To the Editors:
I have read with interest several papers describing the use of cellular interferon (IFN)-γ-based blood tests, including the editorial by Davies and Drobniewski 1. Whilst reviewing the study by Lee et al. 2, Davies and Drobniewski 1 indicate that the T-SPOT.TB assay has higher sensitivity than QuantiFERON-TB Gold, but that the QuantiFERON-TB Gold may have better specificity.
I do not agree with this tentative conclusion as the study by Lee et al. 2 does not report the true specificity of the two tests, as the control group of 15- and 16-yr-old students used to examine the specificity of the assays, although healthy, had a defined risk of existing tuberculosis (TB) infection. This was acknowledged by Lee et al. 2 in the discussion section of their study as follows.
“The present study has several limitations. First, some of the low-risk subjects may actually have been infected with MTB [Mycobacterium tuberculosis] and this might lead to an underestimation of the specificity of the IFN-γ assays. According to a South Korean national survey conducted in 1995, the MTB infection rate was ∼15% in 15 yr olds, but rose dramatically to about 52–60% in 18–33 yr olds. Accordingly, 15–16-yr-old students were selected as a low-risk group because they have a lower chance of being infected with MTB.”
T-SPOT.TB reported a 15.3% infection rate in this healthy control group versus 8.4% for QuantiFERON-TB Gold. In the absence of a true gold standard for latent TB infection (LTBI), it is impossible to definitely resolve whether the discrepancy between the T-SPOT.TB and QuantiFERON-TB Gold results in this group was due to the higher specificity of QuantiFERON-TB Gold or the higher sensitivity of T-SPOT.TB. Nonetheless, the available data suggest that it is more likely that the discrepancy is due to the higher sensitivity of the T-SPOT.TB test rather than the higher specificity of QuantiFERON-TB Gold, for the following reasons.
First, Lee et al. 2 demonstrated that T-SPOT.TB has higher sensitivity than QuantiFERON-TB Gold in the diagnosis of culture-confirmed active TB disease, and this finding has also been reported by Goletti et al. 3. Whilst active TB disease is clearly not the same as LTBI, it might be hypothesised that this difference in sensitivity is also true in LTBI. In the study by Ferrara et al. 4, this hypothesis was suggested by head-to-head evidence of the higher sensitivity of T-SPOT.TB over QuantiFERON-TB Gold in LTBI.
Secondly, both QuantiFERON-TB Gold and T-SPOT.TB use the same antigens (ESAT-6 and CFP-10). Therefore, it is hard to argue that T-SPOT.TB is any less specific for MTB infection than QuantiFERON-TB Gold, as both examine the cellular immune response to identical antigens. Furthermore, to my knowledge, there are no published data showing higher specificity for the QuantiFERON-TB Gold assay over the T-SPOT.TB assay. Additionally, four previous studies 5–8 investigating the specificity of the T-SPOT.TB test (using pre-approval versions of the test) have demonstrated a specificity of 100%, where truly low-risk controls in a low-endemicity country (UK) were studied.
Finally, Lee et al. 2 predicted the prevalence of tuberculosis infection in the healthy control cohort to be 15%. The fact that T-SPOT.TB reported a rate of infection of 15.3% provides further evidence that T-SPOT.TB was detecting true latent tuberculosis infection. It is felt that, on the basis of the above arguments, the lower rate of detection by QuantiFERON-TB Gold is more likely to be attributed to the lower sensitivity of this assay, rather than its higher specificity.
Statement of interest
C. Granger is the director of professional relations of Oxford Immunotec, which manufactures the T-SPOT.TB assay.
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