Research Article: Longitudinal Assessment of an ELISPOT Test for Mycobacterium tuberculosis Infection

Date Published: June 12, 2007

Publisher: Public Library of Science

Author(s): Philip C Hill, Roger H Brookes, Annette Fox, Dolly Jackson-Sillah, David J Jeffries, Moses D Lugos, Simon A Donkor, Ifedayo M Adetifa, Bouke C de Jong, Alex M Aiken, Richard A Adegbola, Keith P McAdam, Philip Hopewell

Abstract: BackgroundVery little longitudinal information is available regarding the performance of T cell-based tests for Mycobacterium tuberculosis infection. To address this deficiency, we conducted a longitudinal assessment of the enzyme-linked immunosorbent spot test (ELISPOT) test in comparison to the standard tuberculin skin test (TST).Methods and FindingsIn tuberculosis (TB) contacts we repeated ELISPOT tests 3 mo (n = 341) and 18 mo (n = 210) after recruitment and TSTs at 18 mo (n = 130). We evaluated factors for association with conversion and reversion and investigated suspected cases of TB. Of 207 ELISPOT-negative contacts, 51 (24.6%) had 3-mo ELISPOT conversion, which was associated with a positive recruitment TST (odds ratio [OR] 2.2, 95% confidence interval [CI] 1.0–5.0, p = 0.048) and negatively associated with bacillus Calmette-Guérin (BCG) vaccination (OR 0.5, 95% CI 0.2–1.0, p = 0.06). Of 134 contacts, 54 (40.2%) underwent 3-mo ELISPOT reversion, which was less likely in those with a positive recruitment TST (OR 0.3, 95% CI 0.1–0.8, p = 0.014). Between 3 and 18 mo, 35/132 (26.5%) contacts underwent ELISPOT conversion and 28/78 (35.9%) underwent ELISPOT reversion. Of the 210 contacts with complete results, 73 (34.8%) were ELISPOT negative at all three time points; 36 (17.1%) were positive at all three time points. Between recruitment and 18 mo, 20 (27%) contacts had ELISPOT conversion; 37 (50%) had TST conversion, which was associated with a positive recruitment ELISPOT (OR 7.2, 95% CI 1.4–37.1, p = 0.019); 18 (32.7%) underwent ELISPOT reversion; and five (8.9%) underwent TST reversion. Results in 13 contacts diagnosed as having TB were mixed, but suggested higher TST sensitivity.ConclusionsBoth ELISPOT conversion and reversion occur after M. tuberculosis exposure. Rapid ELISPOT reversion may reflect M. tuberculosis clearance or transition into dormancy and may contribute to the relatively low reported ELISPOT conversion rate. Therefore, a negative ELISPOT test for M. tuberculosis infection should be interpreted with caution.

Partial Text: Recent work suggests that a T cell-based assay for interferon gamma, the enzyme-linked immunosorbent spot test (ELISPOT), has promise in the diagnosis of Mycobacterium tuberculosis infection after exposure to a known tuberculosis (TB) patient [1–3]. However, commercialisation of two T cell-based tests for the diagnosis of M. tuberculosis infection (T-Spot.TB by Oxford Immunotec and Quantiferon-TB Gold by Cellestis) preceded substantial longitudinal assessment of either test. Apart from two small studies [4,5], longitudinal assessment of an ELISPOT assay for M. tuberculosis infection has been confined to studies of TB patients undergoing treatment. These studies have consistently shown that significant ELISPOT reversion occurs over a treatment course [6–9]. One longitudinal assessment of the Quantiferon test with respect to M. tuberculosis infection has been performed, in India [10].

In this study of over 1,100 individual ELISPOT test results and nearly 800 TST results, we have shown that ELISPOT conversion and reversion occur after an initial post-M. tuberculosis exposure screening process. In contrast to the low rate of TST reversion over time, ELISPOT reversion occurred in 40% of ELISPOT-positive individuals at 3 mo, and in 36% of individuals between 3 and 18 mo. Conversely, the ELISPOT conversion rate was 27% at 18 mo compared to a TST conversion rate of 50% over the same time period. Conversion and reversion of the ELISPOT test are associated with identifiable risk factors that differ from those associated with TST conversion and reversion. These results provide new insights into the possible niche for ELISPOT in the diagnosis of latent M. tuberculosis infection and TB disease.



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