Gaps in Study Design for Immune Parameter Research for Latent Tuberculosis Infection: A Systematic Review

Table 1

Characteristics of studies included in the systematic review.

First author, year of publication

Country where the study was conducted

Outcome of interest

Special feature of the population under study

Number of people with LTBI

Number of people in the control group

Age

Sex (% women)

Proportion with BCG vaccination (%)

Active TB diagnosis method

LTBI diagnosis method

Immune parameters evaluated

Increased immune parameters (with statistical differences)

Samples

Antigen and times used for stimulation

Method of detection of cytokines, commercial kit

Zeev T. Handzel, 2007 [23]

East European, Ethiopian and Israel

LTBI

Immigrant patients from Eastern Europe and Ethiopia and their contacts in Israel

39

NI = 21

Not reported

Not reported

Not reported

Culture, clinical diagnosis, X-ray,

TST

INF-γ, IL-2R, IL-10, IL-6, IL-12p70

Unstimulated; LTBI vs. NI: IL-10 and IL-6; Stimulated; LTBI vs. NI: INF-γ; TB vs. LTBI: sIL-2R, INF-γ, and IL-10; Serum; TB vs. LTBI: sIL-2R, IL-10

Plasma samples from whole blood (unstimulated, antigen-stimulated, or mitogen-stimulated) and serum

PPD; Time: 48 hours

ELISA (R&D Systems, Minneapolis, MN, USA)

Novel N. Chegou, 2009 [24]

South Africa

LTBI

Contacts of people with TB and patients with TB from an endemic area

34

TB: LTBI/NI:

TB: 26; LTBI/NI: 58.8

Not reported

Smear (ZN)

QuantiFERON-TB Gold In-Tube Test, TST

(IL)-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12(p40), IL-12(p70), IL-13, IL-15, IL-17, CXCL8, IL-1ra, sCD40L, CCL11, fractalkine, G-CSF, GM-CSF, IFN-γ, CXCL10, CCL2, CCL3, CCL4, TGF-α, TNF-α, VEGF

Unstimulated; TB vs. LTBI: EGF, TGF-α, TNF-α, and sCD40L; Stimulated; LTBI vs. TB: sCD40L, VEGF.; TB vs. LTBI: IL-1α

Plasma samples from whole blood (unstimulated, antigen-stimulated, or mitogen-stimulated)

ESAT-6, CFP-10, and TB7.7; Time: not specifically referred

Microbead-based method, LINCO-plex® kits (Millipore, St. Charles, Missouri, USA)

R. Biselli, 2010 [25]

Italy

LTBI

Laboratory personnel without M. tuberculosis infection and TB cases of infectious diseases L. Spallanzani, and the Infectious Diseases Department of Sapienza Universita di Roma

20

Median; LTBI: 42.3; TB: 35.7; NI: 31.4

LTBI: 40; TB: 45; NI: 30

LTBI: 0; TB: 35; NI: 0

Culture

QuantiFERON-TB Gold In-Tube Test, TST

INF-γ, IL-2

Stimulated; LTBI and TB vs. NI: INF-γ; LTBI vs. TB and NI: IL-2

Plasma samples from whole blood (unstimulated, antigen-stimulated, or mitogen-stimulated)

ESAT-6, CFP-10, and TB7.7; Time: 18 and 72 hours

ELISA, ELISA assay (DRG GmbH, Germany)

Jayne S. Sutherland, 2010 [26]

South Africa

LTBI

TB case contacts and TB cases

20

Median (IQR); LTBI: 27 (19–39); TB: 25 (20–37); NI: 22 (18–31)

TB: 27; LTBI: 74; NI: 65

Not reported

Smear (ZN, auramine-rodhamine), culture

TST

TNF-α, IFN-γ, IL-10, IL-12(p40), IL-13, IL-17, IL-18

Stimulated; LTBI vs. NI: IFN-γ, IL-13, and IL-17; TB vs. NI: IL-10, IL-12(p40), IL-13, IL-17, IFN-γ, and TNF-α.; TB vs. LTBI: TNF-α and IL-12(p40)

Blood culture supernatant unstimulated or antigen-stimulated

ESAT-6/CFP-10, PPD, or TB10.4; Time: 7 days

Microbead-based method, 7-plex kit, BioRad

Subash Babu, 2010 [27]

India

LTBI

Adult population with and without M. tuberculosis exposure

25

Median (range); LTBI: 32 (19-50); NI: 30 (15-48)

LTBI: 40; NI: 40

All participants

N/A

TST

IL-2, IFN-γ, TNF-α, IL-12, IL-4, IL-5, IL-10, IL-13, IL-17, IL-23, IL-6, IL-1β, IL-23

Stimulated; NI vs. LTBI: IL-17, IL-23

Nonstimulated and antigen-stimulated PBMC culture supernatants

PPD or Mtb CFA; Time: 24 hours

Microbead-based method and ELISA for IL-23, BioRad

Marc Frahm, 2011 [28]

Not reported

LTBI

Adult population with and without TB from two previous cohorts

32

EPTB: 3

Median (range); LTBI: 50 (2–66); TB: 43.5 (4–93); NI: 46.5 (26–62)

LTBI: 47; TB: 33; NI: 27

LTBI: 31; TB: 33; NI: 0

Culture from a clinical specimen or clinical diagnosis

QuantiFERON-TB Gold In-Tube Test, TST

IL-1β, IL-1RA, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 p40/70, IL-13, IL-15, IL-17, TNF-α, IFN-α, IFN-γ, GM-CSF, MIP-1α, MIP-1β, IP-10, MIG, eotaxin, RANTES, MCP

Stimulated; LTBI and TB vs. NI: INF-γ, IP-10, MIG, IL-2, MCP-1, IL-15, IL-RA.; TB vs. LTBI: IL-15. With a more flexible cut-off point: MCP-1, IL-1RA, IFN-α and IL-4

Plasma samples from whole blood (unstimulated, antigen-stimulated, or mitogen-stimulated)

ESAT-6, CFP-10, and TB7.7; Time: 16–24 hours

Microbead-based method, Human Cytokine 25-plex (Biosource, Camarillo, CA)

Ji Young Hong, 2012 [46]

Korea

LTBI

Contacts of patients with confirmed TB. Cases of TB were hospitalized patients with comorbidities

22

Combined EPTB lesion: 2 (4.3%)

Median (range); LTBI: 37.5 (22–53); TB: 30 (22–74); NI: 28 (22–57)

LTBI: 18; TB: 25; NI: 18

LTBI: 90.9; TB: 54.3; NI: 75.0

Culture

QuantiFERON-TB Gold In-Tube Test, TST

IP-10, INF-γ

Unstimulated plasma; TB vs. LTBI and NI: IP-10; Stimulated plasma; LTBI and TB vs. NI: IP-10, INF-γ; Serum; TB vs. LTBI and NI: IP-10

Plasma samples from whole blood (unstimulated, antigen-stimulated, or mitogen-stimulated) and serum

ESAT-6, CFP-10, and TB7.7; Time: 20 hours

ELISA (R&D Systems, Minneapolis, MN, USA)

S.Y. Kim, 2012 [45]

Not reported

LTBI

TB case partners with and without LTBI

19

Median (range); LTBI: 47 (23-60); TB: 31 (20-77); NI: 28 (22-57)

LTBI: 68.4; TB: 46.8; NI: 53.3

LTBI: 94.7; TB: 64.5; NI: 76.7

Smear (ZN), culture, and/or pathology

QuantiFERON-TB Gold In-Tube Test, TST

IFN-γ, IL-2, IL-10, IL-13, IL-17, TNF-α

Stimulated; LTBI and TB vs. NI: IFN-γ, IL-2, IL-10, and IL-13

Plasma samples from whole blood (unstimulated, antigen-stimulated, or mitogen-stimulated)

ESAT-6, CFP-10, and TB7.7; Time: 20 hours

Microbead-based method, MILLIPLEX® MAP human cytokine/chemokine kit (Millipore, Billerica, MA, USA)

Pierre-Alain Rubbo, 2012 [29]

France

LTBI

Healthcare workers with high risk of M. tuberculosis exposure

41

Median (IQ): 44 (36–50)

All participants: 84.3

All participants

N/A

QuantiFERON-TB Gold In-Tube Test

IL-1RA, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12p40/70, IL-13, IL-15, IL-17, TNF-α, GM-CSF, MIP-1α, MIP-1β, IP-10, MIG, eotaxin, RANTES, MCP, IFN-γ

Stimulated; LTBI vs. NI: IL-2, IL-15, IP-10, and CXCL9

Plasma samples from whole blood (unstimulated, antigen-stimulated, or mitogen-stimulated)

ESAT-6, CFP-10, and TB7.7; Time: 24 hours

Microbead-based method, cytokine human panel (Invitrogen, Villebon sur Yvette, France)

Sen Wang, 2012 [30]

China

LTBI

Adults living in an endemic area to TB

73

Median (range); LTBI: 41 (18–83); TB: 45 (16–86); NI: 38 (18–50)

LTBI: 52.1; TB: 40.9; NI: 45.2

LTBI: 74.0; TB: 78.9; NI: 89.5

TB contact history, smear (ZN), culture, clinical diagnosis, and R-rays

QuantiFERON-TB Gold In-Tube Test, TST

IP-10, IL-2, TNF-α, INF-γ

Unstimulated; LTBI vs. TB: IP-10; LTBI and TB vs. NI: IP-10, IL-2, TNF-α, INF-γ; TB vs. LTBI: TNF-α; Stimulated; TB vs. LTBI: IFN-γ, IP-10, and IL-2

Plasma samples from whole blood (unstimulated, antigen-stimulated, or mitogen-stimulated)

ESAT-6, CFP-10, and TB7.7; Time: 20 hours

DuoSet ELISA, the DuoSet ELISA development kit (R&D Systems Inc, MN, USA)

Yang Yu, 2012 [31]

China

LTBI

Individuals exposed to M. tuberculosis, healthy volunteers without infection, and hospitalized patients with TB

20

Mean; LTBI 1: 40.7; LTBI 2: 46.1; TB: 38.5; NI: 30.7

LTBI 1: 60; LTBI 2: 50; TB: 58.3; NI: 41.6

Not reported

Culture, clinical diagnosis, X-ray, and/or HRCT

T–SPOT®, TST

CCL1, CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL13, CCL15, CCL17, CCL20, CCL21, CCL24, CCL26, CCL27, CXCL5, CXCL, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12, CXCL1, IL-2, IL-15, IL-4, IL-13, IL-7, IL-9, IL-5, GM-CSF, IL-6, IL-12, G-CSF, TNF-α, IL-10, IFN-γ, IL-1RA, IL-1β, IL-17

Stimulated PBMCs; LTBI 1 vs. NI: IP-10, CXCL11, and CXCL12; LTBI 2 vs. LTBI 1: IL-2, CXCL10, CXCL11, and CXCL12; TB vs. NI: IL-2, IP-10, CXCL11, IL-6, IL-9, IL-10, CCL-8, CXCL13, CXCL12, CCL1, CCL21; Plasma: TB vs. NI: IL-6, CCL1, IL-9, and CXCL9

Nonstimulated and antigen-stimulated PBMC culture supernatants and plasma

Lysed bacteria proteins and ESAT-6; Time: 72 hours

Microbead-based method, human cytokine/chemokine panel (MPXHCYTO-60K, MPXHCYP2-62K, and MPXHCYP3-63K, Millipore, USA)

Novel N. Chegou, 2012 [32]

South Africa

LTBI

TB case contacts and TB cases from a high TB-endemic community

23

PTB: 15

Mean (SD) 31.5 (15.9)

All participants: 39.5

Not reported

ZN

TST

EGF, fractalkine, IFN-a2, IFN-c, IL-4, IL-10, IL-12(p40), TGF-a, TNF-a, VEGF, IP-10, RANTES

Unstimulated; TB vs. contact: EGF, IFN-a2, and IL-4.; Stimulated; ESAT-6/CFP-10; TB vs. contacts: EGF, TGF-a, and TNF-a.; Stimulated; Rv0081; Contacs vs. TB: IFN-g, IFN-a2, IL-12(p40), IP-10, TNF-a, VEGF, IL-10, and RANTES.; Stimulated; Rv2032; TB vs. contacts: fractalkine, IL-12(p40), TGF-a, TNF-a, VEGF, IL-10, RANTES.; Stimulated; Rv1737c; TB vs. contacts: IL-10, TGF-a, TNF-a, IL-12(p40), and EGF

Plasma samples from whole blood (unstimulated or antigen-stimulated)

Resuscitation-promoting factors (Rv0867c, Rv2389c) and DosR regulon-encoded antigens (Rv2032, Rv0081, Rv1737c); Time: 7 days

Microbead-based method, Milliplex kits (Merck Millipore, St. Charles, Missouri, USA)

D. Anbarasu, 2013 [33]

India

LTBI

Family of TB cases from an endemic area to M. tuberculosis

7

Range; LTBI: 28-55; TB: 26-52

LTBI: 28.6; TB: 30

Not reported

Smear (ZN) and culture

TST

IL-1β, IL-1RA, IL-2, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, eotaxin, FGF basic, G-CSF, GM-CSF, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF, RANTES, and VEGF

Stimulated CFP-10, Rv3716c, and TrxC; LTBI vs. TB: IL-6; Stimulated FbpB/Rv2626c; TB vs. LTBI: G-CSF, IL-7, IL-8, IL-9, and PDGF.; LTBI vs. TB: IL-6

Blood culture supernatant unstimulated or antigen-stimulated

Protein fraction 11_24 (Rv2626c and FbpB); Time: 6 days

Microbead-based method, Bio-Plex multiplex cytokine assay system (Bio-Rad Laboratories, Hercules, CA, USA)

Yun-Gyoung Hur, 2013 [47]

Malawi

LTBI

TB cases from a cohort with their contacts

It is not clear (143 in LTBI and NI)

Mean; TB: 41; LTBI: 40

LTBI: 67; TB: 60

Not reported

Smear (ZN)

TST

IL-10, IL-13, IL-17, CXCL10, TNF-α.

Stimulated; LTBI and TB vs. NI: IFN-γ, CXCL10, IL-10, TNF-α, and IL-17.; LTBI vs. TB and NI: IL-10; LTBI vs. TB: IL-17; TB vs. LTBI: IL-17 and IL-10, in the following

Blood culture supernatant unstimulated or antigen-stimulated

PPD or ESAT-6; Time: 6 days

DuoSet ELISA, R&D Systems

Mayer-Barber, 2014 [34]

China and India (cohort reported by Andrade BB, 2013)

LTBI

TB cases from a Chinese cohort and healthy community controls; India; TB cases (pulmonary and extrapulmonary), LTBI, and healthy donors recruited as part of a TB cohort study

China: 14; India: 39

India: PTB: 97; EPTB: 35; Healthy controls: 40

Median (IQR); PTB: 27 (23-44.7); Healthy controls: 33 (23-40); LTBI: 38.5 (34.2-43.5); India; Median (IQR); Healthy control: 29 (21-59); LTBI: 25 (21-49); EPTB: 33 (18-65); PTB: 40 (19-70)

PTB: 38.3; Healthy controls: 54.5; LTBI: 85.7; India; PTB: 33; EPTB: 84; Healthy controls: 75; LTBI: 77

Not reported

Smear (ZN); India; Smear and culture

QuantiFERON-TB Gold In-Tube Test; India; QuantiFERON-TB Gold In-Tube Test and TST, absence of chest radiograph or pulmonary symptoms

IL-1α, IL-1β, IL-10, IL-1Ra, IL1R1, IL1R2, IFN-γ, IFN-α, IFN-β, TNF-α, PGF2α, PGE2, LXA4, 15-Epi-LXA4; India; IL-1α, IL-1β, IL-10, IL-1Ra, IFN-γ, IFN-α, IFN-β, TNF-α, PGF2α, PGE2, LXA4, 15-Epi-LXA4, IL-1R1, IL-1R2

LTBI vs. NI and TB; IFN-α; NI vs. LTBI and TB: IL-1α, IL-1β, TNF-α, IL1Ra; TB vs. LTBI and NI: IL-10, IL-1RI, IFN-γ, PGF2α, PGE2; India; LTBI vs. NI and TB: IL1Ra, PGF2α; NI vs. LTBI and TB: IL-1α, sIL-1R1; TB vs. LTBI and NI: IL-1 β, PGE2, TNF-α, IFN-γ, IFN-α, IL-10, LXA4, 15-Epi-LXA4

Plasma samples

Not apply

ELISA kits (R&D Systems) and FlowCytomix Multiplex Arrays (eBioscience, San Diego, CA) and Oxford Biomedical Research (Oxford, MI); India; ELISA kits (R&D Systems) and enzyme immunoassay (EIA) kits (Cayman Chemical, Ann Harbour, MI) and Oxford Biomedical Research (Oxford, MI)

Ikaria Sauzullo, 2014 [35]

Italy

LTBI

Healthcare workers studied for LTBI

Total 63

Mean (range); 43 (25–60)

All participants: 50.5

All participants: 3.1

N/A

QuantiFERON-TB Gold In-Tube Test or TST and had one of the following risk factors: chest X-ray suggestive of prior TB infection, a history of exposure to a case of active TB, or coming from an area with a high prevalence of TB infection

IFN-γ, IL-2

Stimulated; LTBI vs. NI: IL-2, INF-γ

Plasma samples from whole blood (unstimulated, antigen-stimulated, or mitogen-stimulated)

ESAT-6, CFP-10, and TB7.7; Time: 72 hours

ELISA (DRG GmbH, Germany)

K. Kim, 2014 [36]

Australia

LTBI

Patients of the Western Australian Tuberculosis Control Program

30

EPTB: ~8 (25%)

Median (IQR); LTBI: 32 (25-39); TB: 35 (29-42.5)

LTBI: 50; TB: 32.3

Not reported

Culture

IGRAs, TST

IFN-γ, TNF-α, IL-10

Stimulated; LTBI vs. TB: IFN-γ; TB vs. LTBI: TNF-α

Nonstimulated and antigen-stimulated PBMC culture supernatants

PPD, ESAT-6, or CFP-10; Time: 6 hours

ELISA, BD OptEIA™ Sets (BD Biosciences, USA)

Yun Hee Jeong, 2015 [37]

South Korea

LTBI

Patients with active TB and contacts with LTBI

20

PTB: 33; NI: 26

Median (range) LTBI: 44 (22–60); TB: 30 (20–63); NI: 25 (22–54)

LTBI: 80; TB: 38.7; NI: 53.8

LTBI: 90; TB: 63.6; NI:5 3.8

Clinical, radiological, microbiological, and/or pathological results

TST

IL-2, IL-6, IL-8, IL-10, IL-13, TNF-α, IFN-γ, MIG, IP-10, I-TAG, and MCP-1

Unstimulated; LTBI vs. TB: IL-2, IL-10, IL-13, IL-8, and IFN-γ; Stimulated; TB vs. NI: IL-2, IL-6, IL-13, MIG, IP-10, I-TAG, MCP-1, and IL-8.; TB vs. LTBI: IL-2, IL-6, IL-10, IL-13, TNF-α, MIG, IP-10, I-TAG, INF-γ; LTBI vs. NI: IL-8

Plasma samples from whole blood (unstimulated, antigen-stimulated, or mitogen-stimulated)

ESAT-6, CFP-10, and TB7.7; Time: 24 hours

Microbead-based method, BD Biosciences, San Jose, CA, USA

Babak Pourakbari, 2015 [48]

Iran

LTBI

Individuals vaccinated and without previous exposure to M. tuberculosis and patients infected with M. tuberculosis, taken at the hospital

30

LTBI: TB: NI:

LTBI: 27; TB: 13; NI: 73

Not reported

Culture

QuantiFERON-TB Gold In-Tube Test, TST

IL-2

Stimulated; LTBI vs. TB and NI: IL-2

Plasma samples from whole blood (unstimulated, antigen-stimulated, or mitogen-stimulated)

PE35 (Rv3872) and PPE68 (Rv3873); Time: 3 days

ELISA, ELISA kit (Mabtech AB, Sweden)

Prachi R. Bapat, 2015; [22]

India

LTBI

Individuals living with TB cases and individuals in the community. Malnourished population

Total 39

Mean (range); 34.4 (12-65)

All participants: 45.9

All participants: 30

N/A

QuantiFERON-TB Gold In-Tube Test, TST

IL-6, IL-10, IL-2, TNF-αR, INF-γ

Stimulated; LTBI vs. NI: IL-6; LTBI and NI vs. community: IL-6, IL-10; NI vs. LTBI: IL-10

Plasma samples from whole blood (unstimulated or antigen-stimulated)

ESAT-6, CFP-10, and/or TB7.7; Time: 20–24 hours

Microbead-based method. IMMULITE-1000 Immunoassay System (Siemens Healthcare Global)

Yun-Gyoung Hur, 2014 [49]

Korea

LTBI

Adults with TB, individuals recently exposed to M. tuberculosis, healthy participants without M. tuberculosis exposure, and patients with non-TB mycobacteria infections

51

EPTB: 1 (1.7%)

Median (range); LTBI: 44 (18-82); TB: 32 (20-76); NI: 31 (20-61); MNT: (43-84)

LTBI: 74.5; TB: 49; NI: 51; MNT: 76.1

LTBI: 84.6; TB: 56.9; NI: 63.6; MNT: 60.5

Smear/culture or R-rays

QuantiFERON-TB Gold In-Tube Test, TST

IL-1β, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p70, IL-13, IL-17A, IL-22, IFN-γ, TNF-α, IFN-α, sCD40L, CXCL10, VEGF-A

Stimulated; TB and LTBI vs. controls: IFN-γ, IL-2, CXCL10; Serum; TB vs. NI: IL-22, CXCL10, and VEGF-A.; TB vs. LTBI: VEGF-A; TB vs. MNT: IL-2, IL-9, IL-13, IL-17, and TNF-α; MNT vs. TB: sCD40L

Plasma samples from whole blood (unstimulated, antigen-stimulated, or mitogen-stimulated) and serum

ESAT-6, CFP-10, and TB7.7; Time: 24 hours

Microbead-based method, BD FACSVerse (BD Biosciences, San Jose, CA, USA)

M. Wei, 2015 [38]

China

LTBI

Controls hospitalized for other causes without radiological signs of TB and patients hospitalized for TB

40

LTBI: TB: NI:

LTBI: 55; TB: 47.5; NI: 50

Not reported

Clinical diagnosis

T–SPOT®, TST

CCL1, CXCL9, IL-6, IL-10, CSF3, CSF2, IL-1α, IL-8, IL-7, IL-2, TGF-β1, CCL2, TNF-α

Unstimulated; TB vs. LTBI and NI: CCL1, CXCL9, IL6, IL-10, CSF3, CSF2, IL-1-α, IL-8, IL-7, IL-2, TGF-β1, CCL2, TNF-α.; Stimulated; TB vs. LTBI: CCL1 (I-309), CXCL9 (MIG), IL-10, IL-6, CSF2, CSF3, IL-8, IL-1α, IL-7, TGF-β1, CCL2, IL-2, and IL-13

Plasma samples from whole blood (unstimulated, antigen-stimulated, or mitogen-stimulated)

ESAT-6 and CFP-10; Time: 20 hours

Quantitative immunomicroarray (Quantibody Human Cytokine Array 1, RayBiotech, Inc., Norcross, GA)

Ji Yeon Lee, 2015 [39]

Korea

LTBI

Healthy and TB patients from the National Medical Center and Community Health Center of Korea

25

Mean (range); LTBI: 48 (23-59); TB: 48 (28-75)

LTBI: 44; TB: 37.5

Not reported

Smear (ZN) and/or cultures and X-rays

TST

IL-1, IL-6, IL-10, TNF-α, IL-17, GM-CSF, IL-4, IL-1β, INF-γ, LXA4, and PGE2

Monocyte stimulated MTSA; LTBI vs. TB IL-10; MTSA+INF-γ: IL-1, IL-6, IL-10; Stimulated CD4+ T cells and monocytes with PPD: TNF-α.; Plasma; TB vs. LTBI: LXA4 and PGE2

Nonstimulated and antigen-stimulated PBMC culture supernatants and plasma samples

H37Rv soluble antigens; Time: 5 days

Microbead-based method (Bio-Rad Laboratories, Hercules, CA); ELISA for IL-1β, ELISA kit (R&D Systems); EIA for LXA4 (Oxford Biomedical Research, Oxford, MI); EIA for PGE2 (Cayman Chemical, Ann Arbor, MI); Bio-Plex Multiplex Immunoassay Systems (Bio-Rad Laboratories, Hercules, CA)

Mulugeta Belay, 2015 [21]

Ethiopia

LTBI

Individuals from health centers in an endemic area to TB

148

Mean; LTBI: 32; TB: 29.4; NI: 32.4

LTBI: 55.5; TB: 41.5; NI: 52.9

LTBI: 37; TB: 28.1; NI: 35.3

Smear (ZN)

QuantiFERON-TB Gold In-Tube Test

IFN-γ, TNF-α, IL-10

Stimulated; Basal: NI vs. LTBI and TB: IFN-γ, TNF-α, IL-10; NI and TB vs. LTBI: IFN-γ, TNF-α, and IL-10; Six months: TB and LTBI vs. NI: INF-γ.; TB and LTBI TNF-α and IL-10:

Blood culture supernatant unstimulated or antigen-stimulated

E6C10 and Rv2031; Time: 48 hours

ELISA, Ready-Set-Go! cytokine ELISA kits (eBioscience, USA)

Sunghyun Kim, 2015 [50]

Korea

LTBI

Adult population, contacts of TB cases with and without M. tuberculosis infection

22

Mean (range); LTBI: 46.5 (22-69); TB: 32.1 (21-69); NI: 30.1 (22-44)

LTBI: 86.3; TB: 71.4; NI: 79.3

LTBI: 95.5; TB: 32.1; NI: 79.3

Culture

QuantiFERON-TB Gold In-Tube Test, TST

IFN-γ, TNF-α, IL-2R, IL-4, IL-10, CXCL9, CXCL10, CXCL11

Stimulated; LTBI vs. NI: IFN-γ, TNF-α, IL-2R, CXCL9, CXCL10; LTBI vs. TB: IL-17; TB vs. NI: INF-γ, TNF-α, IL-2R, CXCL9, CXCL10; TB vs. LTBI: TNF-α, CXCL11

RNA from antigen-stimulated whole blood cell pellets

ESAT-6, CFP-10, and TB7.7; Time: 24 hours

Real-time RT-PCR, TaqMan probe assay, and the ABI 7500 FAST instrument system (Applied Biosystems, Foster City, CA); ELISA

Ida Wergeland, 2016 [51]

Norway

LTBI

TB case and people with LTBI from a hospital

48

EPTB: 4

Median (range); TB: 32 (18–62); LTBI: 40 (13–67); LTBI borderline: 40 (25–53); NI: 47 (16–68)

TB: 66.6; LTBI: 63.8; LTBI borderline: 63.6; NI: 75

Not reported

Culture or clinical diagnosis and X-ray

QuantiFERON-TB Gold In-Tube Test

IL-1β, IL-1, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, basic FGF, eotaxin, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, and VEGF

Unstimulated; LTBI vs. TB: IL-1β, IL-1ra, IL-9, and IL-17A.; LTBI and TB vs. NI: RANTES; NI vs. TB and LTBI: IL-15, eotaxin, and basic FGF; NI vs. TB: IL-2, IL-4, IL-13, IL-17A, and IFN-γ.; Stimulated; TB and LTBI vs. NI: IL-1ra, IL-2, IL-13, IL-15, IFN-γ, IP-10, and MCP-1. LTBI vs. LTBI borderline and NI: IL-1ra, IL-2, IFN-y; LTBI vs. NI: IP-10, IL-13, IL-15, IL-17A, MCP-1

Plasma samples from whole blood (unstimulated, antigen-stimulated, or mitogen-stimulated)

ESAT-6, CFP-10, and TB 7.7; Time: 16–24 hours

Microbead-based method, Bio-Plex Pro Human Cytokine Group 27-Plex Panel (Bio-Rad Laboratories Inc., Hercules, CA)

Tao Chen, 2016 [52]

China

LTBI

TB case and LTBI medical staff who worked at the institute for TB prevention. People with cancer and pneumonia

21

It is not clear

NI: LTBI: TB: Others:

21

Not reported

Cough with blood-tinged sputum; fever; chest X-rays positive; microbiological test, IGRA positive

T–SPOT®, TST

IL-8, MIG, I-309, eotaxin-2, and ICAM-1

TB vs. NI and LTBI: IL-8, MIG, and I-309; LTBI vs. NI and others: eotaxin-2, ICAM-1, and MIG

Serum

N/A

Microarray and quantitative ELISA, Quantibody Human Cytokine Array 1, RayBiotech, Inc., Norcross, GA

Fabiana A. Zambuzi, 2016 [40]

Brazil

LTBI

TB case and people with LTBI from a hospital

14

Mean; LTBI: 31.4; TB: 39.6; NI: 27

LTBI: 78.6%; TB: 17.6; NI: 81.2

Not reported

Microbiology confirmed and clinical diagnosis or X-ray

TST

IL-1b, IL-4, IL-5, IL-6, IL-10, IL-12p70, IFN-a2, TNF-a, IFN-γ, IP-10, RANTES, MCP-1, GM-CSF, IL-17, MIP-1a, MIP-1b, sCD163, and sCD14

TB vs. NI and LTBI: IL-6, IP-10, TNF-a, sCD163, and sCD14.; LTBI vs. TB and NI: RANTES; TB vs. LTBI: GMCSF

Plasma

N/A

DuoSet ELISA for sCD163 and sCD14 and microbead-based method, 16-plex, EMD Millipore Corporation, Billerica, Massachusetts, USA

Miguel Santin, 2016 [41]

Spain

LTBI

Adult population recruited at eight TB centers

43

EPTB: 32 (46.4%)

Median; LTBI: 54 (46-64); TB: 41 (31-52); NI: 57 (44.5-77.3); Discordant: 49 (44.5-54)

Not reported

LTBI: 100; TB: 36.8; NI: 33.3; Discordant: 85.7

Microbiology confirmed or compatible when clinical, radiological, and/or ADA and/or histology positive, and cure was achieved after therapy

QuantiFERON-TB Gold In-Tube Test, TST

IFN-γ, IL-2

Stimulated; LTBI vs. NI: IL-2, INF-γ

Plasma samples from whole blood (unstimulated, antigen-stimulated, or mitogen-stimulated)

ESAT-6, CFP-10, and TB7.7; Time: 72 hours

Quantitative ELISA, Quantikine® ELISA Human IL-2 Immunoassay (R&D Systems Inc., Minneapolis, MN, USA)

Xiangyang Yao, 2017 [42]

China

LTBI

Two cohorts each one with healthcare workers with LTBI and TB case

10 and 15

and 20; and 15

Median (range); TB: 34.5 (20-78) and 29 (16-67); LTBI: 38.5 (20-48) and 38 (20-67); NI: 33 (18-56) and 48 (18-68)

TB: 60 and 45; LTBI: 60 and 60; NI: 44 and 35

TB: 35 and 25.8; LTBI: 100 and 100; NI: 100 and 86.7

Clinical, radiological, microbiological, and histopathological

QuantiFERON-TB Gold In-Tube Test

sCD40L, EGF, eotaxin, FGF-2, Flt-3 ligand, fractalkine, G-CSF, GM-CSF, GRO, IFN-α2, IFN-γ, IL-1α, IL-1β, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17, IP-10, MCP-1, MCP-3, MDC, MIP-1α, MIP-1β, TGF-α, TNF-α, TNF-β, VEGF 6Ckine, BCA-1, CTACK, ENA-78, eotaxin-2, eotaxin-3, I-309, IL-16, IL-20, IL-21, IL-23, IL-28A, IL-33, LIF, MCP-2, MCP-4, MIP-1d, SCF,SDF-1A+β, TARC, TPO, TRAIL, TSLP GCP2, I-TAC, IL-11, IL-29, lymphotactin, M-CSF, MIG, MIP-3α, MIP-3β

Unstimulated; TB vs. NI and LTBI: sIL-2Ra, IP-10, and MIP-1a; TB and NI vs. LTBI: IL-8; Stimulated; TB and LTBI vs. NI: G-CSF, GM-CSF, IFN-γ, IL-1a, IL-2, IP-10, BCA-1, and eotaxin-2.; TB vs. LTBI: G-CSF.; TB vs. LTBI and NI: IL-8, VEGF, MCP-3

Plasma samples from whole blood (unstimulated, antigen-stimulated, or mitogen-stimulated)

ESAT-6 and CFP-10; Time: hours

Microbead-based method, Millipore Milliplex map system (EMD Millipore Corporation, Billerica, MA, USA)

Jing Wu, 2016 [53]

Not reported

LTBI

Contacts of TB cases with and without LTBI

36

Mean (range); LTBI: 48 (7-76); TB: 51 (22-85); NI: 42 (5-80)

LTBI: 66.9; TB: 28; NI: 65.5

LTBI: 86.1; TB: 68; NI: 77.4

TB contact history, smear (ZN), culture, clinical diagnosis

T–SPOT®, TST

IL-1β, IL-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12(p70), IL-13, IL-15, IL-17, eotaxin, FGF, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1α, PDGF-BB, MIP-1β, RANTES, TNF-α, VEGF

Unstimulated; LTBI vs. TB: IP-10, PDGF-BB, and RANTES.; TB vs. LTBI: VEGF; Stimulated; LTBI vs. TB: IL-2, IL-10, IFN-γ, IP-10, and TNF-α.; TB vs. NI: IL-2, IL-10, IP-10

Nonstimulated and antigen-stimulated PBMC culture supernatants

PPD; Time: 24 hours

Microbead-based method, Bio-Plex Pro Human Cytokine 27-plex Assay (Bio-Rad, CA, USA)

R. Kamakia, 2017 [54]

Kenya

LTBI

Patients with suspected active TB and patients with active TB from Mbagathi District Hospital, Kenya, as well as contacts of people with TB

16

Mean (IQR); LTBI: 35.6 (27-39.8); TB: 36.8 (25.8-5.15); NI: 33.5 (23.3-45.3)

LTBI: 50; TB: 21.1; NI: 75

Not reported

ZN, X-ray

QuantiFERON-TB Gold In-Tube Test

IL-17F, IFN-γ, GM-CSF, IL-10, IL-12p70, IL-13, IL-15, IL-17A, IL-22, IL-9, IL-1b, IL-33, IL-2, IL-4, IL-21, IL-23, IL-5, IL-6, IL-17E/IL-25, IL-27, IL-31, MIP-3α, TNF-α, TNF-β, IL-28A

Stimulated; LTBI vs. TB: IL-17F, MIP-3α, IL-13, IL-17A, IL-5, INF-γ, IL-9, IL-2.; LTBI vs. NI: INF-γ, IL-9, and IL-2

Plasma samples from whole blood (unstimulated, antigen-stimulated, or mitogen-stimulated)

ESAT-6, CFP-10, and TB7.7; Time: 2 hours

Microbead-based method, Milliplex MAP Human Th17 Magnetic Bead Kit (Millipore, St. Louis, MO, USA)

Eun-Jeong Won, 2017 [43]

Korea

LTBI

Patients with LTBI, individuals without infection, and cases of TB from a university hospital

15

Median (range); LTBI: 52.0 (36-75); NI: 28.9 (16-74); TB QFT+: 73.0 (15-86); TB QFT-: 73.5 (25-89)

LTBI: 46.7; TB: 58.3 NI: 53.8

Not reported

Culture

QuantiFERON-TB Gold In-Tube Test

EGF, eotaxin, G-CSF, GM-CSF, IFN-α2, IFN-γ, IL-1α, IL-1β, IL-1RA, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p40, IL-12p70, IL-13, IL-15, IL-17, IP-10, MCP-1, MIP-1α, MIP-1β, TNF-α, TNF-β, VEGF

Unstimulated; TB vs. LTBI: TNF-α and VEGF.; TB vs. LTBI and NI: IL-8, IL-13, INF-γ, IL-2, IP-10, and VEGF.; Stimulated; LTBI and TB vs. NI: GM-CSF, IFN-γ, IL-1RA, IL-2, IL-3, IL-13, IP-10, and MIP-1β.; LTBI vs. TB: EGF, GM-CSF, IL-5, IL-10, and VEGF

Plasma samples from whole blood (unstimulated, antigen-stimulated, or mitogen-stimulated)

ESAT-6, CFP-10, and TB7.7; Time: 16-24 hours

Microbead-based method, Milliplex MAP Human Cytokine/Chemokine 29-plex kits (Millipore, Billerica, CA)

Ditthawat Nonghanphithak, 2017 [20]

Thailand

LTBI

All individuals were from Srinagarind Hospital, Khon Kaen. Healthy persons with a history of TB contact and healthy individuals with no known TB exposure

38

PTB: 48; Early clearance: 162; NI: 39

LTBI: TBA: EC: HC:

TB: 35.4; LTBI: 81.6; EC: 66; HC: 82.1

Not reported

Smear (ZN), culture, or a molecular test (Xpert MTB/RIF, clinical diagnosis)

QuantiFERON-TB Gold In-Tube Test

CCL2, CXCL10, IFN-γ

Unstimulated; NI vs. TB and LTBI: CCL2; TB vs. NI, EC and LTBI: CXCL10; LTBI vs. HC and EC: CXCL10; Stimulated; LTBI vs. TB: INF- γ.; TB vs. EC and HC: INF- γ, CXCL10.; TB and LTBI vs. NI: CXCL10

Nonstimulated and antigen-stimulated PBMC culture supernatants

ESAT-6, CFP-10, and TB7.7; Time: 24 hours

ELISA, BioLegend (California, USA)

Marco Pio La Manna, 2018 [55]

Italy

LTBI

Patients with active TB, health workers, and people with LTBI in a hospital

32

PTB: 27; NI: 20; Others non-TB pulmonary infections: 20

Range; LTBI: 17-84; TB: 17-82; Non-TB: 24-76; NI: 21-68

LTBI: 25; TB: 22; Non-TB: 40; NI: 30

Not reported

Culture or GeneXpert MTB/RIF from biopsy specimens and/or biological fluids

QuantiFERON-TB Gold In-Tube Test, TST

IL-1α, IL-1β, IL-1ra, IL-2, IL-2Ra, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12(p40), IL-12(p70), IL-13, IL-15, IL-16, IL-17, IL-18, IFN-α2, IFN-γ, TNF-α, TNF-β, TRAIL, CXCL1 (GRO-α), CXCL9 (MIG), CXCL10 (IP-10), CXCL12 (SDF-1α), CCL2 (MCP-1), CCL3 (MIP-1α), CCL4 (MIP-1β), CCL5 (RANTES), CCL7 (MCP-3), CCL11 (eotaxin), CCL27 (CTACK), G-CSF, M-CSF, GM-CSF, SCF, SCGF-β, LIF, MIF, FGF-β, b-NGF, PDGF-BB, VEGF, HGF

Unstimulated; LTBI vs. NI and non-TB: IL-1β, IL12p70, and VEGF; TB vs. NI and non-TB: PDGF-BB, IL-1β, IL-2, IL-8, IL12p70, MCP-1, and LIF.; Stimulated; TB/LTBI vs. non-TB: IL12-p40, IL-2ra, SCF, TRAIL, IL-2, IFN-γ, IP-10, b-NGF, LIF, and MIG.; TB vs. non-TB: IFNα2, IL-3, and TNF-β.; LTBI vs. non-TB: IL-13.; LTBI and non-TB vs. TB: MIF

Plasma samples from whole blood (unstimulated, antigen-stimulated, or mitogen-stimulated)

ESAT-6/CFP-10; Time: 16–24 hours

Microbead-based method; there is no information

Leonar Arroyo, 2018 [44]

Colombia

LTBI

TB case contacts and TB cases

20

PTB: 21

Median (IQR); LTBI: 38.5 (26.75-52.75); TB: 28 (24-41)

LTBI: 45 TB: not reported

Not reported

Smear (ZN)

Positive response (≥22 pg/ml) to the CFP10 antigen of Mtb and the absence of clinical symptoms compatible with clinical TB

IFN-γ

Stimulated; LTBI vs. TB: IFN-γ in response to all antigens

Nonstimulated and antigen-stimulated PBMC culture supernatants

Mtb DosR (Rv1737c, Rv2029c, and Rv2628) and Rpf (Rv0867c and Rv2389c) antigens; Time: 7 days

Microbead-based method, Millipore (Millipore, Billerica, MA, USA)

EPTB: extrapulmonary TB; PTB: pulmonary TB; TB/NRCF: the article does not report the clinical form of TB. An example of paper 1 for the row increased immune parameter interpretation: unstimulated, TB vs. NI, and LTBI: IL-10 and IL-6 mean that in an unstimulated sample, IL-10 and IL-6 were increased in TB compared to not infected individuals and persons with LTBI.