26. Newer OB Screening Tools  Absolute neutrophil count (Kuppermann, An Emerg Med 1998)  Occult bacteremia, 3-36m  > 10,000 = 8.1% vs. < 10,000 = 0.8%  Sensitivity 76%, specificity 78%  C-reactive protein (Pulliam, Peds 2001)  SBI, 1-36m  CRP > 7, sens 79%, spec 91%  Procalcitonin (Lopez, PIDJ 2003)  SBI vs. viral, 1-36m  PCT > 0.6, sens 70%, spec 94%

27. SBI Markers Study Manzano, et. al., Arch. Dis. Child, Jan 2011  Prospective cohort, Quebec, 11/06-11/07 (90%+ UTD)  1-36m, FWLS (38C), had CBC, BCx, UA/Cx, PCT, CRP  Compared labs vs. PE to detect SBI  Results  328 (of 457) met inclusion criteria, 29% < 6m  16% (N= 54) with SBI  89% UTIs (2 of 48 bacteremic, 2 of 48 had nl UA)  7% (N = 4) “Pneumonia”  2% (N = 1) Meningitis (meningococcal B)  2% (N = 1) Occult bacteremia (S. pneumo 33)

28. SBI Markers ROCs  No significant difference for AUC for all 4 blood tests  All were better than exam alone (VAS)

29. SBI Markers…

30. SBI Markers if UA normal (do they help?) Only had 8 SBIs with normal UA  2 UTIs (would have caught with Ucx)  4 “Pneumonias” (could have been viral)  1 Meningitis (no details provided)  1 Occult bacteremia

31. Does having a PCT change clinical decisions?  Manzano (same) et. al., Am. J. Emer. Med 2010  Same study population  Half knew PCT value, half didn’t know  No difference in abx prescribing  No difference in decision to hospitalize  Value of the test “uncertain”

32. Occult Pneumonia Bachur et al., An Emerg Med 1999  WBC > 20,000, T > 102.2  Normal PE = 26% occult pneumonia  Abnormal respiratory exam = 40% pneumonia  Bacteremia  No difference; pneumonia vs. no pneumonia  6.5% overall, all pneumococcus TCH post-PCV7 experience  WBC > 25k better predictor of + CXR  Lemke D, Allen CH, SPR 2010

33. UTI Screening  “Enhanced urinalysis”  (Hoberman, Peds 1993)  Unspun urine  Pyuria; > 10 WBC/hpf hemocytometer OR  Bactiuria (any) on Gram stain  Sensitivity 95.8%, specificity 92.6%  If neither, NPV 99.8%  Spun urine  Gram stain 93% sensitive  Dip for LE or nitrite 88% sensitive  Sensitivities drop in young infants, 70-80%

34. Management of FWLS 0-28d  Full evaluation  CBC, BCx  Cath UA, UCx  LP,  +/- Rapid viral testing  Consider LFTs in first 2 weeks  Admit  IV Abx  Amp/Gent (or observe off) if “low risk”  UA +, consider 3 rd gen. cephalosporin  Gram stain+, adjust therapy  IV Acyclovir if HSV suspected

35. HSV Risk Factors Caviness, et. Al., PIDJ 5/2008

36. Management FWLS 29-60d  Evaluation  CBC, BCx  Cath Ua, UCx  CSF if high risk, concern for meningitis  Categorize risk  High risk: Admit, LP if not done, IV abx  Abx based on screening  UA +, consider 3rd gen cephalosporin  Abnl WBC, consider ampicillin and cefotaxime  LP abnl, based on stain, if Gram stain-, vanc/ctx  Low risk: Discharge, no abx without LP  Ceftriaxone 50mg/kg if abx  F/u 1 day

37. Management FWLS 2m-3y  Evaluation  CBC (and hold BCx)  Less than 6 months (some say 4m)  Unimmunized (HiB, PCV)  No viral source  Cath/CC UA, UCx  Boys 0-6m, 6-12 if uncirc’d  Girls 0-24m  Low threshold if h/o recurrent UTIs, > 2 d fever  Rapid viral testing if changes care  Flu in high risk populations  Send BCx if ANC > 10k, DON’T if not  CXR if WBC > 20-25k

38. Management FWLS 2m-3y  Disposition  Most discharged home, f/u 1-2 days  Decisions to treat  ANC > 10k; 50mg/kg IM ceftriaxone  UA+; 3 rd gen PO cephalosporin  Pneumonia; PO beta lactam (i.e. amox)  Anticipatory guidance  Antipyretics  What to expect/worry about  Expect fever 3-5+ days for most viral illnesses  Return if SOB, dehydration, irritable/lethargy/AMS

39. Management FWLS 2m-3y Positive Blood Cultures (Allen CH, UpToDate)  All should be reevaluated  Contaminant vs. Pathogen  Gram stain  Time to positivity  GPCs pairs/chains or confirmed Pneumococcus  Febrile: LP, if neg ceftriaxone home on PO amox  30-40 % still bacteremic  4% meningitis  Afebrile/Well: reculture, no LP, PO amox  Other Pathogens: BCX, LP (except E. coli and Staph aureus after 3m), admit IV abx

40. FWLS Epi: National Trends Simon AE, et. Al., Peds Emerg Care, 6/2013  1.6 million visits/yr, for FWLS in 2-24m in 2009  20% of ER visits in 2-24 m are for FWLS  Decreased blood work done since 2004  No significant change in UAs Simon AE, et. Al., Peds, 12/11  No tests in 56% of FWLS, 3-36m  20% get CBC  17% got UA (only 40% of girls with 39 C)

41. Happy Hunting!

42. TCH Algorithm: 0-60 days

48. TCH Algorithm: 2-36 m

53. Q/A