Fig. 2. TB infection, disease spectrum and associated challenges.

Tuberculosis (TB) presents as a spectrum along three axes: disease pathology and severity, bacterial persistence and drug tolerance, and genetic resistance. The pathology of TB disease is a dynamic continuum from fully latent asymptomatic infection to active disease with high bacterial burden in open cavities, leading to transmission and more frequent treatment failure. Individuals with latent TB infection who are progressing towards incipient TB are at high risk of developing active disease and would benefit from reactivation risk assessment and treatment. The spectrum of immunopathology creates a diversity of microenvironments to which the pathogen responds with metabolic and physiological adaptations leading to drug tolerance or phenotypic drug resistance and persistent disease. Drug tolerance as well as other patient and pathogen factors lead to a spectrum of genetic resistance both in terms of the number of drugs a bacterium is resistant to and the level of resistance to each drug. Such variability along three axes creates a gradient of decreased drug efficacy and lesion sterilization within and across patients, constitutes a multidimensional challenge for health-care programmes and complicates clinical trials.