Abstract
BackgroundA more stringent QuantiFERON-TB Gold In-Tube (QFT) conversion (from negative to positive) definition has been proposed to allow more definite detection of recent tuberculosis (TB) infection. We explored alternative conversion definitions to assist the interpretation of serial QFT results and estimate incidence of TB infection in a large cohort study.MethodsWe used QFT serial results from TB household contacts aged ≥15 years, collected at baseline and during two follow-up visits (2006–2011) as part of a cohort study in 24 communities in Zambia and South Africa (SA). Conversion rates using the manufacturers’ definition (interferon-gamma (IFN-g) < 0.35 to ≥0.35, ‘def1’) were compared with stricter definitions (IFN-g < 0.2 to ≥0.7 IU/ml, ‘def2’; IFN-g < 0.2 to ≥1.05 IU/ml, ‘def3’; IFN-g < 0.2 to ≥1.4 IU/ml, ‘def4’). Poisson regression was used for analysis.ResultsOne thousand three hundred sixty-five individuals in Zambia and 822 in SA had QFT results available. Among HIV-negative individuals, the QFT conversion rate was 27.4 per 100 person-years (CI:22.9–32.6) using def1, 19.0 using def2 (CI:15.2–23.7), 14.7 using def3 (CI:11.5–18.8), and 12.0 using def4 (CI:9.2–15.7). Relative differences across def1-def4 were similar in Zambia and SA. Using def1, conversion was less likely if HIV positive not on antiretroviral treatment compared to HIV negative (aRR = 0.7, 95%CI = 0.4–0.9), in analysis including both countries. The same direction of associations were found using def 2–4.ConclusionHigh conversion rates were found even with the strictest definition, indicating high incidence of TB infection among household contacts of TB patients in these communities. The trade-off between sensitivity and specificity using different thresholds of QFT conversion remains unknown due to the absence of a reference standard. However, we identified boundaries within which an appropriate definition might fall, and our strictest definition plausibly has high specificity.
Highlights
A more stringent QuantiFERON-TB Gold In-Tube (QFT) conversion definition has been proposed to allow more definite detection of recent tuberculosis (TB) infection
In this study we explored the use of the proposed zone of uncertainty and several alternatives, to provide “boundaries” to assist in the interpretation of serial QFT results and estimate incidence of TB infection in a large cohort study
Among household contacts eligible for analysis, 1365 (62%) contacts were recruited from 805 households in Zambia, and 822 (38%) contacts were recruited from 474 households in South Africa
Summary
A more stringent QuantiFERON-TB Gold In-Tube (QFT) conversion (from negative to positive) definition has been proposed to allow more definite detection of recent tuberculosis (TB) infection. Since the Centers for Disease Control and Prevention (CDC) has recommended QuantiFERON-TB Gold (QFT) for baseline and serial testing [4], there is growing evidence that IFN-g levels bordering the manufacturer’s recommended assay cutoff of 0.35 IU/ml are more likely to show discordant results upon serial testing [7,8,9,10,11,12] These patterns are seen in settings with varying TB burden, suggesting that at least some of the sources of IGRA variability are immunological (i.e., boosting and modulation) or due to assay reproducibility issues, independent of the risk of exposure [11, 12]. More evidence is needed from larger cohort studies and in other settings to inform guidelines on serial QFT testing
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