Vol.
31,
No.
9
JOURNAL
OF
CLINICAL
MICROBIOLOGY,
Sep .
1993,
p.
2550-2552
0095-1137/93/092550-03$02.00/0
Copy igh
©
1993,
Ame ican
Socie y
o
Mic obiology
Ci cula ing
Candida
An igens
and
An ibodies:
Use ul
Ma ke s
o
Candidemia
JOSE
GUTIERREZ,1*
CARMEN
MAROTO,1
GONZALO
PIEDROLA,'
ESTRELLA
MARTIN,2
AND
JOSE
ANTONIO
PEREZ'
Depa amen o
de
Mic obiologia,
Hospi al
Uni e si a io
San
Cecilio,
Uni e sidad
de
G anada,
18012
G anada,'
and
Se icio
de
Mic obiologia,
Hospi al
Uni e si a io
de
Valme,
Uni e sidad
de
Se illa,'
Se ille,2
Spain
Recei ed
11
Decembe
1992/Re u ned
o
modi ica ion
15
Feb ua y
1993/Accep ed
14
May
1993
To
in es iga e
he
u ili y
o
he
48-kDa
an igen
om
Candida
albicans
in
i s
comme cial
o m
(Di ec igen;
Bec on
Dickinson)
and
h ee
o he
se odiagnos ic
me hods
(de ec ion
o
one
an igen
by
Pas o ex
Candida
[Sano i
Diagnos ics
Pas eu ]
and
de ec ion
o
immunoglobulin
G
[IgG1
and
IgM
an ibodies
o
C.
albicans
blas oconidia
[bioMe ieuxl)
o
diagnosis
o
in asi e
Candida
in ec ion,
we
conduc ed
a
p ospec i e
clinical
ial
among
10
pa ien s
wi h
candidemia
(g oup
1),
30
pa ien s
colonized
by
C.
albicans
(g oup
2),
20
pa ien s
wi h
bac e emia
(g oup
3),
and
20
subjec s
wi hou
clinical
o
mic obiological
e idence
o
in ec ion.
The
Di ec igen
sys em
was
posi i e
o
a
leas
one
se um
sample
each
om
eigh
pa ien s
in
g oup
1.
In
g oups
2,
3,
and
4,
i
was
posi i e
o
only
h ee
pa ien s.
The e
was
no
eac ion
o
he
Pas o ex
sys em
in
any
o
he
pa ien s
in ec ed
wi h
o
colonized
by
C.
albicans
o
in
he
non-Candida-ca ying
con ols.
The
IgG
an ibody
concen a ion
oscilla ed
be ween
100
and
800
(mean,
510
±
268)
IU/ml
o
he
pa ien s
in
g oup
1.
In
his
g oup,
eigh
pa ien s
had
IgG
an ibody
le els
o
>400
IU/ml.
The
pe cen ages
o
pe sons
wi h
IgG
an ibody
le els
o
>400
IU/ml
in
g oups
2,
3,
and
4
we e
43.3,
0,
and
0,
espec i ely.
Speci ic
IgM
an ibody
was
p esen
in
all
g oup
1
pa ien s
bu
no
in
hose
in
g oups
2, 3,
and
4.
The
sensi i i y
and
speci ici y
o
he
Di ec igen
es
we e
65
and
97.1%,
espec i ely.
Fo
he
Pas o ex
es ,
he
sensi i i y
was
0%Y.
The
sensi i i y
o
IgG
an ibodies
was
80%,
wi h
a
speci ici y
o
81.4%,
while
he
IgM
an ibodies
we e
100%
speci ic
and
sensi i e.
Bo h
he
posi i e
and
nega i e
p edic i e
alues
o
speci ic
IgM
an ibodies
appea ed
o
be
supe io
o
hose
o
he
o he
h ee
es s.
In asi e
candidiasis
is
di icul
o
diagnose
and
is
he
cause
o
subs an ial
mo bidi y
and
mo ali y
in
immunosup-
p essed
pa ien s
o
in
hose
supe in ec ed
wi h
he
ungus
(12).
The
only
cu en ly
a ailable,
eliable
diagnos ic
aid
o
de ec ion
o
in asi e
candidiasis
is
open
biopsy
o
deep
issue.
Blood
cul u es
a e
equen ly
nega i e
wi h
p o en
deep
isce al
candidiasis,
while
pa ien s
wi h
cen al
lines
o
o he wise
colonized
a e
posi i e
(11,
20).
Among
he
sys-
ems
a ailable
o
de ec ion
o
ungemia
by
Candida
spp.
a e
an
immunodiagnos ic
assay
o
an ibodies
o
mannop o ein
and
mannan
o
o
he
an igens
hemsel es
(12)
and
de ec-
ion
o
se um
a abini ol
o
mannose
by
gas-liquid
ch oma-
og aphy
(3,
10,
15).
An
immunodominan
cy oplasmic
48-
kDa
an igen
(Candida
enolase
an igen)
has
ecen ly
been
iden i ied
and
de e mined
o
be
p esen
in
many
pa ien s
wi h
in asi e
candidiasis
(1,
22).
To
in es iga e
he
u ili y
o
his
48-kDa
an igen
in
i s
comme cial
o m
(Di ec igen;
Bec on
Dickinson)
and
h ee
o he
se odiagnos ic
eagen s
o
in a-
si e
Candida
in ec ion
( he
de ec ion
o
one
an igen
and
he
wo
emaining
an ibodies),
we
conduc ed
a
p ospec i e
clinical
ial
among
pa ien s
wi h
suspec ed
candidemia.
Eigh y
pa ien s
a
high
isk
o
dissemina ed
candidiasis
we e
s udied.
Two
se um
samples
om
each
we e
e alua ed
o
he
p esence
o
Candida
albicans
an igens
by
wo
me hods
and
o
he
p esence
o
bo h
immunoglobulin
G
(IgG)
and
IgM
an ibodies
o
C.
albicans
blas oconidia.
Pa ien s
we e
di ided
in o
he
ollowing
ou
g oups:
1,
10
pa ien s
wi h
p o en
i s - ime
C.
albicans
sepsis
as
e i-
denced
by
h ee
posi i e
blood
cul u es
(Bec on
Dickinson)
*
Co esponding
au ho .
(Table
1);
2,
30
pa ien s
colonized
by
C.
albicans
(coloniza-
ion
was
de ined
as
he
p esence
o
C.
albicans
isola ed
om
mucosal
su aces
only
when
he e
was
no
e idence
o
deep
in asi e
in ec ion);
3,
20
pa ien s
wi h
bac e emia
and
no
e idence
o
Candida
in ec ion;
4,
20
subjec s
who
we e
conside ed
o
ha e
no
clinical
o
mic obiologic
e idence
o
in ec ion.
When
he
hemocul u e
was
posi i e
(g oups
1
and
3)
and
when
he
subjec
showed
no
signs
o
e e
(g oups
2
and
4),
wo
se um
samples
we e
collec ed
(sepa a ed
by
48
h)
and
ozen
a
-70°C.
The
ollowing
de ec ion
me hods
we e
used:
Di ec igen
(liposome
immunoassay
o
de ec ion
o
he
C.
albicans
48-kDa
p o ein
an igen);
Pas o ex
Candida
(la ex
pa icles
conjuga ed
o
an
an i-mannan
monoclonal
an ibody;
Sano i
Diagnos ics
Pas eu ),
and
Candida-Spo
IFA
(uses
a
C
albicans
blas oconidial
clone
VW32
slide
and
luo escein-labelled
an i-IgG
o
-IgM
human
globulin;
bioMe ieux).
Resul s
o
IgG
we e
exp essed
as
ecip ocal
inal
i e s
(ini ial
dilu ion,
1/100).
S anda diza ion
o
his
es
was
achie ed
by
use
o
a
pool
o
se a
om
pa ien s
wi h
candidiasis
(bioMe ieux).
IgG
concen a ions
o
>400
IU/ml
a e
conside ed
indica i e
o
candidemia
by
he
manu ac-
u e .
IgM
an ibody
was
de e mined
a
an
ini ial
dilu ion
o
1/10
and
exp essed
as
ei he
posi i e
o
nega i e.
The
iden i y
o
IgM
was
con i med
wi h
an i-IgG
Abso ben
RF
(Beh ing
Ins i u e).
The
Di ec igen
sys em
was
posi i e
o
a
leas
one
se um
sample
om
each
o
he
pa ien s
in
g oup
1,
excep
o
pa ien s
3
and
10
(Table
2).
In
g oups
2, 3,
and
4,
i
was
posi i e
only
ou
imes
( h ee
pa ien s)
(Table
2).
The e
was
no
eac ion
o
he
Pas o ex
sys em
o
any
o
he
in ec ed
o
colonized
pa ien s
(g oups
1
and
2)
o
o
he
non-Candida-
ca ying
con ols
(g oups
3
and
4)
(Table
2).
The
IgG
2550
NOTES
2551
TABLE
1.
In o ma ion
abou
pa ien s
wi h
candidemia
(g oup
1)
Pa ien
ou come
Unde lying
diso de
1
Cu e
Ch onic
panc ea i is
2
Cu e
B onchopneumonia
3
Cu e
Duodenos omy
4
Dea h
Neoplasm
5
Dea h
P ema u e
bi h
6
Cu e
Neoplasm
7
Cu e
Neoplasm
8
Cu e
Neoplasm
9
Cu e
Neoplasm
10
Cu e
Neoplasm
an ibody
concen a ion
oscilla ed
be ween
100
and
800
(mean,
510
+
268)
IU/ml
o
pa ien s
in
g oup
1.
In
his
g oup,
eigh
pa ien s
(80%)
had
IgG
an ibody
le els
o
>400
IU/ml,
he
posi i i y
h eshold
sugges ed
by
he
manu ac-
u e .
The
pe cen ages
o
IgG
an ibody
le els
ha
we e
>400
IU/ml
in
g oups
2, 3,
and
4
we e
43.3,
0,
and
0,
espec i ely.
Speci ic
IgM
an ibody
was
p esen
in
all
g oup
1
pa ien s
bu
no
in
hose
om
g oups
2,
3,
and
4
(Table
2).
The
sensi i i y
and
speci ici y
o
he
es s
we e
calcula ed
o
each
pa ien .
The
sensi i i y
and
speci ici y
o
he
Di ec igen
es
we e
65
and
97.1%,
espec i ely.
Fo
he
Pas o ex
es ,
he
sensi i i y
was
0%.
The
sensi i i y
o
IgG
an ibodies
was
80%,
wi h
a
speci ici y
o
81.4%,
while
he
IgM
an ibodies
we e
100%
speci ic
and
sensi i e.
While
he
nega i e
p edic-
i e
alue
o
speci ic
IgG
an ibodies
appea ed
o
be
excel-
len ,
bo h
he
posi i e
and
nega i e
p edic i e
alues
o
speci ic
IgM
an ibodies
appea ed
o
be
supe io
o
hose
o
he
o he
h ee
es s
(Table
3).
The
diagnosis
o
in asi e
candidiasis
is
ex emely
di icul
bo h
clinically
and
mic obiologically,
and
he
ole
o
a en-
dan
candidemia
is
o en
ha d
o
disce n
(12).
To
shed
ligh
on
his
p oblem,
some
se odiagnos ic
me hods
based
upon
de ec ion
o
an igens
o
an ibodies
o
C.
albicans
ha e
been
p oposed
(1-10,
12,
14-22).
Al hough
comme cial
ki s
a e
TABLE
2.
C.
albicans
an igen
and
an ibody
esul s
o
pa ien s
wi h
candidemia
(g oup
1),
Candida
coloniza ion
(g oup
2),
o
bac e emia
(g oup
3)
and
heal hy
subjec s
(g oup
4)
No.
o
samples
G oup
(no.
o
posi i e/ o al
IgG
concn
No.
o
samples
pa ien s)'
(IU/ml)b
IgM
posi i e/ o al
Di ec igen
Pas o ex
1
(10)
1
2/2
0/2
800
2/2
2
1/2
0/2
200
2/2
3
0/2
0/2
400
2/2
4
2/2
0/2
800
2/2
5
2/2
0/2
100
2/2
6
1/2
0/2
400
2/2
7
2/2
0/2
400
2/2
8
2/2
0/2
800
2/2
9
1/2
0/2
800
2/2
10
0/2
0/2
400
2/2
2
(30)
0/60
0/60
545
±
140
0/60
3
(20)
1/40
0/40
100
±
50
0/40
4
(20)
3/40
0/40
110
±
60
0/40
a
Values
o
indi idual
pa ien s
in
g oup
1
and
o
all
o
he
pa ien s
in
g oups
2
o
4
a e
shown.
b
Mean
o
mean
+
s anda d
de ia ion.
TABLE
3.
Sensi i i y,
speci ici y,
and
posi i e
and
nega i e
p edic i e
alues,
calcula ed
pe
pa ien ,
o
Di ec igen,
Pas o ex,
and
IgG
and
IgM
an ibodies
o
C.
albicans
Posi i e
Nega i e
Tes
%
Sensi i i y
%
Speci ici y
p edic i e
p edic i e
alue
(%)
alue
(%)
Di ec igen
65
97.1 76.5 95.1
Pas o ex
0
IgG
an ibody
80
81.4
38.1
96.6
IgM
an ibody
100
100
100 100
a ailable,
issue
in asion
by
C.
albicans
canno
be
eliably
de ec ed
by
es ing
o
he
p esence
o
a
speci ic
an igen
(12).
These
include
he
la ex
es
o
mannan
de ec ion
and
agglu ina ion
wi h
liposomes
o
de ec
he
48-kDa
cy oplas-
mic
p o ein
an igen.
The
sensi i i y
o
bo h
es s
is
imp o ed
when
se ial
assays
using
mul iple
consecu i e
se a
a e
used.
Me hods
in ol ing
an ibodies
also
appea
o
be
mo e
e ec-
i e
when
pe o med
in
se ies.
Fo
example,
a
nega i e
inding
wi h
hemagglu ina ion-based
an ibody
es s
ules
ou
he
possibili y
o
C.
albicans
in ec ion
(12).
Ou
indings
indica e
ha
concen a ions
o
C.
albicans
blas oconidium-
speci ic
IgG
an ibody
le els
highe
han
400
IU/ml
a e
obse ed
in
he
majo i y
o
pa ien s
wi h
dissemina ed
candidiasis.
Pe haps
o
equal
impo ance
is
he
high
p edic-
i e
alue
o
a
nega i e
esul .
We
also
demons a ed
ha
C.
albicans
blas oconidial
IgM
an ibodies
showed
e y
high
sensi i i y
and
speci ici y
o
de ec ion
o
in asi e
candidi-
asis.
We
mus
conside ,
howe e ,
he
ac
ha
hese
pa ien s
had
no
su e ed
any
o he
p e ious
candidemia;
hus,
he
e iciency
o
his
es
is
limi ed
o
a
i s - ime
in ec ion.
I
would
be
in e es ing
o
s udy
speci ic
IgM
p oduc ion
du ing
ein ec ion
and
he
du a ion
o
hese
IgM
an ibodies
should
hey
appea .
Se e al
new
compa a i e
epo s
ha e
p o-
posed
he
clinical
u ili y
o
in es iga ions
conce ning
he
cy oplasmic
C.
albicans
48-kDa
an igen
(22)
and
de ec ion
o
he
C.
albicans
mannan
an igen
by
la ex
(13)
in
subjec s
wi h
o
wi hou
in asi e
candidiasis.
We
ha e
compa ed
he
eliabili y
o
ou
me hods
( wo
an igen
de ec ion
and
wo
an ibody
de ec ion
me hods)
o
he
diagnosis
o
dissemi-
na ed
candidiasis.
The
cy oplasmic
an igen
de ec ion
ki
(Di ec igen)
had
mode a e
sensi i i y
and
high
speci ici y
in
ou
popula ion.
Walsh
e
al.
(22)
ob ained
alues
simila
o
ou s
(sensi i i y,
64%;
speci ici y,
96%),
bu
hese
alues
inc eased
in
cases
o
in asi e
candidiasis.
In
ou
s udy,
he
Pas o ex
ki
could
no
de ec he
Candida
mannan
an igen
and
did
no
show
adequa e
sensi i i y
o
diagnosis
in
ei he
he
dissemina ed-in ec ion
o
colonized
pa ien
g oup.
Ne -
e heless,
He en
e
al.
(13)
ecommended
his
es
because
i
was
mode a ely
sensi i e,
al hough
i
was
di icul
o
ecognize
i s
alue
conside ing
he
complexi y
o
he
esul s.
In
addi ion,
in
his
s udy
a
clea
e alua ion
o
he
ki s
was
u he
hinde ed
by
he
absence
o
clea ly
de ined
pa ien
and
con ol
popula ions.
Se e al
ac o s
may
ha e
con ib-
u ed
o
he
alse-nega i e
de e mina ions
o
in asi e
candi-
diasis
in
ou
s udy
(g oup
1,
pa ien s
3
and
10),
such
as
low
concen a ions
o
he
Candida
an igen,
an ibody-media ed
clea ance
o
he
an igen,
and
in equen
sampling.
Ou
esul s
showed
ha
he
iming
o
se um
collec ion
and
he
numbe
o
samples
we e
pa icula ly
impo an
in
ob aining
a
posi i e
esul .
Specimens
we e
ob ained
om
bo h
pa-
ien s
when
he
hemocul u es
we e
posi i e,
bu
by
ha
ime
he
an igen
could
ha e
clea ed.
I is
appa en
om
ou
esul s
ha
wo
an igen-nega i e
se um
samples
do
no
VOL.
31,
1993
J.
CLIN.
MICROBIOL.
exclude
a
diagnosis
o
candidiasis.
We
he e o e
sugges
ha
a
la ge
numbe
o
specimens
be
analyzed.
P ocessing
should
in ol e
a
maximum
o
one
eeze- haw
cycle
be o e
es ing,
since
epea ed
cycles
o
eezing
and
hawing
a e
known
o
dena u e
and
diminish
de ec able
an igen
ac i i y.
In
conclusion,
when
we
compa ed
ou
me hods,
wo
in ol ing
an igen
de ec ion
and
wo
in ol ing
an ibody
de ec ion,
o
se odiagnosis
o
in asi e
candidiasis,
he
mos
use ul
ma ke s
in
pa ien s
wi h
i s - ime
C.
albicans
sepsis
p o ed
o
be
C.
albicans
blas oconidial
IgM
an ibodies.
Gi en
he
appa en
complemen a i y
o
de ec ion
o
candi-
demia
and
p oduc ion
o
IgM
an ibodies,
o
adequa ely
de ec
in asi e
candidiasis
mul iple
se um
samples
mus
be
ob ained
o
an
an ibody
assay,
ei he
wi h
each
se
o
blood
cul u es
o
la e .
In
pa ien s
wi h
suspec ed
candidemia,
in es iga ion
o
IgG
and
IgM
an ibodies
and
he
48-kDa
an igen
is
p oposed.
The
cos
o
his
mul iple
es ing
may
pe haps
be
con ained
by
limi ing
es ing
o
hose
pa ien s
conside ed
o
be
a
high
isk
o
in asi e
candidiasis.
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2552
NOTES