The Dynamics of QuantiFERON-TB Gold In-Tube Conversion and Reversion in a Cohort of South African Adolescents

Abstract

Rationale: Interferon-g release assays are used to diagnose tuberculosis infection. In developed countries, high rates of reversion following conversion have been described.Objectives: To assess QuantiFERON TB Gold In-Tube test (QFT) conversion and reversion dynamics in a tuberculosisendemic setting.Methods: Adolescents aged 12-18 years residing near Cape Town were recruited. Tuberculin skin tests (TSTs) and QFTs were performed at baseline and after 2 years of follow up. Half of the participants had TST and QFT performed at additional time points. Participants were observed for incident tuberculosis disease for up to 5 years.Measurements and Main Results: Among 5,357 participants, 2,751 (51.4%) and 2,987 (55.8%) had positive QFT and TST results, respectively, at baseline. Annualized QFT and TST conversion risks were 14.0 and 13.0%, respectively, and reversion risks were 5.1 and 4.1%, respectively. Concordance was excellent for conversions (k = 0.74), but poor for reversions (k = 0.12). Among recent QFT converters, the magnitude of the QFT value was strongly inversely associated with risk of reversion (P , 0.0001). When longitudinal QFT data were analyzed in a cross-sectional manner, the annual risk of infection was 7.3%, whereas inclusion of reversions in the analysis showed that the actual risk of infection was 14.0%. Incident tuberculosis was 8-fold higher among QFT reverters than in participants with all negative QFT results (1.47 vs. 0.18 cases/100 person-years, P = 0.011).Conclusions: In this tuberculosis-endemic setting, annual risk of infection was extremely high, whereas QFT and TST conversion concordance was higher and QFT reversion rates were lower than reported in low-burden settings.

Serial QuantiFERON testing and tuberculosis disease risk among young children: an observational cohort study

“…Shah and colleagues 42 found low rates of reversion (15%) among QFT-positive household contacts of tuberculosis cases. In this study, we found high overall rates of QFT reversion among young children (58%) and, as seen in our adolescent study, 20 we found an inverse relation between QFT conversion interferon-γ value and reversion risk; however, reversion rates remained fairly high (20%) even at very high interferon-γ values (>4·00 IU/mL).…”

“…We note that this bimodal distribution differs from the unimodal distribution of QFT values reported in adolescent and adult studies, including one from the same laboratory and community, suggesting that the naive infant immune response to M tuberculosis might differ from that of adults. 20 For our main analyses, we selected a threshold of 4·00 IU/mL based on disease and reversion risks above this inflection point ( figure 3) and availability of interferon-γ standards up to 4·00 IU/mL in the international kits. We note that high rates of disease (2·5 per 100 person-years) were found even among those with QFT values 0·35-4·00 IU/mL, and the optimal threshold from a perspective of targeting interventions might be lower.…”

“…[38][39][40][41] In a study of adolescents in the same high-burden community, we previously reported a reversion rate of 23·7% following QFT conversion. 20 Very few studies of QFT reversion risk among young children have been published. Shah and colleagues 42 found low rates of reversion (15%) among QFT-positive household contacts of tuberculosis cases.…”

“…19,20 Further, because of the absence of natural quanti tative breakpoints in the distribution of interferon-γ concentrations, the conversion threshold value of the QuantiFERON-TB Gold In-Tube test (QFT; interferon-γ ≥0·35 IU/mL), one of the most widely used IGRAs, is subject to debate. 16 Whether higher interferon-γ values represent more recent M tuberculosis exposure, greater aerosolised inoculum, or sustained infection-or simply reflect heterogeneity in human immune responses to M tuberculosis-is unclear.…”

Innovative clinical trial designs to rationalize TB vaccine development

“…A cohort study conducted in adolescents in the Western Cape region of South Africa with high rates of TB showed approximately 50% of high school students were IGRA positive [12,13]. Annual IGRA conversion rates (from negative to positive) in the same population were 14% [14]. Using a conservative estimate in this population of 10% annual IGRA conversion and a 0.05% statistical error, a trial of a vaccine that was 60% effective would require on the order of 1000 participants (500 in each study arm) to be followed for one year after vaccination to detect an impact on infection as determined by IGRA conversion.…”