..the current systematic review and meta-analysis on the accuracy of the IGRAs for LTBI diagnosis confirm the concept that the IGRAs are a valid alternative to the TST. The superior specificity and the good NPV make them the first choice, especially in BCG-vaccinated subjects..
..the predictive value for progression to active disease when testing positive is higher for the IGRAs as compared to the TST.This one is from Diel et al and is published in the European Respiratory Journal, which is the official journal of the European Respiratory Society.
Abstract can be viewed here and I have reproduced a copy of the discussion, below the fold.
Discussion
In the last few years a large number of studies have been published on the performance of IGRAs for the diagnosis of LTBI in different cohorts at risk for progression to active tuberculosis. We performed a systematic review and meta-analysis to assess the accuracy of commercially available IGRAs in terms of specificity, NPV and PPV as the main estimates.
Despite the volume of publications on the subject, only a limited number of studies fulfilled the inclusion criteria for our systematic review and meta-analysis. This is due to the use of non-commercial IGRAs or to methodological limits in the design of individual studies.
Based on the results obtained from our analysis we identified that:
1) the IGRAs show a higher specificity as compared to the TST;
2) the NPV, when using patients with active tuberculosis as a surrogate of LTBI, is high (although with a high variability in values);
3) the ability of the IGRAs to predict that a test-negative individual will not develop disease is even higher; and lastly,
4) the predictive value for progression to active disease when testing positive is higher for the IGRAs as compared to the TST. However, NPV and PPV remain to be established in the paediatric population and in immunocompromized individuals, e.g. patients with advanced HIV-infection, transplant recipients or candidates for TNF antagonists therapies.
The pooled specificity (99.4% [95% CI, 97.8–99.9%]) when measured in low-risk population groups using the QFT-G-IT (the only IGRA for which results could be analysed in all included studies) was clearly higher than the pooled specificity for the TST (88.7% [95% CI, 84.6- 92.0)]. These results suggest that the IGRAs are more certain to correctly identify individuals not infected with M. tuberculosis as compared to the TST. However, the estimates have to be interpreted with caution due to the low number of included studies.
An optimal LTBI diagnostic tool should be predictive of an individual’s risks for developing or not developing active disease when tested. When analyzing the studies using cohorts of active tuberculosis cases as surrogates of LTBI, a high overall NPV value was measured (pooled NPV 94% for T-SPOT.TB and 88% for QFT-G-IT). This would suggest that IGRAs, especially the T-SPOT.TB, are effective at ruling out M. tuberculosis infection. However, caution must be taken when interpreting these results as there was a high variability between the studies (ranging from 70-98% for the QFT-G-IT and 92-100% for the T-SPOT.TB) likely due to the corresponding prevalence of active tuberculosis cases, thus limiting the utility of pooling data across studies. This would therefore refute the conclusion that the IGRAs are an effective “rule-out-test” for LTBI.
Conversely, longitudinal NPV studies on mostly non-immunocompromized adults in low prevalence countries, who are at risk for LTBI, suggest that one can be reasonably confident that, when scoring negative with an IGRA, the likelihood of false negative results is low.
High NPVs were found for both the QFT-G-IT and the T-SPOT.TB (pooled NPV of 97.8% for T-SPOT.TB and 99.8% for QFT-G-IT). This indicates that an individual testing negative will most likely not develop tuberculosis in the future. However, a limitation to this analysis was the low number of individuals included in the studies (total 1442), the short durations of follow up, and the fact that similar studies have not yet been performed in high-burden settings.
The QFT-G-IT and the T-SPOT.TB both showed a similar PPV for progression, with a slightly wider range in values as compared to the TST (2.8%-14.3% for QFT-G-IT; 3.3-10% for T-SPOT.TB and 2.3-3.3% for TST), suggesting that the IGRAs have a higher predictive value for progression to active disease as compared to the TST. If IGRA performance was not conditionally restricted to prior TST positivity (as was the case in one study), the progression rates were higher (8%, 10% and 15%) than those reported for TST, with two years follow up [19, 20, 22]. In the study by Kik et al. [21], a lower PPV value for progression was measured (3%); however, the study was limited to only assessing the IGRA among TST-positive individuals, thereby presenting a source of bias.
Studies on predictive value of the IGRAs with regard to developing active tuberculosis upon testing positive are still very few, with only four studies having fulfilled our inclusion criteria, and they often vary substantially in design and rely on empirical observations of subjects refusing LTBI treatment. Additional larger-sized studies including new markers for LTBI are needed to evaluate the predictive values of IGRAs and other biomarkers in groups with the highest risk of progression to tuberculosis, especially in children and in immunocompromized hosts.
The review of studies investigating the influence of BCG vaccination on TST positivity and the influence of exposures for LTBI clearly confirmed – despite the large heterogeneity in the design of the analysed studies – that, unlike the TST, the newest commercial IGRAs are not affected by prior BCG vaccination. They are subsequently more likely associated with exposure to tuberculosis cases compared to the TST. These results were not influenced by the epidemiological context where the studies were performed (high vs. low incidence countries). The review only assessed TST results in the context of IGRA studies and thus the results on prior studies on accuracy performing the TST solely could not be taken into consideration. Furthermore, we did not evaluate the ability of IGRAs to discriminate recent from remote LTBI and the phenomenon of conversion/reversion over time or after therapy. Although this would be a very important point in a public health programme, the data available today [78-82] are limited and mostly obtained with experimental techniques and in particular settings, making it difficult to interpret their potential clinical value. In conclusion, the current systematic review and meta-analysis on the accuracy of the IGRAs for LTBI diagnosis confirm the concept that the IGRAs are a valid alternative to the TST. The superior specificity and the good NPV make them the first choice, especially in BCG-vaccinated subjects. The current evidence is however still limited to determine whether the IGRAs have a stronger predictive value for developing active disease later in life, as compared to the TST. In the development of guidance on the use of IGRAs in tuberculosis screening programmes, it is vital that such evidence is considered when describing diagnostic algorithms for the diagnosis of LTBI. In this way we can provide support to assure that only assays with proven accuracy are introduced into national screening programmes for further advancement towards the elimination of tuberculosis.
