TABLE 1.

The characteristics of the skin tests and IGRAs.

Terms	Skin tests				IGRAs
	Conventional TST	Diaskintest	C-Tb skin test	EC-Test	T-SPOT.TB	QFT-GIT	QFT-Plus	LIAISON QFT-Plus	LIOFeron TB/LTBI
Manufacturer	Multiple manufacturers	Generium Pharmaceutical, Russia	Statens Serum Institut, Denmark	Zhifei Longcom, China	Oxford Immunotec, United Kingdom	QIAGEN, Hilden, Germany	Qiagen, MD, United States	DiaSorin S.p.A., Italy	LIONEX GmbH, Braunschweig, Germany
Time	> 100 years	2009	2010	2020	1990s	1980s	2015	2017	2019
Antigens	PPD	ESAT-6 and CFP10	ESAT-6 and CFP10	ESAT-6 and CFP10	ESAT-6 and CFP10	ESAT-6, CFP-10, and TB7.7 (p4)	ESAT-6 and CFP10	ESAT-6 and CFP10	ESAT-6, CFP-10, TB7.7, Ala-DH
Tubes	NA	NA	NA	NA	One tube	Nil tube, Antigen tube, and Mitogen tube	Nil tube, TB1 tube, TB2 tube, and Mitogen tube	Nil tube, TB1 tube, TB2 tube, and Mitogen tube	PC tube, TB-A tube, TB-B tube, and NC tube
Technological platform	NA	NA	NA	NA	ELISPOT	ELISA	ELISA	CLIA	ELISA
Sample	NA	NA	NA	NA	PBMCs	Whole blood	Whole blood	Whole blood	Whole blood
Sample transport and storage temperature	Refrigerate at 4°C	Refrigerate at 4°C	Refrigerate at 4°C	Refrigerate at 4°C	Indoor temperature, do not refrigerate or freeze	Indoor temperature, do not refrigerate or freeze	Indoor temperature, do not refrigerate or freeze	Indoor temperature, do not refrigerate or freeze	Indoor temperature, do not refrigerate or freeze
Outcome measure	Millimeters of induration	Millimeters of induration	Millimeters of induration	Millimeters of induration	Number of IFN-γ-producing T cells	Serum concentration of IFN-γ produced by CD4+ T cells	Serum concentration of IFN-γ produced by CD4+ and CD8+T cells	Serum concentration of IFN-γ produced by CD4+ and CD8+T cells	Serum concentration of IFN-γ produced by CD4+ and CD8+T cells
Positive internal control	No	No	No	No	PHA	Mitogen	Mitogen	Mitogen	Unknown
Need for return visit	Yes	Yes	Yes	Yes	No	No	No	No	No
Time required for results	48–72 h	48–72 h	48–72 h	48–72 h	16–20 h	16–24 h	16–24 h	Unknown	16–24 h
in vivo/in vitro	in vivo	in vivo	in vivo	in vivo	in vitro	in vitro	in vitro	in vitro	in vitro
Interpretation of result	Subjective (operator-based)	Subjective (operator-based)	Subjective (operator-based)	Subjective (operator-based)	Objective (instrument-based)	Objective (instrument-based)	Objective (instrument-based)	Objective (instrument-based)	Objective (instrument-based)
False positives with BCG vaccination	Yes	No	No	No	No	No	No	No	No
Cross-reactivity with NTMs	High	Low	Low	Low	Low, but can be influenced by infections of M. kansasii, M. szulgai, M. marinum, and M. gordonae*	Low, but can be influenced by infections of M. kansasii, M. szulgai, and M. marinum (Andersen et al., 2000)	Low, but can be influenced by infections of M. kansasii, M. szulgai, and M. marinum (Andersen et al., 2000)	Unknown	Low
False positives with immunosuppression and deficiency	High	Low	Low	Low	Low	Low	Low#	Unknown	Unknown
Specificity	62% (BCG vaccinated) and 95% (BCG unvaccinated) (Ruhwald et al., 2016)	98% (Starshinova et al., 2020)	99.3% (Aggerbeck et al., 2013)	98% (Steffen et al., 2020)	76.2% (Yang et al., 2021)	99%§	95% (Sotgiu et al., 2019)	Unknown	98% in aTB and 97% in LTBI (Della Bella et al., 2020)
Sensitivity	75% (Aggerbeck et al., 2018)†	86% (Starshinova et al., 2020)	73.9% (Hoff et al., 2016)	86% (Steffen et al., 2020)	83.5% (Yang et al., 2021)	89%§and 73% (Aggerbeck et al., 2018)†	91% (Sotgiu et al., 2019)	Unknown	90% in aTB and 94%in LTBI (Della Bella et al., 2020)
Accuracy	Unknown	95.1% in total population and 92.4% in HIV-positive patients (Starshinova et al., 2020)	Unknown	87%	88.5% (Yang et al., 2021)	Unknown	Unknown	Unknown	Unknown
Limitations	Relatively low specificity, lacks sensitivity in immunosuppressed individuals and requires two clinic visits	Requires two clinic visits	Requires two clinic visits	Requires two clinic visits, Safety need further observed, Data on LTBI high-risk populations and infants are lacking.	Results should be evaluated in conjunction with clinical and other tests, and a negative result does not rule out the possibility of infection with M. tuberculosis	Results must be used in conjunction with individual’s epidemiological history, current medical status, and other diagnostic evaluations	Results must be used in conjunction with risk assessment, radiography, and other medical and diagnostic evaluations	Need to define a borderline range based on clinical diagnostics criteria	Results must be used in conjunction with risk assessment, radiography, and other medical and diagnostic evaluations
Discrimination of LTBI from active TB (Hong et al., 2019; Della Bella et al., 2020; WHO, 2020)	No	No	No	No	No	No	No	No	No

CLIA, chemiluminescence immunoassay; ELISPOT, enzyme-linked ImmunoSpot; IGRAs, interferon-gamma release assays; LTBI, latent tuberculosis infection; NA, not applicable; NC, negative control; NTMs, non-tuberculous mycobacteria; PBMCs, peripheral blood mononuclear cells; PC, positive control; PHA, phytohemagglutinin; PPD, protein-purified derivative; TST, tuberculin skin test.

* These data were obtained from T-SPOT.TB official web (http://tspot.com.cn) and T-SPOT.TB ELISPOT Package Insert. PI-TB8-IVD-CN Rev. 05. September 2019. Accessed May 6, 2021.

§These data were obtained from QuantiFERON official web (https://www.quantiferon.com/products/quantiferon-tb-gold/) and QuantiFERON-TB Gold (QFT) ELISA Package Insert. 1075115 Rev. 07. June 2018. Accessed May 6, 2021.

# Theoretically, the inclusion of peptides for stimulation of CD8⁺ T-cells can improve performance in immunocompromised conditions that affect CD4⁺ T-cell responses and improve discrimination of LTBI from active TB.

†Data are limited in children and HIV-infected persons.