Andi Marmor, MD, MSEd UCSF Associate Professor, … Review... · If urine is +, do I need to do an...

Andi Marmor, MD, MSEd UCSF Associate Professor, Pediatrics June, 2014

Nearly 20% of febrile infants have “fever without a source” (FWS) A few, although well-appearing, have an occult

bacterial infection: UTI: Most common, simple to dx/treat SBI (bacteremia/meningitis): Harder to diagnosis,

worse to miss, decreasing in prevalence

Do all neonates need the full ROS workup? What counts as a fever “source”? If urine is +, do I need to do an LP? What is the role for labs – CBC, CRP, PCT? What if LP attempts fail?

Rhizobium (“Rizzo”) is a 15 day old boy whose mother reports that he felt warm today

The whole family has a cold, and Rizzo has coughed a few times

VS: T 37.9 (R), P 145, R 35, BP 70/40 Slightly fussy, but normal exam, feeding well

A. Unreliable B. As accurate as a rectal temperature C. More sensitive than specific D. Usually due to over-bundling

Parents better at ruling out than ruling in

UTI/SBI more likely with documented fever than with reported1

Vaccines? One time fever May occur 1-3 day later

1Yarden-Bilavsky, 2010

Neonates with FWS have high risk of bacterial infection

Occult infection: 15-20% ~90% of these are UTI’s Bacteremia with UTI is

common (10-15%)

Has the epidemiology of UTI/SBI in neonates changed?

Greenhow et al, Pediatr Infect Dis J; 2014

2-3%

Better GBS screening?

13-18%

A. S. pneumo, H. influenza, N. meningitidis B. E. Coli, S. pneumo, Group B Strep C. E. Coli, Group B Strep, Listeria D. E. Coli, Group B Strep, S. aureus E. Group B Strep, S. pneumo, H. influenza

TABLE 3 . Bacterial Pathogens Detected in 129 Blood, 823 Urine and 16 CSF Cultures

Notice anything missing?


A. S. pneumo, H. influenza, N. meningitidis B. E. Coli, S. pneumo, Group B Strep C. E. Coli, Group B Strep, Listeria D. E. Coli, Group B Strep, S. aureus E. Group B Strep, S. pneumo, H. influenza

E. Coli the most common cause of all types of bacterial infections

Staph and enterococcus are emerging pathogens

Listeria is no longer a major player Amp/Cefotaxime remains a good choice Cefotaxime for broad GP and GN coverage Amp for enterococcus (not listeria!)

Clinical appearance, WBC: poor predictors


Schwartz, 2009

• Risk of UTI/SBI decreases with age

• Reliability of ill appearance increases with age

Ill appearance/low-risk criteria are not reliable in neonates

UTI is the most common bacterial infection E. coli is the most common cause of ALL

UTI/SBI in neonates GBS the major cause of non-UTI SBI Enterococcus, staph are emerging pathogens

In general: collect urine, blood and CSF for culture, and start broad-spectrum antibiotics Ampicillin/cefotaxime

In general: collect urine, blood and CSF for culture, and start broad-spectrum antibiotics Ampicillin/cefotaxime

Risk stratification/observation can be considered in select circumstances Multiple reassuring factors (eg: no documented

fever, + viral infection AND LRC met…)

You decide to get a CBC and blood culture, a cath UA/culture and a rapid flu/RSV test

Results: WBC 15, with 33% neutrophils CRP is 1.2 mg/dL Rapid viral test positive for influenza Cath U/A negative

What do YOU want to do?

1. LP, antibiotics, admit 2. No LP, no antibiotics, admit for observation

overnight 3. Observe in ED for 12 hours for fever 4. NOT an OK option No LP AND start antibiotics/admit

Rochalimea is a 7 week old girl with cough and fever for 2 days at home

VS: T 38.9, P 150’s, R 30’s, O2 sat 100% On exam, she is well-appearing, lungs are

clear, she has slight crusting at the nares, no other findings

UTI Common in girls and uncircumcised boys (10-15%)

SBI (1-2%) S. pneumo becomes the predominant pathogen Significant decrease since S. pneumo vaccination Still a few cases of E. Coli, GBS, others

A. Nasal wash for RSV B. Nasal wash for influenza C. Chest Xray D. CBC and blood culture E. Cath urine for UA and culture

Focal bacterial infection (otitis media, cellulitis) Consider further W/U in neonates

Named viral infection (bronchiolitis, croup) OR + viral test Infants < 3 months: still consider UTI Infants > 3 months: SBI/UTI unlikely

Clear URI symptoms in infants > 3 mo of age

A. Nasal wash for RSV B. Nasal wash for influenza C. Chest Xray D. CBC and blood culture E. Cath urine for UA and culture

You obtain a cath urine sample on Rochalimea UA 2+ for LE, + nitrites

You decide to get a blood culture and admit her for pyelo

Do you need to do an LP before starting abx?

Bacteremia is frequent in infants < 3 mo with febrile UTI (10-15%)

However, meningitis with UTI is extremely rare in well-appearing infants A few cases of meningitis with UTI in well-

appearing neonates been reported LP is not recommended routinely in infants >

1 mo if treating for pyelo

Paquette, 2011

Anaplasma, a 2 mo old boy, presents to the ED with 2 days of tactile fever, no other symptoms Unimmunized Circumcised

T= 38.9, P 150, R 40’s, BP 90/65 Well-appearing, well-hydrated

UA negative RVT negative for influenza/RSV

UTI: Urinalysis Meningitis: CSF cell

counts Pneumonia: Clinical

diagnosis/CXR Bacteremia: Blood

culture The only REALLY occult

SBI !

Screening

Andreola, 2007

Most abnormal

Least abnormal

Most useful in infants 1-3 mo of age Best for ruling OUT SBI in low-moderate risk

infants Does NOT reliably R/O UTI ( but we have

another test for that) May have selective utility in otherwise low-

risk neonates Only when it will change management…

You send a CBC and CRP: WBC 16.7 (5-15), CRP 5.0 mg/dL (< 3)

Next step? You decide to get an LP before starting

empiric antibiotics After 3 attempts, the parents refuse to let you

continue What are your options?

Screen for UTI in all infants <3 mo with FWS If UA +, get blood culture and treat for UTI If UA negative consider RVT

If UA and RVT neg, labs can help stratify risk of SBI LOW risk for SBI if ▪ WBC count 5-15K ▪ PCT < 0.2 ng/ml ▪ CRP <2.0 mg/dL

Screen for UTI selectively based on age/gender Uncircumcised boys < 6 mo of age Girls < 24 mo of age, if fever > 48 hrs

Otherwise, infants > 3 mo are at low risk for occult SBI Even unvaccinated infants are protected Empiric labs/antibiotics NOT recommended

Neonates High risk of UTI/SBI, labs/clinical exam unreliable Generally should be tested/treated/admitted

Infants 1-3 mo Test for UTI in all infants < 3 mo If viral source and/or normal serum inflammatory

markers = reassuring against SBI Infants > 3 mo Selective testing for UTI only

Rhizobium

Rochalimea

Anaplasma

Andi Marmor June, 2014

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Recommendations for Management of Well-Appearing Infants with Fever Without a Source (FWS) ▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪

I. WHAT IS “FEVER WITHOUT A SOURCE”? ▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪

These recommendations are intended to help physicians identify well-appearing febrile infants who are at low risk for serious bacterial infection or UTI. Any ill-appearing infant should be stabilized and treated immediately

• Definitions:

o Fever without a Source (FWS): For nearly 20% of febrile infants and children, no source of infection can be identified after thorough history and physical examination.

o A Fever Source is a bacterial or viral infection that is presumed to be the cause of the fever, and is reassuring against the presence of an additional occult infection. See Section II.

o Serious Bacterial Infection (SBI): A small proportion of infants with FWS, although appearing well, have an occult serious bacterial infection (SBI)* or an occult UTI that is not apparent on history or PE.

*In this document, the term “SBI” refers only to bacteremia, sepsis or meningitis. In many studies, reported rates of “SBI” include UTI, and sometimes pneumonia.

o The most common occult bacterial cause of FWS is UTI/pyelonephritis**. ** UTI is synonymous with pyelonephritis in young infants and children, as the majority of

infants with febrile UTI have upper tract involvement. • Basis for Recommendations:

o Recommendations for management of infants with FWS (Section III) differ for infants in 3 age groups based on both their risk of SBI/UTI and the most likely bacterial causes of SBI

Neonate (< 1 months) Infants 1-3 months Infants 3-24 months

o Major revisions of to guidelines for management of FWS in the last 10 years reflect the impact of introduction of the pneumococcal conjugate vaccine (PCV-7 in 2000 and PCV-13 in 2010)

Prior to PCV, S. pneumo was responsible for about 90% of SBI (not including UTI) in well-appearing febrile infants >3 mo – rates of SBI in this age group have plummeted as a result.

SBI in neonates (< 1 mo) is caused primarily by E. Coli and Group B Streptococcus (GBS), and has NOT been affected by PCV

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II. WHAT IS A LEGITIMATE “FEVER SOURCE”? ▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪ • Finding a source of infection provides a reason for the infant’s fever, and reduces the chance that the fever is due

to an occult SBI or UTI. • Bacterial infections: A clinically diagnosed focal bacterial infection (ie: otitis media, pneumonia, cellulitis) is

generally considered a “legitimate” source for fever in infants > 1 mo (ie: it reduces their chance of having an occult SBI). However, very young infants with focal bacterial infections may also have SBI or UTI

o Eg: Pantell (2004) - among infants < 3 mo treated for OM, there were no infants who also had an SBI. o Eg: Vidwan (2010) - among 197 infants <2 mo with focal infection on exam, 1 had bacteremia, 3 had UTI

• Viral infections: o A named viral syndrome with a distinctive phenotype (eg: croup, bronchiolitis, stomatitis or varicella) can

be considered a legitimate source of fever in infants >1 month of age. Studies have consistently shown that children >1 month of age with these viral syndromes are

at very low risk of SBI (Greens, 2001) Neonates: several studies of neonates with clinical bronchiolitis suggest that these infants have

a greatly reduced risk of SBI, and a reduced but still clinically significant risk of UTI (Liebelt, Antonow, Levine, Titus)

o Rapid viral testing for common viruses such as RSV, influenza, parainfluenza and adenovirus has added an additional option for making a diagnosis of viral source for fever.

Studies to date suggest that young infants with a positive viral test are at very low risk for SBI, and at lower (but still clinically significant) risk of UTI than those with a negative test (Byington, Rocholl, Bonner, Krieff)


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o Non-specific viral symptoms (runny nose, congestion, cough, exanthem): No good data has established the risk of SBI/UTI in febrile children with these symptoms

Infants <1 mo: In general, these non-specific finding cannot be considered a fever source for neonates <1 month of age, who are at the highest risk of SBI.

Infants 1-3 months: most clinicians consider these symptoms somewhat reassuring, but infants with these symptoms may still be at risk for SBI/UTI.

Infants > 3months: a constellation of obvious upper respiratory symptoms (runny nose, congestion, cough), diarrhea or a viral-appearing rash can usually be considered a likely source for fever, especially if there are sick contacts at home or daycare.

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III. RECOMMENDATIONS FOR MANAGEMENT OF WELL-APPEARING INFANTS WITH FWS ▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪

These recommendations are intended to help physicians identify well-appearing febrile infants who are at low risk for serious bacterial infection or UTI. Any ill-appearing infant should be stabilized and treated immediately

1. NEONATES (BIRTH TO 1 MONTH*) T>38: Background:

• Key principle: even well-appearing neonates with FWS may have SBI/UTI o Clinical exam is unreliable, and nonspecific viral symptoms generally cannot be considered a fever source o No clinical score or laboratory value has been found to reliably predict SBI in neonates

• Due to high rates of SBI/UTI, and poor predictive value of clinical exam and laboratory testing, published guidelines recommend a full sepsis workup in febrile infants in this age group (blood, urine and CSF cultures) and empiric antibiotics until 72 hours of negative cultures.

• *Premature infants are considered “neonates” until they are > 1 mo corrected age (>44 weeks chronologic) Rates of SBI/UTI:

• The rates and microbiology of SBI/UTI in this age group has changed substantially in the last 20 years. • Changes in practice have reduced the incidence of neonatal SBI/UTI from both E. Coli and GBS:

o Prenatal ultrasound diagnoses most infants with obstructive urinary tract anomalies, who are at increased risk for urosepsis

o Aggressive screening and treatment for GBS have reduced rates of neonatal GBS disease by an estimated 80% since the 1990’s

• UTI: the most common bacterial cause of FWS in neonates (15-20%) o High rates of UTI in well-appearing febrile neonates regardless of gender/circumcision status o Rates of bacteremia are high in neonates with UTI: 10-15% o UA is not 100% reliable: negative LE has an NPV of ~90% (Schwartz, 2009)

• Bacteremia: occurs in 2-3% of neonates with FWS. o Most cases associated with UTI

• Meningitis: rare and most cases ill appearing. o May occur with UTI, especially when accompanied by bacteremia

• Recent Studies of SBI/UTI in Neonates: 1. SBI/UTI: Schwartz (2009) - 449 neonates < 30 days (with fever)

18% had a UTI (12% with bacteremia, 2 with meningitis) 3% had bacteremia (85% of which was associated with UTI) Rates decreasing with each week of age. 3 cases of meningitis (all ill-appearing, 2 associated with UTI/bacteremia)

2. Bacteremia: Gomez (2010) - 1125 infants < 60 days (with fever) Infants < 30 days:

o Bacteremia in 3.3% (25% with occult bacteremia) o 2 with GBS: both ill-appearing

Infants < 60 days: o 17% had UTI (4.4% with accompanying bacteremia) o 2.2% had bacteremia (35% associated with UTI)

Risk factors for bacteremia (statistically significant OR):


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o Not well-appearing (8); temp> 39.5 (3.37), LE+ (3.7) o 2 infants with bacteremia were afebrile in ED, had documented temp at home

3. Bacteremia: Greenhow (2012) - Blood cx on 4255 healthy infants 7-60 days (not all febrile) Overall, 2.2 % had bacteremia

o 97% were febrile, 18.6% were ill-appearing o 63% had E.Coli (98% had concurrent UTI; 7.6% had meningitis) o 21% had GBS (all but one case in < 30 days; 29% had meningitis; 2 died) o 8 cases of S. aureus, 2 cases of S. pneumo o 10 infants had meningitis: 3 were well-appearing at presentation

Risk factors: o Gender, race, ethnicity, age were NOT independent risk factors o Bacteremia was more likely in infants <30 days

4. Bacteremia: Biondi (2013) - Retro review of + blood cx in 177 hospitalized infants < 90 days (with fever) E. Coli most common pathogen (42%), followed by GBS (23%) 91% of E. Coli bacteremia accompanied a UTI S. pneumo more likely in older infants Concurrent meningitis was found in 13% overall (27% of GBS bacteremia cases) No Listeria found 20% of those with + blood cx were “low risk”

5. SBI/UTI: Greenhow (2014) - Results of blood, urine and CSF cx on 6232 FT infants 7-90 days (not all febrile) Overall, 13.5 % of infants with cultures sent had an occult infection – 92% were UTI’s

o UTI: 17% (of 4599 urine cx) 59% male, 95% uncirc 85% febrile, 7% ill appearing 10% were bacteremic

o Bacteremia: 2% (of 5396 blood cx) 94% were febrile, but only 17% were ill appearing 52% of bacteremia associated with UTI

o Meningitis: 0.9% (of 1796 CSF cx) 63% were ill appearing

The majority of SBI was associated with UTI: only 6.3% of bacteremia and 0.2% of meningitis isolated Younger infants more likely to get complete workup, and to have more than one source of infxn Leading cause of ALL SBI/UTI was E. Coli, followed by GBS

o Most common organisms overall = E. Coli > GBS> Klebsiella> Enterococcus> Enterobacter> S. aureus> S. pneumo> salmonella

o Bacteremia: S. aureus>Enterococcus, klebsiella, salmonella, S. pneumo o Meningitis: S. pneumo > Klebsiella o NO Listeria

Microbiology of SBI/UTI

• SBI and UTI in this age group are caused primarily by E. Coli, followed by Group B Streptococcus (GBS) o E. Coli has replaced GBS as the most common cause of SBI/UTI (Greenes, Biondi, Schwartz) o Additional causes of UTI include Klebsiella, enterococcus o Additional causes of SBI include S. aureus, enterococcus, and other enteric gram-negatives o GBS, E. Coli and S. pneumo are most likely to cause meningitis o Listeria is now a very rare cause of neonatal SBI and has not be reported in recent large cohort studies

(Greenhow 2014, Biondi 2013) • Empiric antibiotics

o Gentamicin: Good coverage for E. Coli and GBS, as well as the other gram negatives Less effective for S. aureus

o Cefotaxime: Good broad-spectrum coverage for the major organisms causing SBI/UTI in neonates (E. coli,

GBS, MSSA, enteric gram negatives, salmonella) Ceftriaxone should be avoided in the neonatal period due to potential displacement of bilirubin


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o Ampicillin: Previous antibiotic recommendations usually include ampicillin for Listeria coverage While Listeria is rarely found, enterococcus is an emerging pathogen – ampicillin provides good

enterococcus coverage. o Vancomycin:

S. pneumo is not typically seen until after 1 mo of age MRSA has not yet been seen as a cause of SBI in the otherwise well neonatal population. If MRSA or S. pneumo are suspected, vancomycin should be added.

Reliability of Low-Risk Criteria (LRC) in Neonates:

o “Low-Risk Criteria” (well-appearance, normal inflammatory markers [WBC, ANC, and/or CRP] and negative UA) cannot be reliably used to exclude SBI/UTI in neonates.

o Schwartz et al (2009): Rate of SBI in those meeting LRC = 6.2% (1 case of bacteremia/meningitis, and 13 cases of UTI) NPV for LRC was 93.8% NPV for –LE on UA was 94% NPV for well-appearing was 82.5% (improved with age)

o Greenhow: WBC a poor predictor: only those with E.Coli had higher WBC than controls o Biondi: 20% of those with + blood culture met LRC

Recommendations: Well-Appearing Neonates with FWS

1. Principles: UTI is the most common occult bacterial infection found in febrile neonates, and a normal urinalysis has good

but not perfect negative predictive value in this high-risk population While incidence of SBI in this age group has declined in recent years, appearance and laboratory values are

still poor predictors of SBI 2. Reasonable management strategies include:

Option 1: Most conservative strategy Full sepsis workup (urine, blood, CSF cultures); admit for IV abx for 72h (see #3 for empiric abx)

Option 2: Cautious risk stratification strategy Obtain cath urine for urinalysis AND culture, and obtain inflammatory markers/blood cultures If UA is + OR if inflammatory markers are abnormal:

o Obtain LP and start IV antibiotics If UA negative AND inflammatory markers are normal (all LRC met):

• Obtain blood cultures, and admit for 24 hours after last documented temp, without starting antibiotics. If clinically well and blood cx negative at 24 hrs, may DC home with close follow up (+ RVT supports viral etiology)

3. Empiric antibiotics for suspected UTI/SBI in febrile neonates: <21 days: ampicillin and cefotaxime is preferred; ampicillin and gentamicin is alternate If >21 days AND not jaundiced: consider ceftriaxone alone Continue antibiotics until all cultures are negative for at least 48 hours

4. In neonates who are ill appearing or have CSF pleocytosis, also start acyclovir and send CSF for HSV PCR. HSV is most likely in infants who have a maternal history of HSV and/or present with seizures, skin/mucous

membrane lesions, or signs of disseminated disease (elevated LFT’s, etc) ▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪ 2. INFANTS: 1-3 MONTHS, T>38: Background:

• After 1 month of age, S. pneumo takes over as the most common cause of SBI. o However, SBI from E. Coli and late-onset GBS can still occur in this age group

• Since the introduction of PCV-7 and PCV-13, large studies of febrile infants in this age group, although unimmunized, have shown a reduction in SBI, likely corresponding to herd immunity

• However, even well-appearing febrile infants < 3 months of age may have SBI or UTI o While at lower risk than neonates, they still have decreased ability to localize infection and show specific

symptoms of illness


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Evidence: • UTI:

o The risk of UTI in febrile infants in this age group is still HIGH (about 9% overall: 20% in uncircumcised boys, 10% in girls and 2% in circumcised boys)

o Laboratory tests such as WBC count are NOT reliable to rule out UTI in this population o Collection of urine

Urine should always be collected by catheter, if possible • Risk of false positives AND false negatives with bag UA/culture

Urinalysis and urine culture should always be performed • While NPV better than in neonates, still insufficient to R/O UTI in these high-risk infants

• SBI o Since the introduction of PCV-7, SBI (mostly due to pneumococcus) has decreased, likely due to herd

immunity. o Pre-PCV-7 rates of SBI ranged from 2-6% in this age group, current rates are reported at 1-3% (primarily

associated with UTI) o Meningitis has also decreased since PCV-7; rates in this age group estimated at~4/1000 (Bonsu, 2003)

• Diagnostic tests: o Urinalysis

Recommended in all febrile infants in this age group, as UTI is the most common bacterial infection associated with FWS.

NPV of negative UA is < 100%, but improves as pretest probability decreases (older age, lower fever, circumcision in boys)

• In high-risk infants, always send urine cx even if UA is negative o Rapid Viral Tests

Availability of rapid viral testing for common viruses such as RSV, influenza, parainfluenza and adenovirus has added an additional option for making a diagnosis of viral source for fever.

Studies to date suggest that young infants with a positive viral test are at very low risk for SBI, and at lower (but still clinically significant) risk of UTI than those with a negative test (Byington, Rocholl, Bonner)

Eg: a recent study by Krief et al (2009) enrolled 844 infants <60 days. • SBI lower in infants with + influenza RVT than those with neg RVT • SBI: 0 vs 3.1%; UTI: 2.4% vs 10.8% • A positive influenza test had a NPV of 97% for UTI, 100% for SBI.

o Serum lab tests Multiple markers have been evaluated as predictors of SBI in febrile infants. Early guidelines (pre-PCV) evaluated WBC count as a way to stratify infants into high or low risk

categories (Baraff, 2000, Bonsu 2003, Hsiao 2005) Newer studies have focused on the use of other markers such as CRP and procalcitonin

(Andreola 2007, Maniaci 2008, Lacour 2008). In general, these studies show that infants with abnormal WBC (>15 or < 5K) procalcitonin (>0.5

ng/mL) or CRP (>20-30 mg/L) have a higher risk of SBI, but NPV is not sufficient to R/O SBI Overall, studies of febrile young infants suggest that there is no single lab value or clinical

finding that reliably distinguishes children with serious infection from those without (Craig 2010, Van de Bruel 2010, Thompson 2009).

o Lumbar puncture Not recommended in well-appearing infants meeting low risk criteria, due to the extremely low

rate of meningitis in that group In infants with a + UA as their only + finding, while E. Coli bacteremia may occur, meningitis is

extremely rare if the child is well-appearing • Paquette (2011) studied 392 infants <90 days with FWS

o Total of 4 cases of meningitis o ALL ill-appearing and with abnormal labs, one with + UA

• Schwartz (2009) o 2 cases of UTI/bacteremia/meningitis (2% of those with UTI) o Both of these neonates were ill-appearing


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Recommendations: Well-Appearing Infants 1-3 Months with FWS

1. Cath UA and urine culture on all infants If UA is positive (for LE or nitrites), begin treatment for pyelonephritis.

PO antibiotics sufficient if > 2 months and able to tolerate PO Send blood culture and admit if < 2 months, consider LP Admit if unable to tolerate PO antibiotics

If UA is negative, send urine for culture (always send urine culture even if UA negative in this age group) If clinical suspicion of viral infection, consider rapid viral testing (RSV, influenza, etc) If viral test +, patient can be managed with close F/U only

2. If UA and RVT negative, check inflammatory markers (CBC/CRP/procalcitonin) Inflammatory markers normal: close outpatient follow up Inflammatory markers abnormal (WBC >15 or <5 or elevated CRP/PCT):

Obtain blood cx and give abx (ceftriaxone IM or IV) Close outpatient follow up for 48 hrs while blood cultures are pending Admit if concern about ability to follow up

3. Perform Lumbar puncture in any irritable or lethargic child, and strongly consider if giving antibiotics (eg: for elevated inflammatory markers)

If CSF pleocytosis, start IV ceftriaxone (100mg/kg/day) Pretreat with IV dexamethasone (0.15mg/kg q6h) if > 2 months

4. Follow up as outpatient the next day if antibiotics are given; admit if unable to follow up. ▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪ 3. INFANT/CHILD 3-36 MONTHS, T>39 Background:

• UTI is much less common in boys in this age group, but continues to occur in girls • S. pneumo now takes over as the most common cause of SBI, but is itself very rare now in the PCV era

Evidence • UTI:

o Prevalence overall in girls <24 months with FWS is 5-10%. o Risk of UTI is very low (<1%) in circumcised boys > 3 mo of age, and all boys > 6 mo of age. o In this age group, in whom risk of UTI is low/moderate, a negative UA can be used to rule out UTI o No single serum test or clinical finding can sufficiently R/O UTI (Herz, Rudinsky, Craig)

• Occult Bacteremia o Unvaccinated Infants (those with < 2 doses of PCV/Hib OR < 2 weeks from 2nd dose)

Post-PCV-7, multiple studies have shown that occult bacteremia is now extremely rare, even in unvaccinated infants (Rudinsky,2009; Herz, 2006, Craig 2010)

These studies also confirm that neither WBC nor height of fever reliably distinguished infants with occult SBI from those without (likely because bacteremia occurred in <1% of infants)

o Vaccinated infants: Post-licensure studies of SBI in vaccinated populations show a risk of SBI of <1% for children in

this age group Serum labs are unlikely to impact management in the otherwise healthy child, and have been

shown to be poor predictors of SBI. (Rudinsky, 2009, Herz, 2006, Craig, 2010) • Meningitis

o Occult meningitis is extremely rare in this age group o In infants with clinical symptoms of meningitis, lumbar puncture should be performed o Several investigators have attempted to develop scoring systems for distinguishing bacterial from aseptic

(viral) meningitis in infants/children with CSF pleocytosis 5-item Bacterial Meningitis Score (BMS) - Nigrovic (2002):

1. + CSF gram stain (2pts) 2. Seizure with this illness 3. Serum neutrophil count ≥10,000 4. CSF protein ≥ 80mg/dL 5. CSF neutrophil count ≥1000


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BMS of 0 had an NPV of 100% in infants > 2 mo (99.5% in infants < 2 mo) Subsequently validated after PCV-7 (Nigrovic 2007, Dubos 2006, Dubos 2008)

Recommendations: Well-Appearing Infants/Children 3-24 Months with FWS

1. U/A and urine culture if T>39 for > 48 hours for all girls, and uncircumcised boys <6 months. Consider in circumcised boys 3-6 mo and uncircumcised boys 6-12 mo, especially if fever >48 hours If the U/A suggests UTI (+LE and/or nitrites), send culture and begin outpatient treatment for

pyelonephritis (1st dose can be given in ER: IM/IV or PO) A negative U/A can be used to rule out UTI in lower risk infants

2. Inflammatory markers and blood cultures are NOT routinely recommended in this age group 3. Consider sending CBC, blood culture and/or CRP/procalcitonin if:

More than one concerning factor (T>39.5, infant < 6 mo, unimmunized, fever > 48 hrs) 4. Give antibiotics (ceftriaxone IM/IV) if:

WBC >15, or other inflammatory markers/clinical signs concerning for SBI (see above) and high concern 5. Perform LP if:

Child is irritable or lethargic, and consider prior to giving antibiotics (ie: for another infection) If CSF pleocytosis, give dexamethasone 0.15 mg/kg q6h and start IV ceftriaxone 100mg/kg/day

In children > 2 mo of age with CSF pleocytosis (≥7 WBC/mm3) without previous antibiotic treatment, a BMS of zero is reassuring for the absence of bacterial meningitis.

These patients can likely be safely managed in one of 2 ways: 1. Admitted for observation, without antibiotic treatment 2. Treated with empiric antibiotic treatment until CSF cultures are final.

• The BMS should NOT be used routinely in infants < 2 mo age group 6. Even vaccinated children may have SBI: assure close clinical follow-up for all children


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▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪ SUMMARY OF RECOMMENDATIONS FOR WELL-APPEARING INFANTS/CHILDREN WITH FWS

▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪ 5 questions to ask about every febrile child 1. Is this child toxic (ill-appearing)? 2. Is there a source for the fever? 3. What is this child’s immunization status? 4. If a boy, is he circumcised? 5. What is the likelihood of good follow-up?

1. Who should get a U/A and/or culture*?

• All infants <3 months, T>38 o Send cath specimen, and send culture even if U/A is negative

• Girls 3-24 months, if T>39 for > 2 days • Uncircumcised boys <6 months, if T>39 for > 2 days

*Catheter specimen if: < 6 mo of age, or if antibiotics will be started 2. Who should get blood cultures?

• Any lethargic, irritable or toxic-appearing febrile infant/child, of any age • Age <1 month, T>38 • Age 1-3 months,

o If UA positive and < 2 months o if UA negative AND RVT negative AND/OR inflammatory markers abnormal

3. Who should get inflammatory markers drawn? • Age 1-3 months, if UA negative and rapid viral test negative

4. Who should get an LP? • Any lethargic, irritable or toxic-appearing febrile infant/child, of any age • Age <1 month, T>38: all infants, unless being admitted/observed without antibiotics • Age 1-3 months, T>38: strongly consider prior to giving antibiotics (eg: for UTI), especially if difficult to assess

clinically, or if inflammatory markers are abnormal 5. Who should get antibiotics?

• Any lethargic, irritable or toxic-appearing febrile infant/child, of any age • Age < 1 month, T>38: all infants, after collecting cultures

o Antibiotics may be held in neonates meeting all LRC, who are being observed • Age 1-3 months, T>38:

o If WBC count >15 or <5, procalcitonin >0.5 ng/mL, or CRP >20-30 mg/L (suspected SBI) or o U/A positive for LE or nitrites (suspected UTI)

• Age 3-36 months, T>39: U/A positive for LE and/or nitrites (suspected UTI: outpatient abx OK) • Choice of antibiotics based on age, suspected source/etiology for infection:

o Suspected UTI/SBI in infant < 1 mo of age: amp/cefotaxime or amp/gentamicin o Suspected UTI/SBI in infant > 1 mo of age: ceftriaxone 50mg/kg IM/IV o Suspected meningitis:

Give dexamethasone prior to antibiotics (0.15mg/kg q6h) if > 2 mo of age Ceftriaxone 100mg/kg/day Add vancomycin if suspected S. pneumo meningitis (ie: CSF pleocytosis in infant > 1 mo) Add acyclovir if suspected HSV sepsis/meningitis (ie: CSF pleocytosis in infant <1 mo)


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▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪ REFERENCES:

▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪▪ 1. ACEP Clinical Policies Committee and the Clinical Policies Subcommittee on Pediatric Fever. Clinical policy for

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3. Baraff LJ. Management of fever without source in infants and children. Ann Emerg Med. 2000; 36(6): 602-614 4. Bilavsky E, et al. Should complete blood count be part of the evaluation of febrile infants aged ≤2 months? Acta

Paediatr 2010; 99: 1380-1384 5. Biondi E, et al. Epidemiology of bacteremia in febrile infants in the United States. Pediatrics 2013; 132 (6): 990-996 6. Black SB, Shinefield HR, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine

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