1.1. Background

Tuberculosis (TB) infection is a state that is characterized by persistent immune response to stimulation by Mycobacterium tuberculosis (Mtb) antigens with no evidence of clinically manifest TB disease (1). It is estimated that about a quarter of the world’s population is infected with Mtb. Testing for TB infection can identify individuals who would benefit the most from TB preventive treatment (TPT). However, there is no gold-standard test to diagnose TB infection. The two classes of tests that are currently available – the tuberculin skin test (TST) and interferon-gamma release assays (IGRAs) – are indirect tests for immune sensitization, and they require an immune response to identify people infected with TB. A positive test result by either method is not, by itself, a reliable indicator of the risk of progression to active disease.

In 2011, the World Health Organization (WHO) issued recommendations on the use of IGRAs for the diagnosis of TB infection, including the blood-based QIAGEN QuantiFERON®-TB Gold (QFT-G), QIAGEN QuantiFERON-TB Gold In-Tube (QFT-GIT) and Oxford Immunotec T-SPOT®. TB (T-Spot) assays. In 2018, WHO updated the recommendations to stipulate that the TST or IGRAs (or both) can be used to test for TB infection in LMIC.

The TST is a widely used point-of-care test that involves intradermal injection of purified protein derivative (PPD), a crude mixture of different mycobacterial antigens, which stimulates a delayed-type hypersensitivity response and causes induration at the injection site within 48–72 hours. This test has relatively low specificity in those with recent bacille Calmette-Guérin (BCG) vaccination and low sensitivity in immunosuppressed individuals (e.g. people living with HIV [People with HIV]); hence, interpretive cut-offs must be adapted for these populations. A follow-up clinic visit is required after the placement of the TST, and results must be read within the suggested time frame to be valid. In contrast, IGRAs are in vitro tests that measure release of interferongamma (IFN-γ) by T-cells following stimulation by the early secretory antigenic target 6 kDa protein (ESAT-6) and culture filtrate protein 10 (CFP-10) antigens that are specific to Mtb. Unlike the TST, IGRAs are not affected by prior BCG vaccination, or by infection with nontuberculous mycobacteria (NTM), with few exceptions. However, IGRA platforms are more expensive to run and require specialized facilities and trained personnel; consequently, the TST is the most commonly used test for TB infection globally. Recent global shortages of PPD have underscored the need for alternatives.

Newer Mtb antigen-based skin tests (TBSTs) based on specific antigens have been developed, using the same ESAT-6 and CFP-10 antigens; these tests combine the simpler skin-test platform with the specificity of IGRAs. TBSTs include the Cy-Tb (Serum Institute of India, India), Diaskintest® (Generium, Russian Federation) and C-TST (formerly known as ESAT6-CFP10 test, Anhui Zhifei Longcom, China). All tests use intradermal injection of antigen and, like the TST, are read after 48–72 hours as induration in millimetres, using the method suggested by Mantoux. Emerging evidence suggests that, compared with IGRAs, the tests may have similar specificity and provide more reliable results in children and adolescents as well as in People with HIV than the TST. However, the evidence has not been systematically reviewed.

The WHO assessment process for TB diagnostics has evolved into a mechanism that focuses on the evaluation of classes of TB diagnostic technologies rather than of specific products. Some of the important elements to guide implementation are diagnostic accuracy, the epidemiological and geographical setting, operational aspects (turnaround times, throughput, existing infrastructure and specimen referral networks), economic aspects and qualitative aspects on acceptability, equity, end-user values and preferences.

The TBST class is defined as in vivo skin tests for the detection of TB infection that use Mtb-specific antigens (ESAT-6 and CFP-10).

In 2021, WHO commissioned a systematic review of published and unpublished data on this new class of tests for TB infection not previously reviewed by WHO. The systematic review included data on diagnostic accuracy, safety, economic aspects and qualitative evidence on feasibility, acceptability, equity, end-user values and preferences. A Guideline Development Group (GDG) was convened by WHO from 31 January to 3 February 2022, to discuss the findings of the systematic reviews and to make recommendations on this class of diagnostic technologies for TB infection.

The following technologies were included in the evaluation:

  • Cy-Tb (Serum Institute of India, India); 
  • Diaskintest (Generium, Russian Federation); and
  • C-TST (formerly known as ESAT6-CFP10 test, Anhui Zhifei Longcom, China)

The current recommendations are based on the evaluation of data for the tests that were included in the present evaluation. The findings cannot be extrapolated to other brand-specific tests; also, any new in-class technologies will need to be specifically evaluated by WHO.

Guidelines are disseminated through the WHO Global TB Programme (WHO/GTB) listservs to WHO regional offices, Member States, the Stop TB Partnership and other stakeholders (e.g. the Global Laboratory Initiative and the TB Supranational Reference Laboratory Network); they are also published on the websites of the WHO/GTB and Global Laboratory Initiative. The updated policy is incorporated into the WHO TB Knowledge Sharing Platform – an online reference resource for global TB policies and derivative products.

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