Figure 1. Schematic representation of the immune response of individuals during the course of infection. The shade areas illustrate when it is possible to detect a response using the given test. As early as two weeks after infection with M. tuberculosis, a cell-mediated immunity response can be measured. This response is associated with both delayed type hypersensitivity (DTH) responses, as measured by the Mantoux test, and production of type 1 T-cell cytokines, IFN-γ, and often correlates with a temporary arrest or delay of bacterial growth. This response is maintained throughout the course of the infection, but it can wane in individuals who develop very severe TB. Mycobacterial load remains low during the early phase of infection and is therefore not accessible for antigen-detection assays. In individuals who develop acute disease, mycobacterial load and soluble antigen increase. Similarly, M. tuberculosis-specific antibody responses are usually undetectable during the early phase of infection, but develop as the infection progresses to active TB.

Figure 2. Distribution of ESAT-6 responses among TB contacts in high endemic settings (e.g. Ethiopia). This figure shows that the immune responses (assessed here as IFN-γ production) to ESAT-6 after exposure to infectious TB patients are not normally distributed. The subjects are grouped into low (<100 pg/ml), medium (100–1000 pg/ml) and high (>1000 pg/ml) responders, based on the distribution of the samples. Data are derived from [52].

Figure 3. Schematic representation showing the postulated relationship between bacterial load, measured as colony forming units (CFUs), ESAT-6 response levels and clinical outcome. Initial infection might be controlled at its onset with minimal bacterial replication and induction of ESAT-6 responses (a,d). However, in most cases, initial bacterial replication reaches a point where it induces an ESAT-6-specific IFN-γ response to increase above the established cut-off value (infection threshold), enabling the identification of an individual as latently infected (b,e). In most cases, individuals control the infection, resulting in latent infection, but some develop acute TB associated with progressive bacterial replication. This is accompanied by increasing ESAT-6 responses and, as hypothesized here, an incipient disease cut-off value that predicts subsequent development of progressive disease (c,f).

Summary of human studies examining the correlation between levels of ESAT-6- and CFP-10-induced IFN-γ response and subsequent progress to disease