Quantitative interferon gamma release assay and tuberculin skin test results to predict incident tuberculosis: a prospective cohort study

Rationale: Development of diagnostic tools with improved predictive value for tuberculosis (TB) is a global research priority. Objectives: We evaluated whether implementing higher diagnostic thresholds than currently recommended for QuantiFERON Gold-in-Tube (QFT-GIT), T-SPOT.TB and the tuberculin skin test (TST) might improve prediction of incident TB. Methods: Follow-up of a UK cohort of 9,610 adult TB contacts and recent migrants was extended by re-linkage to national TB surveillance records (median follow-up 4.7 years). Incidence rates and rate ratios, sensitivities, specificities and predictive values for incident TB were calculated according to ordinal strata for quantitative results of QFT-GIT, T-SPOT.TB and TST (with adjustment for prior BCG). Measurements and Main Results: For all tests, incidence rates and rate ratios increased with the magnitude of the test result (p<0.0001). Over three years’ follow-up, there was a modest increase in positive predictive value (PPV) with the higher thresholds (3.0% for QFT-GIT ≥0.35 IU/mL vs. 3.6% for ≥4.00 IU/mL; 3.4% for T-SPOT.TB ≥5 spots vs. 5.0% for ≥50 spots; and 3.1% for BCG-adjusted TST ≥5mm vs. 4.3% for ≥15mm). As thresholds increased, sensitivity to detect incident TB waned for all tests (61.0% for QFT-GIT ≥0.35 IU/mL vs. 23.2% for ≥4.00 IU/mL; 65.4% for T-SPOT.TB ≥5 spots vs. 27.2% for ≥50 spots; 69.7% for BCG-adjusted TST ≥5mm vs. 28.1% for ≥15mm). Conclusions: Implementation of higher thresholds for QFT-GIT, T-SPOT.TB and TST modestly increases PPV for incident TB, but markedly reduces sensitivity. Novel biomarkers or validated multivariable risk algorithms are required to improve prediction of incident TB.