Critical Evaluation of Tuberculosis Diagnostic Tests in Low- and High-Burden Settings

Author(s): Metcalfe, John | Advisor(s): Reingold, Arthur | Abstract: Tuberculosis (TB) is the second leading cause of death from an infectious disease worldwide and remains a major public health challenge, particularly in resource limited settings. Given the effectiveness of current treatment regimens, enhanced detection of disease in both low- and high-burden settings will be critical in making progress towards TB elimination.As TB case rates have declined in high-income settings, TB control has centered on finding and treating individuals with non-infectious latent TB infection (LTBI) in order to prevent reactivation infectious TB disease. Since 2005, the Centers for Disease Control and Prevention has recommended use of interferon-gamma release assays (IGRAs), in vitro immuno-diagnostic tests that measure effector T-cell mediated interferon-gamma (IFN-gamma) response to M. tuberculosis specific antigens, could be used for targeted screening of LTBI in all circumstances in which the tuberculin skin test (TST) is used. We found that higher quantitative IFN-gamma results were associated with active tuberculosis and added clinical value to a prediction model incorporating conventional risk factors; however, in all settings and especially within low- and middle-income countries, IGRAs are inadequate rule-out or rule-in tests for active TB. Although IGRAs are widely used in high-income countries and numerous studies have evaluated their diagnostic performance for detection of LTBI, there is limited data on the precision of IGRA results. In the largest precision study of an IGRA to date, we found considerable variability in TB response measured by QuantiFERON-TB Gold In-Tube (QFT-GIT, Cellestis, Australia); test results should be interpreted cautiously among low-risk individuals with positive TB response less than 0.59 IU/ml.In contrast to low TB burden, high income settings, TB control in low income settings focuses on early detection and treatment of individuals with active, infectious TB. In the WHO African Region, the incidence of multidrug resistant TB (MDR-TB) has tripled in the past 20 years and poses a major risk to regional TB control programs. Accurate, timely, and affordable drug susceptibility testing for patient management and in support of surveillance programs is urgently needed. In a politically unstable, high HIV prevalence region of southern Africa, we validated use of a low-cost, accelerated phenotypic method for MDR-TB detection, and provide the first report of the prevalence of MDR-TB from this country in 17 years.