Background: 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. Methods: 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. Findings: Although agreement between the tests was high (89% concordance, κ=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). Interpretation: 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.
Bibliographical noteFunding Information:
We thank the students for their participation; Gary Coleby, Alan Anderson, Isobel Pearce, Dean Barnett and the staff of Crown Hills Community College for their generous cooperation; Lorna Briars, Elaine Weare, Alison Woodbridge, and Fiona Booth for interviewing and drawing blood samples from the students; Debbie Modha, Judith West, Wren Hoskyns, Louise Coole, Helen Thuraisingham, Ginder Narle, Niru Rana, Lindsey Abbott, Vicki Lowe, and Barbara Smithson for epidemiological information from the outbreak investigation; Francis Drobniewski and Malcolm Yates of the Mycobacterial Reference Library, London, for RFLP typing; John Watson of the Communicable Disease Surveillance Centre for facilitating the project and valuable advice; Doug Altman, Constantine Gatsonis, Patrick Bossuyt, and Les Irwig for guidance in planning the statistical analysis; Peter Barnes, Luca Richeldi, Peter Wrighton-Smith, Shabbar Jaffar, Paul Newton, Liz Corbett, and Anthony Butterworth for helpful discussions; Ramilla Mistry and Dina Shah for translations; and Ansar Pathan, Katalin Wilkinson and Tilly Pillay for laboratory assistance. This study was funded by the Wellcome Trust. AL is a Wellcome senior research fellow in clinical science.