Objective To evaluate an enzyme-linked immunospot assay (ELISpot) for the diagnosis of tuberculosis (TB) in HIV-infected children with suspected TB and to compare the performance of ELISpot with the tuberculin skin test (TST). Methods IFN-γ responses to Mycobacterium tuberculosis (MTB)-specific antigens were measured by ELISpot in HIV-infected children with suspected TB. HIV-infected and HIV-uninfected children without TB were used for comparison. Results Results were available for 188 children, of which, 139 (74%) were HIV-infected. Of these, 22 were classified as having definite TB, 24 probable TB, 14 possible TB and 128 not having TB. The median (range) age of patients was 20 (10 - 54.1) months. Ninety one percent of ELISpot tests yielded interpretable results. Median IFN-γ responses to early-secreted antigenic target-6 and culture filtrate protein-10 were higher in children with definite or probable TB compared to children without TB (p<0.002). In HIV-infected children with an interpretable result, the ELISpot was positive in 14/21 (66%) with definite TB. A significantly higher proportion of HIV-infected children with definite or probable TB had a positive ELISpot compared to a positive TST (25/39 (64%) vs. 10/34 (29%), p=0.005). In contrast to TST, results from ELISpot were not affected by young age or severe immunosuppression. In HIV-infected children without active TB disease, 27% had a positive ELISpot suggesting latent TB infection. Conclusions ELISpot is more sensitive than TST for the detection of active TB in HIV-infected children. However the sensitivity of current ELISpot assays is not sufficiently high to be used as rule out test for TB.
BackgroundRecent interest has focused on the potential use of serial interferon gamma (IFN-γ) release assay (IGRA) measurements to assess the response to anti-tuberculous (TB) treatment. The kinetics of IFN-γ responses to Mycobacterium tuberculosis (MTB) antigens in HIV-infected children during treatment have not however been previously investigated.MethodsIFN-γ responses to the MTB antigens, ESAT-6, CFP-10 and PPD were measured by an enzyme-linked immunospot assay (IFN-γ ELISpot) at presentation and at one, two and six months after starting anti-tuberculous treatment in HIV-infected children with definite or probable TB. Responses at different time points were compared using a Mann-Whitney U test with paired data analysed using the Wilcoxon signed rank test. A Fisher's exact or Chi-squared test was used to compare proportions when test results were analysed as dichotomous outcomes.ResultsOf 102 children with suspected TB, 22 (21%) had definite TB and 24 (23%) probable TB. At least one follow up IFN-γ ELISpot assay result was available for 31 (67%) of the 46 children. In children with definite or probable TB in whom the IFN-γ ELISpot assay result was positive at presentation, anti-tuberculous treatment was accompanied by a significant decrease in both the magnitude of the IFN-γ response to individual or combined MTB-specific antigens (ESAT-6 median 110 SFCs/106 PBMC (IQR 65-305) at presentation vs. 15 (10-115) at six months, p = 0.04; CFP-10 177 (48-508) vs. 20 (5-165), p = 0.004, ESAT-6 or CFP-10 median 250 SFCs/106 PBMC (IQR 94-508) vs. 25 (10-165), p = 0.004) and in the proportion of children with a positive IFN-γ ELISpot assay (Fisher's exact test: ESAT-6 15/0 vs 5/11, p = 0.0002, CFP-10 22/0 vs 8/17, p = 0.0001, ESAT-6 or CFP-10 22/0 vs. 9/17, p= 0.002). However almost half of the children had a positive IFN-γ ELISpot assay after six months of anti-tuberculous treatment. In addition, there was conversion of the IFN-γ ELISpot assay result during anti-tuberculous therapy in six of 12 children in whom the initial IFN-γ ELISpot assay was negative.ConclusionsIn HIV-infected children with definite or probable TB, anti-tuberculosis treatment is accompanied by a reduction in the magnitude of the IFN-γ ELISpot response to MTB-antigens. However, serial IFN-γ ELISpot measurements appear to have limited clinical utility in assessing a successful response to anti-tuberculous treatment in HIV infected children.
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