Predictive Value of Interferon-γ Release Assays and Tuberculin Skin Testing for Progression From...

CHEST Original ResearchCHEST INFECTIONS

journal.publications.chestnet.org CHEST / 142 / 1 / JULY 2012 63

Although incidence rates are falling in fi ve of the World Health Organization’s (WHO’s) six regions

(the exception being the Southeast Asia region), TB is still a striking global public health problem; the WHO estimates that incident cases exceeded 8 mil-lion and deaths 1.7 million in 2010. 1 The generally accepted tenet, introduced by Comstock in 1974, 2 is that of those who are latently infected, based on the tuberculin skin test (TST), 5% to 10% will develop active TB at some time during their life. In order to meet the WHO’s goal of eliminating TB by 2050,

therefore, it is necessary to establish effective detec-tion and treatment of latent TB infection (LTBI), 3 alongside diagnosing active TB and monitoring treat-ment completion. It is estimated that LTBI treatment alone could prevent 64% of incident cases in the WHO’s Southeast Asia region. 4 Currently, recom-mended courses of preventive chemotherapy are lengthy and require monitoring for side effects. In order to avoid unnecessary treatment, mass therapy of LTBI depends, above all, on the availability and use of adequate screening tests that more accurately

Background: Given the current lack of effective vaccines against TB, the accuracy of screening tests for determining or excluding latent TB infection (LTBI) is decisive in effective TB control. This meta-analysis critically appraises studies investigating the positive and the negative predic-tive value (PPV and NPV, respectively) from a test-determined LTBI state for progression to active TB of interferon- g release assays (IGRAs) and the tuberculin skin test (TST). Methods: We searched MEDLINE, EMBASE, and Cochrane bibliographies for relevant articles. After qualitative evaluation, the PPV and NPV for progression of commercial and “in-house” IGRAs and the TST for persons not receiving preventive treatment in the context of the respec-tive IGRA studies were pooled using both a fi xed and a random-effect model. Weighted rates were calculated for all study populations and for groups solely at high risk of TB development. Results: The pooled PPV for progression for all studies using commercial IGRAs was 2.7% (95% CI, 2.3%-3.2%) compared with 1.5% (95% CI, 1.2%-1.7%) for the TST ( P , .0001). PPV increased to 6.8% (95% CI, 5.6%-8.3%) and 2.4% (95% CI, 1.9%-2.9%) for the IGRAs and the TST, respectively, when only high-risk groups were considered ( P , .0001). Pooled values of NPV for progression for both IGRAs and the TST were very high, at 99.7% (95% CI, 99.5%-99.8%) and 99.4% (95% CI, 99.2%-99.5%), respectively, although they were signifi cantly higher for IGRAs ( P , .01). Conclusions: Commercial IGRAs have a higher PPV and NPV for progression to active TB com-pared with those of the TST, especially when performed in high-risk persons. CHEST 2012; 142(1):63–75

Abbreviations: IGRA 5 interferon- g release assay; LTBI 5 latent TB infection; MTB 5 Mycobacterium tuberculosis ; NPV 5 negative predictive value; PPV 5 positive predictive value; QFT-G 5 QuantiFERON-TB Gold; QFT-GIT 5 Quanti-FERON-TB Gold In-Tube; QUADAS 5 Quality Assessment of Diagnostic Accuracy Studies; TST 5 tuberculin skin test; WHO 5 World Health Organization

Predictive Value of Interferon- g Release Assays and Tuberculin Skin Testing for Progression From Latent TB Infection to Disease State A Meta-analysis

Roland Diel , MD, MPH ; Robert Loddenkemper , MD, FCCP ; and Albert Nienhaus , MD, MPH

Downloaded From: http://journal.publications.chestnet.org/ by a University of Arizona User on 08/01/2012

http://journal.publications.chestnet.org

64 Original Research

The review was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement 9 and the QUADAS (Quality Assessment of Diagnostic Accuracy Studies) checklist. QUADAS aims at identifying potential sources of bias and principally entails 14 predefi ned questions. These questions, described in detail by Whiting et al, 10 assess the eligibility criteria and rep-resentativeness of the study sample, the soundness of the procedures for test verifi cation, the blinding of test interpretation, and the omitting and withdrawal of data.

Materials and Methods

Search Methods for Identifi cation of Studies

Original articles, letters to the editor, and published abstracts were identifi ed by computerized searches of MEDLINE (up to October 10, 2011), EMBASE (up to October 10, 2011), and the Cochrane Central Register of Controlled Trials (CENTRAL; Cochrane Library 2009, issue 3), combining the search terms used in a previous meta-analysis. 5 No restrictions were made with respect to language or basic study design (prospective or retro-spective), determination of predictive values not being the main purpose of the study. We also screened secondary references cited by the studies and guidelines gathered from the databases for retrieving original articles. Studies presenting no original data, such as case reports, editorials, and immunologic (laboratory) and animal studies, as well as reviews, were excluded a priori.

Data Extraction and Analysis

Both study selection and data extraction were conducted inde-pendently in duplicate, reducing the risk of error, by two review-ers (R. D. and A. N.) using a predefi ned form. The form included a fi xed set of fi elds: author, title, journal, year of publication, test, study design (retrospective/prospective), study location, pop-ulation investigated, TST and/or IGRA results, follow-up period, number of participants starting/completing preventive treat-ment, number of participants making up the fi nal study popula-tion, number of people who progressed, and whether fi ngerprinting data were assessed (yes/no).

Treatment of LTBI, when completed, is highly effective in pre-venting progression to active TB disease. 11 For this reason, only results from untreated persons were included in the analysis. We extracted data for treated individuals from our pool in those cases in which the data presented in the work were not already cleansed. Persons lost from sight during monitoring were eliminated from further analysis.

All studies investigating groups that are defi ned as being at high risk of TB according to American Thoracic Society/Centers for Disease Control criteria 12 were further included in a respec-tive subdivision of the meta-analysis. Given that infection with MTB is a prerequisite for later development of TB disease, those studies were not considered in that second analysis, the results of which explicitly excluded a statistical association between the investigated study population and test positivity of the study par-ticipants (TST and/or IGRA) by logistic regression procedures. In such circumstances, no considerable progression to active TB could be expected during the study period, even though the risk of progression is known to be highest in the fi rst 2 years following documented infection. 6,11

predict progression from LTBI to active TB than does the TST.

Over the past 6 years, interferon- g release assays (IGRAs), commercially available as QuantiFERON-TB Gold (QFT-G) and its successor QuantiFERON-TB Gold In-Tube (QFT-GIT) (both from Cellestis Ltd ) and the T-SPOT.TB ELISPOT (Oxford Immunotec Ltd), have become increasingly established world-wide for the in vitro diagnosis of LTBI. These tests use antigens coded by Mycobacterium tuberculosis (MTB) complex specifi c regions of difference that are absent from most nontuberculous mycobacteria and from all strains of Bacille Calmette-Guérin , to solicit secretion of interferon- g as a marker of immune responses by T lymphocytes, thus avoiding the cross-reactivity problems of purifi ed protein deriv-ative from MTB culture fi ltrate antigens used with the TST. In two meta-analyses, 5,6 commercial IGRAs have proven to be highly specifi c for MTB infection. They are also more sensitive than the TST where their ability to detect infection in active TB cases is used as a surrogate for determining sensitivity for latent TB, for which there is no gold standard. 5,7

The key question that remains, however, is how well IGRAs differentiate between those persons who will develop TB and those who will not. Understand-ing the “predictive value” of IGRAs is the subject of ongoing discussion. Two previously published sys-tematic reviews have addressed the question, but in one, the authors disregarded “in-house” assays 6 and in the other, only a very small number of seven studies was eligible for fi nal analysis according to its inclusion criteria. In addition, results from untreated and treated persons were combined. 8 Thus, taking a qualitative approach, we conducted a new, more comprehensive meta-analysis that includes the most recently pub-lished studies. Studies using the commercially avail-able IGRAs (QFT-G, QFT-GIT, and T-SPOT.TB), as well as “in-house” IGRAs, solely or together with the TST, were included wherever there was a defi nite follow-up for the development of active TB assigned.

Manuscript received December 12, 2011; revision accepted March 2, 2012 . Affi liations: From the Department of Pulmonary Medicine (Dr Diel), Medical School Hannover (MHH), Hannover; The Ger-man Central Committee Against Tuberculosis (Dr Loddenkemper), Berlin; and University Medical Center Hamburg-Eppendorf (Dr Nienhaus), Institute for Health Service Research in Derma-tology and Nursing, Hamburg, Germany. Funding /Support: The authors have reported to CHEST that no funding was received for this study. Correspondence to: Roland Diel, MD, MPH, Department of Pulmonary Medicine, Medical School Hannover (MHH), Carl-Neuberg-Straße 1, 30625 Hannover, Germany; e-mail: [email protected] © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.11-3157


mailto:[email protected]

mailto:[email protected]


dence rates per person-year would only have been available in four studies for untreated persons. The pooled value was 2.7% (95% CI, 2.3%-3.2%), ranging from a PPV of 0% when no one progressed during the period of observation for four studies, 13,26,29,40 to a PPV of 17.2% 25 ( Fig 2 ). Because of the extraordi-narily high rate of 66.7% of persons developing active TB in Doherty et al, 15 the pooled PPV among the four eligible studies using different “in-house” IGRAs, comprising 1,225 persons, was nearly identical at 2.9% (95% CI, 2.1%-4.0%) (data not shown ).

Of the studies using commercial IGRAs, four 26,29,31,35 were dubious with respect to being included in a “high-risk” schedule. These explicitly revealed that in the respective collectives there was no associa-tion between study parameters and test positivity and thus their study participants were probably not at increased risk of subsequent progression to active TB. In Bradshaw et al’s 26 study, in which the degree of infectiousness of the index person with pulmonary MDR-TB was not reported, neither exposure of the contacts to the index cases nor any other of the clinical factors, such as diabetes or steroid treat-ment, was associated with IGRA positivity, suggest-ing positive test results were associated with previous infection. Torres Costa et al 35 stated that neither risk assessment nor progression was associated with TST or IGRA results; thus, positive test results in their study must have been predominately due to older

Data Synthesis

To date, only a limited number of studies have investigated progression to active TB by calculating incidence per person-year. 8 Hence, we followed the convention of using positive pre dictive value (PPV) and negative predictive value (NPV) as measures of the probability of development or nondevelopment of TB disease in the fi rst few years, the most vulnerable time frame following documented exposure. As described elsewhere, 6 the NPV for progression was defi ned as the proportion of study participants who scored negative for LTBI by any test and who did not develop active TB during longitudinal follow-up. In con-trast, the PPV for progression was defi ned as the proportion of participants who, given test positivity, subsequently developed active TB. To make TST and IGRA results comparable, cases with indeterminate IGRA results that were monitored for follow-up were considered to have been negative at baseline.

Forest plots were created to investigate whether outcomes were stable over a series of studies. Statistical heterogeneity among studies was assessed using the I 2 test, which describes the per-centage of the total variability in a set of effect sizes caused by true heterogeneity rather than by sampling error. 5 A x 2 test was used to compare the frequencies of test results among different groups of participants. P , .05 was considered to be statistically signifi cant. Statistical analyses were performed by Meta-DiSc soft-ware, version 1.4 (Hospital Ramon Cajal), using both a fi xed and a random-effect model, and by SPSS, version 19.0 for Windows (SPSS Inc).

Results

As shown in Figure 1 , a total of 241 papers were obtained through database searching and, of these, 28 publications were fi nally eligible for inclusion in this review: 18 for the TST, 23 for commercial, and fi ve for “in-house” IGRAs ( Table 1 ). In two studies, 13,14 more than one IGRA had been performed. Accord-ingly, results of both tests were analyzed. Five stud ies used “in-house” tests, 15-19 four QFT-G, 13,20-22 14 QFT-GIT, 14,23-35 and seven T-SPOT.TB. 13,14,36-40

Fourteen studies were contact investigations, 14-22,25-

27,33,34 one of which was retrospective by study design. 22 Five studies included HIV-positive individuals, 24,32,36,37,40 whereas six studies were concerned exclusively with children or adolescents. 16,20,21,29,31,34 Follow-up varied from 1 year 29 to 46 months 27 ; however, a 24-month period of observation was only fulfi lled in 20 of the 28 studies. Six studies were performed in high-burden countries, 13,15,29,31,37,40 12 in intermediate-burden countries, 16-22,30,34,35,38,39 and 10 in low-incidence countries. 14,23-28,32,33,36 In two studies, 14,34 IGRA perfor-mance was restricted to prior TST positivity. The main outcomes of the studies are described in the following.

PPV for Progression to Active TB: IGRAs

Seventeen studies were eligible for the calculation of PPV for progression of commercially available IGRAs, seven of which were performed in low-incidence countries ( Table 1 ). Of these studies, inci-

Figure 1. Flow diagram for study selection. IGRA 5 interferon- g release assay; NPV 5 negative predictive value; PPV 5 positive predictive value; TST 5 tuberculin skin test.




Tabl

e 1—

Bri

ef R

epor

t of

Man

usc

ript

s E

ligi

ble

for

Ana

lysi

s

Stud

y/Ye

arTe

st

Cou

ntry

(B

urde

n)Pa

rtic

ipan

tsF

ollo

w-u

p,

mo

IR I

GR

A a

PPV

IG

RA

b N

PV I

GR

A c

IR T

STPP

V T

ST b

NPV

TST

c

Doh

erty

et a

l 15 /2

002

In-h

ouse

E

LIS

AE

thio

pia

(hig

h)C

onta

ct p

erso

ns24

NA

6/9;

66.7

(29.

9-92

.5) d

1/15

; 93

.3 (6

8.1-

99.8

)N

AN

AN

A

Cla

rk e

t al 36

/200

7T-

SPO

TE

ngla

nd (l

ow)

HIV

-1-p

ositi

ve

adul

ts24

NA

2/20

; 10

(0.1

2-31

.7)

0/47

; 10

0.0

(93.

8-10

0.0)

NA

NA

NA

Hig

uchi

et a

l 20 /2

007

QF

T-G

Japa

n (in

term

edia

te)

Mal

e st

uden

t co

ntac

ts42

NA

NA

e 0/

91;

100.

0 (9

5.7-

100.

0)N

A0/

95;

0.0

(0.0

-3.8

)0/

254;

10

0.0

(98.

6-10

0.0)

Silv

erm

an e

t al 23

/200

7Q

FT-

GIT

Can

ada

(low

)B

ladd

er c

ance

r pa

tient

s/vi

sito

rs24

NA

NA

f 0/

12;

100.

0 (7

7.9-

100.

0)N

A0/

12;

0.0

(0.0

-22.

1)N

A

Bak

ir e

t al 16

/200

8In

-hou

se

EL

ISPO

TTu

rkey

(in

term

edia

te)

Chi

ld c

onta

cts

15 g

43.0

4/54

; 7.

4 (2

.1-1

7.9)

4/52

7;

99.2

(98.

1-99

.8)

26.2

3/83

; 3.

6 (0

.8-1

0.2)

3/35

8;

99.2

(97.

6-99

.8)

Hill

et a

l 17 /2

008

In-h

ouse

E

LIS

POT

Gam

bia

(inte

rmed

iate

)C

onta

ct p

erso

ns24

9.24

11/6

49;

1.7

(0.8

-3.0

)10

/108

7;

99.1

(98.

3-99

.6)

9.02

14/8

43;

1.7

(0.9

-2.8

) h 11

/138

7;

99.2

(98.

6-99

.6)

Aic

helb

urg

et a

l 24 /2

009

QF

T-G

ITA

ustr

ia (l

ow)

HIV

-1-p

ositi

ve

adul

ts19

g N

A3/

36;

8.3

(1.8

-22.

5)0/

749;

10

0.0

(99.

6-10

0.0)

NA

NA

NA

Hal

dar

et a

l 25 /2

009

QF

T-G

ITE

ngla

nd (l

ow)

Con

tact

per

sons

24N

A19

/110

; 17

.3 (1

0.7-

25.7

)0/

835;

10

0.0

(99.

6-10

0.0)

NA

NA

NA

Hig

uchi

et a

l 21 /2

009

QF

T-G

Japa

n (in

term

edia

te)

Stud

ent c

onta

cts

(sch

ool c

hild

ren)

36N

AN

A i

0/30

0;

100.

0 (9

8.8-

100.

0)N

A0/

200;

0.

0 (0

.0-1

.8)

0/10

6;

100.

0 (9

6.6-

100.

0)L

ee e

t al 13

/200

9Q

FT-

GTa

iwan

(hig

h)Pa

tient

s in

en

d-st

age

rena

l di

seas

e

2434

.01/

12;

8.3

(0.0

2-38

.5)

1/20

; j 95

.0 (7

5.1-

99.9

)N

A1/

20;

5.0

(0.1

2-24

.9)

1/12

; 91

.7 (6

1.5-

99.8

)

Lee

et a

l 13 /2

009

T-SP

OT

Taiw

an (h

igh)

See

abov

e24

NA

0/15

; 0.

0 (0

.0-1

8.1)

2/17

; 88

.2 (6

3.6-

98.5

)N

ASe

e ab

ove

See

abov

e

Bra

dsha

w e

t al 26

/201

0Q

FT-

GIT

Nor

ther

n Ir

elan

d (lo

w)

Con

tact

s (p

atie

nts

and

hosp

ital

staf

f)

36N

A0/

37;

0.0

(0.0

-9.5

)0/

394;

10

0.0

(99.

1-10

0.0)

NA

NA

NA

(Con

tinue

d)

Dow

nloa

ded

Fro

m:

http

://j

ourn

al.p

ublic

atio

ns.c

hest

net.

org/

by

a U

nive

rsit

y of

Ari

zona

Use

r o

n 08

/01/

2012


Tabl

e 1—

Con

tinu

ed

Stud

y/Ye

arTe

st

Cou

ntry

(B

urde

n)Pa

rtic

ipan

tsF

ollo

w-u

p,

mo

IR I

GR

A a

PPV

IG

RA

b N

PV I

GR

A c

IR T

STPP

V T

ST b

NPV

TST

c

del C

orra

l et a

l 18 /2

009

In-h

ouse

E

LIS

AC

olom

bia

(inte

rmed

iate

)C

onta

ct p

erso

ns24

-36

NA

NA

k N

A…

NA

NA

Die

l et a

l 27 /2

011

QF

T-G

ITG

erm

any

(low

)C

onta

ct p

erso

ns46

g N

A19

/147

; 12

.9 (8

.0-1

9.4)

0/75

9;

100.

0 (9

9.6-

100.

0)N

A17

/555

; 3.

1 (1

.8-4

.9)

2/34

8;

99.4

(97.

9-99

.9)

Har

stad

et a

l 28 /2

010

QF

T-G

ITN

orw

ay (l

ow)

Asy

lum

see

kers

23-3

2N

A6/

238;

l 2.

5 (0

.9-5

.4)

0/57

6;

100.

0 (9

9.4-

100.

0)N

A6/

415;

1.

4 (0

.5-3

.1)

0/39

4;

100.

0 (9

9.1-

100.

0)Jo

nnal

agad

da e

t al 37

/201

0T-

SPO

TK

enya

(hig

h)H

IV-1

-pos

itive

w

omen

2442

.06/

110;

5.5 m

(2.0

-11.

5)3/

148;

98

.0 (9

4.2-

99.6

)N

AN

AN

A

Kik

et a

l 14 /2

010

T-SP

OT

Net

herl

ands

(lo

w)

Con

tact

per

sons

22 n

NA

6/18

1;

3.3

(1.2

-7.0

)2/

118;

98

.3 (9

4.0-

99.8

)N

A8/

288;

2.

8 (1

.2-5

.4)

0/51

; o 10

0.0

(93.

0-10

0.0)

Kik

et a

l 14 /2

010

QF

T-G

ITN

ethe

rlan

ds

(low

)C

onta

ct p

erso

ns22

n N

A5/

178;

2.

8 (0

.9-6

.4)

3/14

9;

98.0

(94.

2-99

.6)

NA

See

abov

eSe

e ab

ove

Leu

ng e

t al 38

/201

0T-

SPO

TH

ong

Kon

g (in

term

edia

te)

Silic

osis

pat

ient

s15

g 34

.712

/151

; 7.

9 (4

.2-1

3.5)

1/90

; 98

.9 (9

4.0-

100.

0)26

.79/

136;

6.

6 (3

.1-1

2.2)

4/10

5;

96.2

(90.

5-99

.0)

Lie

nhar

dt e

t al 19

/201

0In

-hou

se

EL

ISPO

TSe

nega

l (in

term

edia

te)

Con

tact

per

sons

23 g

13.4

15/5

13; p

2.9

(1.6

-4.8

)6/

380;

98

.4 (9

6.6-

99.4

)11

.816

/629

; 2.

5 (1

.5-4

.1)

5/26

4;

98.1

(95.

6-99

.4)

Tho

mas

et a

l 29 /2

010

QF

T-G

ITB

angl

ades

h (h

igh)

Ado

lesc

ents

12N

A0/

107;

0.

0 (0

.0-3

.4)

0/19

5; q

100.

0 (9

8.5-

100.

0)N

A0/

100;

0.

0 (0

.0-3

.6) r

0/20

1;

100.

0 (9

8.2-

100.

0)Yo

shiy

ama

et a

l 22 /2

010

QF

T-G

Japa

n (in

term

edia

te)

Con

tact

per

sons

21 g

NA

9/11

9; s

7.6

(3.5

-13.

9)19

/2,6

83;

99.3

(98.

9-99

.6)

NA

NA

t N

A

Cha

ng e

t al 30

/201

1Q

FT-

GIT

Sout

h K

orea

(in

term

edia

te)

Art

hriti

s pa

tient

s24

.5 n

NA

NA

u 0/

70;

100.

0 (9

5.8-

100.

0)N

A0/

16;

0.0

(0.0

-17.

1)0/

71;

100.

0 (9

5.9-

100.

0)K

im e

t al 39

/201

1T-

SPO

TSo

uth

Kor

ea

(inte

rmed

iate

)K

idne

y tr

ansp

lant

pa

tient

s22

g N

A4/

71;

5.6

(1.6

-13.

8)0/

201;

10

0.0

(98.

5-10

0.0)

NA

NA

v 4/

270;

98

.5 (9

6.3-

99.6

)M

ahom

ed e

t al 31

/201

1Q

FT-

GIT

Sout

h A

fric

a (h

igh)

Ado

lesc

ents

27 g

6.4

39/2

,669

; 1.

5 (1

.0-2

.0)

13/2

,575

; 99

.5 (9

9.1-

99.7

)6.

040

/2,8

94;

1.4

(1.0

-1.9

)12

/2,3

50;

99.5

(99.

1-99

.7)

(Con

tinue

d)

Dow

nloa

ded

Fro

m:

http

://j

ourn

al.p

ublic

atio

ns.c

hest

net.

org/

by

a U

nive

rsit

y of

Ari

zona

Use

r o

n 08

/01/

2012



Stud

y/Ye

arTe

st

Cou

ntry

(B

urde

n)Pa

rtic

ipan

tsF

ollo

w-u

p,

mo

IR I

GR

A a

PPV

IG

RA

b N

PV I

GR

A c

IR T

STPP

V T

ST b

NPV

TST

c

Sant

in e

t al 32

/201

1Q

FT-

GIT

Spai

n (lo

w)

HIV

-pos

itive

ad

ults

20 n

NA

NA

w

0/10

5;

100.

0 (9

8.0-

100.

0)N

AN

A0/

109;

10

0.0

(98.

0-10

0.0)

Scha

blon

et a

l 33 /2

011

QF

T-G

ITG

erm

any

(low

)H

CW

(nur

sing

st

uden

ts)

24 g

NA

NA

0/15

4;

100.

0 (9

8.1-

100.

0)N

AN

AN

A

Song

et a

l 34 /2

011

QF

T-G

ITSo

uth

Kor

ea

(inte

rmed

iate

)Sc

hool

con

tact

s (a

dole

scen

ts)

24N

A6/

32;

18.8

(7.2

-36.

4)0/

67;

100.

0 (9

5.6-

100.

0)N

A6/

99;

6.1

(2.3

-12.

7)10

/1,5

56;

99.4

(98.

8-99

.7)

Torr

es C

osta

et a

l 35 /2

011

QF

T-G

ITPo

rtug

al

(inte

rmed

iate

)H

CW

scr

eeni

ng41

NA

4/94

5;

0.4

(0.1

-1.1

) x 0/

1,93

1;

100.

0 (9

9.8-

100.

0)N

A4/

2,09

4;

0.2

(0.1

-0.5

)0/

782;

10

0.0

(99.

5-10

0.0)

Zhan

g et

al 40

/201

1T-

SPO

TC

hina

(hig

h)H

IV-1

-pos

itive

s36

NA

0/16

; y 0.

0 (0

.0-1

7.1)

0/16

; 10

0.0

(82.

9-10

0.0)

NA

NA

NA

EL

ISA

5 e

nzym

e-lin

ked

imm

unos

orbe

nt a

ssay

; HC

W 5

hea

lth-c

are

wor

ker;

IG

RA

5 in

terf

eron

- g r

elea

se a

ssay

; IR

5 in

cide

nce

rate

; NA

5 no

t av

aila

ble;

NPV

5 n

egat

ive

pred

ictiv

e va

lue;

PPV

5 p

ositi

ve

pred

ictiv

e va

lue;

QF

T 5

Qua

ntiF

ER

ON

; QF

T-G

5 Q

uant

iFE

RO

N-T

B G

old;

QF

T-G

IT 5

Qua

ntiF

ER

ON

-TB

Gol

d In

-Tub

e; T

ST 5

tube

rcul

in s

kin

test

. a I

R e

stim

ates

per

1,0

00 p

erso

n-ye

ars

from

stu

dies

that

pro

vide

d pe

rson

-tim

e da

ta fo

r un

trea

ted

stud

y m

embe

rs w

ith p

ositi

ve I

GR

A o

r T

ST r

esul

ts.

b Dat

a pr

esen

ted

as N

o. p

rogr

esse

rs/N

o. u

ntre

ated

sub

ject

s sc

orin

g te

st p

ositi

ve a

t bas

elin

e; %

(95%

CI)

. c D

ata

pres

ente

d as

No.

per

sons

dev

elop

ing

TB

who

test

ed fa

lsel

y ne

gativ

e/N

o. p

erso

ns s

cori

ng te

st n

egat

ive

at b

asel

ine;

% (9

5% C

I).

d Nin

e co

ntac

ts w

ere

initi

ally

test

pos

itive

. e O

nly

four

of t

he 8

8 T

ST-p

ositi

ve s

tude

nts

test

ed w

ith Q

FT-

G w

ere

posi

tive;

thes

e fo

ur r

ecei

ved

ison

iazi

d pr

even

tive

trea

tmen

t. f O

nly

the

12 p

atie

nts

who

wer

e T

ST-p

ositi

ve a

nd Q

FT-

nega

tive,

not

the

QF

T-po

sitiv

es, w

ere

follo

wed

clin

ical

ly a

nd r

emai

ned

untr

eate

d.

g Mea

n.

h In

fi ve

of th

ese

14 c

ases

, no

EL

ISPO

T te

st h

ad b

een

perf

orm

ed a

t bas

elin

e.

i The

nin

e co

ntac

ts te

stin

g Q

FT

pos

itive

in a

ny o

f the

thre

e ro

unds

of Q

FT

test

ing

all r

ecei

ved

ison

iazi

d pr

even

tive

trea

tmen

t. j In

clud

ing

two

patie

nts

with

inde

term

inat

e Q

FT-

G r

esul

ts.

k Unc

lear

how

man

y go

t los

t fro

m th

e 1,

977

cont

acts

who

had

bas

elin

e in

terf

eron

- g r

esul

ts a

nd fr

om th

e 50

2 w

ho a

lso

had

TST

res

ults

dur

ing

follo

w-u

p.

l Tw

o ac

tive

TB

cas

es a

mon

g Q

FT-

posi

tives

and

one

act

ive

TB

cas

e am

ong

QF

T-ne

gativ

es, w

ho w

ere

diag

nose

d on

arr

ival

, wer

e ex

clud

ed a

s co

prev

alen

t cas

es.

m T-

SPO

T.T

B n

ot p

erfo

rmed

as

spec

ifi ed

in m

anuf

actu

rer’s

inst

ruct

ions

. n M

edia

n.

o Whe

n us

ing

a T

ST �

10

mm

as

cuto

ff in

der

ogat

ion

from

the

cuto

ff o

f � 5

mm

cho

sen

in th

e st

udy,

in fa

vor

of th

e T

ST.

p Whe

n in

cide

nt T

B c

ases

wer

e re

stri

cted

to th

e 89

3 co

ntac

ts w

ith b

oth

TST

and

EL

ISPO

T r

espo

nse

data

. q I

nclu

ding

75

inde

term

inat

es.

r Aft

er s

ubtr

actio

n of

one

TST

-pos

itive

chi

ld w

ith c

ultu

re-c

onfi r

med

TB

. s A

fter

sub

trac

tion

of 3

00 o

ut o

f 419

QF

T-po

sitiv

es w

ho c

ompl

eted

6-m

o is

onia

zid

prev

entiv

e tr

eatm

ent.

t PPV

and

NPV

for

the

TST

can

not b

e as

sess

ed b

ecau

se in

2,2

46 o

f 3,1

02 c

onta

cts

a T

ST w

as n

ot a

vaila

ble.

A T

ST r

esul

t was

als

o no

t ava

ilabl

e in

12

of th

e 37

cas

es th

at p

rogr

esse

d to

T

B la

ter

on.

u All

36 p

atie

nts

with

pos

itive

QF

T-G

IT r

esul

ts a

nd o

ne w

ith in

dete

rmin

ate

QF

T-G

IT a

nd p

ositi

ve T

ST r

esul

ts r

ecei

ved

ison

iazi

d pr

even

tive

trea

tmen

t. v A

ll 24

TST

-pos

itive

s re

ceiv

ed is

onia

zid

prev

entiv

e tr

eatm

ent.

w O

f the

135

HIV

-pos

itive

s, n

ine

(6.7

%) w

ere

TST

pos

itive

and

13

(9.6

%) Q

FT

pos

itive

. At c

losu

re o

f the

stud

y, th

ree

pers

ons w

ere

lost

to fo

llow

-up

and

thre

e ha

d no

t sta

rted

ison

iazi

d pr

even

tive

trea

tmen

t, bu

t the

re w

as n

o as

sign

men

t giv

en to

TST

or

QF

T p

ositi

vity

. x N

umbe

r of

QF

T-po

sitiv

es a

fter

sub

trac

ting

copr

eval

ent T

B c

ases

. IG

RA

pos

itivi

ty w

as n

ot a

ssoc

iate

d w

ith T

B r

isk

fact

ors.

y A

ll pa

tient

s re

ceiv

ed h

ighl

y ac

tive

antir

etro

vira

l the

rapy

.

Tabl

e 1—

Con

tinu

ed

Dow

nloa

ded

Fro

m:

http

://j

ourn

al.p

ublic

atio

ns.c

hest

net.

org/

by

a U

nive

rsit

y of

Ari

zona

Use

r o

n 08

/01/

2012


stud ies monitoring only untreated healthy contact persons 14,25,27,34 was 8.5% (95% CI, 6.5%-10.9%) for the 55 progressers among 648 contacts and 6.0% (95% CI, 3.1%-10.6%) for the 11 of 182 subjects out of the four HIV studies. 24,36,37,40

PPV for Progression to Active TB: TST

For 16 studies, the calculation of PPVs for progres-sion to TB disease was possible ( Table 1 ). The overall PPV was 1.5% (95% CI, 1.2%-1.7%) ( Fig 4 ). When focusing on high-risk groups as described above, the PPV of the remaining 13 studies increased to 2.4% (95% CI, 1.9%-2.9%), ranging from 0% (in four studies) to 6.6% ( Fig 5 ).

Comparing the PPV for progression between com-mercial IGRAs and the TST without risk stratifi cation produced a highly statistical difference (141 of 5,194; 2.7% vs 124 of 8,479; 1.5%, P , .0001). Comparing commercial IGRAs and the TST for studies contain-ing individuals at high risk, that difference increased further (98 of 1,436; 6.8% vs 80 of 3,391; 2.4%, P , .0001). Of note, when stratifying the latter IGRA studies with respect to performance in low-burden countries (six studies 14,24,25,27,28,36 ) vs intermediate- and high-burden countries (seven studies 13,22,34,37-40 ) in which untreated persons may have developed TB, a difference in PPV could not be shown (60 of 910; 6.6% [95% CI, 5.1%-8.4%] vs 38 of 526; 7.2% [95% CI, 5.2%-9.8%], P 5 .73).

infections, for which the probability of developing TB had generally been decreasing with time. In Thomas et al’s 29 crossover study, only 9.9% of adoles-cents were found to have current or previous TB contact and there was a higher than expected rate of indeterminate results that the authors explained by the fact that nearly 50% of the children were infected with helminths. Although it was mentioned that the participants had been followed for approximately 1 year, IGRA positivity was not associated with any traditional risk factor for TB, suggesting that their MTB infections were not recent but had probably occurred in earlier childhood. In Mahomed et al’s 31 study, only a small proportion (25.4%) of school ado-lescents had a history of TB contact. Among these, there was a paradoxically reverse association between duration of most recent exposure and QFT-GIT or TST positivity. Furthermore, when data from the 20 incident cases, for whom a TB contact prior to enrolment was reported, were stratifi ed bimodally, there was no difference in reported exposure dura-tion between those patients reporting an exposure-to-disease lapse of , 5 years and those reporting a longer lapse following presumed exposure. Given these observations, the four studies were excluded from the fi nal list of high-risk studies.

For studies containing TB high-risk groups, the pooled PPV of commercial IGRAs for progression to active TB increased to 6.8% (95% CI, 5.6%-8.3%) ( Fig 3 ). From these, the pooled value for the four

Figure 2. PPV in % for progression to active TB of commercial IGRAs (all studies). df 5 degrees of freedom. See Figure 1 legend for expansion of other abbreviations.




Figure 3. PPV in % for progression to active TB of commercial IGRAs (high-risk groups only). See Figure 1 and 2 legends for expansion of abbreviations.

Head-to-Head Comparisons of Commercial IGRAs and TST

Nine studies simultaneously compared the PPV of IGRAs and the TST (two studies using both a QFT version and the T-SPOT.TB ), with a total of 4,675 and 6,909 persons, respectively ( Table 2 ). For the IGRAs, pooled PPV (98 of 4,675; 2.1% [95% CI, 1.7%-2.5%] vs 100 of 6,909; 1.4% [95% CI, 1.2%-1.8 %]) was signifi cantly higher than the corresponding rate for the TST ( P 5 .01).

NPV for Progression to Active TB: IGRAs

Twenty-two studies, with a total of 12,154 individ-uals, provided data to allow calculation of the NPV for commercial IGRAs ( Fig 6 ). Two of these studies compared commercial IGRA tests. 13,14 The pooled NPV for studies using commercial IGRAs was high, at 99.7% (12,113 of 12,154 [95% CI, 99.5%-99.8%]). The pooled NPV for progression of the four studies using “in-house” IGRAs, comprising 2,009 subjects, was 99.0% (1,988 of 2,009 [95% CI, 98.4%-99.4%]), signifi cantly lower than that of the commercial IGRAs ( P , .0001).

NPV for Progression to Active TB: TST

To determine NPV for progression for the TST, 17 studies were available, covering 8,618 persons. The pooled NPV value was 99.4% (8,566 of 8,618 [95% CI, 99.2%-99.5%]) ( Fig 7 ). The pooled NPV for progression was signifi cantly higher for the com-mercial IGRAs than for the TST ( P , .01).

Quality of Analyzed Studies

The number of publications meeting the criteria for our analysis was small, and the quality of the trials varied considerably. More than one-fourth (eight) of the 28 studies used for estimation of the PPV and/or the NPV for progression had small study populations; the respective denominators for the proportion of subjects eventually developing (or not developing) active TB in these studies was , 100 individuals. Despite the pooling effect of the meta-analysis, this small sample size enlarges the CI around the “true” estimates and thus limits their signifi cance.

As expected, there was considerable heterogeneity ( P , .0001, I 2 . 75%) with respect to NPV and PPV for progression among the included studies. This refl ects the clinical heterogeneity of the various study settings and populations. With respect to the 14 contact investigation studies, only a minority of these 14,16,17,27 performed genotyping of the disease agent to verify the epidemiologic link between the index cases and the presumed secondary TB cases, given culture-confi rmed TB. Furthermore, in two studies, a PPV could not be assessed because it was impossible to quantify the number of subjects who were lost to fol-low-up after having tested positive at baseline 18 or who had received isoniazid preventive treatment or not, 32 in order to establish the number of untreated persons. When study quality was assessed using the QUADAS tool ( Table 3 ), 11 of the 24 included stud-ies (46%) for whom all 14 quality indicators were applicable scored 100%, and all of the studies met 12 of the 14 indicators.



Figure 4. PPV in % for progression to active TB of TST (all studies). See Figure 1 and 2 legends for expansion of abbreviations.

Discussion

In our meta-analysis, we included 28 studies with totals of 1,225, 5,194, and 8,479 subjects tested by “in-house” IGRAs, commercial IGRAs, and the TST, respectively, to calculate a pooled value for PPV for progression, and totals of 2,009, 12,154, and 8,618 sub-jects, respectively, to calculate an NPV. The IGRAs showed a signifi cantly higher PPV than did the TST, especially when using commercially available IGRAs. PPV for progression largely depends on specifi city, and only truly infected persons can progress to TB. Therefore, it is no surprise, given the higher spec-ifi city of IGRAS as compared with the TST, that

IGRAs have a signifi cantly higher PPV. For the TST, PPV would have been lowered because of poor spec-ifi city if there were considerable proportions of Bacille Calmette-Guérin vaccinees and/or presumed nontuberculous mycobacteria infections in some groups to be monitored. Also, head-to-head com-parison, done in all studies testing subjects with both a commercial IGRA and the TST, confi rmed the sta-tistically higher PPV of the IGRAs as shown by the separated pooling of all eligible studies. This is all the more important because progression to active TB fol-lowing a positive IGRA may be underestimated in studies in which both TST and IGRAs are used. When comparing the outcome of untreated persons

Figure 5. PPV in % for progression to active TB of TST (high-risk groups only). See Figure 1 and 2 legends for expansion of abbreviations.




When excluding only four studies that apparently did not follow subjects at high risk of recently being infected by MTB, the pooled progression rate for IGRA-positive subjects increased almost threefold, from 2.7% (95% CI, 2.3%-3.2%) to 6.8% (95% CI, 5.6%-8.3%). This observation highlights the impor-tance of using IGRAs for “targeted testing” if the desire is to restrict the number of people who need to

only, it must be remembered that physicians may be more inclined to treat a person with discordant posi-tive IGRA/negative TST results than to treat some-one with negative IGRA/positive TST results. The resulting inevitable design shortcoming diminishes the number of untreated IGRA-positive persons and must be kept in mind as a potential intervention bias.

Table 2— Head-to-Head Comparison of PPV of Commercial IGRAs vs TST in Untreated Persons

Study/Year Sample Country IGRA a IGRA Used TST a

PPV Difference Between IGRA and TST,

Percentage Points

Lee et al 13 /2009 Hemodialysis patients Taiwan 1/12 (8.3) QFT-G 1/20 (5.0) 1 3.3Lee et al 13 /2009 Hemodialysis patients Taiwan 0/15 (0.0) T-SPOT 1/20 (5.0) 2 5.0Diel et al 27 /2011 Contact persons Germany 19/147 (12.9) QFT-GIT 17/555 (3.1) 1 9.8Harstad et al 28 /2009 Asylum seekers Norway 6/238 (2.5) QFT-GIT 6/415 (1.4) 1 1.1Kik et al 14 /2010 Contact persons Netherlands 6/181 (3.3) T-SPOT 8/288 (2.8) 1 0.5Kik et al 4 /2010 Contact persons Netherlands 5/178 (2.8) QFT-GIT 8/288 (2.8) � 0.0Leung et al 38 /2010 Silicosis patients Hong Kong 12/151 (7.9) T-SPOT 9/136 (6.6) 1 1.3Song et al 34 /2011 School contacts South Korea 6/32 (18.8) QFT-GIT 6/99 (6.1) 1 12.7Thomas et al 29 /2010 Adolescents Bangladesh 0/107 (0.0) QFT-GIT 0/100 (0.0) � 0.0Mahomed et al 31 /2011 Adolescents South Africa 39/2669 (1.5) QFT-GIT 40/2,894 (1.4) 1 0.1Torres Costa et al 35 /2011 HCWs Portugal 4/945 (0.4) QFT-GIT 4/2,094 (0.2) 1 0.2Total 98/4,675 (2.1) 100/6,909 (1.4) P 5 .01

See Table 1 for expansion of abbreviations. a Data presented as No. progressers/No. untreated subjects scoring test positive at baseline (%).

Figure 6. NPV in % for progression to active TB of commercial IGRAs. See Figure 1 and 2 legends for expansion of abbreviations.



be offered chemoprevention or perhaps followed for development of any symptoms (eg, via chest radiog-raphy examinations) over the subsequent years. The fact that there was no statistical difference between the pooled PPV for low-burden and for intermedi-ate/high-burden countries when comparing IGRA studies including high-risk groups suggests that dili-gent selec tion of persons at risk is key. This fi nding seems to challenge the concept that poor discrimina-tion between recent and remote infection in settings with higher MTB prevalence generally results in a lower PPV.

Our results differ from those of the recently pub-lished meta-analysis of Rangaka et al, 8 who fi rst included only studies providing person-year incidence rates of disease, but without excluding persons who had received chemoprevention. 16,38 Subsequently, the authors excluded studies in which IGRA results were not blinded to the treating physician, arguing (without proof for the single studies) that they could possibly be biased by more extensive investigation into whether TB disease would have developed in IGRA-positive participants (“incorporation bias”). Thus, only seven studies performed in intermediate- and high-incidence countries remained in Rangaka et al’s 8 review, and in only two studies 37,38 published to date was a com-mercial IGRA used. The incidence ratios between positive and negative test results for fi ve of the seven studies in which both a TST and an IGRA were used presented only a doubled risk of subsequent TB disease given positive IGRA results (2.11 [95% CI, 1.29-3.46]) and, even more surprisingly, no signifi cant difference between positive and negative TST results,

irrespective of the TST cutoff, for TB development (5 mm cutoff, 1.43 [95% CI, 0.75-2.72]; 10 mm cut-off, 1.6 [95% CI, 0.94-2.72]).

Generally, if positive IGRA results represent older infections, the risk of subjects developing active TB is lower than that for newly infected persons. This is likely to be the situation for the large studies of Torres Costa et al 35 on health-care workers or Mahomed et al 31 on adolescents, neither of which presented evidence of recent infections in their study populations. This agrees with the old rule “intention to test is intention to treat” and highlights the benefi t of taking into account factors known to trigger pro-gression, such as recent exposure, the individual status of a subject’s immune system, age, or immuno-suppressive treatment. 41

What is arguably more important is that a test detects those truly infected and, in the absence of a gold standard for LTBI, this can be demonstrated by a high NPV for progression. The NPV for progression of the commercial IGRAs was very high, at 99.7%, suggesting that only very few true infections go unde-tected by the test, even (as data from the presented studies show) in immunosuppressed people. The pooled NPV for progression of the TST for exclusion of LTBI was also very high, at 99.4%, although this was signifi cantly lower than for the commercial IGRAs.

Conclusions

In conclusion, positive test results of both com-mercial and “in-house” IGRAs have a higher PPV for progression to active TB than do those of the TST.

Figure 7. NPV in % for progression to active TB of TST. See Figure 1 and 2 legends for expansion of abbreviations.




References 1 . World Health Organization . 2011/2012 Tuberculosis Global

Facts . Geneva, Switzerland: World Health Organization; 2011 . 2 . Comstock GW , Livesay VT , Woolpert SF . The prognosis of

a positive tuberculin reaction in childhood and adolescence . Am J Epidemiol . 1974 ; 99 ( 2 ): 131 - 138 .

3 . Dye C , Williams BG . Eliminating human tuberculosis in the twenty-fi rst century . J R Soc Interface . 2008 ; 5 ( 23 ): 653 - 662 .

4 . Abu-Raddad LJ , Sabatelli L , Achterberg JT , et al . Epide-miological benefi ts of more-effective tuberculosis vaccines, drugs, and diagnostics . Proc Natl Acad Sci U S A . 2009 ; 106 ( 33 ): 13980 - 13985 .

5 . Diel R , Loddenkemper R , Nienhaus A . Evidence-based comparison of commercial interferon-gamma release assays for detecting active TB: a metaanalysis . Chest . 2010 ; 137 ( 4 ): 952 - 968 .

6 . Diel R , Goletti D , Ferrara G , et al . Interferon- g release assays for the diagnosis of latent Mycobacterium tuberculosis infection: a systematic review and meta-analysis . Eur Respir J . 2011 ; 37 ( 1 ): 88 - 99 .

7 . Sester M , Sotgiu G , Lange C , et al . Interferon- g release assays for the diagnosis of active tuberculosis: a systematic review and meta-analysis . Eur Respir J . 2011 ; 37 ( 1 ): 100 - 111 .

8 . Rangaka MX , Wilkinson KA , Glynn JR , et al . Predictive value of interferon-gamma release assays for incident active tuber-culosis: a systematic review and meta-analysis . Lancet Infect Dis . 2012 ; 12 ( 1 ): 45 - 55 .

Pooled NPVs for progression to exclude LTBI are very high for both IGRAs and TST, although the commercial IGRAs show a small, but statistically sig-nifi cant, superiority. Progression rates for commer-cial IGRAs are remarkably higher than those for the TST, but remain low in absolute numbers. Data sug-gest that IGRAs provide signifi cant benefi ts over the TST, but that the use of IGRAs, and testing for LTBI in general, should be targeted at high-risk groups.

Acknowledgments Author contributions: Dr Diel: contributed to the article concept, statistical analysis, and drafting of the manuscript. Dr Loddenkemper : contributed to the article concept, design of the study, and drafting of the manuscript. Dr Nienhaus: contributed to the article concept, design of the study, acquisition and selection of data, and drafting of the manuscript. Financial /nonfi nancial disclosures: The authors have reported to CHEST the following confl icts of interest: Dr Diel has received travel reimbursement and/or fees for speaking at symposia spon-sored by Cellestis Ltd, Oxford Immunotec Ltd, and Pharmore Ltd (exclusive supplier of Tuberculin RT23 for Germany). Drs Loddenkemper and Nienhaus have reported that no potential confl icts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Table 3— QUADAS Assessment of Included Studies

Study

QUADAS

1 2 3 4 5 6 7 8 9 10 11 12 13 14

Aichelburg et al 24 Yes Yes Yes Yes No No Yes Yes Yes Yes Yes Yes Yes Yes a Bakir et al 16 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes YesBradshaw et al 26 Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes YesChang et al 30 Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes YesClark et al 36 Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yesdel Corral et al 18 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No NoDiel et al 27 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes YesDoherty et al 15 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No YesHaldar et al 25 Yes Yes NA b NA NA NA NA NA NA NA NA Yes No YesHarstadt et al 28 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No YesHiguchi et al 20 Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes No YesHiguchi et al 21 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes YesHill et al 17 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes YesJonnalagadda et al 27 No No NA NA NA NA NA NA NA NA NA Yes Yes YesKik et al 14 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes YesKim et al 39 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes YesLee et al 13 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes YesLeung et al 38 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes YesLienhardt et al 19 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes YesMahomed et al 31 No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes YesSantin et al 32 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes YesSchablon et al 33 Yes Yes NA NA NA NA NA NA NA NA NA Yes Yes YesSilverman et al 23 No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes YesSong et al 34 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes YesThomas et al 29 No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes NoTorres Costa et al 35 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes YesYoshiyama et al 22 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes NoZhang et al 40 Yes Yes NA NA NA NA NA NA NA NA NA Yes Yes Yes

QUADAS 5 Quality Assessment of Diagnostic Accuracy Studies. a If there was no evidence that patients withdrew from the study before the results of either the index test or the reference standard or both were known. b Not applicable if only one single test was performed.



9 . Moher D , Liberati A , Tetzlaff J , Altman DG ; PRISMA Group . Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement . PLoS Med . 2009 ; 6 ( 7 ): e1000097 .

10 . Whiting P , Rutjes AW , Reitsma JB , Bossuyt PM , Kleijnen J . The development of QUADAS: a tool for the quality assess-ment of studies of diagnostic accuracy included in systematic reviews . BMC Med Res Methodol . 2003 ; 3 : 25 .

11 . Smieja MJ , Marchetti CA , Cook DJ , Smaill FM . Isoniazid for preventing tuberculosis in non-HIV infected persons . Cochrane Database Syst Rev . 2000 ; ( 2 ): CD001363 .

12 . American Thoracic Society . Targeted tuberculin testing and treatment of latent tuberculosis infection . MMWR Recomm Rep . 2000 ; 49 ( RR-6 ): 1 - 51 .

13 . Lee SS , Chou KJ , Su IJ , et al . High prevalence of latent tuberculosis infection in patients in end-stage renal disease on hemodialysis: comparison of QuantiFERON-TB GOLD, ELISPOT, and tuberculin skin test . Infection . 2009 ; 37 ( 2 ): 96 - 102 .

14 . Kik SV , Franken WP , Mensen M , et al . Predictive value for progression to tuberculosis by IGRA and TST in immigrant contacts . Eur Respir J . 2010 ; 35 ( 6 ): 1346 - 1353 .

15 . Doherty TM , Demissie A , Olobo J , et al . Immune responses to the Mycobacterium tuberculosis -specifi c antigen ESAT-6 signal subclinical infection among contacts of tuberculosis patients . J Clin Microbiol . 2002 ; 40 ( 2 ): 704 - 706 .

16 . Bakir M , Millington KA , Soysal A , et al . Prognostic value of a T-cell-based, interferon-gamma biomarker in children with tuberculosis contact . Ann Intern Med . 2008 ; 149 ( 11 ): 777 - 787 .

17 . Hill PC , Jackson-Sillah DJ , Fox A , et al . Incidence of tuber-culosis and the predictive value of ELISPOT and Mantoux tests in Gambian case contacts . PLoS ONE . 2008 ; 3 ( 1 ): e1379 .

18 . del Corral H , París SC , Marín ND , et al . IFNgamma response to Mycobacterium tuberculosis , risk of infection and disease in household contacts of tuberculosis patients in Colombia . PLoS ONE . 2009 ; 4 ( 12 ): e8257 .

19 . Lienhardt C , Fielding K , Hane AA , et al . Evaluation of the prognostic value of IFN-gamma release assay and tubercu-lin skin test in household contacts of infectious tuberculosis cases in Senegal [published correction appears in PLoS One . 2010;5(12)] . PLoS ONE . 2010 ; 5 ( 5 ): e10508 .

20 . Higuchi K , Harada N , Mori T , Sekiya Y . Use of QuantiFERON-TB Gold to investigate tuberculosis contacts in a high school . Respirology . 2007 ; 12 ( 1 ): 88 - 92 .

21 . Higuchi K , Kondo S , Wada M , et al . Contact investigation in a primary school using a whole blood interferon-gamma assay . J Infect . 2009 ; 58 ( 5 ): 352 - 357 .

22 . Yoshiyama T , Harada N , Higuchi K , Sekiya Y , Uchimura K . Use of the QuantiFERON-TB Gold test for screening tuber-culosis contacts and predicting active disease . Int J Tuberc Lung Dis . 2010 ; 14 ( 7 ): 819 - 827 .

23 . Silverman MS , Reynolds D , Kavsak PA , Garay J , Daly A , Davis I . Use of an interferon-gamma based assay to assess bladder cancer patients treated with intravesical BCG and exposed to tuberculosis . Clin Biochem . 2007 ; 40 ( 12 ): 913 - 915 .

24 . Aichelburg MC , Rieger A , Breitenecker F , et al . Detection and prediction of active tuberculosis disease by a whole-blood interferon-gamma release assay in HIV-1-infected individ-uals . Clin Infect Dis . 2009 ; 48 ( 7 ): 954 - 962 .

25 . Haldar P , Thuraisingam H , Patel H , Hoskyns W , Woltmann G . QuantiFERON testing in close contacts of smear positive pulmonary TB identifi es people at low risk of secondary pro-gression . Thorax . 2010 ; 65 ( suppl 4 ): A148 .

26 . Bradshaw L , Davies E , Devine M , et al . The role of the inter-feron gamma release assay in assessing recent tuberculosis trans-mission in a hospital incident . PLoS ONE . 2011 ; 6 ( 6 ): e20770 .

27 . Diel R , Loddenkemper R , Niemann S , Meywald-Walter K , Nienhaus A . Negative and positive predictive value of a whole-blood interferon- g release assay for developing active tuberculosis:an update . Am J Respir Crit Care Med . 2011 ; 183 ( 1 ): 88 - 95 .

28 . Harstad I , Winje BA , Heldal E , Oftung F , Jacobsen GW . Predictive values of QuantiFERON-TB Gold testing in screening for tuberculosis disease in asylum seekers . Int J Tuberc Lung Dis . 2010 ; 14 ( 9 ): 1209 - 1211 .

29 . Thomas TA , Mondal D , Noor Z , et al. Malnutrition and hel-minth infection affect performance of an interferon gamma-release assay. Pediatrics . 2010 ;126(6):e1522-e1529.

30 . Chang B , Park HY , Jeon K , et al . Interferon- g release assay in the diagnosis of latent tuberculosis infection in arthritis patients treated with tumor necrosis factor antagonists in Korea . Clin Rheumatol . 2011 ; 30 ( 12 ): 1535 - 1541 .

31 . Mahomed H , Hawkridge T , Verver S , et al . The tubercu-lin skin test versus QuantiFERON TB Gold® in predicting tuberculosis disease in an adolescent cohort study in South Africa . PLoS ONE . 2011 ; 6 ( 3 ): e17984 .

32 . Santin M , Casas S , Saumoy M , et al . Detection of latent tuberculosis by the tuberculin skin test and a whole-blood interferon- g release assay, and the development of active tuberculosis in HIV-seropositive persons . Diagn Microbiol Infect Dis . 2011 ; 69 ( 1 ): 59 - 65 .

33 . Schablon A , Diel R , Diner G , et al . Specifi city of a whole blood IGRA in German nursing students . BMC Infect Dis . 2011 ; 11 : 245 .

34 . Song S , Jeon D , Kim JW , et al . Performance of confi rmatory interferon-gamma release assay in school tuberculosis outbreaks . Chest . 2012 ; 141 ( 4 ): 983 - 988 .

35 . Torres Costa J , Sá R , Cardoso MJ , et al . Tuberculosis screening in Portuguese healthcare workers using the tuberculin skin test and the interferon-gamma release assay . Eur Respir J . 2009 ; 34 ( 6 ): 1423 - 1428 .

36 . Clark SA , Martin SL , Pozniak A , et al . Tuberculosis antigen-specifi c immune responses can be detected using enzyme-linked immunospot technology in human immunodefi ciency virus (HIV)-1 patients with advanced disease . Clin Exp Immunol . 2007 ; 150 ( 2 ): 238 - 244 .

37 . Jonnalagadda S , Lohman Payne B , Brown E , et al . Latent tuberculosis detection by interferon g release assay during pregnancy predicts active tuberculosis and mortality in human immunodefi ciency virus type 1-infected women and their children . J Infect Dis . 2010 ; 202 ( 12 ): 1826 - 1835 .

38 . Leung CC , Yam WC , Yew WW , et al . T-Spot.TB outperforms tuberculin skin test in predicting tuberculosis disease . Am J Respir Crit Care Med . 2010 ; 182 ( 6 ): 834 - 840 .

39 . Kim SH , Lee SO , Park JB , et al . A prospective longitudinal study evaluating the usefulness of a T-cell-based assay for latent tuberculosis infection in kidney transplant recipients . Am J Transplant . 2011 ; 11 ( 9 ): 1927 - 1935 .

40 . Zhang LF , Liu XQ , Zuo LY , Li TS , Deng GH , Wang AX . Longitudinal observation of an interferon gamma-released assay (T-SPOT.TB) for Mycobacterium tuberculosis infec-tion in AIDS patients on highly active antiretroviral therapy . Chin Med J (Engl) . 2010 ; 123 ( 9 ): 1117 - 1121 .

41 . Jasmer RM , Nahid P , Hopewell PC . Clinical practice. Latent tuberculosis infection . N Engl J Med . 2002 ; 347 ( 23 ): 1860 - 1866 .



Predictive Value of Interferon-γ Release Assays and Tuberculin Skin Testing for Progression From...

Documents

Transcript of Predictive Value of Interferon-γ Release Assays and Tuberculin Skin Testing for Progression From...