Interferon gamma release assay in diagnosis of pediatric tuberculosis: a meta-analysis

R E S EA RCH AR T I C L E

Interferon gamma release assay in diagnosis of pediatrictuberculosis: a meta-analysis

Lin Sun, Jing Xiao, Qing Miao, Wei-xing Feng, Xi-rong Wu, Qing-qin Yin, Wei-wei Jiao, Chen Shen,Fang Liu, Dan Shen & A-dong Shen

National Key Discipline of Pediatrics, (Capital Medical University), Ministry of Education, Key Laboratory of Major Diseases in Children, (Capital

Medical University), Ministry of Education, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Beijing, China

Correspondence: A-dong Shen, Beijing

Pediatric Institute, Beijing Children’s

Hospital affiliated to Capital Medical

University, 56 Nan Li Shi Road, Xi Cheng

District, Beijing 100045, China. Tel.: +8610

59718655; fax: +8610 59718662; e-mail:

[email protected]

Received 24 March 2011; revised 15 June

2011; accepted 28 June 2011.

Final version published online 23 August

2011.

DOI: 10.1111/j.1574-695X.2011.00838.x

Editor: Patrick Brennan

Keywords

meta-analysis; interferon gamma; diagnosis;

tuberculosis; children.

Abstract

Although interferon gamma release assays (IGRAs) have been widely used for

the diagnosis of latent and active tuberculosis in adults, a relative lack of vali-

dation studies in children has led to caution in their clinical interpretation.

This meta-analysis systematically evaluated two IGRAs (ELISA and ELISPOT)

and the tuberculin skin test (TST). We searched databases (PubMed, MED-

LINE, Ovid) between January 2000 and January 2011 using search terms of

latent tuberculosis infection or tuberculosis and interferon gamma release

assay, or T-SPOT.TB test, or QuantiFERON-TB Gold, or ESAT-6, or CFP-10,

and child, or childhood, or pediatrics. We also collected data by performing a

manual search of references from relevant articles and communicating with

selected authors. The meta-analysis was conducted with random effects models

to account for heterogeneity between selected studies. The sensitivities of all

three tests in active tuberculosis were similar. The pooled sensitivity was 70%

for ELISA studies, 62% for ELISPOT studies and 71% for TST. Calculated sen-

sitivities for IGRAs and the TST differ in culture-confirmed tuberculosis

[ELISA (85%) vs. ELISPOT (76%) vs. TST (85%)] and clinical diagnosed cases

[ELISA (64%) vs. ELISPOT (58%) vs. TST (66%)]. The pooled specificity was

100% for ELISA and 90% for ELISPOT, but was much lower for TST [56% in

all included studies and 49% in children with bacillus Calmette-Guerin (BCG)

vaccination]. The agreement between the TST and IGRAs in non-BCG-vacci-

nated children is higher than that in BCG-vaccinated children. In the diagnosis

of active tuberculosis in children, the TST and IGRAs have similar sensitivity.

By contrast, the specificity of IGRAs is far greater than the TST, particularly in

children with previous BCG vaccination.

Introduction

Childhood tuberculosis is commonly extra-pulmonary,

disseminated and severe, especially in children under

3 years of age, and is associated with high morbidity and

mortality (Marais et al., 2006). In children, diagnosis of

tuberculosis is complicated by its pauci-bacillary nature,

resulting in atypical clinical signs and a lower probability

of bacteriological confirmation (Rigouts, 2009). Currently,

the diagnosis of latent tuberculosis infection (LTBI) is

hindered by the lack of a ‘gold standard’. The tuberculin

skin test (TST) was until recently the main method of

detecting Mycobacterium tuberculosis infection and in

diagnosing active tuberculosis. The TST uses a poorly

defined mix of antigens from M. tuberculosis resulting in

false-positive responses because of nontuberculous myco-

bacteria (NTM) infection or previous bacillus Calmette-

Guerin (BCG) vaccination. False-negative TST results can

occur when children suffer from severe active tuberculosis

or immune suppression.

Therefore, alternative diagnostic tools for the detec-

tion of tuberculosis have been explored. The interferon

FEMS Immunol Med Microbiol 63 (2011) 165–173 ª2011 Federation of European Microbiological SocietiesPublished by Blackwell Publishing Ltd. All rights reserved

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gamma release assays (IGRAs) are based on two antigens:

the early-secreted antigenic target 6-kDa protein (ESAT-6)

and culture filtrate protein 10 (CFP-10). Several com-

mercially available IGRA tests have been developed to

assist in the diagnosis of latent and active M. tuberculosis

infection, including the T-SPOT.TB test (TSPOT)

(Oxford Immunotec, Oxford, UK) and QuantiFERON-TB

Gold (QFT-G) or QuantiFERON-TB Gold In-Tube

(QFT-IT) (Cellestis, Carnegie, Australia). TSPOT uses the

ELISPOT (enzyme-linked immunosorbent spot) tech-

nique to measure the number of individual mycobacte-

rium-specific T cells. QFT-G and QFT-IT measure the

concentration of interferon gamma produced in whole

blood with enzyme-linked immunosorbent assay (ELISA).

The assays have been widely used for identifying or

diagnosing tuberculosis infection and have become useful

additional tests in the diagnosis of active tuberculosis in

adults. In contrast, only a few studies have reported their

utility in children. Therefore, in this meta-analysis, we

aimed to compare the sensitivity and specificity of com-

mercial IGRAs with the TST in pediatric tuberculosis.

Materials and methods

Study strategy

We conducted a literature search of databases (PubMed,

MEDLINE, Ovid) for articles published between January

2000 and January 2011. Search terms included latent

tuberculosis infection or tuberculosis and interferon

gamma release assay, or T-SPOT.TB test, or Quanti

FERON-TB Gold, or ESAT-6 or CFP-10, and child, or

childhood or pediatrics. We performed manual searches

of the references from relevant articles and corresponded

with the authors of some articles for complete informa-

tion.

Articles were included if they met the following selec-

tion criteria.

(1) Articles that reported original data were included;

reviews, case reports and editorials were excluded. Articles

with fewer than five enrolled subjects were excluded.

(2) Studies that presented data on the sensitivity and

specificity of the commercial versions of IGRAs, including

T-SPOT.TB, QuantiFERON-TB Gold or QuantiFERON-

TB Gold In-Tube, were included. For studies assessing

sensitivity, the participants were required to have active

tuberculosis confirmed by bacteriological evidence or

diagnosed by clinical evidence. For studies assessing speci-

ficity, the participants should be low-risk individuals

without identified exposure to active tuberculosis. Partici-

pants coinfected with HIV or other immune compro-

mises and those who had received antituberculosis

treatment were excluded.

(3) In studies that evaluated the concordance of the

tests, all tests should have been done simultaneously and

in the same people to ensure comparability.

Two independent reviewers (L.S. and J.X.) performed

searches and selected articles according to the inclusion

criteria designed in advance. One reviewer abstracted

both the test and participant characteristics of the arti-

cles collected. A second reviewer double-checked these

data.

Statistical analysis

For each study, we calculated sensitivity, specificity, posi-

tive rate and 95% confidence intervals (CIs) and summa-

rized the results in forest plots. Studies were weighted by

total sample size to pool estimates of sensitivity and spec-

ificity across the studies. Statistical analysis was conducted

using META-DISC, version 1.4 (Hospital Ramony Cajal,

Madrid, Spain). We evaluated heterogeneity by using the

chi-square test and I2 test. The random effects model

(DerSimonian and Laird) was performed when heteroge-

neity was present (P < 0.05 and I2 > 50%), and the fixed

effects model (Mantel–Haenszel) otherwise.

Results

Eligible studies

After independent review, 16 articles including 598

patients with tuberculosis and 432 controls were available

for analysis. Twelve of these studies were published in the

last 3 years (Fig. 1). Fourteen studies assessed sensitivity

of IGRAs and the TST among children diagnosed with

active tuberculosis. Of these, nine studies performed

ELISA, and 10 studies performed ELISPOT. Seven studies

assessed specificity of IGRAs and the TST among control

children without identified tuberculosis exposure. Of

these, three studies used ELISA and five studies used

ELISPOT (Table 1).

Sensitivity of IGRAs and the TST

For studies assessing sensitivity, the active tuberculosis

cases were confirmed by culture or by standard clinical

criteria. All cases were without HIV infection. Figure 2

shows the separate sensitivities of all three tests in active

tuberculosis. For ELISA, nine studies could be included,

resulting in a pooled sensitivity of 70% (229/328, 95% CI

65–75%). For ELISPOT, 10 studies were included, result-

ing in a pooled sensitivity of 62% (277/443, 95% CI 57–67%). For the TST, 12 studies were available, resulting in

a pooled sensitivity of 71% (365/512, 95% CI 67–75%).

Levels of heterogeneity between the studies were high

ª2011 Federation of European Microbiological Societies FEMS Immunol Med Microbiol 63 (2011) 165–173Published by Blackwell Publishing Ltd. All rights reserved

166 L. Sun et al.

(I2 = 80.3% for ELISA, 92.3% for ELISPOT, 85.8% for

TST).

Tuberculosis patients were further divided into two sub-

groups: culture-confirmed tuberculosis and clinically diag-

nosed tuberculosis. We observed an increased pooled

sensitivity for ELISA (85%), ELISPOT (76%) and TST

(85%) in the former subgroup, while the pooled sensitivity

dropped distinctly in cases diagnosed clinically, with sensi-

tivity for ELISA (64%), ELISPOT (58%) and TST (66%).

We then divided tuberculosis patients by grouping

their countries according to tuberculosis incidence rates.

High-incidence-rate countries (� 50 per 100 000) included

India, China, South Africa and Lithuania. All acceptable

published studies for ELISA were done in low-incidence-

rate countries and showed a pooled sensitivity of 70%.

Studies on ELISPOT and the TST were conducted in

both high- and low-incidence countries and a similar

pooled sensitivity was found (ELISPOT: 64 vs. 61%; TST:

71 vs. 71%).

Specificity of IGRAs and the TST

For studies assessing specificity, the participants enrolled

were low-risk individuals without identified exposure to

active tuberculosis, regardless of BCG vaccination.

The rate of BCG vaccination of the participants varied

(0–100%). As shown in Fig. 3, the pooled specificity was

100% for ELISA studies (73/73, 95% CI 84–100%), 90%

for ELISPOT studies (342/381, 95% CI 86–93%) and

56% for TST studies (214/385, 95% CI 50–61%). Because

only three studies targeting the evaluation of ELISA dem-

onstrated a high specificity, we chose to focus on the

comparison of ELISPOT and the TST in further analysis.

The specificity of ELISPOT was affected only slightly by

BCG vaccination status (89% for vaccinated vs. 95% for

unvaccinated), or by national incidence status (95% for

high-incidence vs. 86% for low-incidence groups). On the

other hand, the specificity of the TST was significantly

affected by BCG vaccination status (49% for vaccinated

vs. 93% for unvaccinated).

Concordance between IGRAs and the TST

Seven studies assessed the concordance between IGRAs

and the TST with varying rates of BCG vaccination.

Among them, five studies concluded that agreement

between TST and IGRA tests in non-BCG-vaccinated

children is higher than that in BCG-vaccinated children.

For example, one study (Tsolia et al., 2010) assessed the

concordance between ELISA and the TST according to

BCG immunization status, and found that among non-

BCG-immunized patients agreement was excellent (j =0.34–1.00), while among BCG-immunized children it was

fair to poor (j = 0.02–0.28).

Discussion

It is estimated that pediatric cases account for 10–15% of

the global tuberculosis case load. Diagnosis of pediatric

tuberculosis is challenging because of the limitations of

conventional methods. Culture and microscopy findings

are often negative in children. Advances in molecular

biology and genomics have led to alternatives to the TST

(Pai et al., 2006; Starke, 2006). Commercially available

IGRAs have evolved rapidly, and they have been widely

used in many settings. Regrettably, researchers have lim-

ited access to evaluate the assays in the field of pediatric

tuberculosis. Meta-analyses can increase the effective sam-

ple size under investigation through the pooling of data

from individual association studies, thereby enhancing

statistical power for assessing sensitivity and specificity of

IGRAs and the TST.

In our review, the sensitivity of the two commercial

IGRAs and the TST shows an equivalent sensitivity in

active tuberculosis. Results from an earlier review indi-

cated that a lower sensitivity of ELISA and the TST have

been found in pediatric tuberculosis compared with

402 articles screened

16 articles finally included into review Sensitivity: 14 Specificity: 7

52 articles excluded: Using in-house IGRAs other than T-SPOT.TB and QuantiFERON-TB Gold (n = 10)Study on participants with HIV infection or other immune compromises (n = 29)Study on participants received anti-tuberculosis treatment (n = 13)

196 articles included for further screening

206 articles excluded: Reviews and meta analysis (n = 59) Editorials (n = 14) Guidelines (n = 6) Case reports (n = 6) Non-diagnostic tests on TB (n = 88) Animal studies (n = 14) Non-English articles (n = 19)

144 articles included for further review

128 articles excluded: Study enrolled participants aged ≥18 year orincluding both children and adults (n = 95)Insufficient data for the meta analysis (n = 33)

Fig. 1. Flow chart of article selection.


IFN gamma and pediatric tuberculosis 167

Table

1.Characteristicsofstudiesincluded

foran

alysisofsensitivity

andspecificity

Study

Country

Age

(years)

Index

test

Cut-off

Sensitivity

Specificity

TSPO

TQFT-IT/QFT-G

TST(m

m)

TBpatients,

Bac/Clin

(n)

Patien

ts

(n)

BCG

vaccinated

(%)

Sunet

al.(2010)

China

�18

TSPO

T/TST

�6spots

10

18/56

51

90.2

Warieret

al.(2010)

India

�18

TSPO

T�6spots

10

15/38

47

92.5

Han

sted

etal.(2009)

Lithuan

ia10–1

7TSPO

T/TST

�6spots

10

23/0

52

100

Lighteret

al.(2009a)

USA

�17

QFT-IT/TST

17.5

pgmL�

110

7/NR

21

0

Detjenet

al.(2007)

German

y0.3–1

5QFT-IT/TSPOT/TST

�6spots

>0.35IU

mL�

15

28/0

22

0

Cruzet

al.(2011)

USA

0.1–1

8TSPO

T/TST

�6or�8spots

513/18

Nicolet

al.(2009)

South

Africa

>18

TSPO

T/TST

�6spots

10

10/48

Kam

pman

net

al.(2009)

UK

0.25–1

6QFT-IT/TSPOT/TST

�6spots

>0.35IU

mL�

110an

d15

25/38

Bam

ford

etal.(2010)

UK

0.17–1

6QFT-IT/TSPOT/TST

�6spots

>0.35IU

mL�

115

195/0

Grare

etal.(2010)

Fran

ce0.5–1

1QFT-IT/TST

>0.35IU

mL�

115

0/7

Tsolia

etal.(2010)

Greece

�15

QFT-IT/TST

>0.35IU

mL�

110or5

13/12

Bianchiet

al.(2009)

Italy

�16

QFT-IT/TST

>0.35IU

mL�

15

6/10

Lighteret

al.(2009b)

USA

�18

QFT-IT/TST

>0.35IU

mL�

110

30

NR

Domınguez

etal.(2008)

Spain

�18

QFT-IT/TSPOT/TST

�6spots

>0.35IU

mL�

15

9/0

Connellet

al.(2008)

Australia

0.5–1

9QFT-G

/TSPOT/TST

�6spots

>0.35IU

mL�

15

9/NR

Soysal

etal.(2008)

Turkey

6–1

0TSPO

T/TST

�6spots

10an

d15

209

100

TSPO

T,T-SPOT.TB

test;QFT-IT,

Quan

tiFERON-TBGold

In-Tube;

QFT-G

,Quan

tiFERON-TBGold;TST,

tuberculosisskin

test;Bac,bacteriology;

Clin,clinical

course;

NR,notreported

.


168 L. Sun et al.

(a) (b)

(c)

Fig. 2. Forest plot of studies estimating sensitivity of the three tests in patients with active tuberculosis: (a) ELISA, (b) ELISPOT, (c) TST. The red

circles and horizontal lines correspond to the recorded percentage of true positive results among tuberculosis cases and their respective 95% CI.

The area of the red circles reflects the weight each study contributes to the analysis. The diamond represents the pooled value with its 95% CI.

Failed or indeterminate test results were not included in the analysis.



(a)

(b)

(c)

Fig. 3. Forest plot of studies estimating specificity of the three tests in healthy children without identified exposure to active tuberculosis:

(a) ELISA, (b) ELISPOT, (c) TST. The red circles and horizontal lines correspond to the recorded percentage of true positive results among

tuberculosis cases and their respective 95% CI. The area of the red circles reflects the weight each study contributes to the analysis. The

diamond represents the pooled value with its 95% CI. Failed or indeterminate test results were not included in the analysis.


170 L. Sun et al.

adults (Menzies et al., 2007). Our data agree with find-

ings in other studies that the sensitivities of the three tests

(62–71%) are lower than those in adults (70–89%) (Jiang

et al., 2007; Pai et al., 2008; Diel et al., 2010). The results

of the three tests are based on the reaction of the immu-

nological effecter cells. It has been reported that CD4+

T cells were the major cell type producing interferon-

gamma (IFN-c), a type 1 cytokine which plays an impor-

tant role in the host immune response (Leung et al.,

2009). Some authors underline that there were statistically

significant differences in CD4+ T-cell subpopulations

between children at different ages (P < 0.05) (Lee et al.,

1996; Kam et al., 2001). As a consequence, we concluded

that a special diagnostic threshold for a positive result

may be adjusted for children based on their suboptimal

and developmental cellular immune responses.

The relatively poor performance of IGRAs in clinically

diagnosed cases remains a concern. Because of the pauci-

bacillary nature of the disease, the diagnosis of active

tuberculosis is often based on a combination of clinical

signs and symptoms, suggestive radiology, history of

household exposure, as well as the TST reaction. Accord-

ing to the decreased pooled sensitivity in clinical diag-

nosed tuberculosis in this analysis, some of the cases could

be over diagnosed as active tuberculosis due to the overlap

of symptoms with other childhood illnesses. Pediatric

tuberculosis clinicians had high hopes that applying the

results of IGRAs to guide clinical diagnosis would be more

helpful. The disappointing lack of sensitivity of IGRAs in

the context of clinical cases may be a result of failure to

detect IFN-c produced by antigen-specific T cells. To date,

in the absence of bacterial evidence, we cannot determine

if children with active tuberculosis were missing. Large

cohort studies are required to elucidate this issue.

The most important finding in this analysis is the sig-

nificantly low specificity of the TST and a high specificity

of IGRAs regardless of BCG vaccination of the subjects

enrolled. Although all the children enrolled for assessing

specificity have no identified tuberculosis risk, there was a

high rate of TST-positive cases – almost all false positive.

A significant reason is the effect of BCG vaccination.

First, among six studies assessing specificity of the TST,

three were available with BCG-vaccinated children, result-

ing in distinctly low specificities. When these studies were

removed from consideration, the pooled specificity of the

TST was remarkably improved. The specificity of the

IGRAs remained high in mostly BCG-vaccinated children.

Our findings were in line with the study of Menzies et al.

(2007), emphasizing that the average specificity of IGRAs

with RD1 antigens was 97.7 and 92.2% for ELISA and

ELISPOT, respectively, and were both more specific than

the TST in cases of BCG vaccination. Secondly, when

assessing the concordance between IGRAs and the TST

with varying rates of BCG vaccination, five studies con-

cluded that agreement between TST and IGRA tests in

BCG-vaccinated children is lower than that in non-BCG-

vaccinated children. According to our review, BCG

immunization can cause false positive reactions in the

TST but not in IGRAs which use antigens (ESAT-6 and

CFP-10) not present in BCG or in common environmen-

tal mycobacteria. The cut-off value for a TST-positive

result varies greatly, from 5, 10 and up to 15 mm of

induration, and there is no good conclusion supporting a

particular reasonable cut-off for injection of PPD (puri-

fied protein derivative) intradermally as positive in BCG-

immunized children. As a result, despite the cost and

complexity of IGRAs, they will be increasingly used in

screening LTBI in children with or without identified

tuberculosis risk.

Infection with NTM is also associated with high false-

positive results. The effect of NTM infection on IGRAs

and the TST is poorly studied. Only one study (Detjen

et al., 2007) enrolled 23 children with bacteriologically

confirmed nontuberculous mycobacterial lymphadenitis.

The specificity of the TST was only 10.5% in these chil-

dren, with as a consequence false-positive results of NTM

infection. In contrast, the specificity for excluding tuber-

culosis was significantly better using the IGRAs (QFT-G

specificity 100%, 95% CI 91–100%, P < 0.001; T-SPOT

specificity 98%, 95% CI 87–100%, P < 0.001). It was

shown in this analysis that the IGRAs had a higher speci-

ficity and, in contrast with the TST, may be used to con-

firm positive TST results in children in areas with a high

incidence of BCG vaccination or NTM infection.

Our meta-analysis also suffers from a number of limi-

tations. Although sensitivity and specificity are useful in

assessing the diagnostic value of a test, we are compro-

mised by the lack of a gold standard of latent tuberculo-

sis. It is possible that some individuals enrolled in

specificity assessment in this meta-analysis had latent

tuberculosis infection, despite the fact that they had no

identified risk factors. Longitudinal studies are needed to

determine the incidence of active tuberculosis in partici-

pants with positive and negative results. According to our

strict inclusion criteria, only the commercial tests, QFT-G,

QFT-IT and T-SPOT, were within the scope of this analy-

sis, so the number of studies is insufficient and most of

them are small. The heterogeneous nature of the method-

ology also limited the comparability of the studies, so

additional studies are needed to better define their perfor-

mance in diagnosis of pediatric tuberculosis.

Conclusion

Although the results of our analysis should be interpreted

with caution, the results could provide useful information



to practising clinicians. In addition, most of the studies

were published in the past 3 years, making this analysis

up to date and timely.

We hope that research will focus on identifying vari-

ables that were associated with positive results for each

assay in pediatric tuberculosis, for example age, BCG vac-

cination, contact history and tuberculosis incidence rate

of the enrolled countries.

Acknowledgements

A.S. and L.S. conceived and designed the study. L.S. and

J.X. performed searches and selected articles according to

the inclusion criteria designed in advance. Q.M., W.F.,

X.W., Q.Y., W.J., C.S., F.L. and D.S. contributed to

materials/analysis tools. All authors read and approved the

final manuscript. We thank Hugh Nelson and Jifan Hu for

revision of the English text. This study was supported in part

by grants from the National Natural Science Foundation of

China (Nos. 30872788 and 81071315), Beijing Municipal

Science Technology Commission (No. Z09050700940903)

and Young Scientists fund of Beijing Health Bureau (No.

QN2010-025).

Authors’ contribution

L.S. and J.X. contributed equally to this study.

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Interferon gamma release assay in diagnosis of pediatric tuberculosis: a meta-analysis

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