Interferon-gamma release assays for screening of health care workers in low tuberculosis incidence settings: Dynamic patterns and interpretational challenges

There is considerable evidence that both tuberculin skin tests (TSTs) and interferon-gamma release assays (IGRAs) are valid but imperfect for latent tuberculosis (TB) infection (LTBI). Neither test can distinguish LTBI from TB disease and, therefore, have no value for active TB detection (1). Both tests have suboptimal sensitivity in active TB, especially in HIV-infected persons and children (2,3). Both tests appear to correlate well with gradient of exposure (3). While neither IGRAs nor the TST have high accuracy for predicting active TB, the use of IGRAs in some populations might reduce the number of people considered for preventive treatment (4). However, there are key differences between the two tests (5). While the TST has high specificity in Bacille-Calmette-Guerin (BCG) unvaccinated persons, its specificity is lower and variable in those who have received BCG vaccination after infancy or have received multiple BCG vaccinations (6). In contrast, IGRA specificity remains high in BCG-vaccinated and unvaccinated populations (7). From a logistical perspective, IGRAs are more convenient for patients who do not have to return for the reading, and the laboratory readout is more objective than the subjective reading of TST induration. Finally, there is an important difference in terms of cost for the health care system – in general, IGRAs are more expensive to implement than the TST. While many countries have published guidelines on IGRAs (8), the use of IGRAs for routine screening of health care workers (HCWs) remains an area of controversy. The 2005 United States Centers for Disease Control (CDC) guidelines on the QuantiFERON-TB Gold (QFT) assay (Cellestis, Australia) allowed for replacement of the TST with QFT for annual testing of HCWs in the United States (US) (9), and this was expanded to cover both commercial IGRAs in the 2010 update (10). In contrast, the Canadian guidelines on IGRAs have not recommended the use of IGRAs for serial testing of HCWs (11,12). While the performance of IGRAs in serial testing of HCWs was first reported six years ago (13), this topic has received significantly more attention in the past few years, culminating in a recent systematic review (14). In the current issue of the Canadian Respiratory Journal, Joshi et al (15) (pages 84-88) provide useful data on routine implementation of QFT for HCW screening in Arkansas (USA), where QFT replaced the TST in 2008. Joshi et al describe the challenges they faced in implementing the test and raise concerns about high rates of QFT positivity in a setting with very low historical TST conversion rates. They observed high reversion rates on repeat testing of positives and poor short-term reproducibility of positive QFT results. Based on their results, Joshi et al argue for the need for cautious interpretation of QFT results, especially those in the borderline zone around the cut-off. The report by Joshi et al (15) is highly consistent with data that have emerged from many countries (16-25). Table 1 sumarizes the major serial testing studies of IGRAs in HCWs in low and intermediate