1. Pediatric Fever in the ED Marc Francis FRCPC R4 PEM Fellow year 1 Consultant Level Physician: Dr Jeff Grant

2. Objectives  Determination of a fever  Case based look at fever in the ED  A rational and evidence based approach to the 3 major groups of kids with fever  0-30days  1 month to 3 months  3 months to 3 years  Determining the significance of fever in the era of new vaccinations  Evaluation of the work-up for fever and the utility of each variable  Treating Fever in the ED

3. Why do we care?  Febrile infant can be a challenging situation in the ED  Fever is the CC in up to 20% of visits to the ED  Fever is commonly misunderstood  While the vast majority of kids will have self- limiting viral illnesses a few will have serious bacterial infections  300+ articles have been written about the evaluation and management of the febrile child

4. Useful stuff when working with Dr. Bryan Young  Fever –Host response mediated by cytokines –Endogenous pyrogens  IL-1, IL-6, TNF, interferon-alpha –It is IL-6 which triggers the hypothalamic centers to increase body temp set point –Increased metabolic rate, muscle tone and activity and ↓ heat loss through ↓ skin perfusion  PGE2 is likely responsible for the myalgis and arthralgias

5. Fever: Friend of Foe?  Friend –Integral part of inflammatory response –Role in fighting infection? –Decreased length of symptomatology? –Growth or survival of some pathogenic bacteria is impaired in range of 40°C  Foe –Like many defense mechanisms it can go awry –Metabolic changes detrimental in the context of shock or significant illness –Can aggravate cerebral injury –Makes pts uncomfortable –Febrile convulsions

6. Case #1  5 month old Male  Previously Healthy  No medications, Vaccines UTD  HPI  2 day history of tactile fever at home  This AM axillary temp of 38.8 °C by mom  Child more lethargic and decreased PO intake  URTI symptoms of rhinorrhea and unproductive cough

7. Case #1 con’t  P/E –Well appearing child –given tylenol 15mg/kg at triage –T 37.5 °C, HR 120, RR 24, BP 71/52, Sat 98% –Exam normal –ENT  Rhinorrhea  oralpharynx injected, no exudate  TMs clear x 2

8. Questions  Does this child even have a fever?  What is the definition of a fever?  What is the best method to measure a temperature in this child?  Should the measured fever at home factor into your decision making at all?

9. Determination of a fever  What constitutes a fever is debatable  Studies by Wunderlich  1 Million measurements in 25,000 pts  Determined the upper limits of normal –For infants a rectal temp > 38.0 °C > 100.4 °F

10. Determination of a fever  Tactile Fever is useless  Otic thermometers –Not used under 6 months of age  Axillary temp  Unreliable  Elevated temp is indicative of a fever  Low or normal is not useful  An infant determined to be febrile at home by a reliable method must be presumed to have been febrile even if the temp later in the ED is normal

11. What about this thing?

12. Temporal Artery Thermometer  Computes temporal arterial temperature by a heat balance method  infrared sensor  Uses rapidly repeated measurements (1,000/second) of ambient and temple skin surface temperatures  Painless and rapid measurement  Appealing for use in children

13.  Assessed agreement between rectal and noninvasive temporal artery temperature in infants and children  275 subjects –average age was 11.2 months –range from 0 to 24 months

14. Results

16.  Conclusions –Temple temperatures do not reliably predict rectal temperatures –Can be used as an effective screen for clinically important rectal fever in children 3-24 months old –Findings do not support use of temple temperatures to screen young infants for rectal fever >38.0°C

17. Approach to the Febrile Child

18. Caveats  The toxic child always mandates aggressive work- up, abx and admission  Studies of febrile infants exclude pts with complicating risk factors  Immunocompromised  Indwelling medical devices  Currently on abx  Prolonged fevers >5days  In kids < 3 mths with a temp ≥40°C, 38% will have a serious bacterial infection  Stanley R, Pagon Z, Bachur R. Hyperpyrexia among infants younger than 3 months. Pediatr Emerg Care 2005;21(5):291 –4.

19. Case #2  22 day old F  PMHx  Term baby of uncomplicated pregnancy  Vaginal delivery  GBS negative mother  No prolonged ROM  Discharged home less than 48hrs  HPI  Public health nurse saw the child and temp of 38.4 rectally recorded – sent in to ED

20. Case #2 cont  HPI  Child doing well at home  Gaining weight appropriately  No lethargy or irritability  Feeding well, BMs normal, good u/o  Exam  T 38.6, HR 155, RR 35, Sat 99% RA  Child examines very well  Tone normal, good strong suck  No focus for fever found

21. Questions  Could this be a serious bacterial infection?  How do you want to manage this child?

22. Issues in the <30d old  High risk  Exposure to pathogens in birth canal without passively transferred maternal antibodies  Immature immune system  Exhibit few if any classic signs of sepsis  Limited behavioral repertoire  may deteriorate rapidly  May not even be able to mount a fever  Children born premature are at even greater risk

23. Issues in the <30d old  Immature immune system –Decreased opsonin activity –Decreased macrophage activity –Neonatal neutrophils have reduced ability to migrate from blood to sites of infection

24. Issues in the <30d old  The majority will go on to a diagnosis of nonspecific viral illness  12% of all febrile neonates presenting to a peds ED will have serious bacterial illness*  Typically more virulent bacteria  More likely to develop significant sequelae *Baker MD, Bell LM. Unpredictability of serious bacterial illness in febrile infants from birth to 1 month of age. Arch Pediatr Adolesc Med 1999;153(5):508–11 *Kadish HA, Loveridge B, Tobey J, et al. Applying outpatient protocols in febrile infants 1– 28 days of age: can the threshold be lowered? Clin Pediatr (Phila) 2000;39(2):81 – 8.

25. Management  Full Septic W/U –CBC with Diff –Blood culture –Urinalysis and culture –LP –Stool culture and fecal leukocyte count if diarrhea present –+/- Chest radiograph  Admission  IV Abx

26. Antibiotics Pathogens:  First few weeks  GBS  E. coli  Listeria Monocytogenes  Community  Strep Pneumo  H flu  Neisseria Meningitidis  Rarely  Staph aureus  Salmonella Antibiotics:  Ampicillin  3 rd generation cephalosporin  +/- Acyclovir ? Ceftriaxone

27.  ACEP Clinical guidelines:  Level A recommendations –Infants between 1 and 28d with a fever should be presumed to have a serious bacterial infection

28. Case #3  2 month old Male  Previously healthy, no medications and vaccines are UTD  HPI –48hr history of fever –Decreased PO intake and occasional vomiting –Some lethargy noted at the breast –Otherwise well –No diarrhea, no rash, no cough, no URTI symptoms

29. Case #3 cont Exam  T 38.9 tympanic, HR 136, RR 38, Sat 98% RA  Generally looks well and appropriate  CVS – normal  Resp – no distress, clear bilaterally  Abd – soft and nontender no HSM  Derm – no rash  Neuro – good tone, strong suck, interacting well  ENT – throat clear, TM’s normal, no adenopathy

30. Questions?  Does this child need a full septic work-up too?  Is this child high or low risk? –How can you risk stratify him?  What degree of work-up does this child need for his fever without a source?  How would you manage this child

31. Issues in the 1mth to 3mth old  Significant amount of research in this area  Give more clinical clues to their degree of wellness than the <30d olds  Clinical criteria alone do not give adequate accuracy to detect a significant infection  Determination requires clinical and laboratory investigations

32. Lab evaluation of FWS  CBC with diff  Urinalysis –Boys <6mths –Girls <2yrs  Stool for leukocytes if diarrhea  Chest radiograph if respiratory symptoms

33. Approaches

34. Need to identify the high risk pt  Criteria for same are well documented  Pick one and stick to it –The Rochester Criteria are well recognized –Advantage of no CSF criteria!!!  Use your clinical judgment if you are experienced –Good research to show that experienced clinicians are good predictors

35. Rochester Criteria  Dagan and colleagues  Stratifies children less than 60d old into High or low risk categories –Clinical and lab criteria  Low-risk group were unlikely to have serious bacterial infection –NPV of 98.9% Jaskiewicz JA, McCarthy CA, Richardson AC, et al for the Febrile Infant Collaborative Study Group. Febrile infants at low risk for serious bacterial infection–an appraisal of the Rochester criteria and implications for management. Pediatrics 1994;94(3):390– 6.

36. Rochester Criteria 1) previously healthy term infant with uncomplicated nursery stay 2) well appearance 3) No focal infection (except OM) 4) WBC 5,000-15,000/mm3 5) Band count <=1,500/mm3 6) U/A normal (<=10 WBC/hpf) 7) stool <=5WBC/hpf (if diarrhea)

37. Rochester Criteria  Low risk if none  High risk if look toxic or fail the criteria  Numerous studies have shown an increase in serious bacterial infections missed when applied to infants age 1 – 28 days -Ferrera PC et al Neonatal fever: utility of the Rochester criteria in determining low risk for serious bacterial infections. Am J Emerg Med. 1997;15:299-302 -Kadish et al. Applying outpatient protocols in febrile infants 1-28 days of age: can the threshold be lowered? Clin Pediatr. 2000;39:81-88 -Baker MD, Bell LM. Unpredictability of serious bacterial illness in febrile infants from birth to 1 month of age. Arch Pediatr Adolesc Med. 1999;153:508-511

38. High risk management?  Look toxic or fail the criteria –Full septic work up –Hospital admission –Empiric antibiotics  Clear CSF: 24hr empiric ceftriaxone  Urine positive: amp/gent pending cultures  CSF pleocytosis: 48hrs on amp/ceftriaxone and consider Vanco

39. Low risk infants 30d to 90d 2 management strategies: 1) blood, urine and CSF cultures single dose of IM ceftriaxone re-evaluation within 24hrs 2) Urine culture obtained No abx therapy Careful observation

40. Should you LP?  Prevalence of bacterial meningitis in febrile infants < 3 months is 4.1/1000 pts  Neither the clinical exam or WBC is reliable in diagnosis  The LP should be strongly considered  If you forego the LP do not give antibiotics –Confounds the evaluation for meningitis if still febrile on follow-up exam

41. Disposition is Key  Outpatient  Reliable follow-up within 24hrs  Immediate access to health care if required  Good parents  Careful plan derived with parents

43. Do these clinical guidelines actually help the experienced clinician?

44.  Prospective cohort study  Aim to characterize the management and clinical outcomes of febrile infants  N= 3066 infants ≤ 3mths with temp >38°C  Office based practice of 573 practitioners in 44 states (PROS)  Outcome measures assessed:  Management strategies  Illness frequency  Rates and accuracy of treating bacteremia

45.  Results: –Hospitalized 36% of infants –Lab testing in 75% –Bacteremia detected in 1.8% and bacterial meningitis in 0.5%  In the initial visit physicians treated 61/63 cases of bacteremia/bacterial meningitis with abx

46.  Conclusions: –Peds clinicians in the US use individualized clinical judgment –Neither current guidelines or any other clinical model performed with greater accuracy than observed practitioner management –Current guidelines would not have resulted in improved care with more hospitalizations and lab testing

47. Case #4  2yo M  Previously well, no meds, vaccines UTD  HPI –3 day hx of fever responsive to advil prn –Decreased activity level as per parents –poor po intake of solids, but drinking –Good u/o, no diarrhea or vomiting –No URTI symptoms

48. Case #4 con’t  Exam –Well appearing child –T39.1°C, HR 115, RR 24, BP 80/48, Sat 98% –CVS – normal –Resp – Clear and no distress –Abd – soft and nontender –Derm – no rash –ENT - normal

49. Questions  What is the concern in this age group?  What defines a significant fever in this age group?  What diagnostic test are indicated in this scenario?  How would you manage this child?

50. Issues in the 3mth to 3yo child  Remains controversial (surprised?)  Have been considered at risk for occult bacteremia  This age group where widespread vaccination has had its greatest effect  Important to obtain a detailed vaccination history to assess risk

51. The 3mth to 3yo child  Your exam finally matters!!! –Well appearance does not exclude bacteremia but….. –Children who appear unwell are far more likely to have serious illness  Toxic appearing = 92%  Ill appearing = 26%  Well appearing = 3% McCarthy PL, Sharpe MR, Spiesel SZ, et al. Observation scales to identify serious illness in febrile children. Pediatrics 1982;70(5):802 –9

52. The 3mth to 3yo child  A temp ≥ 38°C defines a fever in younger children beyond which diagnostic testing in initiated  In this age group a temp ≥ 39°C is commonly used as the threshold  This higher cutoff is used because of increased risk of occult bacteremia with increasing temp  Kuppermann N, Fleisher G, Jaffe D. Predictors of occult pneumococcal bacteremia in young febrile children. Ann Emerg Med 1998;31(6):679–87.

53. Occult bacteremia  In the mid 1990s the overall prevalance of bacteremia in young febrile children was estimated at 1.6-1.9%  The reason to screen is to minimize the low but worrisome risk of serious complications  Septic arthritis, osteomyelitis, meningitis, sepsis  In retrospective studies of culture + pts, empiric abx reduced the rate of  Complications  Persistent fever  Hospitalisation  In a majority of pts bacteremia will resolve spontaneously

54. Occult Bacteremia  H. flu previously presented a significant burden of disease  With vaccination H influenza type B has been virtually eliminated  Corresponding with this decrease was an increase in the % of invasive disease caused by Strep Pneumo  83% to 93% of + blood cultures in young febrile infants in the 1990s in the US  Recent heptavalent vaccination has further changed the landscape

55. What are predictors of bacteremia?  Hx and PE are poor discriminators  There is ↑ risk of bacteremia with ↑ WBC  Sensitivity of WBC >15,000 is only 80% to 86%  Specificity of WBC >15,000 is 69%-77%  Absolute Neutrophil Count (ANC) >10,000 is a stronger predictor  8% of pts with ANC >10,000 have occult bacteremia  0.8% of pts with ANC <10,000 have occult bacteremia Kuppermann N, Fleisher G, Jaffe D. Predictors of occult pneumococcal bacteremia in young febrile children. Ann Emerg Med 1998;31(6):679–87

56. Approaches Conservative: Well appearing and no identified focus: Urinalysis No other investigations No antibiotic treatment Aggressive: Well appearing and no identified focus: CBC if Temp >39.0°C If WBC > 15000 then blood culture and empiric ceftriaxone

57. Aggressive theory  Well child with FWS may fail to identify occult Strep pneumoniae resulting in possible S. pneumo meningitis –Introduction of the Prevnar vaccine in July 1, 2002 should have drastically decreased this risk –Meningovax addition to the vaccination schedule further reduces the risk

58. PREVNAR (PCV7)  Offered in Alberta since July 1, 2002  Previous vaccine was T-independent antigen  Conjugated heptavalent pneumococcal vaccine  Polysaccharide conjugated to protein  Allows T-dependant response  Substantial primary response among infants and children  Serotypes covered include –4, 6B, 9V, 14, 18C, 19F and 23F  Good antibody response in 90%-100% of children to all seven vaccine serotypes after 3 doses

59. CASPER STUDY (Calgary Area Streptococcus pneumoniae Epidemiology Research)  Dr. J. Kellner  Tracking disease incidence and serotypes in Alberta before and after introduction of routine childhood vaccination in 2002  Preliminary results have shown a 62% decrease in IPD incidence among children between 6 and 23 months of age  Between 1998-2004 only one child receiving 1 or more doses of PCV7 developed invasive pneumococcal infection  16 month old who had 3 doses of PCV7

60. Recommendations  The reduced likelihood of occult bacteremia with S. Pneumonia makes routine CBC and blood cultures in this population excessive  Not cost-effective  Careful follow-up is required if patients are discharged home

61. Rational Approach  Consider using ANC over WBC as a better predictor

62. Case #5  3yo M previously healthy  presents with 3 day history of fever >39°C lethargy and poor po intake  Father has not been treating the fever with anything at home  Received tylenol at triage and fever responded well and now 37.2°C

63. Question  Does a response to antipyretic indicate a lower likelihood of a serious bacterial infection?

64. Response to antipyretic  Trials performed over the last 20yrs have consistently found no correlation

65. Case #6  16 month old F with fever x 48hrs  Pmhx: healthy, vaccines UTD  URTI symptoms but no other source identified  Exam  Generally looks unwell  T=39.1 rectal, HR 130, RR 36, BP 71/48, Sat 95%  CVS: nil acute  Resp: comfortable, clear throughout, no retractions, no stridor or nasal flaring, no cough  Abd: soft + nontender  Derm: no rash

66. Case #6 Con’t  You order cultures and some investigations  The nurse asks you if you want to include a Cxray in your work-up?  Question:  What are the indications for a chest radiograph during the work up of pediatric fever?

67. The issue  Estimated that 7% of children 38°C will have pneumonia  Occult pneumonia with no clinical evidence can be seen in up to 26% of children with FWS and WBC>20,000  Many of these will be viral  Interobserver reliability of cxray findings of bacterial pneumonia is poor

68.  Meta-analysis to determine the need for cxray in the febrile infant work-up  N= 617 infants ≤ 3 mths from 3 different study populations  Evaluated clinical findings as predictors of pneumonia diagnosed radiographically

69. Potential clinical markers

70. Results  361 febrile infants had no evidence of pulmonary disease on Hx or PE and had normal xrays  256 febrile infants had at least one clinical finding of pulmonary disease  85 (33.2%) of these had + chest radiograph for pneumonia  95% CI that a positive cxray in a child with no pulmonary symptoms would occur 1.02% of the time

71.  Conclusions –The policy of obtaining Cxray in work up of all febrile infants should be discontinued –Chest xrays should be obtained only in febrile infants with clinical indications of pulmonary disease

72. So what about urine cultures?  Do all children require urine cultures for w/u of fever without a source?

73. The issues  UTI is an important cause of fever in young children  Prevalence of UTI in kids age 2m – 2yo with no identifiable source for fever is ~3-7%  Estimated that 75% of children <5yo with febrile UTI have upper tract disease  Potential for renal scarring

74. Who is at risk?  Prevalence of UTI in Children < 1yo  6.5% in girls  3.3% in boys  Between age 1-2yo  8.1% in girls  1.9% in boys  Uncircumcised boys at increased risk

75. Clinical decision rule to identify febrile young girls at risk of urinary tract infection Gorelick MH et al. Arch Pediatr Adoles Med 2000;154(4):386-390  Prospective cohort study  Development of a clinical decision rule to identify febrile young girls requiring urine culture  N= 1469 females 38.3°C without an unequivocal source of fever  Multiple logistic regression after screening variables for univariate association and reliability

76. Clinical Decision Rule  Presence of 2 or more of the following 5 variables: 1)Less than 1 yo 2)White race 3)Temp 39°C or higher 4)Fever for 2 days of more 5)Absence of another source of fever on exam

77. Results  Prediction of UTI –Sensitivity 0.95 (95% CI 0.85-0.99) –Specificity 0.31 (95% CI 0.28-0.34)  With their study population and an overall prevalence of UTI of 4.3% –PPV of score ≥2 was 6.4% –NPV of score <2 was 0.8%

78. What about boys?  No clinical decision rule exists  Due to higher prevalence in boys <6mths and higher prevalence in uncircumcised boys general guidelines are: –Urine cultures for all boys < 6mths –Urine cultures for uncircumcised boys <12mths

79. Case #7  You have just finished diagnosing your 8 th viral URTI in the last hour  You recommend fluids, antipyretics and that they find somewhere else to go next time  As you are about to send the child home, the mother asks what is better to treat the fever with Tylenol or Ibuprofen???

80. Questions  Is there evidence that Acetaminophen or Ibuprofen is more efficacious in the treatment of childhood fever?  Is there any difference in the safety profile of the two drugs in children?

81.  Meta-analysis published in 2004  Extensive search of multiple databases found 127 potential studies  17 blinded, randomized controlled trials with children <18yo selected  Compared the efficacy in pain, fever and the safety profile of the two drugs

82.  Compared  Ibuprofen 4-10mg/kg  Acetaminophen 7-15mg/kg  Included only data for the first dose in multi-dose studies  Outcome measures were –Mean temp difference between drugs at 2,4 and 6 hrs –Mean temp difference from baseline at 2, 4 and 6 hrs  Safety measures were –Risk ratio of minor and major harm between the drugs

83.  Results –All point estimates of the mean weighted effect size favored ibuprofen at all times  2hrs 0.19 (95% CI, 0.05-0.33)  4hrs 0.31 (95% CI, 0.19-0.44)  6hrs 0.33 (95% CI 0.19-0.47) –All confidence intervals were fairly narrow and none crossed 0 –The relative superiority was more pronounced at 4 & 6hrs after treatment

84.  Safety Profiles: –Point estimates for risk ratio of harm were calculated  A ratio of 1 indicates the drugs did not differ in safety  RR > 1.0 indicate that Ibuprofen was less safe –Results  RR minor harm = 0.96 (95% CI, 0.68-1.36)  RR major harm = 1.00 (95% CI, 0.55-1.82) –Both data sets had confidence intervals crossing 1

85.  Conclusions: –Ibuprofen 5-10mg/kg (especially a 10mg/kg dose) is a more efficacious pediatric antipyretic –There is no indication that the drugs differ in safety from each other  Limitations –Clinical significance of the difference –Did not look at repeat dosing –Did not look at using both in combination

86. Take Home Points I  Approach to a fever: < 1 month old  Full septic w/u, admission and abx for all 1 month to 3 months  Use documented criteria to determine if high or low risk and management based on same  If you are experienced use your clinical judgment 3 mths to 3 years  With new vaccinations the incidence of occult bacteremia is so low that routine investigations in the well child is of no utility

87. Take home points II  How you measure a temp does matter especially in young kids  Remember that your clinical exam can be misleading in very small children  Reserve Chest xray for those with resp symptomatology only  Ibuprofen may be more effective than Acetaminophen in reducing fever

88. Questions?  I’m Feeling a little warm

91. Further case  You decide that you are not an “experienced clinician” and you’re going to use the Rochester Criteria to work up a fever without source in a 2 month old  Your colleague asks you why you are using the WBC when we know it is such a terrible marker for significant infection?

92. Questions  What is the sensitivity and specificity of the WBC for diagnosing bacterial infection?  Are there markers that we can be using that are better predictors?

93. WBC as a marker  Clearly associated with increased risk of bacteremia at values 15,000 (likelihood ration of 2.0)  However known to have poor sensitivity and specificity and thus inaccurate  Because of its low predictive value and the low prevalence of bacteremia –Results in unnecessary treatment in 85-95% of cases

94. Other potential markers  Band counts  ANC  Band to Neutrophil ratio  ESR  C reactive Protein  Pro-calcitonin

95. CRP  Acute-phase reactant  Sensitive indicator of infection  Shown to have a better predictive value than WBC or ANC for bacterial infection  A CRP < 5 mg/dl (50mg/L) effectively ruled out serious bacterial infection Pulliam PN, Attia M, Cronan K. C-reactive protein in febrile children 1 to 36 months of age with clinically undetectable serious bacterial infection. Pediatrics. 2001;108:1275- 1279.

96. CRP performance