Quantitative IFN-γ Release Assay and Tuberculin Skin Test Results to Predict Incident Tuberculosis. A Prospective Cohort Study

Abstract

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 relinkage to national TB surveillance records (median follow-up 4.7 yr). 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 bacillus Calmette-Guérin [BCG] vaccination). Measurements and Main Results: For all tests, incidence rates and rate ratios increased with the magnitude of the test result (P , 0.0001). Over 3 years' follow-up, there was a modest increase in positive predictive value 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 >5 mm vs. 4.3% for >15 mm). 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 >5 mm vs. 28.1% for >15 mm). Conclusions: Implementation of higher thresholds for QFT-GIT, T-SPOT.TB, and TST modestly increases positive predictive value for incident TB, but markedly reduces sensitivity. Novel biomarkers or validated multivariable risk algorithms are required to improve prediction of incident TB.

Soluble CD14 and Th 17-Related Interleukins in Bronchoalveolar Lavage Fluid are Potential Triage Biomarkers for Pulmonary Tuberculosis

“…Indeed, BALF levels of sCD14, IL-17 and IL-22 all rise in other lung infectious diseases [25,27,28], concordant to sCD14 as a general receptor of LPS and IL-17 and IL-22 as general mediators of T helper 17 cells. Though IGRA can help us to differentiate PTB from non-PTB, it still a pity for these biomarkers could not be diagnostic markers of TB since there were a few IGRA-negative patients with positive results of Xpert test or Mtb culture as reported [29,30]. However, the levels of sCD14, IL-17 and IL-22 re ect the activity of in ammation.…”

Discovery and validation of a personalized risk predictor for incident tuberculosis in low transmission settings

“…By incorporating a quantitative measure of immunosensitization to M.tuberculosis, we facilitate a shift from the conventional paradigm of LTBI as a binary diagnosis, towards personalized risk stratification for progressive TB. This approach takes advantage of stronger T cell responses being a correlate of risk, while guarding against a loss of sensitivity by arbitrarily introducing higher test thresholds programmatically 16 .…”

“…Multiple studies have shown that the magnitude of the T cell response to M.tuberculosis is associated with incident TB risk, raising hope that quantitative tuberculin skin test (TST) or interferon gamma release assay (IGRA) results may improve predictive ability 14,15 . However, implementing higher diagnostic thresholds alone does not improve prediction on a population level due to a marked loss of sensitivity with this approach 16 .…”

Cost-effectiveness of IGRA/QFT-Plus for TB screening of migrants in Oman

“…Oman is considering introducing screening of the migrant population from high TB endemic countries for LTBI. The tools available for this screening are the interferon-gamma release assay (IGRA) and tuberculin skin test (TST), both of which detect immunological memory from previous exposure to TB (Goletti et al, 2018;Gupta et al, 2019).…”