Interferon-γ release assays for the diagnosis of latent Mycobacterium tuberculosis infection

From the authors:

We thank O. Moran Mendoza for his comment on the joint systematic review and meta-analysis on the role of interferon-γ release assays (IGRAs) for the diagnosis of latent infection with Mycobacterium tuberculosis by the Tuberculosis Network European Trials Group (TBNET) and the European Centre for Disease Prevention and Control (ECDC) [1]. O. Moran Mendoza highlights the as-yet limited knowledge about the positive predictive values of IGRAs for the development of tuberculosis, a standpoint that is also expressed in the new European Union guidance on the use of IGRAs in support of the diagnosis of tuberculosis [2].

In our meta-analysis and systematic review, only studies reporting on the diagnosis of latent infection with M. tuberculosis (LTBI) that used the latest commercially available version of IGRAs were included. Studies that were performed with “in-house” IGRAs, e.g. the studies by Hill et al. [3] and by Bakir et al. [4], were not considered. Although it was not the focus of our review, differences between the studies with commercially available IGRAs and these two studies should be highlighted. Among the 26 contacts who developed active tuberculosis in the study by Hill et al. [3] from Gambia, no clear linkage of secondary tuberculosis cases to the putative index cases could be established. In addition, the authors used a slightly different cut-off for IGRA positivity, limiting direct comparison of the results. Bakir et al. [4] performed a primarily interventional study. Most of the household children and adolescent contacts with a positive tuberculin skin test (TST) or IGRA result received isoniazid preventive chemotherapy for a duration of 6 months. This intervention was ∼60% effective at preventing tuberculosis and, thus, substantially influenced the evaluation of the prognostic value of IGRAs for the development of tuberculosis.

In the European region, two large studies that have addressed the positive predictive value of latest-generation IGRAs for the development of tuberculosis have been published to date. While Diel et al. [5] found a clear superiority of an IGRA over the TST for the development of tuberculosis in household contacts, Kik et al. [6] found IGRAs and the TST equally ineffective at predicting the development of tuberculosis in immigrants to the Netherlands. As the study populations investigated were different and Kik et al. [6] performed IGRAs only when the TST was positive, the results of both studies are not directly comparable.

In countries of low-to-medium tuberculosis prevalence, short-term progression rates to tuberculosis in individuals belonging to tuberculosis risk groups have been reported to range from 3.3% to 12.9% [5–9]. Although the potential cost-effectiveness of an IGRA for the investigation of LTBI has recently been demonstrated in immigrant screening in the UK [10], information on the predictive values of IGRAs for the development of tuberculosis still relies on a small number of at-risk individuals who actually developed tuberculosis. Clearly, more information is needed before general recommendations that IGRAs should replace the TST can be made.

Future prospective studies that will address the role of immunodiagnosis in tuberculosis risk assessment should focus on stratification of subjects into different risk groups and be performed in multiple centres.

There is a striking difference in the positive and negative predictive values of the TST and IGRAs for the diagnosis of tuberculosis. While the negative predictive values for all tests in clinical use are >97%, the positive predictive values are low and the large majority of individuals at risk for the development of tuberculosis with a positive TST and/or IGRA result will not develop tuberculosis. Clinical decision makers in many countries are, therefore, hesitant to advocate consequently for preventive chemotherapy despite positive test results. Biomarkers for the prediction of tuberculosis need to be substantially improved beyond the limited performance of the TST and IGRAs, and treatment duration should be shortened substantially. Advocacy of preventive chemotherapy by caregivers and acceptance by individuals at risk for the development of tuberculosis need to be improved. As a general rule, testing should only be offered to those individuals belonging to at-risk groups to identify those with the highest risk for future tuberculosis development.

• ©ERS 2011