Diagnostic accuracy of plasma kynurenine/tryptophan ratio, measured by enzyme-linked immunosorbent assay, for pulmonary tuberculosis
Clement Gascua Adu-Gyamfi, Tracy Snyman, Lillian Makhathini, Kennedy Otwombe, Fatoumatta Darboe, Adam Penn‐Nicholson, Michelle Fisher, Dana Savulescu, Christopher J. Hoffmann, Richard E. Chaisson, Neil Martinson, Thomas J. Scriba, Jaya A. George, Melinda Suchard
Abstract
INTRODUCTION: The World Health Organization has identified the need for a non-sputum-based test capable of detecting active tuberculosis (TB) as a priority. The plasma kynurenine-to-tryptophan (K/T) ratio, largely mediated by activity of the enzyme indoleamine 2,3-dioxygenase, may have potential as a suitable biomarker for active TB. METHOD: We evaluated a commercial enzyme-linked immunosorbent assay (ELISA) in comparison to mass spectrometry for measuring the K/T ratio. We also used ELISA to determine the K/T ratio in plasma from patients with active TB compared to latently infected controls, with and without HIV. RESULTS: The two methods showed good agreement, with a mean bias of 0.01 (limit of agreement from -0.06 to 0.10). Using ELISA, it was found that HIV-infected patients with active TB disease had higher K/T ratios than those without TB (median, 0.101 [interquartile range (IQR), 0.091-0.140] versus 0.061 [IQR, 0.034-0.077], P<0.0001). At a cutoff of 0.080, the K/T ratio produced a sensitivity of 90%, a specificity of 80%, a positive predictive value (PPV) of 82%, and a negative predictive value (NPV) of 90%. In a receiver operating characteristics analysis, the K/T ratio had an area under the curve of 0.93. HIV-uninfected patients with active TB also had higher K/T ratios than those with latent TB infections (median, 0.064 [IQR, 0.040-0.088] versus 0.022 [IQR, 0.016-0.027], P<0.0001). A cutoff of 0.040 gave a sensitivity of 85%, a specificity of 92%, a PPV of 91%, and an NPV of 84%. CONCLUSION: The plasma K/T ratio is a sensitive biomarker for active TB. The K/T ratio can be measured from blood using ELISA. The K/T ratio should be evaluated as an initial test for TB.