RetourTesting for TBI increases the certainty that individuals targeted for TPT will benefit better from it. There is, however, no gold standard test for diagnosing TBI. All the currently available tests – TST, IGRA and TBST – are indirect and require a competent immune response for a valid result. A positive test result by any one method is not by itself a reliable indicator of the risk of progression to TB disease. The evidence and the recommendations for TBI testing are discussed in this section.
- Either a tuberculin skin test (TST) or interferon-γ release assay (IGRA) can be used to test for TB infection. (Strong recommendation, very low certainty of the estimates of effect)
- Mycobacterium tuberculosis antigen-based skin tests (TBST) may be used to test for TB infection. (Conditional recommendation, very low certainty of the estimates of effect)
Justification and evidence
Recommendation 17 was originally published in the 2018 WHO guidelines (17). A previous systematic review was updated to compare the predictive performance of IGRA and TST for identifying incident TB disease in countries with a TB incidence > 100/100 00 population (67). Only studies in which TST was compared with IGRA in the same population were considered, and relative risk ratios for TB for people who tested positive and those who tested negative in those two tests were estimated. (See the GRADE evidence summaries for PICO 4 in Annex 3).
Five prospective cohort studies were identified, with a total of 7769 participants; four were newly identified. Three of the studies were conducted in South Africa and two in India (23,68,69,70,71). The studies included people with HIV, pregnant women, adolescents, health-care workers and household contacts. The pooled risk ratio estimate for TST was 1.49 (95% CI, 0.79 ; 2.80) and that for IGRA was 2.03 (95% CI, 1.18 ; 3.50). Although the estimate for IGRA was slightly higher than that for TST, the 95% CIs for the estimates for TST and IGRA overlapped and were imprecise. Furthermore, there was limited evidence for the predictive value of the tests in specific at-risk populations.
The GDG concluded that comparison of TST and IGRA in the same population does not provide strong evidence that one of the tests should be preferred over the other for predicting progression to TB disease. TST may require significantly fewer resources than IGRA and may be more familiar to practitioners in resource-constrained settings; however, recurrent global shortages and stock-outs of TST limit prospects for its scale-up in PMTPT.
The GDG also noted that equity and access could affect the choice and type of test used. The preferences of people to be tested and programmes depend on several factors, such as the requirement for an adequately equipped laboratory (e.g. for IGRA), possible additional costs for people being tested (e.g. for travel) and the programme (e.g. for infrastructure and testing). The GDG strongly recommended the two tests as equivalent options, with relatively similar advantages and disadvantages.
The GDG cautioned that imperfect performance of these tests can lead to false-negative results, particularly for young children and immunocompromised individuals such as people with HIV with low CD4 counts. The GDG noted the importance of the tests for identifying recent conversion from negative to positive, particularly among contacts of people with pulmonary TB, which is good practice when initiating TPT. Nevertheless, studies among health-care workers tested serially for TBI in the USA showed that conversion from negative to positive and reversion from positive to negative are more commonly identified with IGRA than with TST (72). Thus, clinical judgement must still be used to interpret the results of serial TBI tests.
Although some studies suggest otherwise (73,23), the GDG maintained the past position that people with HIV who have a positive test for TBI benefit more from TPT than those who have a negative TBI test (17,26). TBI testing can be used, where feasible, to identify such individuals. The GDG, however, based on evidence of moderate certainty, strongly emphasized that TBI testing by TST or IGRA should not be a prerequisite for starting TPT in people with HIV and in household contacts aged < 5 years, particularly in settings with a high TB incidence (e.g. > 100 TB cases/100 000 population), given that the benefits clearly outweigh the risks. A negative TBI test in these two groups or in HIV-negative infant household contacts should be followed by a case-by-case assessment for the potential benefit and harm of TPT.
In 2022, WHO issued recommendation 18 on use of new M. tuberculosis antigen-based skin tests (TBSTs) to test for TBI (14). A systematic review of published and unpublished data was conducted for new TBSTs based on specific antigens (ESAT-6 and CFP-10), which combine the advantage of a simpler skin test with the specificity of IGRAs. In all tests, antigen is injected intradermally, and, as in the TST, the tests are read after 48–72 h as induration in millimetres, by the method suggested by Mantoux. In 2022, the WHO GDG concluded that the available evidence showed that the diagnostic accuracy of TBSTs is similar to that of IGRAs and greater than that of the TST (14). TBSTs are recommended for all subpopulations, including people with HIV, children and adolescents and people who have been vaccinated with the bacille Calmette-Guérin (BCG) vaccine.
Implementation considerations
TBI testing is desirable whenever feasible to identify people at highest risk for developing TB disease. It is not required for people with HIV or in household contacts aged < 5 years. In HIV-negative household contacts aged ≥ 5 years and in other risk groups TBI tests are recommended, but their lack of availability should not be a barrier to providing TPT.
The GDG noted that availability and affordability could determine which TBI test is used. Other considerations include the structure of the health system, the feasibility of implementation and infrastructure requirements.
The incremental cost-effectiveness of IGRAs and TSTs appears to be influenced mainly by their accuracy. BCG vaccination decisively reduces the specificity of TST. The GDG noted, however, that the effect of BCG vaccination on the specificity of TST depends on the strain of vaccine used, the age at which the vaccine is given and the number of doses administered. When BCG is given at birth, as recommended by WHO and in practice in most parts of the world, it has a variable, limited impact on TST specificity (74). Therefore, the GDG agreed that a history of BCG vaccination has a limited effect on interpretation of TST results later in life. Hence, BCG vaccination should not be a determining factor in selecting a test.
IGRA testing is more costly than TST and requires appropriate laboratory services. Operational difficulties should be considered in deciding which test to use. For example, IGRA requires a phlebotomy, which can be difficult, particularly in young children; it requires laboratory infrastructure, technical expertise and expensive equipment; and its sensitivity is reduced in children aged < 2 years and those with HIV. Nevertheless, only a single visit is required to conduct an IGRA test (although patients may have to make a second visit to receive the result). Skin testing with TST or TBST is less costly and can be performed in the field, but it requires a cold chain, two health-care visits and training in intradermal injection, reading and interpretation. One other practical advantage of IGRAs over TST is that they are not susceptible to a “booster response”, which necessitates a two-step testing approach when the reactivity to TST has waned since infection.
In 2011, WHO recommended use of three IGRA products for testing for TBI: QIAGEN QuantiFERONGold, QIAGEN QuantiFERON-TB Gold In-Tube and Oxford Immunotec T-SPOT.TB assays (75). In 2021, the list of WHO-recommended IGRAs was extended to include Beijing Wantai’s TB-IGRA and QIAGEN QuantiFERON-TB Gold Plus (76).
The three specific TBST products available for review by the GDG that developed the 2022 WHO recommendations were Cy-Tb (Serum Institute of India, India), Diaskintest® (Generium, Russian Federation) and C-TST (formerly known as ESAT6-CFP10 test, Anhui Zhifei Longcom, China). Users of the tests might have to issue appropriate guidance and explain the difference between the TST and TBSTs (64). It is also important to standardize measurement of the TBST reaction size and its interpretation. As for TSTs, use of TBSTs requires a cold chain, well-trained, skilled staff to administer and interpret test results and multiuse vials for effective operational planning and batching. Procurement and stock management should be considered, including availability on the global market, as for any new class of tests. TBSTs might require regulatory approval from national authorities or other relevant bodies, as they are a relatively new in-vivo tests.
TST, TBST and IGRA are not validated for confirmation of TB disease and should therefore not be used to diagnose TB nor for the diagnostic workup of adults being evaluated for TB disease.