Tuberculosis research in South Africa over the past 30 years: From bench to bedside.

The South African Medical Research Council Centre for Tuberculosis Research has a rich history of high-impact research that has influenced our understating of this hyper-epidemic which is further exacerbated by the emergence and spread of drug-resistant forms of the disease. This review aims to summarise the past 30 years of research conducted in the Centre which has influenced the way that tuberculosis (TB) is diagnosed and treated. The review includes the development of new technologies for rapid screening of people with probable TB and the repurposing of human diagnostics for wildlife conservation.

Hypercytokinaemia accompanies HIV-tuberculosis immune reconstitution inflammatory syndrome.

Increased access to combination antiretroviral therapy in areas co-endemic for tuberculosis (TB) and HIV-1 infection is associated with an increased incidence of immune reconstitution inflammatory syndrome (TB-IRIS) whose cause is poorly understood. A case-control analysis of pro- and anti-inflammatory cytokines in TB-IRIS patients sampled at clinical presentation, and similar control patients with HIV-TB prescribed combined antiretroviral therapy who did not develop TB-IRIS. Peripheral blood mononuclear cells were cultured in the presence or absence of heat-killed Mycobacterium tuberculosis for 6 and 24 h. Stimulation with M. tuberculosis increased the abundance of many cytokine transcripts with interleukin (IL)-1ß, IL-5, IL-6, IL-10, IL-13, IL-17A, interferon (IFN)-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumour necrosis factor (TNF) being greater in stimulated TB-IRIS cultures. Analysis of the corresponding proteins in culture supernatants, revealed increased IL-1ß, IL-2, IL-6, IL-8, IL-10, IL-12p40, IFN-γ, GM-CSF and TNF in TB-IRIS cultures. In serum, higher concentrations of TNF, IL-6, and IFN-γ were observed in TB-IRIS patients. Serum IL-6 and TNF decreased during prednisone therapy in TB-IRIS patients. These data suggest that cytokine release contributes to pathology in TB-IRIS. IL-6 and TNF were consistently elevated and decreased in serum during corticosteroid therapy. Specific blockade of these cytokines may be rational approach to immunomodulation in TB-IRIS.

Highly discordant T cell responses in individuals with recent exposure to household tuberculosis.

BACKGROUND: There are limited data comparing interferon-gamma release assays (IGRAs) for the detection of Mycobacterium tuberculosis infection in highly endemic settings. METHODS: A cross-sectional household contact study was conducted to measure the agreement of two IGRAs in relation to the tuberculin skin test (TST) to detect M tuberculosis infection and to assess the influence of M tuberculosis exposure and age. RESULTS: In 82 individuals in household contact, 93% of children and 42% of adults had a high M tuberculosis contact score. The TST was positive in 78% of adults and 54% of children, the T-SPOT.TB was positive in 89% of children and 66% of adults and the QuantiFERON TB Gold (QTF) was positive in a similar proportion of adults and children (38.1% and 39.6%). In children there was poor agreement between the TST and T-SPOT.TB (kappa = -0.15) and the T-SPOT.TB and the QTF (kappa = -0.03), but good agreement between the TST and the QTF (kappa = 0.78) using 10 mm cut-off. In adults there was fair to moderate agreement between the TST and T-SPOT.TB (kappa = 0.38), the TST and QTF (kappa = 0.34) and T-SPOT.TB and QTF (kappa = -0.50). High levels of exposure to M tuberculosis were associated with at least a sevenfold odds of being T-SPOT.TB positive (95% CI 7.67 to 508.69) and a threefold odds of being QTF positive (95% CI 3.02 to 30.54). There was a significant difference in the magnitude of T-SPOT.TB early secretory antigenic target (ESAT)-6 and culture filtrate protein 10 kD (CFP-10) spot counts between adults and children. CONCLUSIONS: The T-SPOT.TB may be more sensitive than the TST or QTF for detecting recent M tuberculosis infection in children. Differences between assays and the predictive utility of these findings for subsequent disease development should be prospectively assessed.

High level of discordant IGRA results in HIV-infected adults and children.

SETTING: Tygerberg district, Western Cape Province, South Africa. OBJECTIVE: To measure the agreement of two interferon-gamma release assays (IGRAs) and the tuberculin skin test (TST) for the detection of Mycobacterium tuberculosis infection in human immunodeficiency virus (HIV) infected adults and children in a setting highly endemic for tuberculosis (TB). DESIGN: Cross-sectional study. RESULTS: In HIV-infected adults (n=20) and children (n=23), tests yielded discordant results, with 61% of individuals testing positive with T-SPOT.TB, 41% with TST and 28% with QuantiFERON TB Gold (QTF). In children, there was poor agreement between the TST and T-SPOT.TB (kappa [kappa]=-0.02), but moderate agreement between the TST and QTF (kappa=0.44). In adults, there was moderate agreement between the TST and T-SPOT.TB (kappa=0.43), and the TST and QTF (kappa = 0.46). In children and adults, there was fair agreement between the T-SPOT.TB and QTF (kappa=0.33). Twenty per cent of adults had >or=1 indeterminate IGRA results. CONCLUSIONS: There is poor to moderate agreement between the TST and IGRAs in HIV-infected adults and children. T-SPOT.TB may have improved sensitivity for detection of M. tuberculosis infection in HIV-infected individuals compared to the QTF and the TST. In HIV-infected individuals, IGRA test properties are affected by test cut-off point and nil control responses.