Diagnostic accuracy of plasma kynurenine/tryptophan ratio, measured by enzyme-linked immunosorbent assay, for pulmonary tuberculosis.

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.

Indoleamine 2, 3-Dioxygenase-Mediated Tryptophan Catabolism: A Leading Star or Supporting Act in the Tuberculosis and HIV Pas-de-Deux?

Progression from latency to active Tuberculosis (TB) disease is mediated by incompletely understood host immune factors. The definitive characteristic of progressive human immunodeficiency virus (HIV) disease is a severe loss in number and function of T lymphocytes. Among the many possible mediators of T lymphocyte loss and ineffective function is the activity of the immune-modulatory enzyme indoleamine 2,3-dioxygenase (IDO). IDO is the rate-limiting enzyme converting tryptophan to kynurenine. IDO activity was initially recognized to mediate tolerance at the foeto-maternal interface. Recently, IDO activity has also been noted to play a critical role in immune tolerance to pathogens. Studies of host immune and metabolic mediators have found IDO activity significantly elevated in HIV and TB disease. In this review, we explore the link between IDO-mediated tryptophan catabolism and the presence of active TB disease in HIV-infected patients. We draw attention to increased IDO activity as a key factor marking the progression from latent to active TB disease in HIV-infected patients.

Hepatitis B sero-prevalence in children under 15 years of age in South Africa using residual samples from community-based febrile rash surveillance.

INTRODUCTION AND METHODS: Hepatitis B is a vaccine preventable disease and is notifiable in South Africa. Hepatitis B vaccination was incorporated into the Expanded Programme on Immunisation in South Africa in 1995. We used a convenience sample from community-based febrile rash surveillance in 2013 to estimate hepatitis B sero-prevalence. Of samples serologically negative for acute measles infection, 450 samples spanning nine provinces of South Africa were tested for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs) and hepatitis B core antibody (anti-HBc). RESULTS: Two children (2/450; 0.4%) tested positive for HBsAg. Three hundred and three children (67.3%) had evidence of vaccine induced immunity. Vaccine induced immunity was present in 80.2% of 1-5 year olds, but only 60.3% of 10-14 year olds. Natural immunity, indicating exposure to circulating hepatitis B, was present in 13/450 (2.9%) children. CONCLUSION: Chronic hepatitis B in South African has decreased in prevalence from highly endemic levels prior to vaccine introduction to approximately 0.4% in this sample, demonstrating impact of a successful vaccination programme 18 years after introduction. Decreased vaccine-induced immunity with increasing age may reflect waning antibody titres over time.

Missing: a diagnostic technique to enumerate antigen-specific T cells.

T lymphocytes are responsible for immune responses against pathogens, immune surveillance against cancer and maintenance of tolerance to self. While techniques available to detect antigen-specific T cells have been well described, there is a missing technique in our repertoire. While fluorescent multimers can be used for limited research applications, there is no existing technique suitable for detection of antigen-specific T cells in a diagnostic setting. The absence of such a technology has inhibited the search for "correlates of protection" against infectious, autoimmune or malignant disease. This critical review of existing methods will highlight the limitations of the data on which our current understanding of the immune system is based, in an effort to stimulate development of improved techniques.