infant fever, what’s old what’s new

Infant Fever, What’s Old Infant Fever, What’s Old What’s NewWhat’s New

Brian R. Moore, M.D., F.A.A.P.Brian R. Moore, M.D., F.A.A.P.

PEM Fellowship DirectorPEM Fellowship DirectorAssistant Professor, Departments of Assistant Professor, Departments of Emergency Medicine and PediatricsEmergency Medicine and Pediatrics

University of New MexicoUniversity of New MexicoHealth Science CenterHealth Science Center

October 12th, 2011October 12th, 2011

DisclosuresDisclosures

The 5 Second RuleThe 5 Second Rule

ObjectivesObjectives

• Assessment of Infants and Children <36 months of age with fever

• Understand the utility (or lack thereof) of diagnostic tests

• Understand the changing epidemiology of pediatric fevers without a clinically evident source (FWS)

• Develop an evidence based approach to evaluating and treating pediatric fever without source

ExclusionsExclusions

• What we are NOT talking about– “sick” looking kids– Children with chronic dx– Immunospressed children

• What is a “fever”

• Temperature taking methods

Case #1Case #1

• 21 day old female brought to the ED for fever• Temp 38.1, HR 152, RR 36, O2 Sat 95% RA,

Wt 3.8 kg• Term, NSVD, No URI Sxs, nl prenatal care and

birth hx, MOC GBS- neg• 2 y.o. sibling at home with URI• Exam- Alert, nonfocal, well appearing, NL exam• WHAT would you do?

EvaluationEvaluation

1. CBC/Diff

2. Blood Cx

3. LP/CX

4. UA/CX

5. Viral NP Swab

6. CXR

7. Hospitalize for IV Antibiotics

Predictive Models for FWSPredictive Models for FWSTo define Low Risk InfantsTo define Low Risk Infants

Philadelphia Rochester

Age 29-60 days <60 days

WBC <15,000 >5K, <15,000

Bands Band:Neut <0.2 ABCount <1500

UA <10 WBC <= 10 WBC

CSF < 8 WBC No LP

CXR Negative No CXR

Stool (If indicated) <= 5 WBC/hpf <= 5 WBC/hpf

Application to Infants < 4 Weeks Application to Infants < 4 Weeks of Age?of Age?

• Prospective study of 254 febrile infants < than 1 month• 5 of 32 (15.6%) who had SBI would have been classified

to be at low risk of having bacterial disease according to the Philadelphia criteria

• would falsely identify as many as 10 per 100 febrile neonates as having low risk of SBI

• concluded that febrile infants <1 month of age should include a complete evaluation for bacterial illness and the empiric administration of antibiotics

Baker MD, Bell LM, Arch Pediatr Adolesc Med. 1999;153:508-511.

Screening Tests < 28 Days?Screening Tests < 28 Days?

• 225 infants 1-29 days admitted with T>38.0

• SBI in 31– 6 missed by Philadelphia

criteria (Baker)– 8 missed by Boston criteria

(Baskin)

Kadish HA, Bolte RG, Tobey J, Loveridge B. Clin Pediatr 2000 Feb;39(2):81-8

Case #2Case #2

• 31 day old female brought to the ED for fever• Temp 38.1, HR 152, RR 36, O2 Sat 95% RA

Wt 4.3 kg• Term, NSVD, No URI Sxs, nl prenatal care and

birth hx, MOC GBS- neg• 2 y.o. sibling at home with URI• Exam- Alert, nonfocal, well appearing, NL exam• WHAT would you do?

EvaluationEvaluation

1. CBC/Diff

2. Blood Cx

3. LP/CX

4. UA/CX

5. Viral NP Swab

6. CXR

7. Empiric Antibiotics?

How to differentiate?How to differentiate?Boston, ’92

(Baskin)

Philly, ’93

(Baker)

Rochester, ’94

(Jaskiewicz)

# of pts 503 747 931

Age 28-89 d 29-56 0-60

Temp >38 >38.2 >38

WBC <20 <15 5-15

CSF for all Yes Yes No

Abx Yes No No

% in low risk 38.4% 41.3%

SBI in low risk 5.4 % 0.3 % 1.1 %

NPV 94.6% 100% 98.9%

Sensitivity ? 100% 92.4%

Diagnostic tests-CBCDiagnostic tests-CBC

• High wbc counts are 2-3X more common in those with bacterial vs. viral illness

• Positive predictive value for an elevated wbc count is 8-15% as viral illness far more prevalent than bacterial infection


• 955 infants 3-36 months, T > 39.0ºC had CBC & BC -> 27 had bacteremia– mean wbc in children with bacteremia 20,500– mean wbc in children without bacteremia 11,800

• Repeatedly shown: wbc >15,000 is 2-3X more common in bacterial than in viral infections

• However: – specificity 75% (too many FP) – sensitivity 60% (too many FN)

Jaffe DM, Fleisher. Pediatrics. 1991 May;87(5):670-4


• sensitivity: among those with bacteremia, how many are identified by the cutoff point?

• positive predictive value: among those identified by the cutoff point, how many have bacteremia?

TP

TP+FN

TP

TP+FP

WBC PerformanceWBC Performance

• Retrospective review of febrile infants 0-89 days who had CBC and Bld CX at the same time

• 1992-1999

• 38/3810 OB rate (1%)

• Tried to find a threshold of WBC that would help predict OB using AUC

Bonsu BK Ann Emerg Med. 2003;42:216-225

WBC Cutoff (1,000)

Bacteremia (N=38) Sens, %* (95% CI)

No Bacteremia (N=3,772) Spec, %* (95% CI)

>5 30 79 (63-90) 201 5 (4-6) >10 23 61 (43-76) 1,581 42 (40-44) >15 17 45 (29-62) 2,928 78 (76-79) >20 9 24 (11-40) 3,517 93 (92-94) >25 5 13 (4-28) 3,700 98 (97-99) >30 2 5 (1-2) 3,758 99 (99-10)

<5 or >15 25 66 (49-80) 2,727 72 (71-74) <5 or >20 17 45 (29-62) 3,316 88 (87-89)

*Sensitivity is the number of bacteremic infants with test results above the WBC count cutoff. *Specificity is the number of nonbacteremic infants with test results below the WBC count cutoff.

ResultsResults

• The odds of bacteremia were not decreased substantially at any cutoff and were increased only modestly at values outside published norms of the test

• Conclusion: The total peripheral WBC count is an inaccurate screen for bacteremia in febrile young infants; thus, decisions to obtain blood cultures should not rely on this test

WBC and BacteremiaWBC and Bacteremia

• Even among TP’s most will have an infection that is likely either – to clear spontaneously (bacteremia) or

– to respond to tx without serious sequelae even if dx delayed (pneumonia, cellulitis, UTI)

WBC and SBIWBC and SBI

• PPV for more serious infections (meningitis, osteomyelitis, septic arthritis) is much lower

• Majority of children with bacterial meningitis have a WBC < 15,000

• Therefore, NEVER use CBC results to determine the need for an LP

Diagnostic test-blood cultureDiagnostic test-blood culture

• Identify children with OB at risk for more serious sequelae (meningitis)

• Consider – most bacteremia clears spontaneously– delayed dx without serious sequelae

(pneumonia, UTI, cellulitis)– value of early diagnosis -- ED vs. PCP– sensitivity of single culture 45-70%

Diagnostic test-blood cultureDiagnostic test-blood culture

• 2-4% false positive rate – 10-20x FP to TP rate

• Side effects– Cost– Additional testing– Unnecessary hospitalizations and antibiotics– Side effects of antibiotics

What about UTI’s?What about UTI’s?

• Equal gender incidence under 3 months

• Over 3 months, more common in females

• Positive urine cultures - FWS– male infants <6 mo: 7%– female infants < 2 years: 8%

• Incidence as high as 17.5% of white girls under 24 months T39c

Urine Specimens Acceptable for Urine Specimens Acceptable for CultureCulture

• Suprapubic aspiration

• Cathetererized specimen

• Clean mid-stream void

Urine Specimens Unacceptable Urine Specimens Unacceptable for Culturefor Culture

• Bagged specimens of any type at any time– Never– Ever

• Negative UA does not rule out UTI!

Diagnostic Tests-UrinalysisDiagnostic Tests-Urinalysis

• Routine urinalysis not sensitive enough to use as a screening tool– pyuria (by LE or micro): 80-85% sensitivity and

specificity– nitrite: 85-90% specificity, poor sensitivity

• Gram-stained smear of urine sediment is a sensitive screen (>95%)

• Can use as a screen, but urine culture is still gold standard

Urine CultureUrine Culture

• Clean Catch >100,000 cfu/ml

• Straight catheterization > 10,000 cfu/mL

• SPA > 1,000 cfu/mL

Question #1Question #1

Bag urine specimens have a False Positive Rate of approximately:

1. 35%

2. 50%

3. 85%

Question #1Question #1

Bag urine specimens have a False Positive Rate of approximately:

1. 35%2. 50%3. 85%

ALWAYS COLLECT URINE BY CATH OR SUPRAPUBIC ASPIRATION (U/S GUIDED IS BETTER)

Question # 2Question # 2

Which of the following has the highest sensitivity for detecting Urinary Tract Infection?

1. Urine dipstick for LE or Nitrite

2. Gram stain for bacteria on uncentrifuged urine

3. Pyuria (>5 WBC) on centrifuged urine.

Question # 2Question # 2

1. Urine dipstick for LE or Nitrite-Sensitivity 0.88

2. Gram stain for bacteria on uncentrifuged urine

-Sensitivity 0.93, false positive rate .05

3. Pyuria (>5 WBC) on centrifuged urine.-Sensitivity 0.67

Gorelick (1999)

That Fever ArticleThat Fever ArticleVolume 92(1) July 1993 pp 1-12Practice Guideline for the Management of

Infants and Children 0 to 36 Months of Age

With Fever Without Source.

Baraff, Larry J.; Bass, James W.; Fleisher, Gary R.; Klein, Jerome O.;

McCracken, George H. Jr.; Powell, Keith R.; Schriger, David L.

• “Expert” panel• Meta-analysis that pooled data

from RCT and observational studies + opinion

• pre-Hib vaccine data

Harriet LaneHarriet Lane

Baraff LJ Ann Emerg Med 2000;36[6]:602–614

Harriet LaneHarriet Lane

> View this image in its location within the book

Baraff LJ Pediatr Ann 1993;22[8]:497–498, 501–504

Main Sources of Occult BacteremiaMain Sources of Occult Bacteremia

• 19931. Strep. Pneumo 70%2. H Flu 15%3. N. Meningitidis 3%4. Salmonella 1-2%

Baraff and Lee 1992

• 20021. Strep. Pneumo 84%

2. Group A Strept. 5%

3. N. Meningitidis 3%

4. Salmonella 3%

Bandyopadhay 2002

H. influenzaeH. influenzae type b bacteremia type b bacteremia

• Routine use of the vaccine in infants: 1990

• 1989-1995: Hib invasive disease in US

children <5 yr

declined 95%• CA surveillance:

– 1990: 13.9/105

– 1996: 0.1/105

Streptococcus pneumoniaeStreptococcus pneumoniae

• 65-85% of occult bacteremia in children• usually cleared by host • most common cause of bacterial meningitis in

children• PCV7 FDA approved 2001• Prevnar was expected to eliminate (< 6 yr olds)

– 86% of bacteremia

– 83% of meningitis

– 65% of OM

The Future Guidelines?The Future Guidelines?

• “The widespread use of this vaccine (PCV7) will make the use of WBC counts and blood cultures and empiric antibiotic treatment of children with fever without source who have received this vaccine obsolete.”– Baraff, 2000

D’OH WAKE UP!!!!!!D’OH WAKE UP!!!!!!

• YOU IN THE BACK ROW WAKE UP!!!!!

YOU ARE MISSING A VERY GOOD LECTURE

PROSPROS

• 3066 infants > 3 months old in Primary Care with T >38.0

• Feb 95 to April 98• Bacteremia in 1.8% of infants• Bacterial meningitis on 0.5%• Well appearing infants with fever >38.6 had a

rate of OB/BM 0.4%• Practitioners followed current guideline 42% of

episodes

JAMA. 2004;291(10):1203-1212

PROSPROS

• They tx’ed 61/63 BM initially

• Conclusions- Pediatric clinicians use individualized judgment in tx febrile infants

• Relying on current clinical guidelines would not have improved care but would have resulted in more hospitalization, lab testing, and antibiotic use.

Peds ED AdherencePeds ED Adherence

• TCH Denver 2004-06

• 167 patients total, 79 29-59d, 88 60-90d

• 19 ‘SBI’ (11%)– OB 3/1– UTI 11

– BM 0

• Complete SBI W/U as by ‘guideline’– Age 29-59 day old 49%– Age 60-90 day old 8%

Study ConclusionsStudy Conclusions

• We found that pediatric emergency medicine physicians in our institution do not follow existing practice guidelines for the workup of fever in young infants.

• Whether this reflects a lack of awareness of the guidelines or more likely, a culture that favors test minimization over risk minimization, could not be determined from this study.

• We also found that these physicians obtained fewer CBCs, blood cultures, urine cultures, CSF cultures, and viral studies in the infants aged 60 to 90 days than in those infants aged 28-59 days.

SBI in post PCV7SBI in post PCV7

• 985 children, 0-24 months

• Dec 2002- Dec 2003

• Tertiary care military hospital in San Diego

• SBI defined at PNA, UTI, OB, BM

• 79% had received at least one PCV7

Rudinsky SL Acad Emerg Med 2009; 16:585–590

SBI in post PCV7SBI in post PCV7

• OB 0.7%

• No statistical difference in the WBC count between the SBI and Non-SBI groups (p=0.055)

• No WBC cutoff on the ROC curve proved to be an accurate predictor of SBI

• No statistical difference in mean temp between SBI and Non-SBI groups

““SBI”SBI”

• 82 PNA

• 45 UTIs (33F, 12M)

• 5 OB (690 pts had bld cx, 70%)– Contaminated Blood culture rate- 4.9%!– Enterococcus 2, E. Coli, GBS, S. pneumo– S. pneumo OB 0.14%

• 0 meningitis

Herd Immunity?Herd Immunity?

• OB 0.14% - 0.17% but vaccination rate 50-86% (79% in this study)

• Herd immunity for invasive pneumoccocial disease has also been suggested

• Serotyping in both studies were unavailable

SBI 29-90 daysSBI 29-90 days

PROS PROS Denver Denver San Diego

Age 1-2 months 2-3 months 29-59d 60-90d 1-3 months

# patients 1220 1071 79 88 59

Bacteremia 18 8 3 1 1

B. Mngtis 5 (0) 0 0 0 0

What Should I Do?What Should I Do?

• Are you a risk minimizer or a test minimizer?

• Editorial article by Green and Rothrock– suggests that the controversy lies not in the

data itself, but rather in how it is interpreted by the individual physician

Green SM, Rothrock SG: Evaluation styles for well-appearing febrile children: Are you a “risk-minimizer” or a “test-minimizer”? Ann Emerg Med Feb 1999;33:211-214.

Risk MinimizersRisk Minimizers

• Risk-minimizers desire to lower the risk of adverse sequelae from occult infections and use risk stratification to target higher-risk patient subsets for intervention.

• In widely circulated expert practice guidelines, for example, RM believe that this structured, methodical, and laboratory-intensive strategy minimizes adverse sequelae from occult infections and when consistently implemented wlll save lives.

• Many also perceive this strategy as having the lowest possible liability risk.

Test MinimizersTest Minimizers

• In contrast to the RM, TM are willing, for the sake of practicality to take a greater chance of being wrong. Their simple and inexpensive approach consists of the usual careful clinical examination, ensuring close follow-up, and avoiding empiric antimicrobial therapy in children without apparent bacterial source

• Although most TM will acknowledge that omitting the stratification algorithm may lead to missed occurrences of SBI

• They argue that the true risk of such outcomes is so low as to not justify the time, expense, and invasiveness of the routine risk-stratification approach

Test MinimizersTest Minimizers

• They believe that the majority of rare children whose condition does indeed progress to serious bacterial illness will be identified through close follow-up and return ED visits

• They believe that parents prefer less testing and treatment, even if it means a greater risk of an adverse outcome

• Finally, they argue that the liberal ordering of blood cultures necessitates frequent unnecessary reevaluations and hospitalizations for children with FP culture results or OB which, if undetected, would most likely clear without intervention

Premise for Risk StratifyingPremise for Risk Stratifying

• Premise for risk stratifying and empirically treating OB is to prevent disease progression to BM

• Pneumococci are responsible for essentially all meningitis in this post-HIB era, and TM will claim that there is no convincing evidence that early use of antibiotics can prevent pneumococcal meningitis.

• Green/Rothrock reported a meta-analysis* that compiled all studies comparing children with and without empiric antibiotic therapy.

• If the nonsignificant trend toward meningitis prevention in these data is assumed to be a reliable point estimate, then:

*Pediatrics 1997;99:438-444


• 2,190 consecutive febrile children would have to be empirically treated to theoretically prevent 1 case of meningitis (pre-PCV7)

• Assuming adverse outcome (death or neurologic disability) in 33% of meningitis occurrences

• 6,570 children would have to be treated to theoretically prevent a single adverse outcome.


• If antibiotic side effect data from the largest prospective study* of OB are incorporated into this model, adverse effects (eg, rash, allergy, vomiting, diarrhea) would occur in:– 131 to 567 treated children for each case of

meningitis prevented and – 393 to 1,701 children for each adverse

outcome prevented

*J Pediatr 1994;124:504-512

Why are we doing this then?Why are we doing this then?

OB 3-36 monthOB 3-36 month

• 8408 well appearing children 3-36 months FWS at PCH post PCV7 era

• July 2004-June 2007, retrospective

• 21 TP Bld CX (0.25%)

• 14 S. pneumo (0.17%)

• 159 contaminants (1.89%)

• Vaccine rates 49-86% by age groups

NNTNNT

• S. Pneumo OB 0.17%, would need to test 588 children to detect one case.

• Previous studies have shown w/o tx, approx 4% go on to have BM

• Of the children with BM, mortality is about 8% and permanent neurologic sequelae is about 30%

NNTNNT

• Therefore, would need to test 14,700 children to detect or prevent one case of S. Pneumo BM

• 49,000 children to prevent one case of permanent neurological sequelae

• 184,000 children to prevent one death from S. Pneumo meningitis

More RecentlyMore Recently

• “We have likely reached the point where the risks and costs of testing well-appearing young (3-36 month-old) febrile children for the presence of bactermia exceed the potential benefits.”

Avner and Baker ACAD EMERG MED Vol. 6, No. 3 2009

The Future- PECARNThe Future- PECARN

• Project is to incorporate a RNA-based diagnostic technology (called transcriptional signatures)

• To distinguish between bacterial and non-bacterial infections in otherwise well-appearing febrile infants who present to the ED

• Patient enrollment began in 2008 and continues through 2011

Key Points to Consider Key Points to Consider

• The majority of febrile young children with no fever source have a viral illness

• There is a high spontaneous resolution rate and a low rate of serious complications with Pneumococcal bacteremia

• Prophylactic use of antibiotics in children well appearing children older than 3 months is not indicated

Key Points to ConsiderKey Points to Consider

• The indiscriminate use of broad-spectrum antibiotics has contributed to an increasing prevalence of antibiotic-resistant pneumococcus

• The incidence of febrile UTI among this group of patients is significant

ObjectivesObjectives

• Assessment of Infants and Children <36 months of age with fever

• Understand the utility (or lack thereof) of diagnostic tests

• Understand the changing epidemiology of pediatric fevers without a clinically evident source (FWS)

• Develop an evidence based approach to evaluating and treating pediatric fever without source

Management of Low-risk Pediatric Management of Low-risk Pediatric FWSFWS

• 0-28 days– CBC, UA C&S, blood culture, LP, ?CXR– Admit for IV Abx, possible Acyclovir

• 29-90 days– UA, Urine Culture– Consider CBC/diff, blood culture, CXR– Strongly consider LP if planning on outpatient

antibiotics

Management of Low-risk Pediatric Management of Low-risk Pediatric FWSFWS

• 3-36 months– Individualize

• Evaluate social setting re: compliance with treament and follow-up

• Immunization status• Concomitant chronic medical illness

– UA and Urine Culture • girls <24 months• boys <6-12 months

– No role for routine CBC, blood culture, and empiric antibiotic use

EBM and ParachutesEBM and Parachutes

Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of

randomized controlled trials

• Smith, Pell; BMJ 327:1459 (Published 18 December 2003)

Parachute AbstractParachute Abstract

• Objectives To determine whether parachutes are effective in preventing major trauma related to gravitational challenge.

• Design Systematic review of randomized controlled trials. • Data sources: Medline, Web of Science, Embase, and the

Cochrane Library databases; appropriate internet sites and citation lists.

• Study selection: Studies showing the effects of using a parachute during free fall.

• Main outcome measure Death or major trauma, defined as an injury severity score > 15.

• Results We were unable to identify any randomized controlled trials of parachute intervention.


• Conclusions As with many interventions intended to prevent ill health, the effectiveness of parachutes has not been subjected to rigorous evaluation by using randomized controlled trials.

• Advocates of evidence based medicine have criticized the adoption of interventions evaluated by using only observational data.

• We think that everyone might benefit if the most radical protagonists of evidence based medicine organized and participated in a double blind, randomized, placebo controlled, crossover trial of the parachute


A quick Wiki review showed that the parachute does have a strong evidence background (http://en.wikipedia.org/wiki/Parachute):

1. protocols were 'published' (Da Vinci, 1485)

2. animal studies (Setlier, 1785)

3. case reports (Setlier, 1793)

4. commercialization (patented 1913)

5. case control study (German air service 1918)

6. Completion of the audit cycle (Allies, 1941)

7. Continuous quality improvement program (1945-present)

Today the average fatality rate is considered to be about 1 in 80,000. Obviously it would be hard to design a RCT to show how any

intervention would reduce this risk (would need >1million jumps).

Parachute Public Health ProposalParachute Public Health Proposal

• I suggest that this is in fact a public health issue and we should be preventing this fatal disease.

• An alternative is to mandate some additional safety devices (such as seatbelts to prevent them from jumping from planes).

• A public awareness campaign "Don't Jump, Chump!" would probably have an adverse effect on high risk population (teenagers).

• Financial penalties imposed by insurance companies. And local and national laws enacted.

• Currently no country has banned this behavior.

• I am considering starting a online petition to ban this dangerous device for emergency use only.

Questions?Questions?

Thanks!Thanks!

infant fever, what’s old what’s new

Documents

wbc count cutoff

bacteremiamean wbc

threshold of wbc

number of bacteremic

elevated wbc count

nl examwhat

bacteremia n

cutoff point