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      Using ELISPOT to Expose False Positive Skin Test Conversion in Tuberculosis Contacts

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          Abstract

          Background

          Repeat tuberculin skin tests may be false positive due to boosting of waned immunity to past mycobacterial exposure. We evaluated whether an ELISPOT test could identify tuberculosis (TB) contacts with boosting of immunity to non-tuberculous mycobacterial exposure.

          Methodology/Principal Findings

          We conducted tuberculin and ELISPOT tests in 1665 TB contacts: 799 were tuberculin test negative and were offered a repeat test after three months. Those with tuberculin test conversion had an ELISPOT, chest X-ray and sputum analysis if appropriate. We compared converters with non-converters, assessed the probability of each of four combinations of ELISPOT results over the two time points and estimated boosting with adjustment for ELISPOT sensitivity and specificity. 704 (72%) contacts had a repeat tuberculin test; 176 (25%) had test conversion, which increased with exposure to a case (p = 0.002), increasing age (p = 0.0006) and BCG scar (p = 0.06). 114 tuberculin test converters had ELISPOT results: 16(14%) were recruitment positive/follow-up positive, 9 (8%) positive/negative, 34 (30%) negative/positive, and 55 (48%) were negative/negative. There was a significant non-linear effect of age for ELISPOT results in skin test converters (p = 0.038). Estimates of boosting ranged from 32%–41% of skin test converters with increasing age. Three converters were diagnosed with TB, two had ELISPOT results: both were positive, including one at recruitment.

          Conclusions/Significance

          We estimate that approximately one third of tuberculin skin test conversion in Gambian TB case contacts is due to boosting of immunity to non-tuberculous mycobacterial exposure. Further longitudinal studies are required to confirm whether ELISPOT can reliably identify case contacts with tuberculin test conversion that would benefit most from prophylactic treatment.

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          Most cited references26

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          Interpretation of repeated tuberculin tests. Boosting, conversion, and reversion.

          D. Menzies (1998)
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            Comparison of T-cell-based assay with tuberculin skin test for diagnosis of Mycobacterium tuberculosis infection in a school tuberculosis outbreak.

            The diagnosis of latent tuberculosis infection relies on the tuberculin skin test (TST), which has many drawbacks. However, to find out whether new tests are better than TST is difficult because of the lack of a gold standard test for latent infection. We developed and assessed a sensitive enzyme-linked immunospot (ELISPOT) assay to detect T cells specific for Mycobacterium tuberculosis antigens that are absent from Mycobacterium bovis BCG and most environmental mycobacteria. We postulated that if the ELISPOT is a more accurate test of latent infection than TST, it should correlate better with degree of exposure to M tuberculosis. A large tuberculosis outbreak in a UK school resulted from one infectious index case. We tested 535 students for M tuberculosis infection with TST and ELISPOT. We compared the correlation of these tests with degree of exposure to the index case and BCG vaccination. Although agreement between the tests was high (89% concordance, kappa=0.72, p<0.0001), ELISPOT correlated significantly more closely with M tuberculosis exposure than did TST on the basis of measures of proximity (p=0.03) and duration of exposure (p=0.007) to the index case. TST was significantly more likely to be positive in BCG-vaccinated than in non-vaccinated students (p=0.002), whereas ELISPOT results were not associated with BCG vaccination (p=0.44). ELISPOT offers a more accurate approach than TST for identification of individuals who have latent tuberculosis infection and could improve tuberculosis control by more precise targeting of preventive treatment.
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              Use in routine clinical practice of two commercial blood tests for diagnosis of infection with Mycobacterium tuberculosis: a prospective study.

              Two commercial blood assays for the diagnosis of latent tuberculosis infection--T-SPOT.TB and QuantiFERON-TB Gold--have been separately compared with the tuberculin skin test. Our aim was to compare the efficacy of all three tests in the same population sample. We did a prospective study in 393 consecutively enrolled patients who were tested simultaneously with T-SPOT.TB and QuantiFERON-TB Gold because of suspected latent or active tuberculosis. 318 patients also had results available for a tuberculin skin test. Overall agreement with the skin test was similar (T-SPOT.TB kappa=0.508, QuantiFERON-TB Gold kappa=0.460), but fewer BCG-vaccinated individuals were identified as positive by the two blood assays than by the tuberculin skin test (p=0.003 for T-SPOT.TB and p<0.0001 for QuantiFERON-TB Gold). Indeterminate results were significantly more frequent with QuantiFERON-TB Gold (11%, 43 of 383) than with T-SPOT.TB (3%, 12 of 383; p<0.0001) and were associated with immunosuppressive treatments for both tests. Age younger than 5 years was significantly associated with indeterminate results with QuantiFERON-TB Gold (p=0.003), but not with T-SPOT.TB. Overall, T-SPOT.TB produced significantly more positive results (38%, n=144, vs 26%, n=100, with QuantiFERON-TB Gold; p<0.0001), and close contacts of patients with active tuberculosis were more likely to be positive with T-SPOT.TB than with QuantiFERON-TB Gold (p=0.0010). T-SPOT.TB and QuantiFERON-TB Gold have higher specificity than the tuberculin skin test. Rates of indeterminate and positive results, however, differ between the blood tests, suggesting that they might provide different results in routine clinical practice.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS ONE
                plos
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2007
                31 January 2007
                : 2
                : 1
                : e183
                Affiliations
                [1]Bacterial Diseases Programme, Medical Research Council Unit, Banjul, The Gambia
                Columbia University, United States of America
                Author notes
                * To whom correspondence should be addressed. E-mail: phill@ 123456mrc.gm

                Conceived and designed the experiments: RB DJ PH AF RA KM TC DJ. Performed the experiments: RB AF ML RA DJ Bd. Analyzed the data: DJ PH AF ML SD. Wrote the paper: DJ PH.

                Article
                06-PONE-RA-00356R1
                10.1371/journal.pone.0000183
                1779806
                17264885
                f971d653-a7fd-45d1-a41b-429449488caa
                Hill et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 16 November 2006
                : 9 January 2007
                Page count
                Pages: 6
                Categories
                Research Article
                Infectious Diseases

                Uncategorized
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