1. Infant Fever, What’s Old What’s New Brian R. Moore, M.D., F.A.A.P. PEM Fellowship Director PEM Fellowship Director Assistant Professor, Departments of Emergency Medicine and Pediatrics University of New Mexico Health Science Center October 12th, 2011

3. Disclosures

4. Disclosures

5. The 5 Second Rule

6. Objectives Assessment of Infants and Children <36 months of age with fever Understand the utility (or lack thereof) of diagnostic tests Understand the changing epidemiology of pediatric fevers without a clinically evident source (FWS) Develop an evidence based approach to evaluating and treating pediatric fever without source

7. Exclusions What we are NOT talking about –“sick” looking kids –Children with chronic dx –Immunospressed children What is a “fever” Temperature taking methods

8. Case #1 21 day old female brought to the ED for fever Temp 38.1, HR 152, RR 36, O2 Sat 95% RA, Wt 3.8 kg Term, NSVD, No URI Sxs, nl prenatal care and birth hx, MOC GBS- neg 2 y.o. sibling at home with URI Exam- Alert, nonfocal, well appearing, NL exam WHAT would you do?

9. Evaluation 1.CBC/Diff 2.Blood Cx 3.LP/CX 4.UA/CX 5.Viral NP Swab 6.CXR 7.Hospitalize for IV Antibiotics

10. Predictive Models for FWS To define Low Risk Infants PhiladelphiaRochester Age29-60 days<60 days WBC<15,000>5K, <15,000 BandsBand:Neut <0.2ABCount <1500 UA<10 WBC<= 10 WBC CSF< 8 WBCNo LP CXRNegativeNo CXR Stool (If indicated)<= 5 WBC/hpf

11. Application to Infants < 4 Weeks of Age? Prospective study of 254 febrile infants < than 1 month 5 of 32 (15.6%) who had SBI would have been classified to be at low risk of having bacterial disease according to the Philadelphia criteria would falsely identify as many as 10 per 100 febrile neonates as having low risk of SBI concluded that febrile infants <1 month of age should include a complete evaluation for bacterial illness and the empiric administration of antibiotics Baker MD, Bell LM, Arch Pediatr Adolesc Med. 1999;153:508-511.

12. Screening Tests < 28 Days? 225 infants 1-29 days admitted with T>38.0 SBI in 31 –6 missed by Philadelphia criteria (Baker) –8 missed by Boston criteria (Baskin) Kadish HA, Bolte RG, Tobey J, Loveridge B. Clin Pediatr 2000 Feb;39(2):81-8

13. Case #2 31 day old female brought to the ED for fever Temp 38.1, HR 152, RR 36, O2 Sat 95% RA Wt 4.3 kg Term, NSVD, No URI Sxs, nl prenatal care and birth hx, MOC GBS- neg 2 y.o. sibling at home with URI Exam- Alert, nonfocal, well appearing, NL exam WHAT would you do?

14. Evaluation 1.CBC/Diff 2.Blood Cx 3.LP/CX 4.UA/CX 5.Viral NP Swab 6.CXR 7.Empiric Antibiotics?

15. How to differentiate? Boston, ’92 (Baskin) Philly, ’93 (Baker) Rochester, ’94 (Jaskiewicz) # of pts503747931 Age28-89 d29-560-60 Temp>38>38.2>38 WBC<20<155-15 CSF for allYes No AbxYesNo % in low risk38.4%41.3% SBI in low risk5.4 %0.3 %1.1 % NPV94.6%100%98.9% Sensitivity?100%92.4%

16. Diagnostic tests-CBC High wbc counts are 2-3X more common in those with bacterial vs. viral illness Positive predictive value for an elevated wbc count is 8-15% as viral illness far more prevalent than bacterial infection

17. Diagnostic tests-CBC 955 infants 3-36 months, T > 39.0ºC had CBC & BC -> 27 had bacteremia –mean wbc in children with bacteremia20,500 –mean wbc in children without bacteremia11,800 Repeatedly shown: wbc >15,000 is 2-3X more common in bacterial than in viral infections However: –specificity  75% (too many FP) –sensitivity  60% (too many FN) Jaffe DM, Fleisher. Pediatrics. 1991 May;87(5):670-4

18. Diagnostic tests-CBC sensitivity: among those with bacteremia, how many are identified by the cutoff point? positive predictive value: among those identified by the cutoff point, how many have bacteremia? TP TP+FN TP TP+FP

19. WBC Performance Retrospective review of febrile infants 0-89 days who had CBC and Bld CX at the same time 1992-1999 38/3810 OB rate (1%) Tried to find a threshold of WBC that would help predict OB using AUC Bonsu BK Ann Emerg Med. 2003;42:216-225

20. WBC Cutoff (1,000) Bacteremia (N=38)Sens, %* (95% CI) No Bacteremia (N=3,772)Spec, %* (95% CI) >53079 (63-90)2015 (4-6) >102361 (43-76)1,58142 (40-44) >151745 (29-62)2,92878 (76-79) >20924 (11-40)3,51793 (92-94) >25513 (4-28)3,70098 (97-99) >3025 (1-2)3,75899 (99-10) 152566 (49-80)2,72772 (71-74) 201745 (29-62)3,31688 (87-89) *Sensitivity is the number of bacteremic infants with test results above the WBC count cutoff. *Specificity is the number of nonbacteremic infants with test results below the WBC count cutoff.

21. WBC Cutoff (1,000) Bacteremia (N=38)Sens, %* (95% CI) No Bacteremia (N=3,772)Spec, %* (95% CI) >53079 (63-90)2015 (4-6) >102361 (43-76)1,58142 (40-44) >151745 (29-62)2,92878 (76-79) >20924 (11-40)3,51793 (92-94) >25513 (4-28)3,70098 (97-99) >3025 (1-2)3,75899 (99-10) 152566 (49-80)2,72772 (71-74) 201745 (29-62)3,31688 (87-89) *Sensitivity is the number of bacteremic infants with test results above the WBC count cutoff. *Specificity is the number of nonbacteremic infants with test results below the WBC count cutoff.

22. Results The odds of bacteremia were not decreased substantially at any cutoff and were increased only modestly at values outside published norms of the test Conclusion: The total peripheral WBC count is an inaccurate screen for bacteremia in febrile young infants; thus, decisions to obtain blood cultures should not rely on this test

23. WBC and Bacteremia Even among TP’s most will have an infection that is likely either –to clear spontaneously (bacteremia) or –to respond to tx without serious sequelae even if dx delayed (pneumonia, cellulitis, UTI)

24. WBC and SBI PPV for more serious infections (meningitis, osteomyelitis, septic arthritis) is much lower Majority of children with bacterial meningitis have a WBC < 15,000 Therefore, NEVER use CBC results to determine the need for an LP

25. Diagnostic test-blood culture Identify children with OB at risk for more serious sequelae (meningitis) Consider –most bacteremia clears spontaneously –delayed dx without serious sequelae (pneumonia, UTI, cellulitis) –value of early diagnosis -- ED vs. PCP –sensitivity of single culture 45-70%

26. Diagnostic test-blood culture 2-4% false positive rate –10-20x FP to TP rate Side effects –Cost –Additional testing –Unnecessary hospitalizations and antibiotics –Side effects of antibiotics

27. What about UTI’s? Equal gender incidence under 3 months Over 3 months, more common in females Positive urine cultures - FWS –male infants <6 mo:7% –female infants < 2 years:8% Incidence as high as 17.5% of white girls under 24 months T  39c

28. Urine Specimens Acceptable for Culture Suprapubic aspiration Cathetererized specimen Clean mid-stream void

29. Urine Specimens Unacceptable for Culture Bagged specimens of any type at any time –Never –Ever Negative UA does not rule out UTI!

30. Diagnostic Tests-Urinalysis Routine urinalysis not sensitive enough to use as a screening tool –pyuria (by LE or micro): 80-85% sensitivity and specificity –nitrite: 85-90% specificity, poor sensitivity Gram-stained smear of urine sediment is a sensitive screen (>95%) Can use as a screen, but urine culture is still gold standard

31. Urine Culture Clean Catch >100,000 cfu/ml Straight catheterization > 10,000 cfu/mL SPA > 1,000 cfu/mL

32. Question #1 Bag urine specimens have a False Positive Rate of approximately: 1.35% 2.50% 3.85%

33. Question #1 Bag urine specimens have a False Positive Rate of approximately: 1.35% 2.50% 3.85% ALWAYS COLLECT URINE BY CATH OR SUPRAPUBIC ASPIRATION (U/S GUIDED IS BETTER)

34. Question # 2 Which of the following has the highest sensitivity for detecting Urinary Tract Infection? 1.Urine dipstick for LE or Nitrite 2.Gram stain for bacteria on uncentrifuged urine 3.Pyuria (>5 WBC) on centrifuged urine.

35. Question # 2 1.Urine dipstick for LE or Nitrite -Sensitivity 0.88 2.Gram stain for bacteria on uncentrifuged urine -Sensitivity 0.93, false positive rate.05 3.Pyuria (>5 WBC) on centrifuged urine. - Sensitivity 0.67 Gorelick (1999)

36. That Fever Article Volume 92(1) July 1993 pp 1-12 Practice Guideline for the Management of Infants and Children 0 to 36 Months of Age With Fever Without Source. Baraff, Larry J.; Bass, James W.; Fleisher, Gary R.; Klein, Jerome O.; McCracken, George H. Jr.; Powell, Keith R.; Schriger, David L. “Expert” panel Meta-analysis that pooled data from RCT and observational studies + opinion pre-Hib vaccine data

37. Harriet Lane Baraff LJ Ann Emerg Med 2000;36[6]:602–614

38. Harriet Lane > View this image in its location within the book Baraff LJ Pediatr Ann 1993;22[8]:497–498, 501–504

39. Main Sources of Occult Bacteremia 1993 1.Strep. Pneumo 70% 2.H Flu 15% 3.N. Meningitidis 3% 4. Salmonella 1-2% Baraff and Lee 1992 2002 1.Strep. Pneumo 84% 2.Group A Strept. 5% 3.N. Meningitidis 3% 4.Salmonella 3% Bandyopadhay 2002

40. H. influenzae type b bacteremia Routine use of the vaccine in infants: 1990 1989-1995: Hib invasive disease in US children <5 yr declined 95% CA surveillance: –1990: 13.9/10 5 –1996: 0.1/10 5

41. Streptococcus pneumoniae 65-85% of occult bacteremia in children usually cleared by host most common cause of bacterial meningitis in children PCV7 FDA approved 2001 Prevnar was expected to eliminate (< 6 yr olds) –86% of bacteremia –83% of meningitis –65% of OM

42. The Future Guidelines? “The widespread use of this vaccine (PCV7) will make the use of WBC counts and blood cultures and empiric antibiotic treatment of children with fever without source who have received this vaccine obsolete.” –Baraff, 2000

43. D’OH WAKE UP!!!!!! YOU IN THE BACK ROW WAKE UP!!!!! YOU ARE MISSING A VERY GOOD LECTURE

44. PROS 3066 infants > 3 months old in Primary Care with T >38.0 Feb 95 to April 98 Bacteremia in 1.8% of infants Bacterial meningitis on 0.5% Well appearing infants with fever >38.6 had a rate of OB/BM 0.4% Practitioners followed current guideline 42% of episodes JAMA. 2004;291(10):1203-1212

45. PROS They tx’ed 61/63 BM initially Conclusions- Pediatric clinicians use individualized judgment in tx febrile infants Relying on current clinical guidelines would not have improved care but would have resulted in more hospitalization, lab testing, and antibiotic use.

46. Peds ED Adherence TCH Denver 2004-06 167 patients total, 79 29-59d, 88 60-90d 19 ‘SBI’ (11%) –OB 3/1 –UTI 11 –BM 0 Complete SBI W/U as by ‘guideline’ –Age 29-59 day old49% –Age 60-90 day old8%

47. Study Conclusions We found that pediatric emergency medicine physicians in our institution do not follow existing practice guidelines for the workup of fever in young infants. Whether this reflects a lack of awareness of the guidelines or more likely, a culture that favors test minimization over risk minimization, could not be determined from this study. We also found that these physicians obtained fewer CBCs, blood cultures, urine cultures, CSF cultures, and viral studies in the infants aged 60 to 90 days than in those infants aged 28-59 days.

48. SBI in post PCV7 985 children, 0-24 months Dec 2002- Dec 2003 Tertiary care military hospital in San Diego SBI defined at PNA, UTI, OB, BM 79% had received at least one PCV7 Rudinsky SL Acad Emerg Med 2009; 16:585–590

49. SBI in post PCV7 OB 0.7% No statistical difference in the WBC count between the SBI and Non-SBI groups (p=0.055) No WBC cutoff on the ROC curve proved to be an accurate predictor of SBI No statistical difference in mean temp between SBI and Non-SBI groups

50. “SBI” 82 PNA 45 UTIs (33F, 12M) 5 OB (690 pts had bld cx, 70%) –Contaminated Blood culture rate- 4.9%! –Enterococcus 2, E. Coli, GBS, S. pneumo –S. pneumo OB 0.14% 0 meningitis

51. Herd Immunity? OB 0.14% - 0.17% but vaccination rate 50- 86% (79% in this study) Herd immunity for invasive pneumoccocial disease has also been suggested Serotyping in both studies were unavailable

52. SBI 29-90 days PROS Denver San Diego Age1-2 months2-3 months29-59d60-90d1-3 months # patients12201071798859 Bacteremia188311 B. Mngtis5 (0)0000

53. What Should I Do? Are you a risk minimizer or a test minimizer? Editorial article by Green and Rothrock –suggests that the controversy lies not in the data itself, but rather in how it is interpreted by the individual physician Green SM, Rothrock SG: Evaluation styles for well-appearing febrile children: Are you a “risk-minimizer” or a “test-minimizer”? Ann Emerg Med Feb 1999;33:211-214.

54. Risk Minimizers Risk-minimizers desire to lower the risk of adverse sequelae from occult infections and use risk stratification to target higher-risk patient subsets for intervention. In widely circulated expert practice guidelines, for example, RM believe that this structured, methodical, and laboratory-intensive strategy minimizes adverse sequelae from occult infections and when consistently implemented wlll save lives. Many also perceive this strategy as having the lowest possible liability risk.

55. Test Minimizers In contrast to the RM, TM are willing, for the sake of practicality to take a greater chance of being wrong. Their simple and inexpensive approach consists of the usual careful clinical examination, ensuring close follow- up, and avoiding empiric antimicrobial therapy in children without apparent bacterial source Although most TM will acknowledge that omitting the stratification algorithm may lead to missed occurrences of SBI They argue that the true risk of such outcomes is so low as to not justify the time, expense, and invasiveness of the routine risk-stratification approach

56. Test Minimizers They believe that the majority of rare children whose condition does indeed progress to serious bacterial illness will be identified through close follow-up and return ED visits They believe that parents prefer less testing and treatment, even if it means a greater risk of an adverse outcome Finally, they argue that the liberal ordering of blood cultures necessitates frequent unnecessary reevaluations and hospitalizations for children with FP culture results or OB which, if undetected, would most likely clear without intervention

57. Premise for Risk Stratifying Premise for risk stratifying and empirically treating OB is to prevent disease progression to BM Pneumococci are responsible for essentially all meningitis in this post-HIB era, and TM will claim that there is no convincing evidence that early use of antibiotics can prevent pneumococcal meningitis. Green/Rothrock reported a meta-analysis* that compiled all studies comparing children with and without empiric antibiotic therapy. If the nonsignificant trend toward meningitis prevention in these data is assumed to be a reliable point estimate, then: *Pediatrics 1997;99:438-444

58. Premise for Risk Stratifying 2,190 consecutive febrile children would have to be empirically treated to theoretically prevent 1 case of meningitis (pre-PCV7) Assuming adverse outcome (death or neurologic disability) in 33% of meningitis occurrences 6,570 children would have to be treated to theoretically prevent a single adverse outcome.

59. Premise for Risk Stratifying If antibiotic side effect data from the largest prospective study* of OB are incorporated into this model, adverse effects (eg, rash, allergy, vomiting, diarrhea) would occur in: –131 to 567 treated children for each case of meningitis prevented and –393 to 1,701 children for each adverse outcome prevented *J Pediatr 1994;124:504-512

60. Why are we doing this then?

61. OB 3-36 month 8408 well appearing children 3-36 months FWS at PCH post PCV7 era July 2004-June 2007, retrospective 21 TP Bld CX (0.25%) 14 S. pneumo (0.17%) 159 contaminants (1.89%) Vaccine rates 49-86% by age groups

62. NNT S. Pneumo OB 0.17%, would need to test 588 children to detect one case. Previous studies have shown w/o tx, approx 4% go on to have BM Of the children with BM, mortality is about 8% and permanent neurologic sequelae is about 30%

63. NNT Therefore, would need to test 14,700 children to detect or prevent one case of S. Pneumo BM 49,000 children to prevent one case of permanent neurological sequelae 184,000 children to prevent one death from S. Pneumo meningitis

64. History: “…but his fever stayed high” 5 studies: no differences in T reduction with acetaminophen between bacteremic and nonbacteremic groups clinical improvement with defervescence is not a reliable indicator of occult bacteremia no need to keep child to “see if the fever comes down”

65. More Recently “We have likely reached the point where the risks and costs of testing well- appearing young (3-36 month-old) febrile children for the presence of bactermia exceed the potential benefits.” Avner and Baker ACAD EMERG MED Vol. 6, No. 3 2009

66. The Future- PECARN Project is to incorporate a RNA-based diagnostic technology (called transcriptional signatures) To distinguish between bacterial and non- bacterial infections in otherwise well-appearing febrile infants who present to the ED Patient enrollment began in 2008 and continues through 2011

67. Key Points to Consider The majority of febrile young children with no fever source have a viral illness There is a high spontaneous resolution rate and a low rate of serious complications with Pneumococcal bacteremia Prophylactic use of antibiotics in children well appearing children older than 3 months is not indicated

68. Key Points to Consider The indiscriminate use of broad-spectrum antibiotics has contributed to an increasing prevalence of antibiotic-resistant pneumococcus The incidence of febrile UTI among this group of patients is significant

69. Objectives Assessment of Infants and Children <36 months of age with fever Understand the utility (or lack thereof) of diagnostic tests Understand the changing epidemiology of pediatric fevers without a clinically evident source (FWS) Develop an evidence based approach to evaluating and treating pediatric fever without source

70. Management of Low-risk Pediatric FWS 0-28 days –CBC, UA C&S, blood culture, LP, ?CXR –Admit for IV Abx, possible Acyclovir 29-90 days –UA, Urine Culture –Consider CBC/diff, blood culture, CXR –Strongly consider LP if planning on outpatient antibiotics

71. Management of Low-risk Pediatric FWS 3-36 months –Individualize Evaluate social setting re: compliance with treament and follow-up Immunization status Concomitant chronic medical illness –UA and Urine Culture girls <24 months boys <6-12 months –No role for routine CBC, blood culture, and empiric antibiotic use

72. EBM and Parachutes Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomized controlled trials Smith, Pell; BMJ 327:1459 (Published 18 December 2003)

73. Parachute Abstract Objectives To determine whether parachutes are effective in preventing major trauma related to gravitational challenge. Design Systematic review of randomized controlled trials. Data sources: Medline, Web of Science, Embase, and the Cochrane Library databases; appropriate internet sites and citation lists. Study selection: Studies showing the effects of using a parachute during free fall. Main outcome measure Death or major trauma, defined as an injury severity score > 15. Results We were unable to identify any randomized controlled trials of parachute intervention.

74. Parachute Abstract Conclusions As with many interventions intended to prevent ill health, the effectiveness of parachutes has not been subjected to rigorous evaluation by using randomized controlled trials. Advocates of evidence based medicine have criticized the adoption of interventions evaluated by using only observational data. We think that everyone might benefit if the most radical protagonists of evidence based medicine organized and participated in a double blind, randomized, placebo controlled, crossover trial of the parachute

75. Parachute Abstract A quick Wiki review showed that the parachute does have a strong evidence background (http://en.wikipedia.org/wiki/Parachute):http://en.wikipedia.org/wiki/Parachute 1. protocols were 'published' (Da Vinci, 1485) 2. animal studies (Setlier, 1785) 3. case reports (Setlier, 1793) 4. commercialization (patented 1913) 5. case control study (German air service 1918) 6. Completion of the audit cycle (Allies, 1941) 7. Continuous quality improvement program (1945-present) Today the average fatality rate is considered to be about 1 in 80,000. Obviously it would be hard to design a RCT to show how any intervention would reduce this risk (would need >1million jumps).

76. Parachute Public Health Proposal I suggest that this is in fact a public health issue and we should be preventing this fatal disease. An alternative is to mandate some additional safety devices (such as seatbelts to prevent them from jumping from planes). A public awareness campaign "Don't Jump, Chump!" would probably have an adverse effect on high risk population (teenagers). Financial penalties imposed by insurance companies. And local and national laws enacted. Currently no country has banned this behavior. I am considering starting a online petition to ban this dangerous device for emergency use only.

77. Questions?

78. Thanks!