The definition of tuberculosis infection based on the spectrum of tuberculosis disease

Giovanni Battista Migliori; Catherine W.M. Ong; Linda Petrone; Lia D'Ambrosio; Rosella Centis; Delia  Goletti

doi:10.1183/20734735.0079-2021

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Figure 1
The “continuum process” leading from TB infection to disease. BCG: bacille Calmette–Guérin; DX: diagnosis; TX: treatment; IGRAs: interferon-γ release assays; TST: tuberculin skin test; (L)TBI: (latent) TB infection.

Table 1

Tests for diagnosing TB infection

	TST	New skin tests	*IGRAs and in vitro* tests**	*New in vitro* tests**
Examples		Diaskin test, EC-skin test and c-Tb	QuantiFERON-TB Gold Plus and T-SPOT.TB Standard E TB-Feron, AdvanSure TB-IGRA ELISA, LIOFeron TB/LTBI, IP-10 ELISA	QIAreach QuantiFERON-TB, the ichroma IGRA-TB, STANDARD F TB-Feron FIA, Erythra TB-test, IP-10 IGRA LF VIDAS TB-IGRA, AdvanSure I3 TB-IGRA, LIAISON QuantiFERON-TB Gold Plus, GBTsol Latent TB Test Kit
Characteristics	Intradermal administration of PPD in the forearm Cold chain requirement for PPD Induration reading within 72 h Trained staff for administration and reading the skin induration	Intradermal administration of ESAT-6/CFP-10 antigens in the forearm Cold chain requirement for ESAT-6/CFP-10 Induration reading within 72 h Trained staff for administration and reading the skin induration	In vitro tests with internal controls Detection of IFN-γ or other markers in blood or PBMCs using ELISA Need for fresh samples Incubation time of 16–24 h Need for efficient sample transport system Need for different blood collection tubes depending on the altitude Need for laboratory infrastructure Assay time: 20 min for IP-10 ELISA; 1.5–4 h for QuantiFERON-TB Gold Plus, T-SPOT.TB, Standard E TB-Feron, AdvanSure TB-IGRA ELISA, LIOFeron TB/LTBI	In vitro tests with internal controls Detection of IFN-γ or other biomarkers in the blood or isolated T-cells using LFA or chemiluminescence or ELFA systems Need for fresh samples Incubation time of 0^#–24 h Need for efficient sample transport system Need for different blood collection tubes depending on the altitude Need for laboratory infrastructure for some assays^¶ Assay time: 15–20 min for QIAreach QuantiFERON-TB, STANDARD F TB-Feron FIA, ichroma IGRA-TB, AdvanSure I3 TB-IGRA, Erythra TB test; 46 min to 17 h⁺ for LIAISON QuantiFERON-TB Gold Plus, GBTsol Latent TB Test Kit, GBTsol Latent TB Test Kit, IP-10 IGRA LF and VIDAS TB-IGRA
Disadvantages	False positive results in BCG-vaccinated individuals False negative results in immunocompromised hosts Inaccuracy/bias in performing the test and in reading it Second visit needed	False negative results in immunocompromised hosts Inaccuracy/bias in performing the test and in reading it	False negative results in immunocompromised Errors in the pre-analytical phase Misinterpretation of the assays Expensive	Limited data We expect: Errors in the pre-analytical phase Misinterpretation of the assays Expensive
Advantages	Useful for large screening settings Cost-effective No laboratory infrastructure required	Useful for large screening settings Cost-effective No laboratory infrastructure required	Higher specificity for TB infection compared with TST No booster effect compared with TST No need for a second visit compared with TST Faster turn-around time compared with TST	Higher specificity for TB infection compared with TST No booster effect No need for a second visit compared with TST Lower turn-around time compared with IGRAs Very likely: faster^§ and/or less handling^ƒ compared with IGRAs

Assay time: time from post-incubation and result delivery. Incubation time: time of stimulation. BCG: bacille Calmette–Guérin; ELFA: enzyme-linked fluorescence assay; ELISA: enzyme-linked immunosorbent assay; LFA: lateral flow assay; PBMC: peripheral blood mononuclear cells. ^#: incubation time not required for Erythra TB-test; ^¶: VIDAS TB-IGRA, AdvanSure I3 TB-IGRA, LIAISON QuantiFERON-TB Gold Plus; ⁺: VIDAS TB-IGRA assay time is reported to be 17 h and includes incubation, post-incubation and result score; ^§: applies to QIAreach QuantiFERON-TB, the ichroma IGRA-TB, STANDARD F TB-Feron FIA, Erythra TB-test, AdvanSure I3 TB-IGRA; ^ƒ: applies to VIDAS TB-IGRA, LIAISON QuantiFERON- TB Gold Plus.

Table 2

Research priorities for TB infection

Areas for research	Specific areas
Risks of progression from TB infection to TB disease	Evaluation of the likelihood of progressing from TB infection to TB disease in the various at-risk populationsEvaluation of the incidence and risk of progression to TB disease in the following groups of patients: Diabetes mellitus Harmful alcohol use Tobacco use Underweight Silica exposure Steroid treatment Rheumatological diseases CancerEvaluation of the harms including stigmatisation and acceptability of testing and TB preventive therapy in risk groups
Defining the best clinical algorithm to exclude TB disease from TB infection	Performance and feasibility of these algorithms should be assessedCreating algorithms for children and pregnant womenIdentify feasible cost-effective methods for contact tracing
Improved diagnostic tests and defining the performance of latent TB tests in at-risk populations	Tests with improved performance and predictive value for progression to TB diseasePerformance of existing latent TB tests in at-risk populationsTests to determine TB reinfectionHow to use existing tests to best determine LTBI