Interferon-gamma release assay levels and risk of progression to active tuberculosis: a systematic review and dose-response meta-regression analysis

Abstract

Objective: To summarize and quantify the dose-response relationship between interferon-gamma release assay (IGRA) levels and the risk of progression to active tuberculosis (TB) Design: Systematic review and Bayesian dose-response meta-regression Data sources: PubMed and Embase from 2001 to 10 May 2020, and references from relevant systematic reviews. Eligibility criteria and data analysis: Retrospective or prospective cohort studies and clinical trials that followed individuals over time to assess the relationship between IGRA levels and risk of developing TB were included. Study results related to incident TB were extracted and two authors independently assessed the quality of included studies using the Newcastle-Ottawa scale (NOS). Data were pooled using a novel Bayesian meta-regression method to generate a dose-response risk curve. Results: 34 of 1,074 identified studies met the criteria for inclusion in the analysis. Higher levels of interferon-gamma were associated with increased risk of progression to active tuberculosis. In the dose-response curve, the risk increased sharply between interferon-gamma levels 0 and 5 IU/ml, after which the risk continued to increase moderately but at a slower pace until reaching about 15 IU/ml where the risk levels off. Compared to 0 IU/ml, the relative risk of progression to active TB among those with interferon-gamma levels of 0.35, 1, 5, 10, 15, and 20 IU/ml were: 1.67 (1.30 – 2.13), 2.91 (2.12 – 3.96), 10.13 (5.57 – 14.57), 16.42 (11.07 – 23.44), 19.11 (13.01 – 27.82), and 19.65 (13.52 – 28.82), respectively. The dose-response relationship remains consistent when limiting the analysis to studies that scored high in the NOS. Conclusions: The current practice of dichotomizing IGRA test results simplifies the TB infection disease continuum. Evaluating the IGRA test results over a continuous scale could enable the identification of individuals at greatest risk of progression to active TB.