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Detection of Viruses in Young Children With Fever Without an Apparent Source"os#ua $. %ol&in, "ared '. $uen(er, Da&id $. "affe, A&ra#am Smason, )lena De*c#,

+illiam D. S#annon, $a -. Arens, ic#ard S. /uller, +ai$ing 1ee, )rica ".Sodergren +einstoc, eorge $. +einstoc and regor* A. Storc#

Pediatrics 2024304e!554 originall* publis#ed online 6o&ember 5, 2024DOI: 0.5!27peds.20238

'#e online &ersion of t#is article, along wit# updated information and ser&ices, islocated on t#e +orld +ide +eb at:

http://pediatrics.aappublications.org/content/1!/"/e1#$$.full.ht%l

P)DIA'I%S is t#e official 9ournal of t#e American Academ* of Pediatrics. A mont#l* publication, it #as been publis#ed continuousl* since 8!. P)DIA'I%S is owned, publis#ed, and trademared b* t#e American Academ* of Pediatrics, ! 6ort#west Point/oule&ard, )l ro&e ;illage, Illinois, 202 b* t#e American Academ*of Pediatrics. All rig#ts reser&ed. Print ISS6: 003!005. Online ISS6: 08!2=5.

http://pediatrics.aappublications.org/http://pediatrics.aappublications.org/http://pediatrics.aappublications.org/http://pediatrics.aappublications.org/content/130/6/e1455.full.htmlhttp://pediatrics.aappublications.org/http://pediatrics.aappublications.org/content/130/6/e1455.full.html


2/19

A'I%1)

Detection of ;iruses in ?oung %#ildren +it# @e&er +it#out an Apparent Source

A'BOS: "os#ua $. %ol&in, $D,a "ared '. $uen(er , $D,a

Da&id $. "affe, $D,a A&r a#am Smason, /S,a )lena De*c#,

$S, b +illiam D. S#annon, P#D, b $a -. Arens, P#D,a

ic#ard S. /uller, P#D,a +ai$ing 1ee, P#D,c )rica ".

Sodergren +einstoc, P#D,d eorge $. +einstoc, P#D,d

and regor* A. Storc#, $Da

Departments of aPediatrics, and b$edicine, and dt#e enome

Institute, +as#ington ni&ersit* Sc#ool of $edicine, St 1ouis,

$issouri4 and c/iological $imetics, Inc, @rederic , $ar*land

C)? +ODS

fe&er , &iral infection, pol*merase c#ain reaction

A//);IA'IO6S )D

emergenc* department BB;0<

#uman #erpes&irus <

P%pol*merase c#ain reaction

All of t#e aut#ors ecept for Dr 1ee partic ipated in t#e design

of t#e stud*4 patient data were gat#ered b* Drs %ol&in,

$uen(er , "affe, and $r Smason4 laborator* data were

produced b* Drs %ol&in, Arens, /uller, 1ee, and Storc#4 and all

of t#e aut#ors partic ipated in t#e anal*sis of t#e data. '#e

anal*sis of t#e data was led b* Dr Storc# and re&iewed b* $s

De*c# and Dr S#annon, w#o also carried out all statistical

anal*ses4 and all of t#e aut#ors tae responsibilit* for t#e

integrit* of t#e data

and t#e anal*sis. '#e manuscript was written b* Dr Storc#

and all of t#e aut#ors par ticipated in t#e decision to publis#

t#e paper . Procedures for protecting t#e conEdentialit* of

sub9ects were agreed to b* t#e institutional re&iew boards of

+as#ington ni&ersit* and t#e 6ational Institutes of Bealt#. '#estud* database was maintained b* Dr Storc#. It was used b*

t#e stud* statisticians, $s De*c# and Dr S#annon. All aut#ors

meet t#e criteria for aut#ors#ip listed in t#e Pediatrics Aut#or

uidelines and all aut#ors #a&e re&iewed and appro&ed t#e

Enal manuscript.

Portions of t#is wor was presented in part at t#e 2008

Pediatric Academic Societies annual meeting, April 30F$a* 5,

2008, /altimore, $D4 '#e @irst Annual $eeting of t#e Buman

$icrobiome Pro9ect, "anuar* 8F2, 200, Bouston, 'G4 and t#e

200 Pediatric Academic Societies annual meeting, $a* F !,

200, ;ancou&er , %anada.

ww w .pediatrics. o rg7cgi7doi7 0 .5!27peds.20238

doi:0.5!27peds.20238

Accepted for publication "ul 30, 202

Address correspondence to regor* Storc#, $D, Department of

Pediatrics, %ampus /o


3/19

P)DIA'I%S ;olume 30, 6umber


4/19

@e&er wit#out an apparent source is

a common problem in c#ildren t#at

ma* reLuire medical e&aluation.

Since implementation of

immuni(ation pro0 grams in t#e

nited States directed against

Baemop#ilus inuen(ae t*pe b andStreptococcus pneumoniae , s*stemic

bacterial infection #as be come an

uncommon cause, w#ile lo cali(ed

bacterial infections, mostl* urinar*

tract infections, account for

∼5N to 0N of cases.2F5 ;iral infections

are belie&ed to account for most of

t#e r emainder , but t#e speciEc

&iruses re sponsible #a&e not been

s*stematicall* delineated. '#e inabilit*

to accuratel* distinguis# patients

wit# occult bac teremia from t#ose

wit# &iral infection can lead clinicians

to prescribe anti biotic t#erap* for

a substantial pro0 portion of t#ese

patients.! Se&eral

&iruses including #uman #erpes&irus <

c#ildren wit# temperature of 3M% or

greater wit#out an apparent source,

w#o were #a&ing blood obtained for

a blood count and7or a blood

culture for clinical management.

%#ildren wit# clinical s*ndromes

suggesti&e of &iral respirator*infection, suc# as bron c#iolitis,

were not included. '#e de cision to

obtain blood for t#ese studies was

made b* )D p#*sicians as part of

t#eir standard care and was not a

par t of t#is stud*. 6o standard

written clin ical protocol was in

place in t#e )D to go&ern t#ese

decisions. '#e ele&ated temperature

was documented eit#er in t#e )D or

b* a #ealt# care pro&ider wit#in 2!#ours before t#e )D e&alua tion.

%#ildren were ecluded if t#e* #ad an

underl*ing condition t#at predis

posed t#em to infection, including

cancer , immune deEcienc*, immuno

suppressi&e t#er ap*, c*sticEbrosis,

'#e stud* was part of a Demonstr ation

Pro9ect of t#e Buman $icrobiome Pr o0

9ect and was appro&ed b* t#e +as#0

ington ni&er sit* Buman esearc#

Protection OfEce. Inf ormed consent

was obtained f r om parents or

guardians of all sub9ects.

Specimens

/lood samples were obtained from

a &enipuncture performed to obtain

blood for tests ordered b* t#e

p#*sician caring for t#e patient. p

to 3 m1 of blood for &irusspeciEc

P% assa*s was collected into an

)D'A tube t#at was stored at 20M%.

6asop#ar*ngeal secretions were

obtained b* swabbing t#e posterior nasop#ar*n. /efore

200, a standard Dacrontipped swab

and &iral transport media were

used. Starting in 200, t#ese were

replaced

oced swab and uni&ersal transBB;


5/19

'

BO

D

S

S

u b

9

e

c

t

s

%#ildren

aged 2

to 3<

mont#s

were

recruited

from t#e

emergen

c* de

partment

)DJ or

t#e

ambulato

r* sur

ger*

departme

ntafebrile

c#ildrenJ

at St

1ouis

%#ildrenK

s

Bospital

during

s#ifts

w#en

stud* personne

l were

a&ailable.

'#e case

group

consisted

of

sicle

cell

disease,

or

presence

of an

indwelling

&enous

cat#eter .

%#ildr en

wit# a

positi&e

rapid

test for

inuen(a

were

also not

included

.

'wo

comparis

on

groups

were

also in

cluded.

'#e Erst

was

c#ildren

aged 2 to

3<

mont#s

e&aluated

in t#e )D

w#o #ad

temperat

ure of

3M% or

greater

and

deEnite

or

probabl

e

bacterial

infec

tion,

including

bactere

mia,

urinar*tract

infection,

sin and

soft tissue

infection,

bone or

9oint

infection,

and

culture positi&e

bacterial

gastroen

teritis. '#e

second

group

consisted

of well

c#ildren

aged 2 to

3<

mont#s

#a&ing

outpatient

surger*

w#o #ad

been

afebrile f or

at least =

da*s

before

sur ger*.

%#ildren

wit# fe&er

were

enrolled

from mid

@ebruar*

200=

t#r oug#

mid

@ebruar*

200.

Afebrile

control

c#ildren

were

enrolled

during a

2mont#

period

star t0 ing in

mid

@ebruar*

2008.%#ildren

were

enrolled

b* stud*

personnel

w#o ob

tained

#ealt#

informatio

n fromeac#

c#ildKs

caregi&er ,

including

past

#istor*

and

recent

s*mptoms

t#at mig#t

indi cate

t#e

presence

of an acute

infection.

b* a

port

media

%opan

@leible $ini

'i pped

@loced

Swab4

ni&ers

al

'r ans p

or t $e0

dia,

$urr ie

ta, %AJ.

Swab

sample

s were

stored

at

20M%.

;

i

r

u

s

D

e

t

e

c

t

i

o

n

an

d

'

* ping

6ucleic

acid

was

etr act

ed

f r om

000m1

aliLuots

of

plasma

and

w#ole

blood b*using

t#e

$ag6a

Pure

automat

ed pr o0

cessor

wit# t#e

1% 'otal

6ucleic

Acid

Isolationit

oc#e

Applied

Science,

Indiana p

olis, I6J

and f r om

2000m1

ali Luots

of

naso p#ar *ngeal

samples

b* using

a

/ioobot

$!

automate

d

nucleic

acid

processor wit#

t#e

$agAttr a

ct ;irus

$ini it

-IA3)6,

;alencia,

%AJ. All

etr acts

were

eluted in

00 m1.

/lood

samples

were

tested b*

using a

batter * of

&ir us

speciEc

P%

assa*sdescribed

in t#e

Sup p le m e

n ta l 'a bl e

5. F 20

'#is test0

ing was

per f or me

d on

plasma

f or all

&ir uses

ecept

c*tome

galo&ir

us and

) pstein0

/arr

&ir us,

f or w#ic#

testing

was

perfor

med

on

w#ole

blood.

/ecaus

e of

limited

sample

&olume,

not all

tests

were

per f or me

d on

e&er*

sam ple.'esting

of

naso p#ar

*ngeal

samples

was

per f or me

d b*

using

commer ci

al

e!5< %O1;I6 et al

http://pediatrics.aappublications.org/lookup/suppl/doi:10.1542/peds.2012-1391/-/DCSupplementalhttp://pediatrics.aappublications.org/lookup/suppl/doi:10.1542/peds.2012-1391/-/DCSupplementalhttp://pediatrics.aappublications.org/lookup/suppl/doi:10.1542/peds.2012-1391/-/DCSupplementalhttp://pediatrics.aappublications.org/lookup/suppl/doi:10.1542/peds.2012-1391/-/DCSupplementalhttp://pediatrics.aappublications.org/lookup/suppl/doi:10.1542/peds.2012-1391/-/DCSupplementalhttp://pediatrics.aappublications.org/lookup/suppl/doi:10.1542/peds.2012-1391/-/DCSupplementalhttp://pediatrics.aappublications.org/lookup/suppl/doi:10.1542/peds.2012-1391/-/DCSupplementalhttp://pediatrics.aappublications.org/lookup/suppl/doi:10.1542/peds.2012-1391/-/DCSupplementalhttp://pediatrics.aappublications.org/lookup/suppl/doi:10.1542/peds.2012-1391/-/DCSupplementalhttp://pediatrics.aappublications.org/lookup/suppl/doi:10.1542/peds.2012-1391/-/DCSupplemental


6/19

A'I%1)

multiple assa*s supplemented b*

laborator*de&eloped assa*s. P% re

sults were not a&ailable for patient

management. /ecause t#e multiple

respirator* panels do not distinguis#

r#ino&iruses from entero&iruses, t#e

identiEcation of &irus present in naso p#ar*ngeal samples t#at were

positi&e for r#ino&irus7entero&irus

was deter mined b* nucleotide

seLuencing.2

;iruses detected in blood samples b*

t#e entero&irus re&erse

transcriptionF P% assa* were

considered to be en tero&iruses

wit#out additional testing. '#e

serot*pe of adeno&iruses from

nasop#ar*ngeal samples was deter

mined b* molecular met#ods at t#e

%enters for Disease %ontrol and Pre0

&ention Atlanta, 3AJ.22

Statistical Anal*ses

+e used @is#er Ks eact test to

compare t#e freLuenc* of &iruses in

different groups. @or continuous

&ariables, we used A6O;A and t#e

+ilcoon test to compare groups,

depending on &ari able distribution.

+e used logistic re gression for ad9usted anal*ses.

)S1'S

Sub9ects

After c#ildren wit# fe&er were enr olled,

'A/1) Demograp#ic %#aracteristics of Stud* Sub9ects, $aimum 'emperatures, and Specimens Obtained

%#aracteristics Sub9ect roup, 6o. N of totalJ P

;alue

$aimum temperature in

emergenc* department

$ean SDJ 38. 0.

$edian I-J 38. 3.


7/19

or nasop#ar*ngeal secretions. '#e

numbers of c#ildren positi&e for eac#

&irus are s#own in 'able 3. Se&ent*si

percent of t#e c#ildren wit# fe&er

wit#out a source were positi&e for

one

' A/1) 2 Serious /acterial Infections

Infection 6o. of%ases

Abscess

5a /acteremia

3 b rinar* tract infection

3c S#igella gastroenteritis

3

$astoiditi s

a @our cutaneous abscesses caused b* Sta p#*lococcus

aureus 3 met#icillinresistantJ, retr op#ar*ngeal

abscess. b 'wo Streptococcus pneumoniae, met#icillin

sensiti&e S. aureus.c All 3 caused b* )sc#eric#ia coli, including wit#

positi&e blood culture.



8/19

'A/1) 3 ;iruses Detecteda

;irus 'otal Sub9ects Positi&e N of 'otal 'estedJ b P

dren wit# fe&er and deEnite or proba

ble bacterial infection and 8N of

0

@e&er @e&er andDeEnite or

P

ro ba

ble

Af

afebrile

c#ildren

P , .

00 for

differences

among

t#e 3

groupsJ

.

;iruses /acterial Infection

patientsJe

a Sub9ects were considered positi&e if t#e indicated &irus wasdetected in eit#er t#e blood or t#e nasop#ar*ngeal sample.

b

/ecau

s

e o

f

limited

sa

m p

l

e &olum

e, no

t

al

l

su

b 9ects wer

e

t

ested f or eac

#

&i

r

us.c %onErmed

as

entero&irus

b* nucleotide

seLuencing

for &iruses

detected in

nasop#ar*ng

eal samples

but not for

t#ose

detected in

plasma .d Detected

b*r#ino&irus7entero&irus P%

performedonnasop#ar*ng

Adeno&irus 20 32J 2 J <


9/19

eal samples, but nucleotide seLuence to allow dis

crimination between r#ino&irus and entero&iruscould not be performed for tec#nical reasons.e '#e numbers in parent#eses are t#e percent positi&e for of t#e ! &iruses

listed, calculated b* using as t#e denominator t#e number of c#ildren in t#e

stud* group. If t#e percentages are calculated b* using as t#e denominator

t#e number of c#ildren w#o were positi&e for or more of t#e ! &iruses

plus t#e number of c#ildren w#o were tested and were negati&e for eac# of

t#e ! &iruses, t#e percentages of c#ildren positi&e for of t#e ! &iruses

are: c#ildren wit# fe&er wit#out a source,


10/19

of afebrile c#ildren.;iruses detected in

c#ildren wit# fe&er

wit#out a source

tended to be &iruses

recogni(ed as

pat#ogenic, w#ereas

&iruses of low pat#ogenicit* suc# as

r#ino&iruses or &iruses

of uncertain

pat#ogenicit* suc# as

boca&irus and t#e CI and

+ pol*oma&iruses

made up a #ig#er

proportion of t#e

&iruses detected in t#e

comparison groups.

;iruses

Detected in

/lood

;iruses detected in blood

are s#own in @ig .

One or more &iruses

were detected in blood

samples from


11/19

A'I%1)

@I3) ;iruses detected in blood. Sub9ects are represented b* rows and &iruses b* columns. Detection of a &irus is indicated b* a #ori(ontalline. A, %#ildren wit# fe&er wit#out a source. /,%#il dren wit# fe&er and deEnite or probable bacterial infection. %, Afebrile c#ildren.

differences compared wit# t#e ot#er patient groups were not signiEcant.

'#e &irus detected most freLuentl* in

nasop#ar*ngeal secretions was

r#ino &irus, w#ic# was detected in


12/19



13/19

Antibiotic utili(ation according to &irus

detected is s#own in 'able !. @ift*one

percent of c#ildren wit# one or

more &iruses detected and


14/19

detected recei&ed antibiotics. c#ildren,

including

some of

t#e same

&iruses

t#at

weredetected

in f ebrile

c#ildren.

Bowe&er,

man* of

t#ese

were

&iruses

of low

pat#ogen

icit* suc#

as

r#ino&iru

ses and

t#e CI

and +

pol*oma&

iruses.

@inall*,

our anal

*sis was

limited

to bloodand

naso

p#ar*nge

al

samples.

'esting

of ot#er

specime

ns,

especiall

* stoolmig#t

#a&e

re&ealed

t#e

presence

of addi

tional

&iruses.

e!


15/19

A'I%1)

$ore t#an #alf of c#ildren in t#is

stud* wit# e&idence of &iral infection

and no e&idence for bacterial

infection re cei&ed antibiotics. It is

our #ope t#at better awareness of

&iral infection could lead to a

signiEcant decrease in antibioticutili(ation in c#ildren wit# fe&er

wit#out a source. Pre&iousl* t#e use

of r apid tests for inuen(a #as been

associated wit# decreased antibiotic

use,32 and de&elopment of rapid tests

for t#e agents implicated in t#is

stud* mig#t #a&e a similar effect.

6ew tec# nolog* allows P% test

results to be

a&ailable wit# a turnaround time of ∼

#our .33 Bowe&er, it is also important

to be aware t#at patients ma* #a&e

seri ous bacterial infection concurrent

wit# &iral infection. @or t#is reason,

t#e de cision to wit##old antibiotics

based on presence of a &irus, e&en

one recog ni(ed as a pat#ogen,

must be made car efull*, wit#

consideration of all clinical

Endings to a&oid wit##olding

antibiotics from a patient wit# serious

bacterial infection. A biomarer t#at

accuratel* identiEes patients wit#

ac ti&e bacterial infection would be

an important ad9unct to &iral

diagnostic testing and de&elopment of

suc# a bio marer s#ould be a

priorit* for future researc#.

%O6%1SIO6S

Cnown pat#ogenic &iruses were

detected muc# more freLuentl* in

c#ildren wit# fe&er wit#out an

apparent source, compared wit#

c#ildren wit# fe&er and deEnite or

probable bacterial infection or

afebrile c#ildren, suggest0 ing a

causalr elations#ip. '#e Ending t#at! &iruses were predominant is an

important consideration for t#e

design of future diagnostic tests.

'esting of blood is reLuired to

maimi(e *ield in c#ildren wit# fe&er

wit#out an apparent source.

Additional stud* is reLuired to

determine w#et#er speciEc &iral di

agnosis would be useful in clinical

management. '#ese studies s#ould be

pursued, because better recognition of

&iral etiologies ma* #elp a&oid un

necessar* use of antibiotics.

A%C6O+1)D3$)6'S

+e t#an t#e staff of t#e )D, t#e Ambulator* Surger* Department, and t#e

;irolog* 1abor ator* at St 1ouis %#ild

renKs Bospital for t#eir assistance in

carr*ing out t#is stud*. +e t#an

"ennifer 1oug#man, P#D, and Da&id

Bunstad, $D, for assistance wit#

Egures bot# from t#e Department of

Pediatrics, +as#ington ni&ersit*J4

%are*Ann /urn#am, P#D from t#e

Department of Pat#olog*, +as#ington

ni&ersit*J, and Da&id Bunstad, $D,for t#eir critical reading of t#e

manu script 4 Dean )rdman, P#D, and

Giao*an 1u, $S, of t#e %D% f or

adeno&irus t*ping4 and /ar bar a

Bar tman from t#e Depar t0 ment of

Pediatr ics, +as#ington ni&er 0 sit*J

f or assistance wit# manuscript

prepar ation.

)@))6%)S

. Crauss /S, Baraal ', @leis#er 3. '#e

spectrum and freLuenc* of illness pre

senting to a pediatric emergenc* de

partment. Pediatr )merg %are. 884=2J:


16/19

3. Beim A, )bnet %, Barste 3, PringAerblom

P. apid and Luantitati&e detection of

#u man adeno&irus D6A b* realtime

P%. " $ed ;irol. 20034=02J:22F238

!. %one +, Buang $1, Bacman %, %ore* 1.

%oinfection wit# #uman #erpes&irus <

&ariants A and / in lung tissue. " %lin

$icrobiol. 88


17/19

pol*oma&irus infection, St. 1ouis, $issouri.

)merg Infect Dis. 200=432J:83


18/19

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@I6A6%IA1DIS%1OS): '#eaut#ors#a&eindicatedt#e* #a&eno Enancialrelations#ip

s rele&ant tot#is articleto disclose.

@6DI63: @unding for t#is stud* was pro&ided

b* grant AB2AI032


19/19

Detection of Viruses in Young Children With Fever Without an Apparent Source"os#ua $. %ol&in, "ared '. $uen(er, Da&id $. "affe, A&ra#am Smason, )lena De*c#,

+illiam D. S#annon, $a -. Arens, ic#ard S. /uller, +ai$ing 1ee, )rica ".Sodergren +einstoc, eorge $. +einstoc and regor* A. Storc#

Pediatrics 2024304e!554 originall* publis#ed online 6o&ember 5, 2024DOI: 0.5!27peds.20238

&pdated 'nfor%ation (Services

Supple%entar) *aterial

+eferences

Citations

Subspecialt) Collections

,er%issions ( -icensing

+eprints

including #ig# resolution figures, can be found at:#ttp:77pediatrics.aappublications.org7content7307

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