A positive TST has previously been considered the gold standard in screening for M. tuberculosis infection. However, there is currently no definitive way to decide whether a person is latently infected with M. tuberculosis. A recent prevalence study by Soborg et al. in a Danish hospital confirmed earlier findings that TST is hampered by low specificity in BCG-vaccinated individuals [10, 11]. The authors found a 34% prevalence among TST-positive HCWs, but the only significant risk factor associated with a positive TST was prior BCG immunisation; no association was observed with other important risk factors, such as occupational exposure to TB or hospital staff position . Other low-endemic country studies have also found that a positive TST test is primarily associated with prior BCG vaccination and the boostering effect of prior TST testing [12–15]. Nevertheless, how can we conclude that the low post-exposure rate of infection detected by T-SPOT.TB in our study represents the real situation if there is no gold standard? One possible strategy is to estimate the likelihood of having latent TB infection by calculating a contact score that quantifies exposure to and infectiousness of the index case, as was done by Shams et al. . A range of other studies also provide extensive evidence that the IGRAs correlate better to exposure than does TST. Therefore, we based our conclusions regarding the prevalence of TB infections on the T-SPOT.TB test [5, 12–14, 16–21].
Of 155 exposed HCWs and 48 healthy controls, all but one had a visible scar from BCG immunisation, which has been compulsory in Norway at the age of 14 until recently. Norwegian legislation also demands that all HCWs are asked for a certificate of TST at the time of appointment, and if the existence of a recent TST cannot be documented then a new TST is performed. The high correlation between BCG vaccination and a positive TST and the high specificity of the T-SPOT.TB test for Mtb infection (98%) make it likely that these are mostly false positive TST reactions rather than false negative T-SPOT.TB results. In addition, as found by Nienhaus et al. , the boosting effect of repetitive skin testing in health personnel may also contribute to the somewhat surprisingly low concordance between infection status according to T-SPOT.TB and TST that was observed in this study (12%). Still, there is no diagnostic gold standard for latent TB and the fact that 88% of employees recently defined as infected by TST tested negative with the T-SPOT.TB test calls for further studies of kinetics and immune mechanisms in TB infection. In our study all five T-SPOT.TB-positive individuals also had a strong positive TST. Nienhaus et all found that 5.1% of the HCWs in three German hospitals had a negative TST and a positive QFT . While the combination of a negative IGRA and a positive TST is largely explained by prior BCG immunisation and TST boostering, the other combination is not readily explained, and further research is needed.
In contrast to most other studies related to TB transmission within health institutions, we have in this work compared the performance of T-SPOT.TB and TST in a group of HCWs with well-defined short-term exposure to contagious TB patients in a hospital setting. In addition, the results have been used to evaluate the role of IGRAs in improving the surveillance of TB transmission to health personnel in a low-incidence country like Norway.
Provided that the T-SPOT.TB results are the most reliable compared to TST results, our study indicates that the risk of infection among health care workers after short-term exposure to TB patients in a hospital setting is low (2%). This somewhat contradicts the findings of a Swiss long-term institutional study in which 15% of contacts were T-SPOT.TB-positive after prolonged unprotected exposure . Although both studies were performed in health care institutions in low incidence countries, the exposure time may account for the observed differences in transmission. A study from Denmark also reported a low proportion (1%) of latent TB among HCWs as detected by the QFT test . However, these data were not based on recent exposure, but rather represent the general prevalence level among hospital personnel working in departments with TB patients. We found a prevalence level of 3% in our cohort. Not surprisingly, these results are in contrast to findings from a high-endemic country like Russia, where a study utilizing QFT revealed a prevalence level of 41% among hospital staff working with infectious diseases . Several reports based on TST conversion indicate that the risk of being infected may be high, even within a limited time frame of exposure [23, 24]. This has also been confirmed by a T-SPOT.TB study in Italy in which 32% of the staff in a maternity ward became positive for TB after a mean exposure time of 6 hours . Compared to these findings, our study detected a low degree of transmission. However, it should be noted that the majority of the individuals in this study had been exposed for less than 8 hours before precautions were taken. Still, among the three persons with positive T-SPOT.TB tests (believed to be recently infected), two were exposed for less than 8 hours. The absence of a statistically significant correlation between exposure time and both TST and T-SPOT.TB results is probably due to both the low exposure time and the small number of participants, since these correlations have been demonstrated in many other studies [19, 23, 24].
Importantly, the results indicate that using IGRAs as an alternative to the present follow-up strategy based on TST results could save substantial resources. Although TST by itself will be less expensive than a comprehensive laboratory procedure, the utilization of Mtb-specific blood tests has the potential to save major resources as the number of persons who must be followed up for 3 years can be reduced by up to 88%. In this context, the possibility of avoiding unnecessary and costly treatment, including serious side effects, is also of considerable importance. In addition, most exposed health care workers will avoid long-term anxiety by obtaining a negative result at a very early investigational stage. Finally, the small number of infected persons who require treatment can be identified immediately.
Oxlade et al. performed a 20-year cost-benefit analysis that used Markov modelling to compare the costs of TB screening with different strategies among hypothetical cohorts of foreign-born immigrants to Canada and contacts of TB cases. Model inputs were derived from published literature and utilization of the QFT test. For entering immigrants, screening with Chest X-Ray would be the most cost-effective and QFT the least cost-effective strategy. Sequential screening with TST followed by QFT was more cost-effective than either QFT or TST alone. In contact tracing after exposure, however, screening with TST followed by QFT, if positive, was more cost-effective than any other strategy. This was largely because TST alone was not effective if the exposed group had been vaccinated with BCG after infancy . These findings were also confirmed by a Swiss study by Wrighton-Smith et al., estimating the costs of screening a cohort of 1000 individuals for latent tuberculosis; screening with TST alone followed by Chest X-Ray and clinical follow up of the positive cases was estimated to €695820; T-SPOT.TB alone was estimated to €387135; TST followed by T-SPOT.TB of the positives was estimated to €342563, i.e. the less costly .
Due to the fact that BCG immunization has been administered routinely in Norway, specific blood tests should be introduced in all post-exposure contact tracing situations. Because TB transmission to health personnel in Norway seems to be rather low, the two-step screening approach (TST followed by IGRA) might be attractive. However, some studies indicate an unacceptable low sensitivity of TST; Nienhaus et al. found that 40% of the HCW with latent TB infection according to IGRA results had a negative TST, and would have been missed utilizing TST followed by QFT of the TST positives. There is also evidence that a positive IGRA is a much better predictor of future reactivation than a positive TST , which is of particular interest because the Norwegian guidelines recommend prophylactic treatment in all documented cases of latent TB infection aged < 35 years. Further research is obviously needed to define improved screening strategies in low-endemic settings, both in the light of sensitivity and cost-effectiveness.
It should also be noted that the QFT method, although less sensitive in immuno-suppressed individuals, has both logistic and economic advantages compared to the T-SPOT.TB assay, and implementation of the QFT test has recently been suggested in Norway's national guidelines. The introduction of specific T-cell based assays for post-exposure screening and subsequent prophylactic treatment will become a rational and important component of the national TB control strategy.