Abstract
BackgroundAlthough interferon-gamma release assays (IGRA) are promising alternatives to the tuberculin skin test, interpretation of repeated testing results is hampered by lack of evidence on optimal cut-offs for conversions and reversions. A logical start is to determine the within-person variability of T-cell responses during serial testing.Methodology/Principal FindingsWe performed a pilot study in India, to evaluate the short-term reproducibility of QuantiFERON-TB Gold In Tube assay (QFT) among 14 healthcare workers (HCWs) who underwent 4 serial QFT tests on day 0, 3, 9 and 12. QFT ELISA was repeated twice on the same sets of specimens. We assessed two types of reproducibility: 1) test-retest reproducibility (between-test variability), and 2) within-person reproducibility over time. Test-retest reproducibility: with dichotomous test results, extremely high concordance was noticed between two tests performed on the same sets of specimens: of the 56 samples, the test and re-test results agreed for all but 2 individuals (κ = 0.94). Discordance was noted in subjects who had IFN-γ values around the cut-off point, with both increases and decreases noted. With continuous IFN-γ results, re-test results tended to produce higher estimates of IFN-γ than the original test. Within-person reproducibility: when continuous IFN-γ data were analyzed, the within-person reproducibility was moderate to high. While persons with negative QFT results generally stayed negative, positive results tended to vary over time. Our data showed that increases of more than 16% in the IFN-γ levels are statistically improbable in the short-term.ConclusionsConservatively assuming that long-term variability might be at least twice higher than short-term, we hypothesize that a QFT conversion requires two conditions to be met: 1) change from negative to positive result, and 2) at least 30% increase in the baseline IFN-γ response. Larger studies are needed to confirm our preliminary findings, and determine the conversion thresholds for IGRAs.
Highlights
In many high-income countries with low rates of tuberculosis (TB), serial testing for latent TB infection (LTBI) is recommended for persons at increased risk of TB exposure, such as healthcare workers.[1]
interferon-gamma release assays (IGRA) have characteristics that are ideal for serial testing[5]: they are more specific than TST, can be repeated without concerns about sensitization and boosting, and testing protocol requires fewer visits
Because health care workers (HCWs) in India have a high risk of TB exposure,[10] and because our prior work has demonstrated a high rate of conversions among HCWs in India,[9] long-term reproducibility was not considered feasible, given the high likelihood of new infections, and the inability to distinguish between real conversions and non-specific variations over time
Summary
In many high-income countries with low rates of tuberculosis (TB), serial testing for latent TB infection (LTBI) is recommended for persons at increased risk of TB exposure, such as healthcare workers.[1] the conventional tuberculin skin test (TST) has known limitations in accuracy and reliability,[2] and the interpretation of repeated TST results is complicated because of non-specific variations in test results (due to test related error and biological variations over time), boosting, conversions, and reversions.[3]. IGRAs are highly specific, especially in BCG vaccinated populations.[4] IGRAs have characteristics that are ideal for serial testing[5]: they are more specific than TST, can be repeated without concerns about sensitization and boosting, and testing protocol requires fewer visits. Interferon-gamma release assays (IGRA) are promising alternatives to the tuberculin skin test, interpretation of repeated testing results is hampered by lack of evidence on optimal cut-offs for conversions and reversions. A logical start is to determine the within-person variability of T-cell responses during serial testing
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