We have found extreme discordance between the results of a clinical diagnostic algorithm and the results of QFT-G testing for diagnosis of LTBI in our HCWs. Specifically, of 82 TST-positive HCWs (most of whom had a TST induration size of 15 mm or more) who had increased pretest probability of LTBI according to clinical criteria that were based on standard and widely accepted guidelines4,5
—all of whom would accordingly have been offered treatment according to preexisting EOHS protocol—57 (70%) tested negative with the QFT-G assay. A repeat QFT-G test confirmed these negative test results in 41 (95%) of 43 HCWs tested, and a different IGRA, T-SPOT.TB, generated only 5 positive test results among the 36/43 HCWs who received this additional testing. We could reasonably conclude either that our clinical algorithm incorrectly identified these HCWs as being at increased risk of having LTBI when they actually do not have LTBI, or that IGRAs are insensitive for diagnosing LTBI in our population. (Of note, a recent study of the use of the QFT-G assay in US Navy recruits13
also questioned the sensitivity of the QFT-G assay for a subset of recruits who were born in countries with high tuberculosis prevalence and who had TST induration sizes of 15 mm or more.) However, a third, intriguing hypothesis would be that our clinical algorithm identifies all persons with LTBI (both recent and remote), whereas IGRAs detect a specific subset of that group—perhaps those at highest risk of reactivation. The fact that the CDC has stated that the QFT-G assay can be used in place of the TST for screening of HCWs and other populations1
makes it imperative that we consider these very different conclusions.
It is taught that tuberculosis reactivation risk is concentrated in the first 2 years after infection.14–16
Certainly there is also no doubt of the potential for remote infection to reactivate in individuals with immunosuppression or with other well-known medical risk factors.4
In contrast, there is little guidance regarding the risk of reactivation of remote infection in an immunocompetent, otherwise healthy individual. Notably, at least half of the TB cases among foreign-born persons occur more than 5 years after arrival.17
If our clinical criteria did indeed identify a population with a high prevalence of LTBI, one explanation for the discordance between the TST and IGRA results seen in our study could be that the 2 antigens (CFP-10 and ESAT-6) used in the IGRAs are insufficient for comprehensive detection of LTBI, compared with the complex mix of antigens in the PPD. However, in contact investigations, the IGRAs have appeared to detect recent tuberculosis infections with a sensitivity at least equal to that of the TST and to have better correlation with gradient of exposure to Mycobacterium tuberculosis
Although the latter has been ascribed to higher specificity of the IGRAs, some of the excess positive TST results could also be due to remote tuberculosis infections. Studies of the sensitivity of IGRAs for detection of active tuberculosis likewise suggest sensitivity similar to that of the TST.23
The integration of this data with ours might suggest that the IGRAs are in fact quite sensitive for detection of recently acquired
LTBI, but less so for remotely acquired
Of course, an alternative explanation for the observed discordance could be that our IR HCWs are TST positive only because of remote BCG vaccination, rather than because of LTBI.2
However, the fact that all of our IR, QFT-G negative HCWs (36/36) reacted very strongly to PPD in extended (3-and 5-day) in vitro T cell stimulation assays, and that 12 (33%) of the 36 reacted strongly to ESAT-6 and CFP-10 in these assays (including 7 HCWs who tested negative with both the QFT-G assay and T-SPOT.TB), could suggest that many of our IR HCWs were indeed infected with tuberculosis at some point in the past. Such a difference in “sensitivity” between overnight and longer-incubation IGRAs in individuals with suspected LTBI has been noted before.25,26
However, extended stimulation with ESAT-6 and CFP-10 only partially corrected the discordance we observed between the results of commercial IGRAs and the TST, and this may have a number of explanations. First, we would not necessarily expect ESAT-6 and CFP-10 alone to provide 100% sensitivity for detection of LTBI even in extended assays, given the limitations of the sensitivity of IGRAs using ESAT-6 and CFP-10 for detection of active tuberculosis. Second, it may be that waning of immunologic memory in the context of remote (or cleared) infection would result in decreased response to ESAT-6 and CFP-10, even in extended assays. Third, it is possible that not all individuals have the immunologic recognition repertoire to respond to ESAT-6 or CFP-10, even if they do have LTBI; this concept is supported by data from mouse models.27,28
Finally, 14 (39%) of the 36 samples were not tested with ESAT-6 in extended assays due to unavailability of the antigen, and some of these samples might have generated additional positive test results. We do not have an explanation for why we had more positive test results with the proliferation assays than with the extended IGRAs when ESAT-6 and CFP-10 were used, in contrast to the strong responses in both assays to PPD. Of note, it is unlikely that response to ESAT-6 and CFP-10 in extended IGRAs was due to nonspecific stimulation by lipopolysaccharide, as very low levels of lipopolysaccharide were present and only 2 of the 36 samples tested positive with the extended IGRAs.
Unfortunately, previous studies of the performance of the QFT-G assay in Japanese, Indian, and Russian HCWs29–31
do not inform the interpretation of our results, partly because their HCW populations (unlike ours) were essentially ethnically homogenous and overall rates of QFT-G positivity varied widely with study location. Notably, many of our HCWs have previously worked in healthcare facilities in areas where tuberculosis is endemic.
We recognize that some limitations inherent to the TST may have contributed to the misclassification of some of our HCW as IR. First, for a minority of positive TST results, we had to rely on documentation from outside readers. We also did not know the timing of BCG vaccination (eg, infancy or childhood) for most of our HCWs, so cannot assess its potential contribution to TST size.2
American Thoracic Society guidelines state that “targeted tuberculin testing programs should be designed for one purpose: to identify persons at high risk for TB who would benefit by treatment of LTBI.”4(pS233)
Perhaps, then, our focus in screening programs (in nonimmunocompromised populations) should not be on the identification of any
tuberculosis infection, but rather of those with higher reactivation risk.32
If the IGRAs are indeed able to distinguish these individuals, then using IGRAs for tuberculosis screening could focus our attention on a group most worthy of treatment and surveillance. This is supported by our finding that QFT-G positive IR HCWs were more likely to have spent 5 years or more in an area where tuberculosis is highly endemic and to have recently immigrated, suggesting that they could have been more recently infected. However, our findings show that if we base our treatment decisions on IGRA results alone, a sizable proportion of individuals with clinical risk factors historically considered suggestive of true LTBI will suddenly be exempt from treatment that we otherwise would have recommended—and some of these risk factors have historically been associated with increased reactivation risk.
It is likely that, by using established US clinical guidelines, we have been historically overidentifying individuals as “increased LTBI risk” and thus overtreating. However, there are many data underlying our assessment of the positive predictive value of the TST for the risk of development of active tuberculosis,33–35
and moreover, the TST has been used to define LTBI in studies that show the benefits of LTBI treatment.15,36
The critical question is whether LTBI, if not detected by an IGRA, could still reactivate, especially in patients with immunosuppression and other medical risk factors. At the current time, studies of the positive predictive value of IGRAs are few (eg, see Richeldi et al.37
and Doherty et al.38
), and studies of their negative predictive value are in a relatively early stage (reviewed in Andersen et al.39
In summary, the marked difference between the performance of the QFT-G assay in our IR HCWs, many of whom may have remote TB infection, and its performance in the contact setting suggests that the test may perform quite differently in these 2 common testing circumstances. This contrast may be telling us that the TST, which appears to be sensitive to both recent and remote infection, may be greatly overestimating the very high risk subpopulation that we need to target for LTBI treatment. When screening HCWs for LTBI, the finding of fewer positive test results with IGRAs may be their strength, rather than their weakness. However, in the absence of the long-term follow-up data necessary to definitively answer these questions, we feel that we cannot at this time replace the TST with the QFT-G assay for screening of our HCWs, for fear of missing IR, QFT-G negative individuals who may be at higher risk of tuberculosis reactivation. In the frustrating absence of a gold standard for the diagnosis of LTBI, our data suggest that, for now, we must continue to interpret negative QFT-G results with some caution.