Fast track — ArticlesComparison of T-cell-based assay with tuberculin skin test for diagnosis of Mycobacterium tuberculosis infection in a school tuberculosis outbreak
Introduction
Identification and treatment of people who have latent tuberculosis infection by targeted tuberculin skin testing and preventive therapy is a cornerstone of tuberculosis control in developed countries.1 The main drawback of the tuberculin skin test (TST) is poor specificity, since previous Mycobacterium bovis BCG vaccination and environmental mycobacterial exposure can lead to false-positive results.2, 3, 4 More than half the burden of tuberculosis in developed countries is carried by foreign-born immigrants from high-prevalence countries, among whom BCG vaccination and environmental mycobacterial exposure are common.5, 6 The TST also has several operational drawbacks, including the need for a return visit and operator-dependent variability in placement and reading of the test. A more accurate rapid test for latent infection is a major priority for improved tuberculosis control.7
The identification of genes in the M tuberculosis genome that are absent from M bovis BCG8 and most environmental mycobacteria9 offers an opportunity to develop more specific tests for M tuberculosis infection.10 Early secretory antigen target-6 (ESAT-6) and culture filtrate protein 10 (CFP10) are two such gene products that are strong targets of the cellular immune response in tuberculosis patients and contacts.11, 12 The presence of ESAT-6-specific T cells, detected by the rapid ex-vivo enzyme-linked immunospot (ELISPOT) assay for interferon-gamma,13 is a highly sensitive and specific marker of M tuberculosis infection in patients who have culture-confirmed tuberculosis; its sensitivity is substantially higher than that for the TST.14, 15 In a UK pilot study of 50 contacts at risk of latent tuberculosis infection, we noted a correlation between ESAT-6 ELISPOT results and the extent of exposure to tuberculosis cases,16 whereas unexposed people were uniformly ELISPOT-negative.17, 18
In February, 2001, a secondary school student who had had a chronic cough for 9 months was diagnosed with sputum-smear-positive cavitatory pulmonary tuberculosis. The health authority screened 1128 of 1208 students at the school with TST and diagnosed 69 secondary cases of active tuberculosis and 254 cases of latent infection. This outbreak presented a unique opportunity to compare the effectiveness of the ELISPOT assay with the TST.
In the absence of a gold standard reference test, direct assessment of the sensitivity and specificity of a new test for latent tuberculosis infection is impossible.4 However, since airborne transmission of M tuberculosis is promoted by increasing duration and proximity of contact with an infectious case,19, 20, 21 a key determinant of infection is the amount of time spent sharing room air with the source 22, 23 We formed the hypothesis that if the ELISPOT assay is a more sensitive and specific test than the TST, it should correlate more closely than the TST with degree of exposure to M tuberculosis and should be independent of BCG vaccination status. Two measures of exposure were prespecified at the time of study design: proximity to the index case, based on school class and year, and hours of direct classroom contact. Three features of this outbreak made it particularly suitable for this investigation: there was one infectious index case with several hundred contacts; the outbreak occurred in an enclosed environment; and school timetables permitted precise quantification of the amount of time each child spent sharing room air with the source case.
Section snippets
Participants
The study was approved by the Leicestershire research ethics committee. We invited 963 students, aged 11–15 years, from the same school as the index case to participate. We obtained written informed consent from 594 (62%) children and their parents. In May and June, 2001, the school nurses interviewed 550 (57% of the total invited) of these children about place of birth and history of tuberculosis exposure outside school. At the same time they drew 10 mL blood samples that were stored in
Results
ELISPOT and TST results were available for 535 students—44·3% of the school. Our sample was representative in terms of the proportion of non-white children (97% in our sample vs 93% in the whole school); UK-born children (86 vs 86%); children diagnosed with active tuberculosis (5 vs 6%); and participants deemed to have latent tuberculosis infection on the basis of TST result (24 vs 23%, table 1).
The odds of a test result being positive for each increase across the four stratified exposure
Discussion
In the absence of a gold standard test for latent tuberculosis infection, the sensitivity and specificity of the ELISPOT assay or the TST cannot be directly quantified.4 However, given that the likelihood of latent tuberculosis infection is determined by exposure to M tuberculosis,19, 20, 21, 22, 23 we were able to rank the tests according to their diagnostic accuracy. Agreement between TST and ELISPOT results was high, but discordance in 11% of students shows that the tests are not equivalent.
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