Testing for LTBI increases the certainty that individuals targeted for treatment will benefit from it. However, there is no gold standard test to diagnose LTBI. Both currently available tests – TST and IGRA – are indirect and require a competent 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. The evidence and the recommendations for LTBI testing are discussed in this section.
16. Either a tuberculin skin test (TST) or interferon-gamma release assay (IGRA) can be used to test for LTBI. (Strong recommendation, very low certainty in the estimates of effect)
Justification and evidence
This recommendation was first published in the 2018 WHO guidelines (16). A previous systematic review was updated to compare the predictive performance of IGRA and TST for identifying incident active TB in countries with a TB incidence >100 / 100,00 population (59). Only studies in which TST was compared with IGRA in the same population (“head-to-head” studies) were included. Relative risk ratios for TB for people who tested positive and those who tested negative with TST and IGRA were estimated (see the GRADE evidence summaries for PICO 4 in Annex 2).
Five prospective cohort studies were identified, with a total of 7,769 participants; four were newly identified. Three of the studies were conducted in South Africa and two in India (20),(60),(61),(62),(63). The studies included People with HIV, pregnant women, adolescents, healthcare 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 utility of the tests in specific at-risk populations.
The evidence reviewed and the recommendations apply only to the use of the two commercially available IGRAs (QuantiFERON®-TB Gold In-Tube and T-SPOT®.TB). The GDG concluded that the comparison of TST and IGRA in the same population does not provide strong evidence that one test should be preferred over the other for predicting progression to active 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 reduce 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 adequately equipped laboratory (e.g. for IGRA) and possible additional costs for people being tested (e.g. for travel) and programmes (e.g. for infrastructure and testing). The GDG strongly recommended the two tests as equivalent options, with relatively similar advantages and disadvantages.
The GDG stressed that the global shortage of TST should be addressed urgently and called for more investment into research on novel tests for LTBI with better predictive value.
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 to identify recent conversion from negative to positive, particularly among contacts of people with pulmonary TB, which is good practice when initiating TB preventive treatment. Nevertheless, recent studies among healthcare workers tested serially for LTBI in the USA showed that conversions from negative to positive and reversions from positive to negative are more commonly identified with IGRA than with TST (64). Thus, clinical judgement must still be used to interpret the results of serial LTBI tests.
Although some studies suggest otherwise (19),(20), the GDG maintained the past position that People with HIV who have a positive test for LTBI benefit more from TB preventive treatment than those who have a negative LTBI test (11),(16). LTBI testing can be used, where feasible, to identify such individuals. However, based upon evidence of moderate certainty, the GDG strongly emphasised that LTBI testing by TST or IGRA should not be a prerequisite to start TB preventive treatment in People with HIV and household contacts aged < 5 years, particularly in settings with a high TB incidence (e.g. >100 TB cases/ 100,000 population), given that benefits clearly outweigh the risks. A negative LTBI test in these two groups, as well as in HIV-negative infant household contacts, should be followed by a case-by-case assessment for the potential benefit and harms of TB preventive treatment.
LTBI testing is desirable whenever feasible to identify persons at highest risk for developing active TB. However it is not required in People with HIV or in household contacts aged < 5 years. In HIV-negative household contacts aged 5 years and more and in other risk groups LTBI tests are recommended, but their unavailability should not be a barrier to treat people who were judged to be at higher risk.
The GDG noted that the availability and affordability of the tests could determine which LTBI test is used. Other considerations include the structure of the health system, feasibility of implementation and infrastructure requirements.
The incremental cost-effectiveness of IGRAs and TSTs appears to be influenced mainly by their accuracy. Bacille Calmette-Guérin (BCG) vaccination plays a decisive role in reducing the specificity of TST. The GDG noted, however, that the impact 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 is the case in most parts of the world, it has a variable, limited impact on TST specificity (65). 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 a laboratory infrastructure, technical expertise and expensive equipment; its sensitivity is reduced in children aged <2 years and those with HIV. However, only a single visit is required to do an IGRA test (although patients may have to make a second visit to receive the result). TST is less costly and can be performed in the field, but it requires a cold chain, two healthcare 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 makes a two-step approach necessary in situations where the reactivity to TST has waned since infection.
Neither TST nor IGRA are to be used to diagnose active TB disease nor for diagnostic workup of adults suspected of having active TB.