A Systematic Review of Interferon-Gamma Release Assays in Tuberculosis: Focus on Likelihood

A systematic review of interferon-gamma release assays in tuberculosis: focus on likelihood ratios

KwokChiu Chang1, ChiChiu Leung1

1 Tuberculosis & Chest Service, Department of Health, Hong Kong SAR, China

Online supplement

Table E1Included adult studies using healthy low-risk subjects as controls

Investigators, publication year / Countries, estimated TB incidence* / Sampling period / Study design / Case/
Control / TB cases / Healthy low-risk controls
Culture
-proven†,% / Age, years / Male, % / Co-morbidity (HIV), % / Age, years / Male, %
QFT-G
Ravn et al, 2005[E1] / Denmark,
8-9 / NA / P / 48/39 / 27 / Median 41
(IQR 34-51) / 67 / NA (6 ) / Median 36.5 (IQR 29-45) / 18
Bua et al, 2007[E2] / Italy,
7-8 / NA / CC / 25/16 / NA / Overall:
median 45
(range 20-70) / Overall 52 / NA (0) / Overall:
median 45 (range 20-70) / Overall 52
Palazzo et al, 2008[E3] / Italy,
7-8 / NA / P
(cases)‡ / 18/16 / 100 / Mean 36
(SD8.9) / NA / 0 for cortisone therapy (0) / Mean 36.6 (SD9.8) / NA
Mori et al, 2004[E4] / Japan,
21-29 / Jul - Oct 2002 / P / 118/213 / 100 / Mean 54
(range 13-86) / 66 / 3 (0) / Mean 20
(range 18-33) / 7
Kobashi et al, 2006[E5] / Japan,
21-29 / Apr 2005- June 2006 / P / 45/47 / 100 / Mean 60.4 (SD10) / 74 / 38 (0) / Mean 24
(range 22-26) / 64
Harada et al, 2008[E6] / Japan,
21-29 / NA / P / 97/162 / 100 / Mean 53.3
(range 18-90 or above) / 73 / 27 (1) / Mean 22.3 (range 18-59) / 17
Higuchi et al, 2009[E7] / Japan,
21-29 / NA / P / 47/84 / NA / Mean 52.7
(range 17-91) / 79 / NA / Mean 31.1 (range 19-40) / 41
Soysal et al, 2008[E8] / Turkey, 28-30 / Mar 2005 -
Jun 2006 / P / 99/47 / 97 / Mean 35 (SD16) / 56 / NA (0) / Mean 22 (SD1.2) / 62
Kanunfre et al, 2008[E9] / Brazil,
48-57 / NA / P / 29/23 / 76 (sputum) / Mean 38 / 62 / 36 (0) / Adults;
no details / NA
Kang et al, 2005[E10] / South Korea,
80-90 / 1 Feb2004 -
28 Feb 2005 / P / 54/99 / NA / Median 43 (17-84) / 59 / NA (0) / Median 25 (range 24-36) / 59
Lee et al, 2006[E11] / South Korea,
80-90 / Jul 2004 - Jun 2005 / P / 79/131 / 63 / Mean 48.0 (SD16.4) / 67 / 33 (0) / Mean 15.7 (SD0.5) / 100
Kobashi et al, 2008[E12] / Japan,
21-29 / Oct 2005 - Dec 2006 / P / 42/50 / 100 / Mean 59.6 (SD10.6) / 75 / 38 (0) / Mean 25 (range 22-28) / 70
QFT-G-IT
Palazzo et al, 2008[E3] / Italy,
7-8 / NA / P (cases)‡ / 17/14 / 100 / Mean 36
(SD8.9) / NA / 0 for cortisone therapy (0) / Mean 36.6 (SD9.8) / NA
Harada et al, 2008[E6] / Japan,
21-29 / NA / P / 94/162 / 100 / Mean 53.3
(range 18-90 or above) / 73 / 27 (1) / Mean 22.3 (range 18-59) / 17
Leung et al, 2009[E13] / Hong Kong, 62-76 / Dec 2006 - Feb 2007 / P, XS, blinded / 17/12 / 59 / Mean 43
(range 18-79) / 65 / NA (0) / Mean 43
(range 24-55) / 25
Chen et al, 2009[E14] / China, 98-103 / Apr 2007 - Oct 2008 / P / 47/101 / NA / NA / NA / NA (0) / NA / NA
T-SPOT.TB
Chapman et al, 2002[E15] / Zambia(case),506-652;
UK(controls),12-15 / NA / P / 50/40 / NA / Mean 33
(range 16-68) / 58 / NA (78) / Mean 32 (23-49) / 53
Higuchi et al, 2009[E7] / Japan,
21-29 / NA / P / 47/84 / NA / Mean 52.7 (range 17-91) / 79 / NA (NA) / Mean 31.1 (range 19-40) / 41
Soysal et al, 2008[E8] / Turkey,
28-30 / Mar 2005 - Jun 2006 / P / 96/46 / 100 / Mean 35 (SD16) / 56 / NA (0) / Mean 22 (SD1.2) / 62
Lee et al, 2006[E11] / South Korea, 80-90 / Jul 2004 - Jun 2005 / P / 87/131 / 63 / Mean 48.0 (SD16.4) / 67 / 33 (0) / Mean 15.7 (SD0.5) / 100
Wang et al, 2007[E16] / Taiwan,
72.6 / Jan - June 2005 / P / 39/12 / 95 / Mean 52.2
(range 2-84) / 57 / 62 (5) / NA / NA
Kobashi et al, 2008[E12] / Japan,
21-29 / Oct 2005 - Dec 2006 / P / 45/50 / 100 / Mean 59.6 (SD10.6) / 75 / 38 (0) / Mean 25 (range 22-28) / 70
TST (cut-off = 5 mm)
Predominantly BCG-vaccinated
Mori et al, 2004[E4] / Japan,
21-29 / Jul - Oct 2002 / P / 76/113 / 100 / Mean 54.7 (SD2.3) / 65 / 3 (0) / Mean 19.2 (SD0.238) / 7
Soysal et al, 2008[E8] / Turkey,
28-30 / Mar 2005 - Jun 2006 / P / 100/47 / 100 / Mean 35 (SD16) / 56 / NA (0) / Mean 22 (SD1.2) / 62
Lee et al, 2006[E11] / South Korea,
80-90 / Jul 2004 -
Jun 2005 / P / 58/131 / 63 / Mean 48.0 (SD16.4) / 67 / 0 (0) / Mean 15.7 (SD0.5) / 100
Kobashi et al, 2008[E12] / Japan,
21-29 / Oct 2005 - Dec 2006 / P / 48/50 / 100 / Mean 59.6 (SD10.6) / 75 / 38 (0) / Mean 25 (range 22-28) / 70
TST (cut-off = 10 mm)
Predominantly BCG-vaccinated
Soysal et al, 2008[E8] / Turkey,
28-30 / Mar 2005 - Jun 2006 / P / 100/47 / 100 / Mean 35 (SD16) / 56 / NA (0) / Mean 22 (SD1.2) / 62
Kobashi et al, 2006§[E5] / Japan,
21-29 / Apr 2005 - June 2006 / P / 50/50 / 100 / Mean 60.4 (SD10) / 74 / 38 (0) / Mean 24
(range 22-26) / 64
Kang et al, 2005[E10] / South Korea, 80-90 / 1 Feb 2004 - 28 Feb 2005 / P / 54/99 / NA / Median 43 (17-84) / 59 / NA (0) / Median 25 (range 24-36) / 59
Lee et al, 2006[E11] / South Korea, 80-90 / Jul 2004 -
Jun 2005 / P / 58/131 / 63 / Mean 48.0 (SD16.4) / 67 / 0 (0) / Mean 15.7 (SD0.5) / 100
TST (cut-off = 15 mm)
Predominantly BCG-vaccinated
Soysal et al, 2008[E8] / Turkey,
28-30 / Mar 2005 - Jun 2006 / P / 100/47 / 100 / Mean 35 (SD16) / 56 / NA (0) / Mean 22 (SD1.2) / 62
Kang et al, 2005[E10] / South Korea, 80-90 / 1 Feb 2004 - 28 Feb 2005 / P / 54/99 / NA / Median 43 (17-84) / 59 / NA (0) / Median 25 (range 24-36) / 59
Lee et al, 2006[E11] / South Korea, 80-90 / Jul 2004 -
Jun 2005 / P / 58/131 / 63 / Mean 48.0 (SD16.4) / 67 / 0 (0) / Mean 15.7 (SD0.5) / 100
TST (cut-off = uncertain)
Predominantly BCG-unvaccinated
Palazzo et al, 2008[E3] / Italy,
7-8 / NA / P
(cases)‡ / 12/8 / 100 / Mean 36
(SD8.9) / NA / 0 for cortisone therapy (0) / Mean 36.6 (SD9.8) / NA
Bua et al, 2007[E2] / Italy,
7-8 / NA / CC / 25/16 / NA / Overall:
median 45
(range 20-70) / Overall: 52 / NA (0) / Overall:
median 45 (range 20-70) / Overall: 52

Abbreviations: BCG = Bacille Calmette Guérin, CC = case-control, HIV = human immunodeficiency virus infection, NA = not available, P = prospective, QFT-G = QuantiFERON-TB Gold, QFT-G-IT = QuantiFERON-TB Gold in-Tube, SD = standard deviation, TB = tuberculosis, TST = tuberculin skin test, XS = cross-sectional

*Estimated TB incidence (per 100000 persons) were based on figures for the years 2002 – 2007 published by the World Health Organization[E17], except for that for Taiwan, which was based on another published reference[E18].

†Besides culture, the diagnosis of tuberculosis in the majority of cases in most studies was confirmed by one or more the followings: acid fast bacilli smears, polymerase chain reaction for tuberculosis, histopathology.

‡Controls were enrolled from blood donors.

§The cut-off value was probably 10 mm but not stated clearly.
Table E2Included adult studies using non-tuberculosis patients as controls

Investigators, publication year / Countries, estimated TB incidence* / Sampling period / Study design / Case/
control / TB cases / non-TB patients
Culture
-proven†,% / Age, years / Male, % / Co-morbidity (HIV), % / Age, years / Male, % / Co-morbidity (HIV), %
QFT-G
Goletti et al, 2005[E19] / Italy,
7-8 / Apr 2004-
Nov 2004 / P / 27/41 / 100 / Mean 37 (SD10.4) / 74 / 0 for cortisone therapy (0) / Mean 41.5 (SD16.2) / 59 / 0 for cortisone therapy (0)
Goletti et al, 2006[E20] / Italy,
7-8 / Apr 2004- Nov 2004 / P / 23/32 / 100 / Mean 33 (SD9.6) / 65 / 0 for IS therapy (0) / Mean 41.4 (SD19.6) / 59 / 0 for IS therapy (0)
Vincenti et al, 2007[E21] / Italy,
7-8 / Jan 2002- Apr 2006 / P / 13/28 / 100 / Median 38 / 56 / NA (100, non-anergic) / Median 41 / 44 / NA (100, non-anergic)
Sauzullo et al, 2008[E22] / Italy,
7-8 / NA / P / 77/215 / NA / Overall 0.46 >60 years / Overall 65 / Overall
19 (14) / Overall 0.46 >60 years / Overall 65 / Overall
19 (14)
Kobashi et al, 2006[E5] / Japan,
21-29 / Apr 2005- Jun 2006 / P / 45/93 / 100 / Mean 60.4(SD10) / 74 / 38 (0) / Mean 64.4 (SD10.2) / 38 / 26 (0)
Nishimura et al, 2008[E23] / Japan,
21-29 / Jan 2004- Jan 2007 / P / 77/114 / 81 / Mean 56
(range 19-82) / 56 / 0 for IS therapy (0) / Mean 56 (range 18-86) / 40 / 8 (0)
Ravn et al, 2005[E1] / Denmark,
8-9 / NA / P / 48/25 / 27 / Median 41 (IQR 34-51) / 67 / NA (6) / Median 47
(IQR 34-55) / 60 / NA (16)
Mori et al, 2004[E4] / Japan,
21-29 / Jul-Oct 2002 / P / 118/33 / 100 / Overall:
mean 54
(range 13-86) / Overall
66 / 3 (0) / Overall:
mean 54 (range13-86) / Overall66 / 3 (0)
Baba et al, 2008‡[E24] / South Africa,
780-948 / 2004-2005 / P / 18/5 / 35 / Overall: median 39 (range 20-70) / Overall 65 / NA (82) / Overall:
median 39 (range 20-70) / Overall 65 / NA (33)
Kobashi et al, 2009§[E25] / Japan,
21-29 / Jan 2005- Dec 2007 / P / 57/42 / 45 / Mean 60.8 (SD13.1) / 65 / 40 (2) / Mean 63.1 (SD13.6) / 60 / 44 (0)
Song KH et al, 2009§[E26] / South Korea, 80-90 / Feb 2006- Mar 2007 / P / 48/51 / 38 / Mean 50 (SD20);
range 19-96 / 38 / 23 (0) / Mean 44 (SD19); range 16-75 / 46 / 15 (0)
QFT-G-IT
Goletti et al, 2008[E27] / Multiple, countries,
96 (weighted) / Nov 2005- Mar 2008 / P / 155/97 / NA / Median 34 / 60 / 4 (1) / Median 48 / 66 / 4 (2)
Chegou et al, 2008‡[E28] / South Africa, 780-948 / Apr-Oct 2005 / P / 30/36 / NA / Mean 35 (SD13) / 60 / NA (30) / Mean 52.7 (SD12.9) / 47 / 64 (0)
Leung et al, 2009[E13] / Hong Kong,
62-76 / Dec 2006- Feb 2007 / P, XS, blinded / 17/11 / 59 / Mean 43 (range 18-79) / 65 / NA (0) / Mean 45.5 / 91 / NA (0)
Ang et al, 2009[E29] / Singpapore, 27-33 / Aug 2005- Feb 2007 / RC / 55/102 / 4 / NA / NA / NA (NA) / NA / NA / NA
Bartu et al, 2008[E30] / Czechoslo-
-vakia, 9-13 / Jan 2006- Dec 2006 / P / 50/20 / 42 / Mean 49 / 68 / NA (0) / NA / NA / NA
T-SPOT.TB
Meier et al, 2005[E31] / Germany, 6-9 / Sep 2003- Sep 2004 / P / 72/17 / 88 / Overall:
median 51 (range 18-92) / Overall
63 / Overall:
14 (2) / Overall:
median 51 (range 18-92) / Overall
63 / Overall
14 (2)
Goletti et al, 2006[E20] / Italy,
7-8 / Apr 2004-
Nov 2004 / P / 23/32 / 100 / Mean 33 (SD9.6) / 65 / 0 for IS therapy (0) / Mean 41.4 (SD19.6) / 59 / 0 for IS therapy (0)
Vincenti et al, 2007[E21] / Italy,
7-8 / Jan 2002-
Apr 2006 / P / 13/28 / 100 / Median 38 / 56 / NA (100, non-anergic) / Median 41 / 44 / NA (100, non-anergic)
Fathy et al, 2007[E32] / Egypt,
21-26 / Feb 2006- Aug 2006 / P / 24/16 / 100 / Mean 39.3 (SD10.4) / 59 / NA / Mean 49.0 (SD15.4) / 80 / NA
Goletti et al, 2008[E27] / Multiple, countries,
96 (weighted) / Nov 2005- Mar 2008 / P / 88/97 / NA / Median 34 / 60 / 4 (1) / Median 48 / 66 / 4 (2)
Wang et al, 2007[E16] / Taiwan,
72.6 / Jan-June 2005 / P / 39/26 / 95 / Overall: mean 52.2 (range 2-84) / Overall 57 / Overall
55 (5) / Overall: mean 52.2 (range 2-84) / Overall 57 / Overall
55 (5)
Losi et al, 2007‡[E33] / Multiple, especially Europe,
49-50 / Jan 2005- Nov 2006 / P / 20/21 / 40 / Mean 39.6 (SD16.7) / 65 / NA / Mean 64.5 (SD20.8) / 71 / NA
Kim et al, 2007§[E34] / South Korea,
80-90 / 1 Apr - 31 Dec 2006 / P / 32/33 / 69 / Mean 51.2 (SD15.2) / 56 / 50 (13) / Mean 47.7 (SD17.3) / 63 / 49 (9)
Kim et al, 2008ll[E35] / South Korea,
80-90 / Sep 2006- Aug 2007 / P / 11/24 / NA / Mean 45.5 (SD16.5) / 42 / 17 (8) / Mean 39.3 (SD16.5) / 60 / 28 (4)
Lee et al, 2009‡ [E36] / Taiwan,
72.6 / 1 Jan -31 Dec 2006 / P / 18/21 / 79 / Mean 60.5 (range 21-102) / 79 / 42 (0) / Mean 65.5 (range 25-87) / 57 / NA (0)
Kim et al, 2009[E37] / South Korea,
80-90 / Apr 2006- Sept 2007 / P / 51/62 / Overall 59 / Overall:
Mean 48.3 (SD17.8) / Overall 48 / 0 (0) / Overall:
Mean 46.2 (SD17.8) / Overall 52 / 0 (0)
Kim et al, 2009[E37] / South Korea,
80-90 / Apr 2006- Sept 2007 / P / 24/35 / Overall 59 / Overall:
Mean 48.3 (SD17.8) / Overall 48 / 100 (17) / Overall:
Mean 46.2 (SD17.8) / Overall 52 / 100 (17)
TST (cut-off = 5mm)
Predominantly BCG-vaccinated
Bartu et al, 2008[E30] / Czechoslo-
-vakia, 9-13 / Jan 2006-
Dec 2006 / P / 53/20 / 42 / Mean 49 / 68 / NA (0) / NA / NA / NA
TST (cut-off = 10 mm)
Predominantly BCG-vaccinated
Kobashi et al, 2006**[E5] / Japan,
21-29 / Apr 2005- Jun 2006 / P / 50/94 / 100 / Mean 60.4 (SD10) / 74 / 38 (0) / Mean 64.4 (SD10.2) / 38 / 26 (0)
Kim et al, 2007§[E34] / South Korea,
80-90 / 1 Apr - 31 Dec 2006 / P / 32/35 / 69 / Mean 51.2 (SD15.2) / 56 / 50 (13) / Mean 47.7 (SD17.3) / 63 / 49 (9)
Kim et al, 2008ll[E35] / South Korea,
80-90 / Sep 2006- Aug 2007 / P / 11/24 / NA / Mean 45.5 (SD16.5) / 42 / 17 (8) / Mean 39.3 (SD16.5) / 60 / 28 (4)
Song KH et al, 2009§[E26] / South Korea,
80-90 / Feb 2006- Mar 2007 / P / 25/30 / 38 / Mean 50(SD20); range 19-96 / 38 / 23 (0) / Mean 44 (SD19)
(range 16-75) / 46 / 15 (0)
Kim et al, 2009[E37] / South Korea,
80-90 / Apr 2006- Sept 2007 / P / 51/62 / Overall 59 / Overall:
Mean 48.3 (SD17.8) / Overall 48 / 0 (0) / Overall:
Mean 46.2 (SD17.8) / Overall 52 / 0 (0)
Kim et al, 2009[E37] / South Korea,
80-90 / Apr 2006-
Sept 2007 / P / 24/35 / Overall 59 / Overall:
Mean 48.3 (SD17.8) / Overall 48 / 100 (17) / Overall:
Mean 46.2 (SD17.8) / Overall 52 / 100 (17)
TST (cut-off = 15mm)
Predominantly BCG-vaccinated
Ang et al, 2009[E29] / Singpapore, 27-33 / Aug 2005- Feb 2007 / RC / 55/102 / 4 / NA / NA / NA (NA) / NA / NA / NA
TST (cut-off = 5mm)
Predominantly BCG-unvaccinated
Vincenti et al, 2007[E21] / Italy,
7 / Jan 2002- Apr 2006 / P / 13/28 / 100 / Median 38 / 56 / NA (100, non-anergic) / Median 41 / 0.44 / NA (100, non-anergic)
TST (cut-off = 10-15 mm)
Predominantly BCG-unvaccinated
Goletti et al, 2008[E27] / Multiple, countries,
96 (weighted) / Nov 2005- Mar 2008 / P / 177/150 / NA / Median 34 / 60 / 4 (1) / Median 48 / 66 / 4 (2)

Abbreviations: BCG = Bacille Calmette Guérin, HIV = human immunodeficiency virus infection, IQR = interquartile range, IS = immunosuppressive, NA = not available, P = prospective, QFT-G = QuantiFERON-TB Gold, QFT-G-IT = QuantiFERON-TB Gold in-Tube, RC = retrospective cohort analysis, SD = standard deviation, TB = tuberculosis, TST = tuberculin skin test, XS = cross-sectional

‡Focus on pleural diseases

§Focus on extrapulmonary diseases

llFocus on central neurological diseases

**The cut-off value was probably 10 mm but not stated clearly.

Table E3Using bivariate random effects models to compare test characteristics of different diagnostic methods among studies using healthy low-risk subjects as controls

Sensitivity
Modality / QFT (based on non-Japanese studies) / QFT
(based on Japanese studies) / T-SPOT.TB / TST (5 mm)
QFT (based on Japanese studies) / 0.01
T-SPOT.TB / 0.004 / NS
TST (5 mm) / NS / 0.002 / <0.001
TST (10 mm or 15 mm) / 0.02 / <.0001 / <.0001 / NS
Specificity
Modality / QFT (based on non-Japanese studies) / QFT
(based on Japanese studies) / T-SPOT.TB / TST (5 mm)
QFT (based on Japanese studies) / 0.01
T-SPOT.TB / NS / 0.002
TST (5 mm) / <.0001 / <.0001 / <.0001
TST (10 mm or 15 mm) / <0.001 / <0.0001 / 0.02 / 0.02
Diagnostic odds ratio
Modality / QFT (based on non-Japanese studies) / QFT
(based on Japanese studies) / T-SPOT.TB / TST (5 mm)
QFT(based on Japanese studies) / 0.001
T-SPOT.TB / NS / 0.02
TST (5 mm) / <.0001 / <.0001 / <.0001
TST (10 mm or 15 mm) / <.0001 / <.0001 / <.0001 / NS

Abbreviations: NS = p-values larger than 0.05;QFT-G = QuantiFERON-TB Gold; QFT-G-IT = QuantiFERON-TB Gold in-Tube; TST (x mm) = tuberculin skin test with cut-off at x mm

Table E4Using bivariate random effects models tocomparetest characteristics of different diagnostic methods among studies using non-tuberculosis patients as controls

Sensitivity
Modality / QFT-G / QFT-G-IT / T-SPOT.TB
(based on studies with mean or median age47.1 years) / T-SPOT.TB
(based on studies with mean or median age ≤ 47.1 years)
QFT-G-IT / 0.04
T-SPOT.TB (based on studies with mean or median age > 47.1 years) / NS / 0.003
T-SPOT.TB (based on studies with mean or median age ≤ 47.1 years) / NS / NS / NS
TST (10 mm) / <.0001 / 0.02 / <.0001 / <.0001
Specificity
Modality / QFT-G / QFT-G-IT / T-SPOT.TB
(based on studies with mean or median age > 47.1 years) / T-SPOT.TB
(based on studies with mean or median age ≤ 47.1 years)
QFT-G-IT / NS
T-SPOT.TB (based on studies with mean or median age > 47.1 years) / NS / NS
T-SPOT.TB (based on studies with mean or median age ≤ 47.1 years) / NS / NS / 0.04
TST (10 mm) / NS / NS / NS / NS
Diagnostic odds ratio
Modality / QFT-G / QFT-G-IT / T-SPOT.TB (based on studies with mean or median age > 47.1 years) / T-SPOT.TB
(based on studies with mean or median age ≤ 47.1 years)
QFT-G-IT / 0.005
T-SPOT.TB (based on studies with mean or median age > 47.1 years) / NS / 0.0002
T-SPOT.TB (based on studies with mean or median age ≤ 47.1 years) / NS / NS / 0.02
TST (10 mm) / <.0001 / NS / <.0001 / 0.01

Abbreviations: NS = p-values larger than 0.05;QFT-G = QuantiFERON-TB Gold; QFT-G-IT = QuantiFERON-TB Gold in-Tube; TST (x mm) = tuberculin skin test with cut-off at x mm

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