Abstract
BackgroundChemoprophylaxis of contacts of infectious tuberculosis (TB) cases is recommended for TB control, particularly in endemic countries, but is hampered by the difficulty to diagnose latent TB infection (LTBI), classically assessed through response to the Tuberculin Skin Test (TST). Interferon-gamma release assays (IGRA) are proposed new tools to diagnose LTBI, but there are limited data on their ability to predict the development of active TB disease. To address this, we investigated the response to TST and IGRA in household contacts of infectious TB cases in a TB high-burden country and the potential correlation with development of TB.Methodology/Principal FindingsProspective household contacts study conducted in two health centres in Dakar, Senegal. A total of 2679 household contacts of 206 newly detected smear and/or culture positive index TB cases aged 18 years or greater were identified A TST was performed in each contact and an ESAT6/CFP10 ELISPOT assay performed in a random sample of those. Contacts were followed-up for 24 months. TB was diagnosed in 52 contacts, an incidence rate of 9.27/1000 person-years. In univariable analysis, the presence of positive TST (≥10 mm) and ELISPOT (>32 SFC/million PBMC) responses at baseline were associated with active TB during follow-up: Rate Ratio [RR] = 2.32 (95%CI:1.12–4.84) and RR = 2.09 (95%CI:0.83–5.31), respectively. After adjustment for age, sex and proximity to index case, adjusted RRs were 1.51 (95%CI:0.71–3.19) and 1.98 (95%CI:0.77–5.09), respectively. Restricting analysis to the 40 microbiologically confirmed cases, the adjusted RR for positive ELISPOT was 3.61 (95%CI:1.03–12.65). The median ELISPOT response in contacts who developed TB was 5-fold greater than in those who did not develop TB (p = 0.02).Conclusions/SignificanceTST and IGRAs are markers of a contact of the immune system with tubercle bacilli. In a TB endemic area, a high ELISPOT response may reflect increased bacterial replication that may subsequently be associated with development of TB disease and may have a prognostic value. Further longitudinal data are needed to assess whether IGRAs are reliable markers to be used for targeting chemoprophylaxis.
Highlights
The diagnosis of Latent Tuberculosis Infection (LTBI) has relied on the Tuberculin Skin Test (TST), which measures a delayed-type hypersensitivity response to a purified protein derivative (PPD) of more than 200 M. tuberculosis antigens [1]
Based on the hypothesis that T cell response to TB specific antigens correlate with bacterial replication, it has been suggested that Interferon-gamma release assays (IGRA) may help to identify individuals at greatest risk for development of active TB disease who may benefit from preventive therapy [8,9]
We report here results of a prospective household contact study carried out in Senegal, in which contacts of active TB cases were tested at baseline with an in-house ESAT-6/CFP10 ELISPOT assay in the rest of the article and followed-up for two years to detect occurrence of tuberculosis
Summary
The diagnosis of Latent Tuberculosis Infection (LTBI) has relied on the Tuberculin Skin Test (TST), which measures a delayed-type hypersensitivity response to a purified protein derivative (PPD) of more than 200 M. tuberculosis antigens [1]. The characterisation of immunogenic antigens in the Region of Difference 1, a genomic region present in the M. tuberculosis complex but deleted from M. bovis BCG and most environmental mycobacteria, has allowed the development of highly-specific immuno-diagnostic tests for TB infection [3]. These tests measure the release of interferon-c by blood T cells that have been activated in-vitro by M. tuberculosis specific antigens, mainly ESAT6 and CFP10 [4]. Studies have suggested that Interferon-c Release Assays (IGRAs) using the ESAT-6/CFP-10 antigens were more specific than the TST for the diagnosis of latent TB infection [5] and at least as sensitive. We report here results of a prospective household contact study carried out in Senegal, in which contacts of active TB cases were tested at baseline with an in-house ESAT-6/CFP10 ELISPOT assay (referred to as ‘‘ELISPOT’’) in the rest of the article and followed-up for two years to detect occurrence of tuberculosis
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