Fever in Infants: Pediatric Dilemmas in Antibiotherapy

Fever in Infants: Pediatric Dilemmas in Antibiotherapy Jahzel M. Gonzalez Pagan, MD, FAAP Pediatric Emergency Medicine Associate Professor, UPH Medical Advisor, SJCH June 9 th, 2017 S

Objectives S Review definition of fever without a source(fws) and serious bacterial infection(sbi) S Review epidemiology of FWS S Discuss clinical decision rules and their validity S Discuss Viral illness and SBI S Discuss variation in FWS management and outcomes S Review ACEP Guidelines

Fever Without a Source S

Fever without a Source S Acute onset, duration of less than 1 week, and absence of localizing signs* S rectal temperature of greater than or equal to 38.0C (100.4F), documented in the clinical setting or at home within the past 24 hours* *Ann Emerg Med. 2016;67:625-639 http://kjworks.pbworks.com/w/page/99133546/definitions

Fever without a Source S Most common chief complaint among infants and children presenting to an emergency department (ED) S 15% of all ED visits* S Majority of febrile children will have a benign, self-limited viral infection *CDC Hospital Rates 2011

Fever Without a Source S A small number (<3 months) will have a serious infection S The dilemma is to differentiate the well-appearing febrile infant or child with a SBI

Serious Bacterial Infection S

Serious Bacterial Infection SBI S The definitions vary greatly S Studies may includes bacteremia, bacterial meningitis, UTI, pneumonia, septic arthritis, osteomyelitis, cellulitis, and enteritis S Most studies define SBI as a positive culture result from a sample of blood, urine, cerebrospinal fluid, or stool

Epidemiology S https://www.cdc.gov/careerpaths/scienceambassador/resources/lesson-plans/index.html

Prevention Strategies S Dramatic reduction in vaccine preventable infections following the widespread use of immunizations S Active prevention strategies have also decreased not vaccine preventable diseases (GBS) http://dhhs.ne.gov/publichealth/immunization/pages/home.aspx

Invasive Pneumococcal Disease (IPD) S Overall IPD incidence declined from 100 cases per 100,000 in 1998 to 9 cases per 100,000 in 2015* S IPD caused by PCV13 serotypes declined from 91 cases per 100,000 in 1998 to 2 cases per 100,000 in 2015* *https://www.cdc.gov/pneumococcal/surveillance.html

Invasive Pneumococcal Disease (IPD) Changes in the incidence of invasive pneumococcal disease (IPD) among children <5 years old from 1998 through 2015 in the United States. CDC Active Bacterial Core Surveillance

H. influenza S Since the implementation of conjugate vaccines for infants (1990) and children (1987), rates of Hib disease among children younger than five years old have declined by 99% in the United States * S Nontypeable disease now causes the majority of invasive H. influenzae disease among all age groups in the United States* *https://www.cdc.gov/hi-disease/clinicians.html

Group B Streptococcus (GBS) S GBS emerged in the 1970s as the most common cause of sepsis in newborns S Early-onset disease (younger than 1 week old) has declined by 80% since increased use of intrapartum prophylaxis has occurred * *https://www.cdc.gov/groupbstrep/clinicians/clinical-overview.html

Changes in Pathogens https://www.babyq.com/lens/lifestyle/what-is-group-b-strep/

Epidemiology of Bacteremia in Febrile Infants in the United States. Eric Biondi et al. Pediatrics 2013;132;990 S Retrospective Review S Positive blood culture results in febrile infants < 90 days admitted to ward S Data from ED and ward of 6 hospital systems through US, 2006 2012

Ø Non-low risk bacteremic infants were significantly more likely than low risk bacteremic infants to have E. coli (P =.001) or GBS (P =.01) Ø Infants who had S. pneumoniae bacteremia were significantly more likely to be older than infants who had other causes of bacteremia (P =.01).

Epidemiology of Bacteremia in Febrile Infants in the United States. Eric Biondi et al. Pediatrics 2013;132;990 S Most common pathogens were Escherichia coli (42%), group B Streptococcus (23%), and Streptococcus pneumoniae (6%) S No Listeria monocytogenes was identified S Emergence of S. aureus as a leading pathogen in bacteremia in young infants S Concurrent UTI or meningitis more common with E.coli(92%) and GBS(27%) respectively

Younger Infants and Clinical Decision Rules S http://testing.carabineyecare.com/wp-content/uploads/2016/01/baby-wearing-glasses-hd-wallpaper.jpeg

Clinical Decision Rules S Before 1985 S all febrile infants <60 days of age S hospitalized and treated with parenteral antibiotic therapy after a full sepsis evaluation S unnecessary hospitalizations, nosocomial infections, injudicious use of antibiotics, emergence of resistant bacteria, and adverse effects of antibiotics S After 1980 s S development of low risk criteria: clinical decision rules

Clinical Decision Rules https://www.slideshare.net/mauron/fever-without-a-source-in-pediatrics-1892072

Performance of Low-Risk Criteria S

Performance of Low-Risk Criteria in the Evaluation of Young Infants With Fever: Review of the Literature Anna R. Huppler, MD,a Jens C. Eickhoff, PhD,b,c and Ellen R. Wald, Mda. PEDIATRICS 2010 S Data published after 1985 from 21 studies, total of 8540 infants between 0-90 days S Objective: Determine the performance of low-risk criteria for SBIs in febrile infants S Compare prospective studies where empiric antibiotic treatment was withheld vs. studies (prospective and retrospective) in which empiric antibiotic treatment was administered S SBI: bacteremia, meningitis, bacterial diarrhea, pneumonia, and UTI

Performance of Low-Risk Criteria in the Evaluation of Young Infants With Fever: Review of the Literature Anna R. Huppler, MD,a Jens C. Eickhoff, PhD,b,c and Ellen R. Wald, Mda. PEDIATRICS 2010 S Prospective studies without empiric antibiotic treatment S Six patients low-risk category had SBIs S all recovered uneventfully S 2 bacteremia and 4 with UTIs S Rate of SBIs in these low-risk patients was 0.67% S Relative risk (RR) of SBIs in high-risk versus low-risk patients in these studies was 30.56 (95% confidence interval: 7.0 68.13)

Performance of Low-Risk Criteria in the Evaluation of Young Infants With Fever: Review of the Literature Anna R. Huppler, MD,a Jens C. Eickhoff, PhD,b,c and Ellen R. Wald, Mda. PEDIATRICS 2010 S Studies with empiric antibiotic treatment of low risk patients S 89 low risk infants (2.71%) were diagnosed as having SBI s S 2 cases of meningitis (1 with UTI and 1 with bacteremia), 22 cases of bacteremia (1 with gastroenteritis and 1 with osteomyelitis), 39 cases of UTI, and 14 cases of gastroenteritis S 12 cases of SBI did not have a source identified

Performance of Low-Risk Criteria in the Evaluation of Young Infants With Fever: Review of the Literature Anna R. Huppler, MD,a Jens C. Eickhoff, PhD,b,c and Ellen R. Wald, Mda. PEDIATRICS 2010

Performance of Low-Risk Criteria in the Evaluation of Young Infants With Fever: Review of the Literature Anna R. Huppler, MD,a Jens C. Eickhoff, PhD,b,c and Ellen R. Wald, Mda. PEDIATRICS 2010 S Rate of SBIs in low-risk patients in studies without empiric antibiotic treatment was different from the rate in all other studies (0.67% vs 2.71%; P 0.01) S The total number of SBIs was 931(10.9%) consistent with rates reported in the literature S Rate of SBIs in low-risk patients in all studies was 2.23% S With the use of low-risk criteria, ~ 30% of febrile infants can be identified as being at low risk for SBIs and can be treated with observation alone

New Low Risk Criteria? S

Validation of the ''Step-by-Step'' Approach in the Management of Young Febrile Infants Borja Gomez et al. Pediatrics 2016 S Prospective study including infants 90 days with fever without source S Followed the retrospective study done on 2014 by same group with 7 European Peds ED S 11 European pediatric emergency departments between September 2012 and August 2014 S Objective: Compare the accuracy of the Step-by-Step approach, the Rochester criteria, and the Lab-score in identifying patients at low risk of IBI (invasive bacterial infection)

Validation of the ''Step-by- Step'' Approach in the Management of Young Febrile Infants Borja Gomez et al. Pediatrics 2016 Ø Different definitions Ø IBI(+ culture blood or CSF) Ø Non IBI(UTI or bacterial gastroenteritis) Ø Different cut off age Ø 21 days vs. 28 days

Validation of the ''Step-by-Step'' Approach in the Management of Young Febrile Infants Borja Gomez et al. Pediatrics 2016 S Eighty-seven(4.0%) of 2185 infants were diagnosed with an IBI S IBI higher in infants classified as high risk or intermediate risk according to the Step by Step than in low risk patients S Sensitivity and negative predictive value for ruling out an IBI S Step by Step: 92.0% and 99.3% S Rochester Criteria: 81.6% and 98.3% S Lab Score: 59.8% and 98.1% S Infants with an IBI misclassified S Step by Step: 7, Rochester criteria: 16, Lab-score: 35

Validation of the ''Step-by-Step'' Approach in the Management of Young Febrile Infants Borja Gomez et al. Pediatrics 2016 S The study validated the Step by Step as a valuable tool for the management of infants with fever without source in the emergency department S Confirmed its superior accuracy in identifying patients at low risk of IBI, compared with the Rochester criteria and the Lab-score

What about viral illness and SBI? S http://www.healthline.com/health/bronchiolitis#outlook8

Occult serious bacterial infection in infants younger than 60 to 90 days with bronchiolitis a systematic review Ralston S, Hill V, Waters A. Arch Pediatr Adolesc Med. 2011;165:951-956. S Systematic review of the literature and meta-analysis S Objective: summarize the risk of occult SBI in the youngest febrile infants presenting with clinical bronchiolitis or RSV infection S SBI: meningitis, bacteremia, and UTI S Only applies to fever evaluated at the time of presentation to an acute care setting

Occult serious bacterial infection in infants younger than 60 to 90 days with bronchiolitis a systematic review Ralston S, Hill V, Waters A. Arch Pediatr Adolesc Med. 2011;165:951-956

Occult serious bacterial infection in infants younger than 60 to 90 days with bronchiolitis a systematic review Ralston S, Hill V, Waters A. Arch Pediatr Adolesc Med. 2011;165:951-956 S Rate of UTI in the 11 studies analyzed was 3.3% (95% CI, 1.9%-5.7%) S No case of bacteremia was reported in 8 of 11 studies S No case of meningitis was reported in any of the studies S Clinical bronchiolitis performs better than RSV positivity in characterizing an infant as low risk for UTI

Occult serious bacterial infection in infants younger than 60 to 90 days with bronchiolitis a systematic review Ralston S, Hill V, Waters A. Arch Pediatr Adolesc Med. 2011;165:951-956 S Screening with cultures for SBI in febrile infants presenting with bronchiolitis or RSV infection is very low yield and a more selective approach may be rational S UTI is the only SBI reported with significant frequency S universal screening is relatively low risk S significant association with bacteremia in the youngest infants S data do not strongly support any modification to this approach S though asymptomatic bacteriuria may confound these results

So UTI if is the most common SBI when do we screen and treat? S

CLINICAL PRACTICE GUIDELINE Urinary Tract Infection: Clinical Practice Guideline for the Diagnosis and Management of the Initial UTI in Febrile Infants and Children 2 to 24 Months American Academy of Pediatrics S Objective: Revise the American Academy of Pediatrics practice parameter regarding the diagnosis and management of initial urinary tract infections (UTIs) in febrile infants and young children

CLINICAL PRACTICE GUIDELINE Urinary Tract Infection: Clinical Practice Guideline for the Diagnosis and Management of the Initial UTI in Febrile Infants and Children 2 to 24 Months American Academy of Pediatrics S For ill patients requiring antibiotics S Urine specimen is obtained for both culture and urinalysis before an antimicrobial agent is administered S specimen needs to be obtained through catheterization or supra pubic aspiration, because the diagnosis of UTI cannot be established reliably through culture of urine collected in a bag (evidence quality: A; strong recommendation)

CLINICAL PRACTICE GUIDELINE Urinary Tract Infection: Clinical Practice Guideline for the Diagnosis and Management of the Initial UTI in Febrile Infants and Children 2 to 24 Months American Academy of Pediatrics S Febrile infant with no apparent source for the fever as not being so ill as to require immediate antimicrobial therapy, then the clinician should assess the likelihood of UTI (see below for how to assess likelihood) (evidence quality: A; strong recommendation).

CLINICAL PRACTICE GUIDELINE Urinary Tract Infection: Clinical Practice Guideline for the Diagnosis and Management of the Initial UTI in Febrile Infants and Children 2 to 24 Months American Academy of Pediatrics S If the clinician determines the febrile infant to have a low likelihood of UTI then clinical follow-up monitoring without testing is sufficient (evidence quality: A; strong recommendation).

CLINICAL PRACTICE GUIDELINE Urinary Tract Infection: Clinical Practice Guideline for the Diagnosis and Management of the Initial UTI in Febrile Infants and Children 2 to 24 Months American Academy of Pediatrics S If the urinalysis suggest a UTI (positive leukocyte esterase test results or nitrite test or microscopic analysis results positive for leukocytes or bacteria) S urine specimen should be obtained through catheterization or SPA and cultured S If urinalysis of fresh (<1 hour since void) urine yield negative leukocyte esterase and nitrite test results S it is reasonable to monitor the clinical course without initiating antimicrobial therapy, recognizing that negative urinalysis results do not rule out a UTI with certainty

CLINICAL PRACTICE GUIDELINE Urinary Tract Infection: Clinical Practice Guideline for the Diagnosis and Management of the Initial UTI in Febrile Infants and Children 2 to 24 Months American Academy of Pediatrics S Diagnosis of UTI S both urinalysis results that suggest infection (pyuria and/or bacteriuria) and the presence of at least 50,000 colonyforming units (CFUs) per ml of a uropathogen cultured from a urine specimen obtained through catheterization or SPA (evidence quality: C; recommendation).

CLINICAL PRACTICE GUIDELINE Urinary Tract Infection: Clinical Practice Guideline for the Diagnosis and Management of the Initial UTI in Febrile Infants and Children 2 to 24 Months American Academy of Pediatrics S Initiating treatment orally or parenterally is equally efficacious S Based the choice of agent on local antimicrobial sensitivity patterns (if available) and should adjust the choice according to sensitivity testing of the isolated uropathogen (evidence quality: A; strong recommendation). S choose 7 to 14 days as the duration of antimicrobial therapy (evidence quality: B; recommendation).

CLINICAL PRACTICE GUIDELINE Urinary Tract Infection: Clinical Practice Guideline for the Diagnosis and Management of the Initial UTI in Febrile Infants and Children 2 to 24 Months American Academy of Pediatrics S Febrile infants with UTIs should undergo renal and bladder ultrasonography (RBUS) (evidence quality: C; recommendation). S VCUG should not be performed routinely after the first febrile UTI S indicated if RBUS reveals hydronephrosis, scarring, or other findings that would suggest either high-grade VUR or obstructive uropathy, as well as in other atypical or complex clinical circumstances (evidence quality B; recommendation). S Further evaluation should be conducted if there is a recurrence of febrile UTI (evidence quality: X;recommendation).

With all this evidence what s going on? http://wuky.org/post/dr-greg-discusses-whats-going-other-end-stethoscope#stream/0 S

Variation in Care S

Variation in Care of the Febrile Young Infant <90 Days in US Pediatric Emergency Departments Paul L. Aronson, MD, et al. Pediatrics 2015 S Retrospective cohort study of infants < 90 days of age with a diagnosis code of fever S 37 pediatric Eds between July 1, 2011- June 30, 2013 S Objective: S Assessed patient and hospital level variation in testing, treatment, and disposition for patients in 3 distinct age groups: < 28, 29 to 56, and 57 to 89 days S Compare interhospital variation for 3-day revisits and revisits resulting in hospitalization

Variation in Care of the Febrile Young Infant <90 Days in US Pediatric Emergency Departments Paul L. Aronson, MD, et al. Pediatrics 2015 S Proportion of patients who underwent comprehensive evaluation decreased with increasing patient age S Significant interhospital variation in testing, treatment, and hospitalization rates overall and across all 3 age groups S but little variation in outcomes S Hospitalization rate in the overall cohort did not correlate with 3- day revisits or revisits resulting in hospitalization S Opportunities for hospitals to improve resource use for management of the febrile young infant?

Revisits? Sicker patients? S

Repeated Emergency Department Visits Among Children Admitted With Meningitis or Septicemia: A Population-Based Study Samuel Vaillancourt, MDCM, MPH et al. Annals of Emergency Medicine 2014 S Retrospective cohort study S all children aged 30 days - 5 years hospitalized with a final diagnosis of meningitis or septicemia between 2005 and 2010 S Objective: Describe the frequency of repeated emergency department visits among children admitted with meningitis or septicemia in Ontario, Canada

Admitted on initial visit and with repeated visits had similar median lengths of stay (13 versus 12 days, P=0.37), critical care use (21.1% versus 16.7%, P=0.28), and mortality (P= 0.86) S

Repeated Emergency Department Visits Among Children Admitted With Meningitis or Septicemia: A Population-Based Study Samuel Vaillancourt, MDCM, MPH et al. Annals of Emergency Medicine 2014 S Of 521 children,114 (21.9%) had repeated ED visits before admission S One in 3 children repeating visits returned to a different hospital S Revisit associated with older age, less acute triage score, and initial visit to a community hospital without available pediatric consultation

Sick Kids Look Sick?

Sick Kids Look Sick Steven M. Green, MD*; Lise E. Nigrovic, MD, MPH; Baruch S. Krauss, MD, EdM S Commentary S Vaillancourt et al. S children identified on a second ED visit will have a similar clinical outcome S sepsis and meningitis are not occult conditions and that, accordingly, sick kids look sick (outside of the neonatal period) S after ED discharge, a more serious infection may in rare cases develop S child will then look sick and be clinically identifiable

Sick Kids Look Sick Steven M. Green, MD*; Lise E. Nigrovic, MD, MPH; Baruch S. Krauss, MD, EdM S Progression of illness to sepsis or meningitis is unpredictable in normal healthy children S The addition of screening interventions is unwarranted S Sepsis and meningitis are rare S Revisits often involve different EDs S Careful evaluation remains the best approach S The status quo is working

What ACEP says? S

Clinical Policy for Well-Appearing Infants and Children Younger Than 2 Years of Age Presenting to the Emergency Department With Fever Approved by the ACEP Board of Directors, January 27, 2016 Endorsed by the Emergency Nurses Association, February 29, 2016 S

ACEP Policy S Systematic review of the literature for EBM recommendations S Evidence was graded and recommendations were made based on the strength of the available data

Guidance: Recommendations Levels S A: Generally accepted principles for patient care that reflect a high degree of clinical certainty (eg, based on evidence from 1 or more Class of Evidence I or multiple Class of Evidence II studies). S B: Patient care that may identify a particular strategy or range of strategies that reflect moderate clinical certainty (eg, based on evidence from 1 or more Class of Evidence II studies or strong consensus of Class of Evidence III studies). S C: Patient care that are based on evidence from Class of Evidence III studies or, in the absence of any adequate published literature, based on expert consensus.

For well appearing immunocompetent full-term infants aged 1 month to 3 months (29 days to 90 days) presenting with fever (38.0C [100.4F]) Ø are there predictors that identify patients at risk for meningitis from whom cerebrospinal fluid should be obtained? S

Level C recommendations S (1) Although there are no predictors that adequately identify full-term well-appearing febrile infants aged 29 to 90 days from whom CSF should be obtained the performance of a lumbar puncture may still be considered

Level C recommendations S (2) In the full-term well-appearing febrile infant aged 29 to 90 days diagnosed with a viral illness, deferment of lumbar puncture is a reasonable option, given the lower risk for meningitis S When LP is deferred antibiotics should be withheld unless another bacterial source is identified S Admission, close follow-up with the primary care provider, or a return visit for a recheck in the ED is needed

For well-appearing immunocompetent infants and children aged 2 months to 2 years presenting with fever (38.0C [100.4F]) Ø are there clinical predictors that identify patients at risk for urinary tract infection? S

Level C recommendations S Infants and children at increased risk for UTI include: S Females < than 12 months, uncircumcised males, nonblack race, fever duration > than 24 hours, higher fever (39C), negative test result for respiratory pathogens, and no obvious source of infection. S Although the presence of a viral infection decreases the risk, no clinical feature has been shown to effectively exclude urinary tract infection.

Level C recommendations S Physicians should consider urinalysis and urine culture testing to identify urinary tract infection in well-appearing infants and children aged 2 months to 2 years with a fever 38C (100.4F), especially among those at higher risk for urinary tract infection.

For well-appearing febrile infants and children aged 2 months to 2 years undergoing urine testing, Ø which laboratory testing method(s) should be used to diagnose a urinary tract infection? S

Level B recommendations S Physicians can use a positive test result for any one of the following to make a preliminary diagnosis of urinary tract infection in febrile patients aged 2 months to 2 years S urine leukocyte esterase, nitrites, leukocyte count, or Gram s stain.

Level C recommendations. S (1) Physicians should obtain a urine culture when starting antibiotics for the preliminary diagnosis of urinary tract infection in febrile patients aged 2 months to 2 years. S (2) In febrile infants and children aged 2 months to 2 years with a negative dipstick urinalysis result in whom urinary tract infection is still suspected, obtain a urine culture.

For well-appearing immunocompetent infants and children aged 2 months to 2 years presenting with fever (38.0C [100.4F]), Ø are there clinical predictor that identify patients at risk for pneumonia for whom a chest radiograph should be obtained? S

Level B recommendations S In well-appearing immunocompetent infants and children aged 2 months to 2 years presenting with fever (38C [100.4F]) and no obvious source of infection, physicians should consider obtaining a chest radiograph for those with cough, hypoxia, rales, high fever (39C), fever duration greater than 48 hours, or tachycardia and tachypnea out of proportion to fever.

Level C recommendations S In well-appearing immunocompetent infants and children aged 2 months to 2 years presenting with fever (38C [100.4F]) and wheezing or a high likelihood of bronchiolitis, physicians should not order a chest radiograph.

The question is what are you going to do now?

To Consider History Time and degree of fever Associated symptoms Follow up Past medical conditions High risk? Physical Exam Appearance Well appearing vs. ill Other source of infection

To Consider S Level of comfort S Risk tolerance S Experience S Parents/Family S Group practice patterns

Questions? S