Reversion and conversion of Mycobacterium tuberculosis IFN-γ ELISpot results during anti-tuberculous treatment in HIV-infected children

Abstract

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.

Bifunctional T-Cell-Derived Cytokines for the Diagnosis of Tuberculosis and Treatment Monitoring

“…These results are in line with another report [11] describing that neither ESAT6 nor CFP10 could separate untreated tuberculosis patients from another cohort of successfully treated tuberculosis patients. However, the results are in contrast with other studies on serial IGRAs where a decline in IFN-γ production during tuberculosis treatment was observed [17,18,19]. We presume that the kinetics of the immunological recall during tuberculosis treatment may take longer than observed in this study.…”

Serial interferon‐γ release assay in children with latent tuberculosis infection and children with tuberculosis

“…However, there is lack of data on the kinetics of IFN‐γ concentration during LTBI or active TB, especially in children. Three studies have investigated the kinetics of IFN‐γ with Quantiferon15, 26 and two with Elispot 27–29. Our results show that most patients with LTBI and TB remained IFN‐γ positive after treatment, and that IGRA should not be used to monitor the effect of treatment or to discriminate between various stages of TB infection or response to therapy, which is consistent with the findings of a Norwegian study by Dyrhol‐Riise et al15 In a French study, IGRA was performed at baseline, and on days 10, 30, 60, and 90 in children with LTBI, and on additional days 120 and 180 in children with TB.…”

Interferon gamma release assays for monitoring the response to treatment for tuberculosis: A systematic review

“…Forty-five articles were excluded after review of the full texts. Of these 45 articles, 14 used an in-house ELISPOT [1,2,[4][5][6][7][8][9][10][11][12][13][14][15], five were excluded because they did not use ESAT-6/CFP-10-specific stimulation [16][17][18][19][20] , 4 were cross-sectional [21][22][23][24], two did not include original data [25,26], 15 did not provide longitudinal follow-up treatment-specific data [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41], two were published in a language other than English [42, 43] and three were conference abstracts [44][45][46]. A total of 30 articles were eligible for inclusion in the review (figure 1, tables 1 and 2).…”