Longitudinal Assessment of an ELISPOT Test for Mycobacterium tuberculosis Infection

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.

LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement

“…Others recommend that IGRAs completely replace the tuberculin skin test for identifying latent infection [85]. Today, some data from prospective studies are now emerging that look at the risk of tuberculosis in those with a positive IGRA [86,88,121,122].…”

Spectrum of latent tuberculosis — existing tests cannot resolve the underlying phenotypes

“…Repeated tuberculin tests are rarely carried out because of the belief that, once positive, a TST is likely to remain positive and, therefore, not clinically useful; even when tests are repeated, the results are hard to interpret. Serial IGRA testing shows that IGRAs are highly dynamic, with high rates of conversions and reversions [8][9][10][11][12][13][14] . Although some of the dynamic changes may be due to test reproducibility 13,15 , some of the kinetics might signal the underlying transitions that occur in the TB spectrum.…”

“…Although some of the dynamic changes may be due to test reproducibility 13,15 , some of the kinetics might signal the underlying transitions that occur in the TB spectrum. For example, rapid reversion of a positive IGRA after exposure is well documented 10 and could imply that infection was eliminated in association with transient T cell priming.…”

“…On the basis of the research that I and others have carried out [8][9][10][11][12][13][14] , I believe that serial IGRA testing can reveal interesting underlying phenotypes that have different histories and trajectories (FIG. 1).…”

New Advances in Diagnosis of Latent Tuberculosis Infection: A Review Article

“…Although there is some evidence that QFT-GIT conversion is related to a greater risk of progression to TB (60), spontaneous reversions are more likely to occur in subjects with borderline results, (56,61). Such cases are interpreted as self-clearance of infection, yet there is not enough evidence for this conclusion (52,62). Serial testing with QFT-GIT and T.SPOT-TB should be considered unreliable and is not recommended at least until the conversion and reversion phenomena are better understood.…”