Monitoring and Diagnosis of Cytomegalovirus Infection in Renal ...

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here was designed to monitor renal transplant recipients prospectively and ...... after transplant). On the other hand, if no evidence of antigenemia develops.
Monitoring and Diagnosis Renal Transplantation BRIAN JOSEPH

M. MURRAY, DANIEL GERBASI, and ROCCO

Departments

of Medicine

Center,

In this

Abstract.

pared.

Buffalo,

study,

tigen (CMV-AG) and monitoring

the

Previous

antibodies

to detect

the

leukocytes

(PBL)

viral may

tional

and

nogbobulin

M CMV

expressed

by

correlated fection.

a more

the

peripheral

and

retinitis),

with

despite

of positive

per

cipients

of

infection) cell

an as

agents

well

as

from

infection

early

symptomatic

to blanket

emptive

therapy” until

infection, have

treated

( 1 ).

there

is

patients

This

could

to prevent seen

the

Antiviral point

full-blown

development

symptoms;

therefore,

permit

particu-

phase,

but

will

progress

also

an

alternative

infection,

namely

could

evidence would infection. of a number

initially

of

MYERS, County

Medical

ap“pre-

be with-

incipient

CMV

be

instituted

in an

last

few

of candidate

Received June 26, 1996. Accepted February 25, 1997. Correspondence to Dr. Brian M. Murray. Nephrology Division. Medical Center, 462 Grider Street, Buffalo, NY 14215. 1448$03.00/0

Journal of the American Society of Nephrology Copyright tO 1997 by the American Society of Nephrology

Erie

this

to the

symptomatic

CMV-AG

it can

as a guide

count

institution

that

permit

The

the

more

rapid

(SV)

reaction

to identify

invasive

assay that

time

to therapy

is and

(J Am Soc

therapy.

diagnosis

(6), the detection of viral genetic

here

was

infection,

of CMV antimaterial by the

designed

prospectively

and

(CMV-AG) of CMV

a subgroup

infection

of CMV

of the conventional

(8).

presented

symptomatic

in

SV

likelihood

response

modification

technique the detection

recipients

ability

the

the processing

of preemptive

vial

chain

study

the

not

findings

1997)

the shell

buffy coat culture genemia (7), and

to

an ap-

patients

the

the

and

it was

a high

Such

upon

determine

virus

be used

had

of

superior

to monitor

8: 1448-1457,

and

infection.

is

helps

of the

be used

to the

Nephrol

test

is related were moni-

could

treatment

Based

threshold

because

of symptoms

symptomatic.

actual

threshold therapy,

unnecessary

are a result

shorter,

onset

fever

of

and,

to monitor

compare

the

renal

utility

of

test and the SV test in as well as their

infection

patients

liable

therefore,

to progress

at high

risk

to

of tissue-

disease.

to

of The

the

symptoms

the same

subsequent

the

Materials This ents

and Methods

was

a prospective

at the

January

Erie

years

urine after

tech-

1gM antibody,

County

County

1992 onwards.

samples transplant

techniques,

I 046-6673/0809-

Erie

the cytomegabovirus antigen the diagnosis and monitoring

anti-T

after transplant not only of de-

who

agents

therapy

at Buffalo,

antiviral

obviate

study,

transplant

(primary

to be

of CMV capable

of CMV

laboratory

at which

test

presymptomatic

prophylaxis

JEAN

transplant,

to become

because

re-

with

for

polymerase

mortality

donor appear

those

infection.

proach

attempt

in the

identifying

GRAY,

instituting

prior

could

including

still

Seronegative

after for

reached

niques

enteritis,

occasional

(1-5).

(reactivation/superinfection)

accurately

held

and

patients

larly at risk. Ideally, management requires a sensitive and reliable tecting

( 10 to 30%)

pneumonitis,

a seropositive

seropositive

PBL

organ transplants (CMV) infection

number (e.g.,

regimens

allograft

the as

50,000

serially

this

degree of symptomatic in> 10 positive cells/5O,000

morbidity

prophylactic

York

clinical

a trigger

destined

for immuthat

developed

proach

of antigenemia

cells

PBL

specificity

than the SV test in

but that the degree

considerable

current

of New

in

could be useful in deciding clinically whether to CMV infection. Alternatively, if antigenemia

often

specific

discovered

sensitive

and a significant invasive disease

University

as

blood

and

tests

As many as 70 to 80% of recipients of solid show laboratory evidence of cytomegalovirus after transplant, develop tissue

VANESSA

tored

was followed-up as well as conven-

urine

likelihood and with a count

center

monoclonal

sensitive

It was

more

number

with the All patients

and

an-

authors’

uses

recipients testing,

antibody.

infection,

the

in circulating

transplant CMV-AG

test was not only

detecting

from

SV for blood

(1gM)

cytomegalovirus

tests in the diagnosis infection were com-

which

be both

of 32 renal with serial

State

(SV) CMV

test,

antigen

Microbiology,

of the

studies

CMV-AG

test. A cohort prospectively

CMV-AG

vial

and

AMSTERDAM, VENUTO

Infection

York.

utility

retrospective

that

culture

New

and the shell of posttransplant

suggested

of Cytomegalovirus

study

involving

Medical

Center,

Starting

all renal

transplant

Buffalo,

New

at the time

of transplant,

CMV and

at least

about

the

CMV

infection.

viremia

viruria

biweekly presence

by both the SV and conventional

by conventional in the renal of symptoms,

Complete

blood

culture transplant and counts,

of urine.

was

and

clinic,

were

any

reason

immunosuppression

to suspect consisted

clinical

were

for

serum

creatinine

CMV

infection. with

were

questioned

examined

and

of induction

culture

Patients

serum transaminase levels were measured at least every Additional viral studies were obtained if the patient became if there

from

blood

were obtained at least every two weeks up to 6 months and tested for CMV-AG level, presence of anti-CMV

seen

plant

recipi-

York,

signs

of and

2 weeks. febrile or Posttrans-

antilymphocyte

Antigenemia

globulin

(Minnesota

MN]

until

8/92,

roids,

and

serum

creatinine

peutic

cycbosporine

ALG

[Upjohn,

azathioprine.

treatment

[University

ATGAM

Cyclosporine

concentration were

was discontinued. except

seropositive

donor

who

a significant

3 mg/dl,

and

anti-CMV

recipients

received

level

once

with

according

infection

was

many) a

CYTOGAM#{174}

of Sny-

as the detection

a new

monoclonal

from

to the protocol

was defined

of 1gM antibody,

thera-

prophylaxis

positive

blood

of

culture

for CMV by conventional techniques, or a new positive urine culture. CMV disease was considered to be present when any of the abovementioned laboratory tests were positive for CMV infection and was associated

with

one

or more

of the

following:

leukopenia

white blood cells (wbc)/mm2), thrombocytopenia lets/mm3), hepatitis (de novo elevation of serum ferase),

pneumonitis

(pulmonary

infiltrates

funduscopic

associated with itis (histological patients

with

changes).

alanine

evidence

infection

of Peripheral

Blood

with

allowed

(charchanges

developed

kocytes media.

(Sigma

polymorphonuclear PBL was divided

the

for SV inoculation

Shell

Vial

0.3

ml

inoculated

PBL

at 700

medium comycin

(100

incubated second

5%

fetal

p.g/ml),

was

Chaska,

The

kit

MN)

contains

polypeptide,

MD).

was

antibody reported

At 24 h after

was

contain approximately were examined. Slides permeabilized.

Two

Culture mL

that

infection,

as described

were

prepared

PBL)

125 WA).

Detection

pp 65 and

a fluores-

(Biotest).

Positive

No significant

(IF) using

difference

of Blood

(urine

or PBL

16 mm MRC-5

X

The

inoculum

culture

nuclear

stain-

the appropriate as number of poswas

and

seen

in mean

Urine

preparations)

culture

was

tubes

remained

tubes

of Anti-CMV

inoculated

(Bartels

Diagnos-

on the monolayer

determined Biowhittaker).

minimizes

positive

false

and

rheumatoid

for

I h

results

resulting

test

Index

by dividing

are interpreted >1.1,

high

Tests

to the manufacturer’s

sample

values

controls.

M

from

interference.

low positive standard (LPS) absorbance value is calculated. each

as negative

using an enzyme-linked capture assay The capture 1gM assay methodology

factor

according

served

Immunoglobulin

Levels were (CMV CAP-M,

was

levels

were

package

of CMV-

performed

insert.

in

In brief,

a

is assayed in triplicate and a mean A ratio or index is then prepared for its absorbance

by the mean

as follows:

50, they were treated with 14 days of intravenous gancicbovir 5 mg/kg iv (adjusted for renal function) supplemented by CYTOGAM#{174} 100 mg/kg iv every 4 d for four doses.

Preparation

ing when microscopy.

1449

October 15, 1993, CMV-AG (IF) staining method, using

the lower

goat

Vial Assay

CMV-AG

technique

(CMV

against

demonstrated

0.2

of evidence with dem-

(tubulointerstitial

of CMV

cells

Cell

plate-

the presence of inclusion bodies), and/or gastroenterevidence of inclusion bodies in the mucosa). When

laboratory

directed

Initially,

(IP)

antibodies

cein-conjugated

aminotrans-

in the absence

nephritis

antigenemia.

the Shell

(50/50,000

as frequently,

was

positives



test

could

be

10 during

that

that

94)

±

Seventeen (mean value, of a course of antiviral

asymptomatic note that infection

recurrence in the (Patient

higher

infection

two CMV-AG samples not of 14 and 34, respectively)

devel-

of infection.

before

only

days

CMV-AG

the

onset

level

10

than

of symptoms.

during

test

was re-

of CMV counts

>10

20 of 72 (mean

when

± 50) therapy

ten

it was

count

symptoms

of antigenemia.

only patient who No. 8), symptoms

the

the

CMV-AG

CMV-AG

Indeed on

drawn

of

In contrast,

10 developed

drawn

count nine

No. 9), in whom

all individual

were

in

whose

symptoms.

of symptomatic

bout

(Patient

patient

less than not

CMV-AG > 10

thereafter. no

with

initial

patients

symptomatic. Another 33 (mean value, during antiviral therapy after clinical

resolved. completion

use of different threshold count of > 10 was both

far

However, 274

328 ±173

was

patient

10 shortly

>

so

associated

value,

5, the

symptoms

persistently

infection. were

7 days

to in

mained

first positive culture, culture specimen was

of

and in the final

6, it rose

a sample drawn 10 days before the whereas in the remaining case a positive

in Table

onset

patients,

185 1061

±169

as shown the

1722

167

12

in which

74

1722

±8

transplant,

oped

CMV-AG

(PRE)

1

CMV-AG

highly

Initial

before

1

In cases

Both

reached

3

SEM

day.

counts

(PEAK)

Pre-CMV-AG

Mean

this

CMV-AG

4

8

the

and count

were

85 ± 32) were symptoms had developed after and represented

It was

interesting

to

had recurrent symptomatic appeared to develop at a the initial

associated with were obtained

infection. symptoms in patient

The

last

(values No. 1

Antigenemia

Finally,

tended tions,

Figure

2 shows

that

although

the

peak

Diagnosis been

groups.

and

The

utility

preemptive pares

of

these

antiviral

various therapy

the number

tests was

of patients

to

assessed.

would

instituting

Table

have

been

6 com-

parameters, would have

identified

urine

cultures

that

particular

test.

could

not

be used

because

detected after

until-on the

onset

antibody

was

tients

detected

SV test

before

onset

ten; CMV-AG, of these therapy sequently

before after

would

developed threshold the PBL

initial

values

as a trigger

of intervention

would

have

with

therapy

of symptoms detection

resulted

(SV,

who

six;

CMV-AG, allows

instituted

never

of

sub-

I 1). The one

to select therapy.

10 positive

cells

of all ten

an average

46 days

of unexplained

four

for preemptive

in treatment

a

use of either

test to

(range,

paBoth

of preemptive

of patients (SV,

1gM

per

symp-

of 8 days

before

to 16 days

1000.0

-

100.0

-

can

the

sibility

of preemptive

onset

in

presymptomatic

administered after

can

timed

to coincide way,

widespread study of renal

transplant

test

and

SV

tiveness ondary

was the

detect

the

goal

Unlike

to assess technique

0

c,) 10.0

if either

infection

. .

.

..

0 1.0

-

S. 0.1

-

Asymptomatic Figure

2. Distribution

of peak

Syndrome Only CMV-AG

counts

Hepatitis in patients

with

CMV

Retinitis infection.

shorten

the

while

encourage

to compare

thus

monitor-

CMV their

antigen effec-

A sec-

could

guide

limiting resistance.

infection.

technique

and

is In

will

CMV

to

and

replication.

of serial

I

-

>

viral

the

I

0

infection

the utility

of symptomatic

.

I

of

both

is

be restricted

with and

pos-

of or shortly

can

treatment could

the

infection

at the time

hospitalization

that

so

even

opened CMV

of early

recipients

to determine

viremia

which

evidence

such

or

are

prophylaxis,

therapy

early

presymptomatic

has

chain plasma

tests

of

(1 1). This

beginning

designed

was

presence

of posttranspbant

that

in diagnosis

polymerase these

the period

culture

the

peripheral

cases,

of antivirals

ing

technology

In many

and prevent

This

similar

16 h after

in circulating

(8).

exhibiting

use

(7) uses

of such

as

in the

preemptive

it is hoped

with

monoclonal

DNA

phase.

of infection

and

rapidly

the presence

Finally,

therapy

with

the

CMV

to all patients

patients

duration

test

of

permit

uses

as early

directly

of symptoms

transplantation,

those this

to detect

preparations

to detect

patient

before the

(6)

antigen

prompt

a number

which

more

antigens

they

years,

technique

of the patient.

that

few

to be made SV

traditionally

permitting

introduced,

antigens

be used of the

to detect

fever).

viral

leukocytes

reaction sensitive

be detected

cases

to institution

CMV-AG

not

symptomatic

However,

of the

threshold

patients onset

led

of

1453

has

tests

last

been

culture

CMV

early

leukocytes

respectively,

test could

in many

number

were

of symptoms.

respectively.

have

blood

presence

of ten

onset

CMV-AG

symptoms

nature

different

tomatic

six of ten),

criteria

seven

symptoms

results

The

after

or a positive

in a considerable

quantitative

50,000

in only

and

15 days,

symptoms.

of 2 days

of clinical

positive and

of clinical

at an average

positive

Raising

average-l4

Positive

blood

viral

in cell

The

to detect

as been

The

to early

products

inoculation.

identified

for empiric therapy by a number of potential well as the time after transplant at which they by

viral

have

infection

sensitivity.

infection

of suitable

In the

tests

of CMV

greater antibodies

as guides

also

who

diagnosis.

diagnostic

diagnosis

as

of CMV

by the lack

accurate

newer

Tests

treatment

hampered

and

Diagnostic Therapy

Vial Assay

Discussion

CMV-AG

to be higher in patients with CMV disease manifestait did not appear to clearly differentiate between these

Comparison of Utility of Various Guides to Instituting Preemptive

the Shell

Versus

be used

preemptive

1454

Journal

Table

of the American

6. Utility

of various

Factor

Society

tests

of Nephrology

in guiding

the

institution

of preemptive

therapy

for

CMV

Positive Blood Culture (Shell Vial)

infection

Positive Blood Culture (Conventional)

Positive Urine Culture

Positive 1gM

CMV-AG >0

CMV-AG >10

CMV-AG >50

21

11

8

16

11

18

11

10

10

8

10

9

10

9

42

46

43

42

58

72

47

Numberof patients identified

Number symptomatic

Days

after

transplant Days

(-)

before

or after

-8

-8

-3

-6

+15

+14

+7

(+)

symptoms

institution of antiviral therapy such as pneumonitis and retinitis

CMV

antigenemia

before serious ensued.

was detected

CMV

complications

in a high percentage

(76%)

of renal transplant recipients in this study. As shown in Figure 1 CMV-AG was usually first detected 4 to 8 wk after transplant, which is in agreement with the known natural history of ,

posttransplant

CMV ( 1 ). The

investigators

positive difference

and previous reports of other of positive SV tests (50%) and

conventional cultures could be explained

more

sensitive

virus

at a lower

than

less specific, Without

sible

to resolve

this

the

burden

counts

being

issue

likely

that

a positive

greater

it was

CMV-AG

tests

of a kidney tests done low counts

that

patients

tests

for

the

these

low

extremely

patients

and

and

may

have

nous peroxidase switched to the detection,

which

been

of

risk

rule

and

Such false positives when the peroxidase the

result

carries

of

was

an even

doing this, our experience was similar Ferguson (12). Finally, this data suggests

(70%) the

of

posttransplant

all with very occurred in laboratory with

were identified technique was in by

endoge-

specificity.

In

to that of Landry that the incidence

and of

of

antibody,

suggestfor

again

proved

more

their

sensitive

(nine

patients)

of these

clinical

highly

specific

utility.

for

in obtain-

Although

the blood

sensitivity However,

tests

Conven-

the long delay

than

enhanced cases.

patients SV blood

CMV.

to be

diag-

CMV-AG

the specificity symptomatic

were

although

culture

the

by SV

consisted in the as in our previous

nature of the CMV-AG test proved symptomatic from asymptomatic ill-

ness

with

in that

only

patients

CMV-AG

counts

of

> 10 were

symptomatic. studies

have

as early

compared

detectors

the

CMV-AG

40. They detected antigenemia cultures were positive in almost of these

sis. However,

most

CMV-AG

and

test

antigenemia have

week

also

not only found

earlier.

that

Erice

tests

other

was

to be more CMV-AG et al.

in only 70%, and required

studies

SV cultures

(14)

test

of posttransplant

tion. Wunderli et a!. (13) prospectively transplant recipients and found evidence

a combination

why we CMV-AG

ten

study (9), the quantitative helpful in differentiating

Previous

probably

all

sensitive

cultures

1gM

laboratory

Positive

urine

but unfortunately

most of this of asymptomatic

SV technique

expo-

1gM

infection.

diagnosis

reduces

was

and culture,

reducing

cultures

ing the results

with

blood

CMV

culture

of a new

in the majority of asymptomatic at low levels, whereas positive

CMV,

CMV-AG technique, detection

recovery positive

together

blood

posttrans-

and sufficiently

of

warrant

urine

symptoms,

is not

conventional

the

with

detectable

assay

to

in detecting

2 1 patients

urine

developed

latter

symptomatic

load.

of the

and

low

or development

developed

counts were detected (nine of 1 1), albeit

tional

positive,

tests

greater

seven that

infection CMV-AG,

in confirming

recipients

one reason technique for

by

CMV-AG

86 CMV-AG

interference

of

positive

ten

in the group

too

compared

(84%)

Only

and

inadvertent

these

evidence

nosis

culture

(58%).

antibody

only

blood

not uncommon,

viral

positive

out

of CMV,

symptoms

activity. This immunofluorescence we feel

any other

SV

is

sensitive

(89%)

also

the

tests that were not were bow counts seen

Of the

(95%),

infection

patients)

were

a higher

CMV

(six

or during the illness. Finally,

cannot

at low

lack

cultures

plant

were

that

the

five were positive, These five positives

we

were

counts

higher

donor.

or asymptomatic, transplants

CMV-AG

believe

rare in seronegative

did not exhibit

Although

represent false positives. only during the period use

symptoms of clinical

a seronegative

who

CMV.

the

of

it is impos-

of the

requires

CMV-AG cultures

in this group, only ( 1/50,000 PBLs).

three sure,

were

from

we

sensitivity

culture

the onset of clinical after the resolution

in the absence

but

symptomatic

prophylactic monitoring. The CMV-AG test proved

ing

if it was

standard,

the

The was

circulating

alternatively,

detected

First,

Second, many of the positive accompanied by positive blood before phase

or,

reference

reasons:.

more

in detecting

definitively,

to the

following

suggesting

tests

of viral

low

is due the

count,

two

an independent

discrepancy for

(33%) was much lower. either if the CMV-AG test

the other

bevel

with

virus.

test

infection incidence

infection,

seronegative-seronegative

104

infection

25%, whereas they suggested optimal

the detection SV cultures

be detected, the

CMV-AG

on

in

diagno-

found than

renal

SV that

compared

sensitive can

screened

of CMV

for

the

infec-

that have

have

found

with

CMV

the of but

average, test

1 to be

Antigenemia

more organ

sensitive transplants.

itive

bone

than the Boeckh

marrow

SV

assay

in

transplant

CMV-AG

test carried

transplant

CMV

1 70 recipients

et a!. (15),

recipients,

and

was

length

the first positive of time between

detectable

versus

7 days)

CMV-AG reasons

may

CMV-AG screening have

at an earlier and to permit

ever,

in light

testing

at

period

(4

of our

least

evidence

accounted

to

8 wk

of

antigenemia

We the

also

found

study,

On

develops and

the

by

we

within remained

tomatic.

As

between

I 2 and

level

immediately CMV-AG the

infection

of

risk

as shown

syndrome small,

and

This

may

have

in patients 2 the

with

mortality infection,

result

policy

antiviral

and

signs

within

a few

days

emia

Table

of

>

of CMV

alone

will

use

but not

of

disease short.

prophylactic

symptoms

to-

Indeed,

symptomatic (Table 7).

often

be

and the viral

therapy.

in the presence

status

to

transplants,

early

patient with was excellent

some

The achieved

with

(fever,

no CMV chills,

resolved

rapidly

antigen-

exhibited

on patient

and

a dramatic

graft

of

further

graft

be less

draw larger

many

related viremia

and

Infection

Development

7, the

survival

of CMV

incidence

of a concurrent

over

patients

control

conclusions. of patients

for

our

therapy. the question

count

ex-

have

been

with

preemp-

it impossible

controlled to assess

of which

of >50/50,000

the criterion for institution eight of the ten patients antiviral therapy. However, most

were

CMV

test is the therapy

we had used

to institute

therapy,

of an additional

symptomatic,

albeit

the criterion this

15 patients,

tomatic. If the objective and to include as many

None

(n

=

11)

0

Asymptomatic (n

actually

used

mildly.

of a positive

357 10)

as

would

have

most

of whom

If, on the

CMV-AG

resulted

in treatment

were

never

is for treatment to be truly subsequently symptomatic

survival

Graft

Survival ( 1 yr)

Patient Survival

( 1 yr)

54%

63%

91%

±

1

36%

91 %

91%

±

180

10%

100%

symp-

preemptive patients as

11)

Symptomatic (n

4

is

degrees therapy.

of preemptive therapy; this led to with symptomatic CMV receiving treatment was not truly preemptive

already

hand,

was

to

studies in the cost-

preemptive

PBLs

of This

rather than waiting disease developed. was small, and the

makes

when

was

group

previous

may

of intervening

group

and in

infection.

(9) and

Prospective, will be required

surveillance

in the

CMV

improvement CMV

in part, to our policy

A CMV-AG

Rejection

infec-

of rejection

highest

symptomatic

infected

suitable

Peak CMV-AG

fati-

to ongoing viremia. should be treated, and

I-Yr Survival CMV

often

easy

being contemplated. We evaluated the utility of several of antigenemia in identifying patients for preemptive

test

when

“asymptomillness,

malaise

patient

efficacy of preemptive Finally, there remains

in that

symp-

than

such

a febrile

nonspecific

in Table

and

a considerable

definitive groups

most

with

symptomatic

while

study.

experienced

with

at least

other

of persistent

patients

recurrences,

reported to increase posttransplant morbidity ( 16). This, however, was not our experience

who

perience

two

not experiencing

As shown

and

due,

may initially.

may have been “asymptomatic”

require

this study. patients

therapy although

tion has been even mortality

absence

counts

manifestations the

the classic

to develop

could

of patients

(transaminasemia) even

10, and although

7. Impact

when,

had

counts of 35 and 74 and 67 and 186, that a similar degree of antigenemia

of a feeling

that such

l455

of > 10 after a course of antideveloped recurrent symptoms

patient

develops

patients,

Vial Assay

tive therapy early in the course of infection until manifestations of tissue-invasive However, the number of patients involved

corresponds

with disease

of

patients asymp-

peak

positive-to-negative

therapy,

sweats)

after

antigenemia

represents

were there-

manifestations,

count

of vigorous

was seen in any and graft outcome

With

disease

of disease

the

all patients

symptoms. The

the number

duration

been

our

onset

patients

However, the

with

for

10 either shortly

that usually

CMV-AG

CYTOGAM#{174} in high-risk gether

the

to a peak

between

alone.

was

is

specific

CMV-AG

symptomatology.

used to differentiate

testing

tended

mean

after

then rises

maximum

in Figure

subsequent

other hand 10 remained

5, symptoms

and

to be higher

favor if no

in that

On the below

respective

,

count

time

tended

in Table 2 1 1 the

before

recurring

gability Whether

hand,

10 was

>

8). That

complained

other

antigen

No.

antigenemia only one

toms developing between respectively. This suggests

lowest

one week. persistently

shown

now

(Patient

the Shell

count, more often it took a week or two for to fall to < 10. As many as five of the patients

exhibited recurrent viral therapy, but

atic”

detect

highest

12 weeks,

surveillance

of symptomatic

usually counts

to

the

who developed a CMV-AG of greater than symptomatic at the time or developed symptoms after, whose

of 8

we did not SV result

failure

during

that a CMV-AG

development

our

in this

transplant).

CMV infection is unlikely no longer cost-effective.

above, positive

although the longer that we utilized (14

for

particularly

after

the

chose 2 weeks for logistical (6-month) follow-up. How-

experience

weekly,

fall in CMV-AG antigen counts

post-

an average

result, samples

time. We long-term

that

in diagnosing

days prior to shell vial culture. As outlined detect any difference in the time to the first

versus

of solid

of 59 seroposfound

of 95%

a sensitivity

infection

in a study

Versus

100%

1456

Journal

possible,

then

might

be

have 4

our

in

the

counts

positive

to low

blood

delayed

culture

therapy

results

were,

qualified

at 34

and

as symptoms

48,

as

One

and

opinion,

for

guiding

preemptive

problem

with

this study

time

SV

a guide

then

Use

of

and

earlier

than

niques

remain

tive.

can the

Their

detect

patients, six of blood and urine late

to be

1gM antibodies patients, making

poorly

very

high

sensitivity

more likely than the who are not destined studies

The and

be

test

as performed

required

nor

Drug

Standardization

thus

of symptoms

findings

are

and

is the

similar

we

labor costs, can months of weekly

of

cost.

test

be done profiling

for approximately $40. would cost approximately

we

followed-up

that

of CMV

as expressed

by

per 50/000

PBLs

renal

biweekly

peripheral

findings

evidence

the

blood

samples.

CMV-AG

infection quantification

correlated

test

and

whether

of antigenemia antiviral

therapy.

fever

could

TB,

We was

Balfour

for for

6.

7.

because

it was

often

result

in the

the

pre-

This

Chace

level to

the

transplan-

globulin

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confirmed

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4.

by two correspon-

is somewhat including

3.

de-

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that

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the

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test,

reported

Rubin

Strom

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by the

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thank

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the

simultaneously

test,

authors

disease

available.

threshold

to those

The

of the

therapy

asymptomatic

cytomegalovirus

the CMV-AG

impressed

the

result

to

determine

(48 to 72 h) for the SV, and use of the

to preemptive

of more

CE, Shapiro GPJ. Levin

available

with

the

2.

issue.

be transferred

immunofluorescent

question

but

this

currently

and

,

intensive,

vious

can

1.

therefore,

is not

with

results

groups ( 1 1 17), and we were between the values assayed

munoperoxidase

counts

our

are,

it directly

a concern

The

tech-

infected patients but prospective

kits

our

the

is superior

helps

manuscript.

nonquantita-

they

laboratory

compared

remains

velopment

might blanket

we

are

is longer

seen

Acknowledgments

even

PCR

are

resolve

in our

whether

However,

there

that

to definitively

have

laboratories.

other dence

means

Administration-approved

and it is not clear

most

antigen test to identify to become symptomatic,

will

commercially

and

symptoms

count

of asymptomtest

were

infection

(1 1). However,

standardized

actual

CMV-AG

References

of CMV

test

the

treatment

the

symptomatic

it too

is the fact that we did not do a

antigenemia

that

for

have

therapy.

evidence

as

treatment

specificity

have

concurrent evaluation of detection of viral DNA in peripheral blood leukocytes by polymerase chain reaction (PCR). Furthermore, there is evidence that PCR techniques are even more

sensitive

that

a high

unnecessary

believe

because

likelihood

would

too

assay

cessing

and would

obtained

SV

had

avoiding We

their

but

criterion

patients

the

and

thus

patients.

Both

and

resolved.

additional eight Conventional

in our

two

therapy.

respectively,

the

in our eight

atic

the

of symptoms

infection,

would

symptoms

useful for guiding preemptive therapy. not seen in up to 30% of symptomatic insensitive

threshold

for

levels

onset

threshold

by approximately

treated,

clinical

(SV)

by 4 days

of this

mild

in treatment of an were never symptomatic.

culture

Use

a suitable

of therapy

have

peaked

spontaneously

that

actually

would

developed

CMV-AG

resulted whom

> 10.

institution patients

patients

of Nephrology

suggest

count

eight

subsequently

Society

would

in earlier

additional

a

study

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with

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