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Sarah S. Long, M.D.

Fever without a Focus. . Sarah S. Long, M.D. Professor of Pediatrics Drexel University College of Medicine Chief, Section of Infectious Diseases St. Christopher’s Hospital for Children Philadelphia, Pennsylvania. Dr. Long has no conflict of interest to disclose.

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Sarah S. Long, M.D.

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  1. Fever without a Focus  Sarah S. Long, M.D. Professor of Pediatrics Drexel University College of Medicine Chief, Section of Infectious Diseases St. Christopher’s Hospital for Children Philadelphia, Pennsylvania Dr. Long has no conflict of interest to disclose

  2. FEVER, NO FOCUS OF INFECTIONWHAT IS NEW? Case 1 A 17-day old white male has an 8-hour history of fussiness and poor intake. Mother took temperature, which was 101.6. She brings him for evaluation. Labor and delivery were uncomplicated. Pregnancy was uncomplicated except for urinary tract infection. Physical examination reveals temperature 38.6, HR 180, RR 46, BP 96/56. The infant is fussy, does not make eye contact, and has good color and tone. Fontanelle is flat. There is no exanthem, enanthem or respiratory tract finding. Remainder of examination also is normal. There are no anomalies and the infant is circumcised.

  3. Case 1 17-day old with short duration fever and no clues or physical findings. Reassuring examination. My management plan would be A. Observe at home with follow-up < 24 hrs B. Blood culture + observe at home … C. Blood, urine and CSF tests/cultures + observe at home … D. C above + Ceftriaxone (if C tests negative) E. Blood, urine, CSF tests/cultures + admit + ampicillin/gentamicin

  4. Case 2 A 6-week old white male has the same history and findings as Case 1 My management plan would be A. Observe at home with follow-up < 24 hrs B. Blood culture + observe at home … C. Blood, urine and CSF tests/cultures + observe at home ... D. C above + Ceftriaxone (if C tests negative) E. Blood, urine, CSF tests/cultures + admit + ampicillin/gentamicin

  5. Case 1 17-day old with short duration fever and no clues or physical findings. Reassuring examination. My management plan would be A. Observe at home with follow-up < 24 hrs B. Blood culture + observe at home … C. Blood, urine and CSF tests/cultures + observe at home … D. C above + Ceftriaxone (if C tests negative) E. Blood, urine, CSF tests/cultures + admit + ampicillin/gentamicin

  6. Case 2 A 6-week old white male has the same history and findings as Case 1 My management plan would be A. Observe at home with follow-up < 24 hrs B. Blood culture + observe at home … C. Blood, urine and CSF tests/cultures + observe at home ... D. C above + Ceftriaxone (if C tests negative) E. Blood, urine, CSF tests/cultures + admit + ampicillin/gentamicin

  7. FEVER IN VERY YOUNG INFANTS DIAGNOSISISOLATES Bacterial meningitis E. coli Urinary tract inf Grp B streptococcus Bloodstream infection S. aureus Otitis media Enterococcus Gastroenteritis Salmonella Pneumonia Listeria Syphilis Others Viral meningitis Herpes simplex pneumonia Enterovirus disseminated Influenza Others

  8. HIGH RISK FOR SERIOUS INFECTION Younger age High/low temp Ill appearing High/low WBC

  9. IDENTIFYING LOW RISK FOR SBI ROCHESTER APPROACH* Clinically well with no risk factor No soft tissue/skeletal site Total WBC >5000 & < 15,000 Urinalysis <10 WBCs Stool <5 WBCs PITTSBURGH APPROACH** Add negative CSF Add neg Enhanced UA & Gm stain *Neg Pred Value 95-99% for SBI **NPV 100%

  10. “PRACTICE GUIDELINES 1993”<90 DAYS, WELL, W/O SOURCE < 28 DAYS> 28 DAYS& LOW-RISK ConsensusOption 1 Option 2 Evaluate* Evaluate* Urine culture Hospitalize Ceftriaxone OPD Observe OPD Abx (Y or N) Re-evaluate 24h Baraff, Bass, Fleisher, et al. Pediatrics 1993 *Includes blood, urine & CSF cultures

  11. RELATIVE RISK IN FEBRILE YOUNG INFANTS Urban EDsILLNOT ILLLOW RISK Serious bacterial 17% 9% 2% Bloodstream inf 11% 2% 1% Meningitis 4% 1% 0.5% Office (PROS)* Serious bacterial 14% <10% Bact/Meningitis 4% 1% *Pantell et al JAMA, 2004

  12. MULTIVARIATE PREDICTORS BSI/MENINGITIS (PROS) FactorsOdds Ratio Age < 30 days 5.5 31-60 days 3.0 Ill, very 9.0 moderately 1.8 Temp > 38.60 2.5 URI 0.2 (NS) Ill family 0.5

  13. SUMMATIVE RISK BY PROS CLINICAL PREDICTORS Well or minimally ill + Age > 25 days + Temperature< 38.60 __________________ Total= 1/3 patients Risk = 0.4%

  14. PROS PRACTITIONER ADHERENCE “GUIDELINES” Age/AppearRecommendationFollow < 30 days Complete W/U 46% +hosp+abx 31-90 days WBC/UA 42% Min ill 31-90 days Complete W/U 36% Mod/very ill +hosp+abx

  15. PERFORMANCE CLINICAL PREDICTION MODEL SensitivitySpecificity Clinical 58% 68% Clinical+Abn WBC 84% 54% Clinical+Abn WBC+UA 87% 51% Guidelines model 95% 35% PROS model* 94% 27% PROS actual exp** 97% 35% *Min ill + age > 25 days + Temp < 38.6 **Initial Rx with Abx

  16. PREVALENCE HSV BSI HOSP NEONATES* NoSBIVirus All hosp 5817 4.6% 8.4% Fever 960 14.2% 17.2% (0.3% HSV) Bact menHSV CSF pleo 204 5.4% 1.0% CSF poly pleo 80 14.9% -- CSF mono pleo 124 0.8% 1.6% Age 8-14 days 1400 0.2% 0.6% Hypothermia 187 -- 1.1%

  17. 2011;30:556 • 32 cases perinatally acquired HSV • 50% had only nonspecific S/S at presentation, which was fever in 75% • 75% had CNS HSV (40% presented with mucocutaneous only, 83% with seizures, 94% with nonspecific S/S only) • Age ≤ 21 days at onset S/S captured 90% of all cases and 94% with nonspecific S/S only

  18. Don’t forget to look Don’t forget to evaluate and treat empirically well appearing neonates with vesicular skin lesions 2012;161:134

  19. Journal Club…in Context…with Attitude Pearls and Perils of PCR Testing

  20. CNS Human Parechovirus – Kansas City Study Retro 388 CSF specimens from children < 18 yrs who had EV testing performed, 2009 RT–PCR  HPeV+ All were < 6 mo Compared clinical of all patients tested < 6 mo Results HPeV+ (66)EV+ (47)Negative (66) Age (d) 41 31 43 PICU 12% 2% 0 T max >39 38.4 38 Days fever 2.7 2 1.6 CSF WBCs 2% 38% 12% Periph WBCs 5.8 9.2 10.1 HPeV3 is an emerging CNS pathogen & should be considered in young infants w or w/o CSF pleocytosis

  21. CNS Human Parechovirus – Los Angeles Study Retro 440 CSF specimens from children who had evaluation for infection Compared HPeV+ vs EV+ Results HPeV+ (12)EV+ (43) Age < 6 mo 67% 67% Seizures 42% 14% CNS S/S 75% 30% URI 58% 16% Vomiting 25% 26% CSF WBCs 25% 82% HPeV is a CNS pathogen and should be considered

  22. FEVER IN YOUNG INFANTS: MY WAY • “All” infants <30 days should be hospitalized • Usual tests/cultures + CSF/Plasma for PCR HSV + EV, HPeV • Infants >60 days can be evaluated clinically • Individualize management for ages between - Clinical + temp + sex/circcumcision  - Selective use lab/hosp/abx - Minimize W/U + Ceph3 @ home for low risk • OPD blood culture + no Rx = Not allowed

  23. FDA/LABEL CHANGE RE CEFTRIAXONE Ceftriaxone must not be co-administered with calcium-containing IV solutions because of risk of precipitation of ceftriaxone–calcium salt Fatal reactions w Cef-Ca precip in lungs/kidneys CONTRAINDICATION (Neonates < 28 days): 8/2007 2007

  24. Case 3 A 6-month old white male has the same history and findings as Case 1. Temperature is 38.6 and except for URI, he has no other abnormalities. He has received two doses of PCV13 My management plan would be A. Observe at home with follow-up < 24 hrs B. Urinalysis with further management pending results C. CBC with further management pending results D. CBC, urinalysis & culture, blood culture + ceftriaxone IM and observation at home E. Tests of D + CSF + admit to hospital

  25. Case 3 A 6-month old white male has the same history and findings as Case 1. Temperature is 38.6 and except for URI, he has no other abnormalities. He has received two doses of PCV13 My management plan would be A. Observe at home with follow-up < 24 hrs B. Urinalysis with further management pending results C. CBC with further management pending results D. CBC, urinalysis & culture, blood culture + ceftriaxone IM and observation at home E. Tests of D + CSF + admit to hospital

  26. “PRACTICE GUIDELINES 1993”3-36 MOS, WELL, W/O SOURCE Temp >39C: Consider blood culture Consider urine exam Perform WBC (unless virus S/S) WBC>15,000: Perform blood culture Perform urine culture (M < 6 mo;F < 2 yr) Give ceftriaxone Baraff, Bass, Fleisher, et al. Pediatrics 1993

  27. GLITCHES IN “GUIDELINES” Then • Risk bacteremia/meningitis variable • No treatment stat  meningitis • Pneumococcal meningitis rapid onset • >90% patients pursued + treated have no bacterial infection • F/U is clouded,  tests, contam cultures • Practitionersdidn’t/don’t subscribe

  28. GLITCHES IN “GUIDELINES” Now • Pneumococcal invasive disease   • White blood count no longer useful as doesn’t predict other pathogens • Invasion of non-vaccine serotypes pneumococcus occurs in patients with underlying conditions; not “occult” but “obvious”

  29. OCCULT BACTEREMIA & VACCINES Bacteriology Pneumococcus Haemophilus b Meningococcus Strep/Staph Salmonella/Other <1990 3% 80% 10% Rare 10% >1990* 2% 90% -- Rare 10% *Hib conj >2000** <0.5% 40% -- Rare 60% PCVs

  30. Journal Club…in Context…with Attitude Pearls and Perils of PCR Testing 2014; 130: e1455 2014; 133:e538

  31. Journal Club…in Context…with Attitude Pearls and Perils of PCR Testing • Study >200 children 2 to 36 mos fever w/o source • vs probable/definite bacterial infection vs well • PCR respiratory specimen + blood Respiratory Viruses – Saint Louis Results Fever w/o source 75% virus Fever w bacterial inf 40% virus Well 35% virus ( Adeno, HHV6, EV, HPeV esp febrile vs well) Also 34% positive PCRs detected only in blood 51% patients w virus-only were given antibiotics Conclusion Viral infections are frequent in ill, and in healthy

  32. OUTPATIENT BACTEREMIA: MY WAY 1993 2000 2010 2014 PLAN A Careful clinical assessment No WBC No blood culture No antibiotic Reassess

  33. Journal Club…in Context…with Attitude Journal Club…in Context…with Attitude 2011;128:595 Sept 11, 2014

  34. The RIVUR Study Question Does antibiotic pro prevent recurrent UTI in children w vesicoureteral reflux (VUR)? Method 2 yr, 19-site, RD-BPCT 607 children 2-71 mos with VUR Gr I-IV after 1-2 febrile UTIs TMP-SMX 3 mg/kg TMP or placebo daily 10 Outcome = Recurrent febrile or sympt UTI 20 Outcome = Renal scarring, Rx failure (recurrence or scarring) TMP resistance Results Recurrent UTI 27% (P  15% (TMP) HR.55 Renal scarring 12% (P)  10% (TMP) Recur/TMP R org 25% (P)  68% (TMP)

  35. Significant  UTIs with prophylaxis* • Female • Gr I or II VUR • Index UTI = first UTI • Index UTI = febrile • Index UTI = TMPS • Bowel/bladder dysfunction • Absent constipation • * Hazard ratio + 95% CI < 1

  36. AAP PRACTICE GUIDELINES Risk and pursuit UTI in febrile 2 mo – 2 yr GirlUncirc BoyCirc Boy > 3 risks > 1 risk 4 UTI risks    3% - 17% UTI 10% - 25% UTI >3% UTI Girls Girls & Boys Boys

  37. Pediatrics 2013;132:e749-e755 Pediatrics 2013;132:437-444

  38. UTI : Urine Testing in Outpatients Treated for UTI Objective: Characterize urine test use in ambulatory children treated for UTI Methods: Outpatients <18 yrs w dx UTI + Abx script ’02-’07 Claims database 50 states/39 million insured Results: >40,000 UTIs in ~29,000 children UA performed in 76% Urine culture performed in 57% Of children <2 yrs, 32% had no UA Over time use of culture ↓ Compared w <2 yrs, OR culture ↑ w age & ↓ w male Compared w Family/IM docs Odds Ratio culture ↑ w Peds (2.6) ↑ w EM (1.2) ↓ w Urology (.5) Conclusion: Yikes! Implications Rx w/o confirmation

  39. Management First UTI: AAP 2011 Guidelines • Pursue febrile according to risk UTI • Pursue stepwise only if not ill / low risk / no antibiotic • UA by clean catch • If UA pos, culture by clean catch vscath • No antibiotic before cath urine for culture • Treatment (IV or PO re degree illness) • First UTI >95% E. coli (OccasKleb, Enterococcus) • E. colisusc : Amox 47% Cephalexin 90% • Amox/Cl 66% Cefuroxime 96% • TMP-SMX 76% • Ultrasonography: Kidneys and bladder • VCUG only if abnormal US • No prophylaxis unless Gr V VUR • Alert family re: fever/recurrence

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