REVIEW ARTICLE
324 | VOLUME 5 • ISSUE 6 www.hospitalpediatrics.org
AUTHORSPui-Ying Iroh Tam, MD,1 Ethan Bernstein, BA,2 Xiaoye Ma, MS,3 Patricia Ferrieri, MD1,4
1Department of Pediatrics, Division of Pediatric Infectious Diseases and Immunology, University of Minnesota Masonic Children’s Hospital, Minneapolis, Minnesota;2University of Minnesota Medical School, Minneapolis, Minnesota;3Department of Biostatistics, University of Minnesota School of Public Health, Minneapolis, Minnesota; and 4Department of Laboratory Medicine and Pathology, University of Minnesota Medical Center, Minneapolis, Minnesota
KEY WORDSblood culture, bacteremia, community-acquired pneumonia, pediatric, systematic review, meta-analysis, pneumococcal conjugate vaccine, Haemophilus infl uenzae type b vaccine, Streptococcus pneumoniae
ABBREVIATIONSBC: blood cultureCAP: community-acquired pneumoniaCI: confi dence intervalED: emergency departmentICD-9: International Statistical Classifi cation of
Diseases and Related Health Problems, Ninth Revision
PCV: pneumococcal conjugate vaccinePERCH: Pneumonia Etiology Research for Child
Health
www.hospitalpediatrics.orgdoi:10.1542/hpeds.2014-0138
Address correspondence to Pui-Ying Iroh Tam, MD, 3-210 MTRF, 2001 6th St SE, Minneapolis, MN 55455. E-mail: [email protected]
HOSPITAL PEDIATRICS (ISSN Numbers: Print, 2154 - 1663; Online, 2154 - 1671).
Copyright © 2015 by the American Academy of Pediatrics
abstractBACKGROUND AND OBJECTIVE: Current guidelines strongly recommend collection of blood cultures (BCs) in children requiring hospitalization for presumed moderate to severe bacterial community-acquired pneumonia (CAP). Our objective was to systematically review the international pediatric literature to evaluate how often BCs are positive in hospitalized children with CAP, identify the most commonly isolated pathogens, and determine the impact of positive BCs on clinical management.
METHODS: We identifi ed articles in PubMed and Scopus published from January 1970 through December 2013 that addressed BCs in children with CAP. We extracted total number of BCs collected and prevalence of positive BCs and used meta-regression to evaluate whether subgroups had any impact on prevalence.
RESULTS: Meta-analysis showed that the overall prevalence of positive BCs was 5.14% (95% confi dence interval 3.61–7.28). Studies focusing on severe CAP had a signifi cant effect on prevalence (P = .008), at 9.89% (95% CI 6.79–14.19) compared with 4.17% (95% confi dence interval 2.79–6.18) for studies not focusing on severe CAP. The most commonly isolated organisms were Streptococcus pneumoniae (76.7%) followed by Haemophilus infl uenzae(3.1%) and Staphylococcus aureus (2.1%). Contaminants accounted for 14.7%. Only 3 studies reported on BC-driven change in management, with contrasting fi ndings.
CONCLUSIONS: BCs in pediatric CAP identifi ed organisms in only a small percentage of patients, predominantly S. pneumoniae. False-positive BC rates can be substantial. The 3 studies that examined BC-driven changes in management had confl icting results. This systematic review was limited by heterogeneous case defi nitions, which may overestimate the true prevalence of positive BCs in hospitalized children.
Blood Culture in Evaluation of Pediatric Community-Acquired Pneumonia: A Systematic Review and Meta-analysis
Guidelines from the Infectious Diseases Society of America on management of community-acquired pneumonia (CAP) in children strongly recommend collec-tion of blood cultures (BCs) in those requiring hospitalization for presumed mod-erate to severe bacterial CAP.1 The support for these recommendations, however, is based on low- or moderate-quality evidence. Although management guidelines have demonstrated a decrease in morbidity and mortality in adults with presumed pneumonia,2,3 BCs are generally considered to be of limited utility because they infrequently identify organisms and rarely alter antimicrobial management even when positive.4–7 Other considerations complicating BC collection in children
(Continued on last page)
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are the high prevalence of viral and mixed bacterial and viral respiratory infections in children,8 the concern for potential discomfort and distress to the child, and the possibility of false-positive BCs leading to unnecessary antimicrobial use and hospitalization.
We performed a systematic review of the literature with 2 objectives: to identify how often BCs were positive and which pathogens were most com-monly isolated in hospitalized children with CAP and to determine the impact of positive BCs on antimicrobial man-agement in hospitalized patients.
METHODSData Sources
Pertinent articles were identified using the stepwise approach speci-fi ed in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement.9 We searched PubMed and Scopus databases to identify articles published in English from January 1970 through December 2013 that addressed BCs in children with CAP. We conducted keyword searches to identify articles with at least 1 of the following Medical Sub-ject Headings terms in the title or abstract: community-acquired infec-tions, community-acquired pneumo-nia, blood culture, blood/microbiology, infant, child, or adolescent (Table 1). At least 1 of the terms from each category
was needed for inclusion. Additional references were identifi ed by hand-searching the reference lists of included articles and snowballing.
Study Selection
Two reviewers (PI and EB) indepen-dently scored abstracts for relevance to the clinical questions using a validated methodology.10,11 If at least 1 reviewer judged the full text of an article to be clinically relevant, then 2 independent reviewers critically appraised the arti-cle using a structured data collection form based on published guidelines.12,13 These 2 reviewers determined by con-sensus whether the article should be cited in the systematic review. The senior author (PF) assessed the identi-fi ed articles for completeness.
Criteria for inclusion were studies involving patients up to 18 years of age with a diagnosis of CAP who were eval-uated in the emergency department (ED) or hospitalized. CAP was defi ned as a case with clinical, radiographic, and/or microbiologic diagnosis of pneu-monia at time of or within 48 hours of admission to hospital. Studies using an International Statistical Classifi cation of Diseases and Related Health Problems, Ninth Revision (ICD-9) code of pneumo-nia in any position were also accepted. A positive BC was defi ned as a BC with growth of an organism. A false-positive BC was defi ned following the National
Healthcare Safety Network defi nition of skin contaminants.14 To be included in the review, BCs were included only from participants in the study who also met their study’s defi nition of CAP. We included peer-reviewed studies but excluded case reports, guidelines, and reviews if no new data were provided. We excluded studies that were based in the ambulatory setting and those that predominantly included patients with comorbidities (underlying chronic heart and lung conditions, malnutrition, immunodefi ciency, or immunosuppres-sion). We also excluded studies evalu-ating known positive isolates, such as studies evaluating diagnostic methods for detection of Streptococcus pneu-moniae in children with pneumonia or studies focusing on pneumonia or invasive disease caused by particular pathogens.
Quality Assessment
The methodologic quality of the included studies was evaluated using a modifi ed version of the Downs and Black critical appraisal tool.15 This vali-dated tool comprises 27 questions, each with a maximum score of 1 or 2 points, that address reporting, external validity, internal validity (bias and con-founding), and power.15,16 Because the majority of studies were not designed to detect a clinically important effect, we removed power in our modifi ed ver-sion. On the basis of the score (assigned by PI), study quality was determined to be excellent (25–27), good (19–24), fair (14–18), or poor (13).
Data Extraction
Data on total number of BCs col-lected and prevalence of positive BCs in patients with a diagnosis of pneu-monia were extracted. Studies with insuffi cient data or data that did not
TABLE 1 Search Strategy
Database Search terms
PubMed (((((children OR child))) AND ((((((pneumonia) AND community acquired infections)) OR community acquired pneumonia)) AND ((((blood culture) OR
blood cultures)) OR blood/microbiology[MeSH Terms])))) OR (((((((pneumonia) AND community acquired infections)) OR community acquired pneumonia)) AND ((((blood culture) OR blood cultures)) OR blood/microbiology[MeSH Terms])) AND (medline[sb] AND (infant[MeSH] OR child[MeSH] OR adolescent[MeSH])))
Scopus (((TITLE-ABS-KEY(pneumonia) AND TITLE-ABS-KEY(community acquired infections))) OR (TITLE-ABS-KEY(community acquired pneumonia))) AND
((TITLE-ABS-KEY(children) OR TITLE-ABS-KEY(child))) AND ((TITLE-ABS-KEY(blood culture) OR TITLE-ABS-KEY(blood cultures)))
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suffi ciently differentiate total num-ber of BCs from positive BCs were excluded. Communications were sent to authors if clarifi cations from a study were needed. The primary outcome was the rate of positive BCs. The sec-ondary outcome was whether there was a change in the antimicrobial pre-scribed. Data extraction was recorded in Microsoft Excel (version 14.4.4).
Statistical Analysis
Statistical modeling was performed using the “metafor” package in R sta-tistical software (version 2.14.1).17,18 Logistic transformations were used to calculate the 95% confi dence interval (CI) for study-specifi c prevalence esti-mates to avoid exceeding the 0–1 lim-its.19 Meta-analysis of the prevalence of the positive BCs in patients with CAP was conducted using random
effects models20 to incorporate hetero-geneity across studies. Studies were also grouped by study-level charac-teristics and pooled proportions were calculated within these subgroups using random effects models. We used meta-regression to test differ-ences in the prevalence of positive BCs between particular subgroups, and subgroup meta-analysis was con-ducted for subgroups with signifi cant impact on prevalence. Publication bias was examined and adjusted by the trim and fi ll method.21 The signifi cant level for all tests was set at 5%.
RESULTSThe search identifi ed 220 articles of which 199 were systematically excluded, and 21 were included in this review (Fig 1). The studies included 15 prospective and 6 retrospective studies,
comprising a total of 8621 patients (Table 2). The majority of studies were from Europe (7), followed by Asia (5), United States (5), the Middle East (2), and South America and Africa (1 each). Studies ranged from publication dates in 1989 to 2013. Ten studies focused on the etiology of CAP.22–31 One study was focused on infl uenza A–related CAP.32 Two studies examined radiographic features in CAP,33,34 1 evaluated antimi-crobial use in the treatment of CAP,35 and 1 examined infl ammatory markers in CAP.36 Four studies evaluated bac-teremia in children with CAP,37–40 1 study examined management of CAP,41 and another focused on severe CAP admis-sions to the ICU.42 The majority of stud-ies used observational cohort design, except for 1 study that used a nested case-control design.40
Quality Assessment
The included studies ranged in meth-odologic quality (Table 3). Six stud-ies were assessed as good,36,37,39–42 11 were fair,23,24,26–28,30–32,34,35,38 and 4 were poor.22,25,29,33 Poorly rated studies suf-fered from outcomes that were not clearly described, omission of follow-up of participants, and lack of ade-quate adjustment of confounding in the analyses.
Diagnostic Criteria
The diagnostic criteria for CAP were diverse. Only 2 studies had clinical, laboratory, and radiographic crite-ria for CAP.30,35 One study based the diagnosis on clinical features alone,24 whereas 1 study based the diagnosis on microbiologic data alone25 and 1 on radiographic fi ndings alone.38 Four studies identifi ed pneumonia cases using ICD-9 billing codes for pneu-monia.37,39–41 Five studies did not docu-ment any exclusion criteria.26,30,35,37,42FIGURE 1 Search summary.
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TAB
LE 2
Stu
dies
that
add
ress
BC
, mic
robi
olog
y, a
nd/o
r B
C-d
rive
n ch
ange
s in
ant
imic
robi
al m
anag
emen
t in
pedi
atric
CA
P
Stud
yLo
catio
nSt
udy
Des
ign
and
Setti
ngA
ge
(Ran
ge)
Incl
usio
n C
riter
iaEx
clus
ion
Crit
eria
Defi
niti
on
of C
AP
BC
s, n
; TP
BC
s, n
(%
); FP
BC
s, n
(%
)
Bac
teria
Isol
ated
in
TP
BC
s, n
(%
)B
C-D
irect
ed
Cha
nge
in
Man
agem
ent
Uni
ted
Stat
es
Hic
key
et
al
1996
38
USA
Ret
ro, E
DM
edia
n 27
mo
(0–2
1 y)
CX
R d
iagn
osis
of
pne
umon
ia,
infi l
trat
e,
cons
olid
atio
n
CX
R d
iagn
osis
of
bron
chiti
s,
atel
ecta
sis,
or
bron
chio
litis
Not
doc
umen
ted
409;
11
(2.7
%);
33
(8.1
%)
S pn
eum
onia
e 10
(23
%),
H p
arai
nfl u
enza
e 1
(2%
), co
ntam
inan
ts
33 (
75%
)
No
chan
ge
in th
erap
y in
all
case
s
Sa
ndor
a
et a
l 20
0941
USA
Ret
ro c
ohor
t, in
patie
nt18
mo–
18 y
; 56
% <
5 y
18 m
o–18
y,
ICD
-9 c
ode
of p
neum
onia
Imm
unod
efi c
ienc
y,
chro
nic
med
ical
co
nditi
ons
othe
r th
an
asth
ma;
infa
nts
born
<
32 w
k; d
iagn
osis
of
bron
chio
litis
CX
R fi
ndin
gs p
lus
clin
ical
feat
ures
in
a p
atie
nt n
ot
hosp
italiz
ed o
r lo
ng-t
erm
car
e re
side
nt w
ithin
pr
evio
us 1
4 d
139;
2
(1.4
%);
1 (0
.7%
)
S pn
eum
onia
e 1
(33%
), no
ntyp
eabl
e H
infl u
enza
e 1
(33%
), co
agul
ase-
nega
tive
Stap
hylo
cocc
us 1
(3
3%)
Not
docu
men
ted
Sh
ah
et
al
2011
40
USA
Nes
ted
case
-con
trol
re
tro,
ED
Med
ian
2 y
(0–1
8 y)
≤18
y,
eval
uate
d in
ED
and
IC
D-9
cod
e w
ith C
AP
Req
uire
d ho
spita
lizat
ion
≤14
d be
fore
dia
gnos
is
of p
neum
onia
; im
mun
ocom
-pr
omis
ing/
chro
nic
med
ical
con
ditio
n
ICD
-9 c
ode
291;
6
(2.1
%);
3 (1
%)
S pn
eum
onia
e 4
(44%
), S
aure
us 1
(11
%),
H in
fl uen
zae
1 (1
1%),
coag
ulas
e-ne
gativ
e St
aphy
loco
ccus
3
(33%
)
17%
had
ap
prop
riate
br
oade
ning
, 67
% h
ad
appr
opria
te
narr
owin
g;
17%
had
pa
thog
en n
ot
sens
itive
to
empi
rical
th
erap
y
Hei
ne
et
al
2013
37
USA
Ret
ro,
inpa
tient
Mea
n 4.
9 y
(0–1
8 y)
ICD
-9 c
ode
of
pneu
mon
iaN
ot d
ocum
ente
dIC
D-9
cod
e of
pn
eum
onia
155;
5
(3.2
%);
5 (3
.2%
)
S pn
eum
onia
e 3
(30%
), E
coli
1 (1
0%),
S py
ogen
es 1
(10
%),
cont
amin
ants
5 (
50%
)
Not
docu
men
ted
M
yers
et a
l 20
1339
USA
Mul
ticen
ter
retr
o,
inpa
tient
Med
ian
3.1
y (1
.3–6
.7 y
)
60 d
–18
y,
ICD
-9 c
ode
of
pneu
mon
ia/
effu
sion
, pos
itive
C
XR
and
/or
clin
ical
feat
ures
an
d la
bora
tory
re
sults
Hos
pita
lized
sin
ce
birt
h, c
hron
ic
com
orbi
d co
nditi
on
or p
rimar
y di
agno
sis
of tr
aum
a
ICD
-9 c
ode
369;
26
(7.0
%);
8 (2
.2%
)
S pn
eum
onia
e 19
(5
6%),
H in
fl uen
zae
1 (3
%),
S au
reus
6
(18%
), co
ntam
inan
ts
8 (2
4%)
39%
had
th
erap
y br
oade
ned,
27
% w
ere
narr
owed
, 35
% h
ad
no c
hang
e
Wes
tern
Eur
ope
Is
aacs
1989
25
UK
Pro,
inpa
tient
Med
ian
53 m
o,
(1 m
o–12
y)
1 m
o–14
y
with
clin
ical
fe
atur
es a
nd
posi
tive
CX
R
Hos
pita
l-ac
quire
d pn
eum
onia
and
th
ose
with
und
erly
ing
pulm
onar
y or
im
mun
olog
ic d
isea
se
Posi
tive
BC
/ple
ural
fl u
id
57; 2
(3.5
%)
S pn
eum
onia
e 2
(100
%)
Not
docu
men
ted
Ju
ven
et
al
2000
26
Finl
and
Pro,
inpa
tient
Mea
n 3.
8 y
(0.1
–16
.7 y
)
Chi
ldre
n w
ith
CA
PN
ot d
ocum
ente
dFe
ver
>37
.5°C
and
/or
res
pira
tory
sy
mpt
oms
and
posi
tive
CX
R
125;
1
(0.8
%)
S pn
eum
onia
e 1
(100
%)
Not
docu
men
ted
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Stud
yLo
catio
nSt
udy
Des
ign
and
Setti
ngA
ge
(Ran
ge)
Incl
usio
n C
riter
iaEx
clus
ion
Crit
eria
Defi
niti
on
of C
AP
BC
s, n
; TP
BC
s, n
(%
); FP
BC
s, n
(%
)
Bac
teria
Isol
ated
in
TP
BC
s, n
(%
)B
C-D
irect
ed
Cha
nge
in
Man
agem
ent
M
oulin
et a
l 20
0136
Fran
cePr
o, in
patie
ntM
ean
1.9
y (0
.4–5
y)
Seve
re fe
brile
C
AP
and
imm
uno-
com
pete
nt
Chr
onic
dis
ease
, an
timic
robi
al 1
0 d
befo
re a
dmis
sion
, no
t adm
itted
to
hosp
ital,
or n
o B
C
T >
38°C
and
a
posi
tive
CX
R88
; 10 (
11.4
%)
S pn
eum
onia
e 10
(10
0%)
Not
docu
men
ted
La
undy
et a
l 20
0332
UK
Pro,
ED
, ou
t-pa
tient
Med
ian
1.3
y (2
wk–
4.8
y)
Chi
ldre
n ≤5
y
rega
rdle
ss
of r
isk
fact
ors
Youn
g ch
ildre
n w
ith o
bvio
us
bron
chio
litis
Feve
r ≥3
8.5°
C a
nd
tach
ypne
a pe
r W
HO
crit
eria
±
cou
gh, w
ith
posi
tive
clin
ical
ex
am/C
XR
51; 4
(8%
)S
pneu
mon
iae
3 (7
5%),
N m
enin
gitid
is 1
(2
5%)
Not
do
cum
ente
d
Ku
rz
et
al
2013
27
Aus
tria
Pro,
inpa
tient
Med
ian
36 m
o (2
mo–
17 y
)
2 m
o–18
y
hosp
italiz
ed
with
di
agno
sis
of C
AP
Pree
xist
ing
lung
di
seas
e, im
mun
o-de
fi cie
ncy,
imm
uno-
supp
ress
ive
ther
apy
Clin
ical
feat
ures
, po
sitiv
e C
XR
173;
5
(2.9
%);
2 (1
.2%
)
S pn
eum
onia
e 2
(29%
), S
aure
us 1
(14
%),
M c
atar
rhal
is 1
(14
%),
Rot
hia
1 (1
4%),
coag
ulas
e-ne
gativ
e St
aphy
loco
ccus
2
(29%
)
Nar
row
ing
of
trea
tmen
t ba
sed
on
test
res
ults
Inte
rnat
iona
l
Leib
ovitz
et a
l 19
9035
Isra
elPr
o, in
patie
nt,
outp
atie
ntA
vera
ge
3 y,
7 m
o (5
mo-
14.5
y)
2 m
o–16
y w
ith
diag
nosi
s of
sev
ere
bact
eria
l pn
eum
onia
Not
doc
umen
ted
Clin
ical
feat
ures
, la
bora
tory
fi n
ding
s an
d po
sitiv
e C
XR
147;
16
(10
.9%
); 1
(0.7
%)
S pn
eum
onia
e 13
(76
%),
H in
fl uen
zae
3 (1
8%),
S vi
ridan
s 1
(6%
)
Not
docu
men
ted
C
hong
et a
l 19
9723
Sing
a-po
rePr
o, in
patie
ntM
ean
0.6
y (1
1 d–
11.8
y)
<12
y w
ith
CA
-LR
TIN
osoc
omia
l pn
eum
onia
, im
mun
o-co
mpr
omis
ed
host
Cou
gh/f
ever
<
2 w
k du
ratio
n,
clin
ical
feat
ures
or
pos
itive
CX
R
121;
4
(3.3
%)
S pn
eum
onia
e 1
(25%
), H
infl u
enza
e 1
(25%
), En
tero
bact
er 1
(2
5%),
S pn
eum
onia
e,
H in
fl uen
zae
1 (2
5%)
Not
docu
men
ted
H
ijazi
et a
l 19
9724
Kuw
ait
Pro,
inpa
tient
Med
ian
14 m
(1
0 d–
12 y
)
CA
-LR
TI, n
ot
prev
ious
ly
adm
itted
or
visi
ted
hosp
ital i
n pr
evio
us 8
wk
Sym
ptom
s >
1 w
k,
chro
nic
dise
ase,
br
onch
ial a
sthm
a,
mal
nutr
ition
Cou
gh a
nd
clin
ical
fe
atur
es
390;
38
(9.
7%)
Not
doc
umen
ted
Not
docu
men
ted
D
elpo
rt
et
al
2002
42
Sout
h A
fric
aPr
o, in
patie
ntM
edia
n 10
wk
(2 w
k–5
y)
Adm
itted
to
PIC
U;
intu
bate
d in
ER
; RR
>80
–90
/min
with
an
ticip
ated
ap
nea;
po
sitiv
e C
XR
Not
doc
umen
ted
Not
doc
umen
ted
23; 4
(17.4
%)
K pn
eum
onia
e 2
(50%
), no
t sp
ecifi
ed 2
Not
docu
men
ted
TAB
LE 2
Con
tinue
d
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Stud
yLo
catio
nSt
udy
Des
ign
and
Setti
ngA
ge
(Ran
ge)
Incl
usio
n C
riter
iaEx
clus
ion
Crit
eria
Defi
niti
on
of C
AP
BC
s, n
; TP
BC
s, n
(%
); FP
BC
s, n
(%
)
Bac
teria
Isol
ated
in
TP
BC
s, n
(%
)B
C-D
irect
ed
Cha
nge
in
Man
agem
ent
Ta
jima
et
al
2006
30
Japa
nPr
o, in
patie
nt1
mo–
13 y
Initi
al
diag
nosi
s of
pn
eum
onia
Not
doc
umen
ted
Clin
ical
cou
rse
befo
re a
dmis
sion
, C
XR
, lab
orat
ory
test
s
157;
2
(1.3
%)
H in
fl uen
zae
1 (5
0%),
S pn
eum
onia
e 1
(50%
)
Not
docu
men
ted
Se
cmee
r
et a
l 200
828
Turk
eyR
etro
, inp
atie
ntM
ean
6.5
± 3
.5 y
(2
–16
y)
2–16
y
hosp
italiz
ed
with
CA
P an
d pa
rapn
eum
onic
ef
fusi
on
Nos
ocom
ial
infe
ctio
nN
ot d
ocum
ente
d96
; 2 (2
.1%
); 2
(2.1
%)
S pn
eum
onia
e 1
(25%
), St
enot
roph
omon
as
mal
toph
ilia
1 (2
5%),
coag
ulas
e-ne
gativ
e St
aphy
loco
ccus
2
(50%
)
Not
docu
men
ted
Fe
rrer
o
et a
l 201
033
Arg
entin
a,
Bra
zil,
Dom
i-ni
can
Rep
ublic
Pro m
ultic
ente
r ob
serv
atio
nal,
inpa
tient
3–59
mo;
m
ajor
ity
(37.2
%)
wer
e 12
–23
mo
3–59
mo
hosp
italiz
ed
with
sev
ere
CA
P
No
evid
ence
of
CA
P on
CX
R
Pres
ence
of
coug
h/cl
inic
al
feat
ures
2536
; 18
1 (7
.1%
)S
pneu
mon
iae
181
(100
%)
Not
docu
men
ted
Z
hang
et a
l
2011
31
Chi
naPr
o, in
patie
ntM
ean
2.3
y (2
–14
y)2
mo–
14 y
, ad
mitt
ed
dire
ctly
from
co
mm
unity
w
ith C
AP
Tube
rcul
osis
di
agno
sis,
sen
t to
pul
mon
ary
hosp
ital f
or c
are
Feve
r ≥3
7.5°C
and
/or
res
pira
tory
sy
mpt
oms
and
posi
tive
CX
R
821;
7
(0.9
%)
S pn
eum
onia
e 7
(100
%)
Not
docu
men
ted
C
hen
et a
l
2012
22
Taiw
anPr
o, in
patie
ntM
edia
n 4
y 3
mo
(7 m
o-16
y, 7
mo)
3 m
o–18
y,
clin
ical
fe
atur
es,
posi
tive
CX
R
Chr
onic
com
orbi
d di
seas
e, m
alig
nanc
y im
mun
odefi
cie
ncy,
or
imm
unos
uppr
essi
on
One
clin
ical
sy
mpt
om a
nd
posi
tive
CX
R
209;
2
(1%
)S
pneu
mon
iae
2 (1
00%
)N
ot docu
men
ted
Su
r et
al
20
1229
Rom
ania
Pro,
inpa
tient
1–18
yC
linic
al
feat
ures
, po
sitiv
e C
XR
Und
erly
ing
lung
di
seas
e/m
alfo
rm-
atio
n, n
onac
ute/
recu
rren
t pn
eum
onia
Clin
ical
fe
atur
es56
0;
38 (
6.8%
)S
pneu
mon
iae
31 (
82%
), K
pneu
mon
iae
4 (1
1%),
H in
fl uen
zae
3 (8
%)
Not
docu
men
ted
La
khan
i
et a
l 20
1334
Indi
aPr
o, in
patie
nt,
rura
l po
pula
tion
1 m
o–5
y;
maj
ority
(4
8.5%
) w
ere
12–6
0 m
o
Clin
ical
ly
susp
ecte
d pn
eum
onia
Crit
ical
/ter
min
al
illne
ss, a
cute
br
onch
ial a
sthm
a ex
acer
batio
n,
chro
nic
lung
dis
ease
; im
mun
ocom
prom
ise,
an
timic
robi
al a
gent
s >
48 h
ear
lier
WH
O
clas
sifi c
atio
n66
; 4 (6
.1%
)N
ot d
ocum
ente
dN
ot docu
men
ted
CA
-LR
TI, c
omm
unity
-acq
uire
d lo
wer
res
pira
tory
tra
ct in
fect
ion;
CX
R, c
hest
x-r
ay; F
P, f
alse
-pos
itive
; IP,
inpa
tient
; OP,
out
patie
nt; P
ro, p
rosp
ectiv
e; R
etro
, ret
rosp
ectiv
e; R
R, r
espi
rato
ry r
ate;
TP,
tru
e-po
sitiv
e; W
HO
, Wor
ld H
ealth
Org
aniz
atio
n.
TAB
LE 2
Con
tinue
d
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Positive BCs
Of the 6975 total BCs obtained in pedi-atric patients with CAP, 425 were posi-tive (6.1%). The proportion of positive BCs in studies of CAP ranged from 0.8% to 17.4% (Table 4). Studies con-ducted before availability of pneumo-coccal conjugate vaccine (PCV) had a higher positive BC rate of 7.7% (range 0.8%–17.4%), compared with the post-PCV era, which had a rate of 4.0% (range 0.9%–7.8%).
Of 382 known BC results, the most commonly isolated organisms were S pneumoniae (76.7%), followed by Haemophilus infl uenzae (3.1%) and Staphylococcus aureus (2.1%; Table 5). In the pre-PCV era, 83.3% of iso-lates were S pneumoniae, compared with 61.7% post-PCV. Contaminants accounted for 14.7% of isolates, which in individual studies ranged from 5.9%–75% of positive BCs.27,28,35,38–41 However, reporting varied across
studies, with contaminants docu-mented in all US studies but reported in only 3 studies conducted outside of the United States.27,28,35
Severity of Disease
Severe disease was part of the inclusion criteria in 4 studies.33,35,36,42 However, only 1 study described parameters of severe disease as admission directly to the PICU or intubation in the ED for anticipated apnea.42 Diagnostic criteria
TABLE 3 Quality Assessment of the Included Studies
Study Modifi ed Downs and Black Criteria14
Reporting (n/11) External Validity (n/3) Internal Validity—bias (n/7)
Internal Validity—Confounding (n/6)
Total Score (n/26) Quality Rating
Heine et al 201337 9 2 6 3 20 GoodKurz et al 201327 7 1 4 2 14 FairLakhani et al 201334 6 1 5 2 14 FairMyers et al 201339 10 2 6 3 21 GoodChen et al 201222 4 1 4 2 11 PoorSur et al 201229 4 1 5 2 12 PoorShah et al 201140 10 1 5 3 19 GoodZhang et al 201131 6 1 5 2 14 FairFerrero et al 201033 5 1 4 2 12 PoorSandora et al 200941 11 2 6 4 23 GoodSecmeer et al 200828 7 2 5 3 17 FairTajima et al 200630 7 1 6 3 17 FairLaundy et al.200332 8 1 6 3 18 FairDelport et al 200242 10 1 5 3 19 GoodMoulin et al 200136 9 1 6 3 19 GoodJuven et al 200026 6 2 5 3 16 FairChong et al 199723 7 1 4 3 15 FairHijazi et al 199724 7 1 3 3 14 FairHickey et al 199638 8 1 5 3 17 FairLeibovitz et al 199035 9 1 3 3 16 FairIsaacs 198925 5 1 3 3 12 Poor
TABLE 4 BC Rates Among Studies
Subgroup No. of Studies Total Patients Estimate (95% CI) I2 Observed Range of Positive BC (%)
All studies22–42 21 8621 5.14 (3.61–7.28) 91.3% 0.8–17.4Studies pre-PCV23–26,33,35,36,38,42 9 4301 8.06 (5.74–11.20) 68.6% 0.8–17.4Studies post-PCV22,27–32,34,37,39–41 12 4320 3.04 (1.46–6.21) 83.0% 0.9–7.8Prospective studies only22–27,29–36,42 15 6035 4.83 (2.98–7.73) 91.2% 0.8–17.4Studies pre-PCV23–26,33,35,36,42 8 3892 6.75 (3.6–9.9) 89.6% 0.8–17.4Studies post-PCV22,27,29–32,34 7 2143 3.22 (1.09–5.34) 88.5% 0.9–7.8US studies37–41 5 2488 6.03 (3.40–10.48) 85.0% 2.2-10.8US and Western Europe studies25–27,32,36–41 10 3217 5.79 (3.83–8.66) 75.2% 0.8–11.4International studies22–24,28–31,33–35,42 11 5404 4.70 (2.62–8.29) 93.5% 0.8-17.4Studies in children ≤5 y32–34,36,42 5 2764 8.35 (6.12–11.28) 29.9% 6.1–17.4Studies that focus on severe CAP33,35,36,42 4 2794 9.89 (6.79–14.19) 61.6% 7.1–17.4Studies that do not focus on severe CAP22–32,34,37–41 17 5827 4.17 (2.79–6.18) 85.4% 0.8–10.8
BC, blood culture; CAP, community-acquired pneumonia; PCV, pneumococcal conjugate vaccine
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internationally33,35,42 with the excep-tion of 1 study from France,36 were all before the availability of PCV.
Antimicrobial Therapy
Four studies documented the propor-tion of patients who were treated with antimicrobial agents before hospital-ization. These studies, performed in China, Israel, the United States, and Kuwait, reported preadmission antibi-otic rates of 14%, 27%, 36%, and 50%, respectively.24,31,35,41
Seven studies documented antimicro-bial therapy at admission.26–28,30,36,37,41 However, these studies did not all clearly indicate whether antimicrobial therapy was given before or after BC collection, and only 3 studies docu-mented whether BC results led to antimicrobial narrowing or broaden-ing.38–40 In the fi rst study, children were evaluated in the ED and appropriate changes in antimicrobial manage-ment occurred in all 6 cases of posi-tive BCs.40 In the second, a change in antimicrobial management occurred in more than two-thirds of the posi-tive BCs, as well as in a third of false-positive BCs.39 The third study, which reviewed BCs drawn on 409 pediatric patients in the ED and relied solely on radiographic criteria for the diagnosis of pneumonia, nevertheless found that a positive BC identifi ed in 11 patients did not lead to any changes in their management.38 Overall, combining the data in these 3 studies, BCs led to antimicrobial management changes in 53.5% of the patients for whom BC were positive, and 2.2% of the aggre-gate population who had BCs drawn.
Meta-analysis Results
There was a high level of heterogene-ity across the included studies (P < .001; I 2 = 91.32%).43 Consequently, we
TABLE 5 Summary of Bacteria Isolated in Positive BCs
Positive BC (Sample Size) and Most Commonly Isolated Organisms Percentage (%)
All studies (8621)22,23,25–33,35–42
Streptococcus pneumoniae 76.7 Haemophilus infl uenzae 3.1 Staphylococcus aureus 2.1 Klebsiella pneumoniae 1.6 Streptococcus pyogenes 0.3 Haemophilus parainfl uenzae 0.3 Moraxella catarrhalis 0.3 Escherichia coli 0.3 Neisseria meningitides 0.3 Enterobacter spp 0.3 Stenotrophomonas maltophilia 0.3 Contaminants 14.7 Studies conducted in pre-PCV era (4301)23,25,26,33,35,36,38,42
Streptococcus pneumoniae 83.3 Studies conducted in post-PCV era (4320)22,27–32,37,39–41
Streptococcus pneumoniae 61.7Prospective studies only (6035)22,23,25–27,29–33,35,36,42
Studies conducted in pre-PCV era (3892)23,25,26,33,35,36,42
Streptococcus pneumoniae 81.3 Studies conducted in post-PCV era (2143)22,27,29–32
Streptococcus pneumoniae 57.7US studies (2488)37–41
Streptococcus pneumoniae 29.8 Staphylococcus aureus 5.6 Haemophilus infl uenzae 2.4 Contaminants 50.0US and Western Europe studies (3217)25–27,32,36–41
Streptococcus pneumoniae 44.4 Staphylococcus aureus 6.5 Haemophilus infl uenzae 2.4 Contaminants 42.7International studies (5404)22,23,28–31,33,35,42
Streptococcus pneumoniae 92.2 Haemophilus infl uenzae 3.5 Klebsiella pneumoniae 2.3 Contaminantsa 1.2Studies in children ≤5 y (2764)b32,33,36,42
Streptococcus pneumoniae 98.5 Klebsiella pneumoniae 1.0 Neisseria meningitidis 0.5Studies that focus on severe CAP (2794)33,35,36,42
Streptococcus pneumoniae 97.1 Haemophilus infl uenzae 1.4 Klebsiella pneumoniae 1.0 Contaminantsc 0.5Studies that did not focus on severe CAP (5827)22,23,25–32,37–41
Streptococcus pneumoniae 51.7 Haemophilus infl uenzae 5.2 Staphylococcus aureus 4.7 Contaminants 32.0
Data not available in several studies.24,34 BC, blood culture; CAP, community-acquired pneumonia; PCV, pneumococcal conjugate vaccine.a Only 2 studies reported on contaminants.28,35
b No study reported on contaminants.c Only one study reported on contaminants.35
for CAP in the other studies required clinical, laboratory, and radiographic fi ndings consistent with CAP and did
not include ICU admission or intuba-tion in their criteria for severe disease. These studies, conducted primarily
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applied random effects models in our meta-analysis to calculate the preva-lence of positive BCs and 95% CI, for all subgroups (Table 4). Meta-regression of the subgroups showed that the only subgroup indicator that had a signifi cant impact on prevalence of positive BCs was severe CAP (P = .008). Subgrouping also reduced the heterogeneity within the subgroup on severe CAP (I2 = 61.6%), which supports our original analysis that severe CAP has a signifi cant impact on prevalence of positive BC.
The effect of meta-regression on the other subgroups were not signifi cant (P > .05), indicating that the prevalence can be considered the same between subgroups of US and Western Europe studies and international studies, and between subgroups of prospective and retrospective studies. The exception was
the subgroup of studies on children ≤5 years (I2 = 29.9%). Studies not included in this subgroup covered a broader range of ages (from 0 to 21 years), and meta-regression between these 2 groups did not result in a signifi cant P value (P = .06). Hence, there is no statis-tical evidence that studies with children ≤5 years report different prevalence than children of a broader range of ages.
The overall prevalence of positive BCs for all studies was 5.14% (95% CI 3.61–7.28; Fig 2). Studies that focused on severe CAP had a prevalence of 9.89% (95% CI 6.79–14.19), compared with a prevalence of 4.17% (95% CI 2.79–6.18) for studies not focusing on severe CAP.
Funnel plot of the observed studies showed asymmetry and signifi cant publication bias (P = .003; Fig 3). We
then adjusted for publication bias using the trim and fi ll method.21 This method infers the existence of unpublished hid-den studies as determined from a fun-nel plot, and corrects the meta-analysis by ascribing the presence of missing studies to yield an unbiased pooled estimate. With the adjusted analysis, the overall adjusted prevalence was 4.71% (95% CI 3.07–6.34).
DISCUSSIONOn the basis of meta-analysis of these studies, children with CAP had posi-tive BCs in 5.14% of cases. However, because of publication bias, the adjusted prevalence is lower at 4.71%. The most frequently isolated organ-isms from the blood of children with CAP were S pneumoniae, H infl uenzae, and S aureus. These bacteria have been noted to be the predominant causes of severe pneumonia before conjugate vaccines and are similar to the literature in adults.44 Notably, 8 studies in our review were conducted before the licensure of the PCV in 2000,23–26,35,36,38,42 and a ninth study was conducted in South America in which none of the patients had received PCV.33 S pneumoniae remained the predominant pathogen isolated from positive BCs even after introduction of PCV. However, in the post-PCV era, S pneumoniae isolates made up 2.4% of all BC obtained in pediatric CAP compared with 5.6% pre-PCV. This is consistent with other pediatric stud-ies demonstrating effi cacy of PCV in reducing cases of invasive pneumo-coccal disease as well as pneumococcal pneumonia45,46 and suggests that in countries with high PCV uptake, the likelihood of a positive BC is low.
Geographic differences in BC positivity and predominant organisms isolated were evident, although no signifi cant
FIGURE 2 Forest plot demonstrating the pooled prevalence of positive BCs in pediatric CAP. Pooled prevalence was calculated using random effects (RE) models using the DerSimonian-Laird method.
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differences were seen on meta-regression. US and Western European studies had a combined BC positivity rate of 5.79% (95% CI 3.83–8.66), with S pneumoniae accounting for 44.4% of isolates followed by S aureus at 6.5% and H infl uenzae at 2.4%. International studies had a combined BC positiv-ity rate of 4.70% (95% CI 2.62–8.29) with 92.2% of isolates identifi ed as S pneumoniae, followed by H infl uenzae at 3.5% and K pneumoniae at 2.3%. We excluded studies that evaluated diagnostic methods for detection of S pneumoniae in children with pneu-monia to reduce selection bias. If we had included other diagnostic meth-ods in addition to culture, such as polymerase chain reaction or antigen
testing,26 rates of S pneumoniae identi-fi cation would have been even higher.
Collection of BCs in all patients with pneumonia has traditionally been considered a marker of high-quality care.47 The American Thoracic Society has recommended this test since the 1990s as part of the initial evaluation of patients with CAP.48 This recommen-dation was based on the belief that BC results facilitate more effective antimi-crobial treatment because bacteremia refl ects more severe disease and a higher risk of mortality.49 In adults, BC in management of pneumonia was adopted as a quality measure after a study showed that BCs obtained within 24 hours of admission were
associated with lower 30-day mortal-ity.50 However, there were concerns about selection bias and confounding by variations in hospital quality.50,51 In addition, the mean age of patients was 79 years, and 58% of the patients had at least 1 comorbid illness,50 features that are generally not applicable to the pediatric population.
The studies included in this review all lacked a study design that rigorously evaluated the value of BC in manage-ment of pediatric CAP. There were no randomized controlled studies, and the majority of studies were observational. In the few studies that listed severity of CAP as criteria for inclusion, the study’s diagnostic criteria were not always refl ective of severe disease.33,35,36 None of the studies required collection of BC in all patients admitted with CAP. Because the majority of hospitalized patients with CAP may not have been perceived to have a high probability of bacteremia, this selection bias for BC collection in more ill-appearing patients may have resulted in higher rates of documented bacteremia.
Only 3 studies documented antimicro-bial changes in management based on BC results, and all 3 studies had dif-fering results.38–40 However, the study showing that positive BC did not lead to any change in antimicrobial man-agement was performed almost 2 decades ago and may not refl ect cur-rent management practice. In addition, none of these studies documented poor clinical outcomes for patients with either positive or negative BCs.
This impact of diagnostic testing on clinical outcomes has been an area of increasing scrutiny. Studies in the pedi-atric population have demonstrated that diagnostic testing has been shown to
FIGURE 3 Funnel plot testing for publication bias in studies of positive BCs in pediatric CAP. Solid circles are observed studies. Empty circles are fi lled studies by the trim and fi ll method.
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lead to higher hospitalization rates but no signifi cant difference in ED revisit rates,52 nor to signifi cant changes in clinical management.53 Other stud-ies have demonstrated the low yield of positive cultures, the lack of sensitivity in detecting bacterial pneumonia, and the low impact that positive cultures have on altering antimicrobial treatment.4,7,54,55 On the basis of the combined data from the 3 studies that documented antimi-crobial changes in management, ther-apy changes occurred in only slightly more than of the cases. However, this accounted for 2.2% of the total popula-tion in these studies who had BCs drawn.
Our review of the literature did point out situations in which BC collection is likely to be most helpful. The high-est yield of positive BCs in studies were from patients who were manifestly sick,34,42 and severe CAP was the only subgroup that had a signifi cant effect on prevalence in the meta-regression model. However, we were unable to determine the benefi t of BC collection in cases of presumed moderate CAP, as is suggested by the current guidelines, because the majority of studies did not stratify patients by severity of illness.
This is also complicated by the sub-stantial number of false-positive BCs in these studies, ranging from 0.7% to 8.1% of all BCs collected, which cor-relates with fi ndings in adult pneu-monia studies.4,56 Contaminants were reported in all the US studies and overall accounted for half of all posi-tive isolates. These results may have been skewed by the large proportion of contaminants identifi ed in 1 United States study conducted in the 1990s,38 which accounted for 75% of positive BCs. Outside of studies conducted in the United States, only 1 study in
Austria,27 Israel,35 and Turkey,28 respec-tively, reported on contaminants.
Our review was limited not only by the discrepancy in reporting of con-taminants but also by the varied cri-teria used to diagnose pneumonia in children.57 Several studies used World Health Organization criteria that defi nes mild to moderate CAP based on cough and tachypnea.32,34 This defi nition is clearly limited because it is nonspe-cifi c for all types of lower respira-tory tract disease. Other studies did not provide a case defi nition of CAP, although this was implied by their inclu-sion criteria and thus were included in the review.28,38,42 Nonetheless, this may affect the consistency of the included studies. Heterogeneity of case defi ni-tions was a major limitation, which may overestimate the true prevalence of positive BCs in hospitalized children. Although there was variation in results, there was consistency in the direction of effect, and therefore it was reason-able to calculate an average prevalence based on the included studies. We also accounted for this by performing a random effects model on the data as well as the subgroups to incorporate heterogeneity among studies, meta-regression to investigate differences for categorical explanatory variables among subgroups, and regression coef-fi cients to evaluate differences between subgroups. However, comparisons of subgroups where there are overlapping studies may not be meaningful, as these are observational by nature and are not based on randomized comparisons.58 In addition, false-negative and false-positive signifi cance tests increase in likelihood rapidly as more subgroup analyses are performed.58
Next, our review included retrospective studies, and this may lead to sampling
bias, even though when we restricted our analysis to prospective studies, we had similar results, and no difference was determined on meta-regression. We did fi nd evidence of publication bias in the included studies, but adjusted for it in our analyses. Although we excluded studies that predominantly involved patients with comorbidities, some studies did include patients with comorbidities in their analysis, most commonly asthma.31,40–42 The comorbid population accounted for roughly 6% of all hospitalized patients with CAP in our review, not large enough to shift the context of our fi ndings. In addition, since the introduction of conjugate vaccines for H infl uenzae type b and S pneumoniae, rates of associated pneu-monia in children have decreased.45,59 We attempted to account for this in our analysis by stratifying our data into pre- and post-PCV eras, but this review may consequently not refl ect the current epidemiology.
This systematic review furthers our general understanding of the utility of BC in evaluation of pediatric CAP. Given that the heterogeneous study designs and case defi nitions may lead to overestimation of the prevalence of positive BCs, the true prevalence may be <4.71%. Additional data from ongo-ing projects such as the Pneumonia Etiology Research for Child Health (PERCH)57 will assist countries in mak-ing program decisions on health invest-ment priorities, and provide evidence for clinicians to revise their protocols and guidelines for empirical therapy regimens. PERCH can also serve as a model for further studies in pediatric CAP, where research should attempt to quantify the true risk for bacteremia in pediatric patients with CAP, and assess the impact of bacteremia on
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clinical outcomes. Studies determining whether BC collection is cost-effective in patients hospitalized with moderate CAP may help inform whether admis-sion to hospital is suffi cient justifi ca-tion for this procedure. Further studies are needed to evaluate whether BCs in moderate to severe CAP in children shorten hospital stay, reduce complica-tions, and decrease mortality.
ACKNOWLEDGMENTSWe thank Jim Beattie for assistance with the database search, and Haitao Chu for assistance with statistical analysis.
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FINANCIAL DISCLOSURE: The authors have indicated they have no fi nancial relationships relevant to this article to disclose.
FUNDING: Dr Iroh Tam has received grant support from Pfi zer for an unrelated study. Dr Ma was supported in part by the US Agency for Healthcare Research and Quality grant R03HS020666 and the US National Institute of Allergy and Infectious Diseases grant AI103012.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential confl icts of interest to disclose.
(Continued on First page)
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DOI: 10.1542/hpeds.2014-01382015;5;324Hospital Pediatrics
Pui-Ying Iroh Tam, Ethan Bernstein, Xiaoye Ma and Patricia FerrieriSystematic Review and Meta-analysis
Blood Culture in Evaluation of Pediatric Community-Acquired Pneumonia: A
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