A significant portion of this document is devoted to IGRAs;
Changing the diagnosis of LTBI in the last decade: IGRAs
The development of IGRAs in the past 10 yrs has tried to address some of these difficulties [56]. IGRAs work on the principle of measuring the IFN-γ released from T-cells specific to M. tuberculosis as a marker of infection. By using specific protein antigens secreted from M. tuberculosis encoded in the region of difference 1, which is not present in the BCG or in the majority of nontuberculous mycobacteria, they are theoretically more specific than the TST. IGRAs exist in two formats: the ELISpot-based IGRA, where individual IFN-γ producing T-cells responding to M. tuberculosis antigens are counted, and the ELISA-based IGRA, where the IFN-γ itself is measured in a whole blood assay after stimulation with the antigens. There are currently two commercially available preparations: the ELISpot-based T-SPOT™.TB (Oxford Immunotec, Abingdon, UK) and the ELISA-based QuantiFERON™-TB Gold In-Tube (Cellestis, Carnegie, Australia). The first proof-of-principle work demonstrating their potential usefulness was in comparing patients with active TB disease and healthy BCG vaccinated volunteers with low epidemiological risk of TB infection. These early studies showed that (in comparison with patients with culture confirmed TB, the gold standard) the assays were sensitive and importantly not confounded by prior BCG vaccination [57, 58]. In systematically reviewing this work, PAI et al. [59] have found the sensitivity of the ELISpot-based approach to be 90% (range 83–100%) and the ELISA-based approach to be 70% (range 64–93%). The pooled specificities of both in this review were >93%.
The evidence supporting their role in the diagnosis of LTBI has been extensively reviewed and will be briefly summarised here [56, 60]. As there is no gold standard for the diagnosis of LTBI (as no bacilli are by definition culturable) surrogate markers have been used to assess the sensitivity of IGRAs in this respect. As infection with LTBI is determined by duration and closeness of contact with the index case, contact tracing studies have been used to compare the performance of these platforms with the TST. In summary, these studies with both ELISpot and ELISA platforms show that IGRAs correlate better with TB exposure than the TST and are not confounded by prior BCG vaccination [61]. The majority of these studies have been in low-burden countries, where remotely acquired M. tuberculosis infection is less likely to confound the results; however, these studies have now been successfully replicated in high-burden countries [62] and more recently in a high-burden country with high rates of HIV infection, with similar results [63].
Unlike the TST, IGRAs, particularly the ELISpot-based test, appear to perform reasonably well in patients with defects in cellular immunity. The majority of this evidence comes from studies on children [62, 64] or in patients with HIV [63, 65]. There is also some evidence in smaller studies in patients with autoimmune conditions [66] and in patients with chronic kidney disease [67–70] that the IGRAs remain more sensitive than the TST. This latter group is particularly important, as individuals with LTBI and chronic kidney disease have a much higher risk of progression to active TB [71]. The performance of the ELISA-based test in HIV-infected individuals appears to be poorer, with reduced sensitivity in patients with lower CD4 counts [72–74].
A key development in the treatment of patients with inflammatory conditions such as rheumatoid arthritis and psoriasis has been the development of TNF antagonist therapies, in the form of monoclonal antibodies or soluble receptor antagonists. Perhaps unsurprisingly, given the key role TNF-α has in the host response to M. tuberculosis, particularly in granuloma formation and stability [75], individuals treated with these therapies are at significantly higher risk of reactivating LTBI. This increased risk may be up to 25 times higher, depending on the type of drug used [31]. Given this increased risk, all patients with LTBI who are going to receive a TNF antagonist therapy should receive chemoprophylaxis. The background to this topic and the use of IGRAs and TST in the screening of patients with chronic inflammatory conditions has been well-summarised in a recent European Respiratory Society consensus statement [31]. They recommend either the use of IGRAs or TST in patients without BCG vaccination for screening and note that in the paediatric population both strategies are used. Given this, and the high risks associated with a failure to identify LTBI in these individuals, our personal practice is to give chemoprophylaxis to any patient with either a positive TST or a positive IGRA.
In the absence of a gold standard for the diagnosis of LTBI, arguably the best indicator of true LTBI is the subsequent development of active TB disease. A good test for LTBI in this respect will therefore predict who progresses to active TB disease and hence allow the better targeting of appropriate chemoprophylaxis. As only 5–10% of immunocompetent individuals will do this, large numbers of patients need to be tested in order to have a study of sufficient power to test this hypothesis. As a result, such evidence of longitudinal progression in patients who are IGRA positive is more limited but the work that has been performed in low-incidence countries suggest that the IGRAs may predict progression to active disease at least as well as the TST [76–79]. One study in the Gambia did not replicate this finding, although this may relate to its high-burden setting [80].
From this work, a significant number of national guidelines in low-burden countries have now incorporated the use of IGRAs in algorithms for the diagnosis of LTBI. Variation exists on whether this utilises them in place of the TST, as in the USA [81], or alongside the TST, as in the UK [82] and elsewhere in Europe. As more longitudinal data emerges on the cost-effectiveness of different screening strategies, these algorithms are likely to be refined over time.
