1. health and fitness
2. disease

Febrile Neonates, Infants and Children
Is it time to forget what you’ve learned in residency
Is it time to revaluate your approach
Dr. David Turkewitz
Chairman Pediatrics York Hospital
Director Pediatric Emergency Medicine York Hospital
Objectives
—  Febrile babies
—  Practice variation
—  Lessons to be learned from primary care
—  Clinical judgment, labs
—  What to do….
Objectives
—  FYI
—  UTI, urethral catheterization, urine dipstick
—  Blood cultures for well appearing febrile 3 to 36 month old
children
—  CBC, acute phase reactants, cytokines, surface cell markers
and more
—  Fever reduction & decision making
—  Fever for more than 5 days without obvious focus
—  HSV….
—  Azithromycin…what good is it
—  Look familiar…febrile
neonates, do lots of stuff;
start antibiotics and
admit….
Hamilton, et al. Evaluation of fever in infants and young
children. Am Fam Physician 2013
Observing infants
Yale Observation Score
Observation Item
1 (Normal)
Point Value
3(Moderate Impairment)
Quality of cry
Strong with normal tone or
content and not crying
Cries briefly, then stops or
content and not crying
If awake: stays awake or if
asleep and stimulated, wakes
up quickly
Pink
Whimpering or sobbing
Reaction to parent
stimulation
State variation
Color
Hydration
Response (talk,
smile) to social
overtures
5 (Severe Impairment)
Weak or moaning or high
pitched
Cries off and on
Continual cry or hardly
responds
Eyes close briefly if awake or Falls to sleep or will not
awakes with prolonged
rouse
stimulation
Pale extremities or
Pale or cyanotic or mottled
acrocyanosis
or ashen
Skin normal, eyes normal and Skin and eyes normal and
Skin doughy or tented and
mucous membranes moist
mouth slightly dry
dry mucous membranes or
sunken eyes
Smiles or alert (< 2 mo.)
Brief smile or alert briefly
No smile; face anxious, dull,
(< 2 mo.)
expressionless or no alerting
(< 2 mo.)
Score > 10 equals 13 times greater occurrence of serious illness than if < 10
(sensitivity = 88%; specificity = 77%)
2.7% of patients with a score <10 have a serious illness
92.3% with a score >16 have a serious illness.
Pediatrics 1982 , Vol. 70, Page 806
Practice variation
Aronson, Thurm, Alpern, et al.
Variation in care of the febrile young infant < 90 days in US Pediatric
Emergency Departments.
Pediatrics 2014;134:667
Studied patient level variation in management and outcomes of
infants < 90 days of age with dx of fever across 37 Pediatric ED’s
Background
—  Febrile infants undergo diagnostic evaluation urine, blood, CSF
(Baker, Bell, Avner NEJM 1993); (Baskin, Fleisher, O’Rourke. J Peds 1993); Jaskiewicz, McCarthy,
to dichotomize low vs. high risk for SBI. All
studies done > 20 years ago….and testing was similar but not
exact; and management and need for hospitalization varied
Richardson, et al. Pediatrics 1994)
Objectives/Study Cohort
—  Describe variation in management within and across Children’s
Hospital Emergency Departments including testing, treatment,
hospitalization rates and outcomes of febrile infants < 90 days old
—  Evaluate patterns of variations across 3 age groups
—  < 28 days of age
—  29-56 days of age
—  57 -89 days of age
—  35,070 enrolled
—  22%
< 28 days
—  42.9%
29-56 days
—  35.1%
57-89 days
Results
< 28 days
n = 7712
29-56 days
n = 15,033
57-98 days
n = 12,325
Urine + blood + CSF
72.0%
49.0%
13.1%
Urine + Blood
5.1%
27.3%
42.1%
Urine
1.4%
3.2%
12.3%
Other combinations of Urine,
Blood, CSF
3.6%
4.2%
4.9%
None
17.9%
16.2%
27.7%
CXR
28.2%
29.0%
27.7%
Laboratory Testing
Radiographic Testing
Results
< 28 days
n = 7712
29-56 days
n = 15,033
57-98 days
n = 12,325
n = 6035
78.3%
n = 6628
44.1%
n= 2015
16.3%
Ampicillin + 3rd generation cephalosporin
72.0%
49.0%
14.3%
Ampicillin + Gentamicin
5.1%
27.3%
0.8%
Ampicillin + 3rd generation cephalosporin
and gentamicin
1.4%
3.2%
2.4%
3rd generation cephalosporin
3.6%
4.2%
42.8%
Other IV or IM antibiotic combination
17.9%
16.2%
12.6%
No IV or IM antibiotics
3.9%
12.3%
27.1%
Acyclovir
32.3%
12.4%
5.0%
n = 1,677
21.7%
n = 8,405
55.9%
n = 10,310
83.7%
Ceftriaxone
1.4%
20.3%
14.1%
Other IV or IM antibiotic combination
2.7%
1.0%
0.2%
No IV or IM antibiotics
95.9%
78.7%
85.7%
Hospitalized (n = 14,678)
Discharged from the ED n = 20,392
Results
< 28 days
n = 7712
29-56 days
n = 15,033
57-98 days
n = 12,325
p
Serious bacterial illness
(UTI, bacteremia/sepsis, pneumonia,
bacterial enteritis)
11.1%
7.5%
7.7%
< .001
3 day ED revisits among discharged
patients
3.0%
6.6%
7.1%
< .001
3 day ED revisits among discharged
patients resulting in hospitalization
2.3%
2.3%
1.4%
< .001
Outcomes
—  22 (0.06%) with HSV infection
—  6 deaths (3 < 28 days; 3 29-56 days of age)
Discussion
—  “Substantial…hospital level variation wide was
observed….without concomitant differences in outcomes.”
Jain, Cheng, Alpern, et al.
Management of febrile neonates in US pediatric
emergency departments.
Pediatrics 2014 Feb; 133(2):187-195.
—  Patients 0-28 days evaluated in the pediatric emergency
department diagnosed with fever
Results: Variation between hospitals in
Recommended Testing
Results: Variation in Recommended Treatment
Results: details of antibiotic
treatment
Variation of the recommended Empirical Antibiotic regimen between those
who were discharged and those who were admitted
Results: Variation in recommended
management, treatment and admission
Median hospital: 67.5% (IQR 58.9-76.5)
—  8.4% of discharged neonates had recommended testing compared to 85.6% of admitted
neonates
—  2.8% no testing, no treatment, and discharged from the ED
Results
—  Of the 269 neonates with serious illnesses 223 (82.9%) received
recommended management (“full” evaluation, treatment, admission)
—  Of the 369 febrile neonates discharged form the ED at the
index visit, only 3 had a final diagnosis of a serious illness
Discussion
—  “High rates of SBI in admitted patients but low return rates for missed
infections in discharged patients suggest a need for additional studies
to understand variation from the current recommendations”
What About Primary Care Physicians in Their Office
Pantell , Bergman, Takayama, Newman, Bernzweig, Spitalny, Finch, Wasserman.
Detecting Serious Bacterial Illness in Febrile Infants: Do Guidelines Help?
Pediatric Research in Office Settings (PROS)
APA Annual Meeting 2000
Pantell,Newman, Bernzweig, et al. Management and outcomes of care
of fever in early infancy JAMA 2004;291:1203-1212
Sites and Patients
—  Sites and Practitioner Participants – PROS network
—  Patient participants –
—  Infants 3 months or younger > 380C+ at home or in clinician’s office
(maximal rectal temperature in past 24 hours).
—  3066 infants met eligibility criteria
Results
—  64% managed exclusively outside of the hospital
Sensitivity and specificity of different approaches to
identify infants with bacteremia/bacterial meningitis
PROS practitioner’s outperformed models 1, 2 3, 4 and 5
Conclusions
—  if close follow up care is attainable, the management by
experienced clinicians using clinical judgment may be more
appropriate than strict adherence to published
recommendations with the potential benefit of reducing costs,
pediatric pathogenesis (Turk added) and iatrogenic morbidity
Febrile Neonates – Turk’s take
—  If in your clinical judgment the baby looks ill, then full
evaluation, antibiotics and admission
Febrile Neonates – Turk’s take
—  If in your clinical judgment the baby looks well; has nothing
else worrisome about the history, parents are capable of shared
decision making, follow up can be assured
—  reasonable to consider no laboratory or imaging studies
—  reasonable to consider a partial evaluation - CBC, CRP, urinalysis and
culture (girls and uncircumcised boys).
—  If evaluation suggests serious bacterial infection à admit and
parental antibiotics
Febrile 1 to 3 month old infants – Turk’s take
—  If in your clinical judgment the baby looks ill, then full
evaluation, antibiotics and admission (lumbar puncture…
clinical judgment)
Febrile 1 to 3 month old infants – Turk’s take
—  If in your clinical judgment the baby does not look ill
appearing; has nothing else worrisome about the hx, parents
capable of shared decision making, f/u assured
—  very reasonable to consider no testing, no treatment
—  very reasonable to consider a partial evaluation after discussion with the
parents and assurance of close follow up-- CBC, CRP, urinalysis and
culture (girls and uncircumcised boys).
—  If evaluation suggests serious bacterial infection à parental
antibiotics, consider admission or IM ceftriaxone 75 mg/kg and
discharge
FYI – think UTI
—  PROS Study incidence of UTI’s – young infants
—  girls 7.5%
—  uncircumcised boys 11.5%
—  circumcised boys 1.3%
—  AAP Practice Guideline UTI. Pediatrics 2011
—  prevalence of UTI in febrile infants who have no source for their
fever ~ 5%
—  prevalence of UTI among febrile infant girls is ~ 2.2 times that
among febrile infant boys
—  uncircumcised boys is 4 to 20 times higher than that for circumcised
boys, whose rate of UTI is only 0.2% to 0.4%.
FYI -- catheterizing babies
—  Is this difficult for your staff…
—  What’s the incidence of contaminated cultures?
FYI – urine dipstick
Kanegaye, Jacob, Malicke. Automated Urinalysis and Urine Dipstick in
the Emergency Evaluation of Young Febrile Children. Pediatrics 2014
—  Leukocyte counts ≥ 100/microL
—  Sensitivity: 86%
—  Specificity: 98%
—  Bacterial counts ≥ 250/microL
—  Sensitivity: 98%
—  Specificity: 98%
—  POC Urine dipstick with ≥ 1+ LE or positive nitrite:
—  Sensitivity: 95%
—  Specificity: 98%
FYI -- blood cultures, fever infants > 3
months of age
—  Rates of invasive Hib infection in
—  Invasive pneumococcus infection in
children < 5 years have fallen by more
than 99% since the 1990’s.
children declined by 77% between
1998 to 2005
—  CDC. Progress toward elimation of
—  CDC. Invasive pneumococcal disease in
haemophilus influenza type b invasive
diease amongh infants and children –
United States; MMWR
2002;11:234-237
children 5 years after conjugate vaccine
introduction – eight states, 1998-2005.
MMWR 2008;57:144-148
—  Plummeting positive predictive value compared to original studies
—  Correct outcome measure not bacteremia; rather bacteremia leading to
serious illness
—  No blood cultures unless…..underlying predisposition, focal infection
with higher risk bacteremia, ill appearing, no focus of infection,
considering IM ceftriaxone
FYI – fever reduction, clinical decision
making
OK if you want to get repeat temperatures…not sure who this
helps…can make things worse for the parents…not useful in
clinical decision making
FYI -- laboratory tests
past…present…future
Fibrinogen
—  The sedimentation test
CRP
—  Acute phase reactant synthesized by liver
—  It takes 10 to 12 h to see changes from
baseline
—  T1/2 of 24-48 h
—  Useful for monitoring response to
treatment
—  Serial measurements
—  Sensitivity: 70-93%
—  Specificity: 78-94%
Procalcitonin
—  Like CRP, an APR synthesized in
hepatocytes
—  Rises within 4 h after exposure to bacteria
—  Peaks at 6-8 h; elevated for at least 24 h
—  T1/2 of 25-30 h
—  Unlike CRP, not elevated in:
—  MAS, trauma, ischemia, viral infections
—  Sensitivity: 83%
—  Specificity: 89%
Andreola, et al. Procalcitonin and C-reactive protein as diagnostic markers of severe
bacterial infections in febrile infants and children in the emergency department. Ped
Infect Dis J 2007
Procalcitonin vs. CRP – evaluating febrile infants
and children
Yo CH, et al. Comparison of the test characteristics of procalcitonin to C-reactive protein
and leukocytosis for the detection of serious bacterial infections in children presenting with
fever without source: a systematic review and meta-analysis. Ann Emerg Med 2012 Nov;
60(5):591-600.
•  Procalcitonin
•  a superior discriminative capability compared with CRP
and WBC count as demonstrated by AUROC
Cytokines
Emerging Biomarkers
—  More rapid response than
acute phase reactants
—  Interleukin -1 Beta
—  Interleukin-6
—  Interleukin-2 soluble
receptor
—  Tumor necrosis factor alpha
—  More rapid response than
acute phase reactants
Diagnostic
test
Sensitivity
(%)
Specificity
(%)
IL-6
87
93
IL-8
91
93
TNF-α
75
88
—  Cell Surface
—  CD11 Beta and CD64
—  Expression within minutes
following exposure to
bacterial products
Diagnostic
test
Sensitivity
(%)
Specificity
(%)
CD11β
96-100
100
CD64
95-97
68
Emerging Biomarkers
—  Inter α inhibitor proteins
—  Proteases that protect from inflammation
—  Decrease in septic neonates
—  Help guide prognosis: [lower] = worse
outcomes
Diagnostic
test
Sensitivity
(%)
Specificity
(%)
IAIP
89.5
99
PPV
(%)
95
NPV
(%)
98
Shah, Padbury. Neonatal sepsis. An old problem with new insights. Virulence 2014
Samir S. Shah, MD, MSCE
CCRF Endowed Chair in Hospital Medicine
Cincinna; Children's Hospital Medical Center
Professor, Department of Pediatrics
—  “The PROS study was terrific and I think a good model that
might be reasonable to implement in areas where high phone
and in-person follow up rates can be achieved.”
—  “I am not aware of any pediatric places that use a bedside
procalcitonin…I think that will change in a few short years. I
agree that the early data suggest that it will have better
specificity than CRP and possibly better sensitivity.”
—  “I think a few things will happen over the next few years that
will change how we manage these young infants. There is a push
towards viral testing which I am not convinced will be the long
term solution. But I think additional studies of procalcitonin
will vindicate its inclusion as a major criteria for screening to
help determine whether an LP or antibiotics are warranted.”
—  On the horizon…. metabolomics and host cell response, the
latter is the subject of an ongoing PECARN trial and the
former is starting to attract attention. Neither can at the
moment be run within a time frame that makes them useful
as an ER tool but I think the technology will be there soon to
change how we think about risk in these young infants.
Metabolomics Society
—  “Metabolomics is a newly emerging field of "omics" research
concerned with the comprehensive characterization of the small
molecule metabolites in biological systems. It can provide an
overview of the metabolic status and global biochemical events
associated with a cellular or biological system. As such, it can
accurately and comprehensively depict both the steady-state
physiological state of a cell or organism and of their dynamic
responses to genetic, abiotic and biotic environmental
modulation.
FYI…fever for more than 5 days without obvious
source…Turk comments
Etiology
Caveats
—  Unlikely…multiple viral
—  History and Physical exam
or atypically prolonged
course
—  Adenovirus
—  Urinary tract infection
—  Pneumonia
—  Kawasaki
—  Laboratory testing
FYI – neonatal HSV infection
Think HSV if….test and treat
—  Hypothermia
—  Fever and lethargy
—  Elevated AST
—  Vesicular rash
Caviness, et al. The prevalence of neonatal herpes simplex virus infection compared with serious bacterial illness in hospitalized
neonates. Editorial by Kimberlin. J Peds 2008
— 
STUDY DESIGN: Retrospective prevalence study
— 
RESULTS: prevalence of neonatal herpes simplex virus (HSV) infections among neonates admitted to Texas Children's Hospital in a 5-year period.
—  10 neonates with HSV disease were identified
—  5 had a normal temperature in the ED, 3 were febrile, 2 were hypothermic.
—  Six neonates had skin rashes, all of which were vesicular.
Alanine aspartase (AST) levels were markedly elevated in the 3 neonates with disseminated HSV disease.
—  All subjects with neonatal HSV disease had either markedly elevated AST level with fever (n = 1), respiratory distress with hypothermia
(n = 2), fever and lethargy (n = 1), or vesicular rash with or without fever (n = 6).
—  CSF infection…mononuclear CSF pleocytosis
— 
FYI -- Azithromycin
—  Taste good, simple dosing, high safety profile….and covered wide
gamut of pediatric pathogens
—  And now…Azithromycin resistance
—  S. pneumoniae isolates displayed 56.7% susceptibility
—  H. influenzae isolates displayed 0% susceptibility
—  No longer recommended for AOM, sinusitis, community acquired
pneumonia
The Role of Azithromycin in Pediatrics
Infectious Diseases in Children, July 2014
Bell
Turk’s take: never use as solo antibiotic if suspect serious bacterial illness
Febrile Neonates, Infants and Children
Is it time to forget what you’ve learned in residency
Is it time to revaluate your approach
Dr. David Turkewitz
Chairman Pediatrics York Hospital
Director Pediatric Emergency Medicine York Hospital