Host- and pathogen-specific factors interplay with the environment in a complex fashion to determine the outcome of infection with Mycobacterium tuberculosis (Mtb), resulting in one of three possible outcomes: cure, latency or active disease. Although much remains unknown about its pathophysiology, latent tuberculosis infection (LTBI) defined by immunologic evidence of Mtb infection is a continuum between self-cure and asymptomatic, yet active tuberculosis (TB) disease. Strain virulence, intensity of exposure to the index case, size of the bacterial inoculum, and host factors such as age and co-morbidities, each contribute to where one settles on the continuum.

Currently, the diagnosis of LTBI is based on reactive tuberculin skin testing (TST) and/or a positive interferon-gamma release assay (IGRA). Neither diagnostic test reflects the activity of the infectious focus or the risk of progression to active TB. This is a critical shortcoming, as accurate and efficient detection of those with LTBI at higher risk of progression to TB disease would allow for provision of targeted preventive therapy to those most likely to benefit. Host biomarkers may prove of value in stratifying risk of development of TB. New guidelines are required for interpretation of discordance between TST and IGRA, which may be due in part to a lack of stability (that is reproducibility) of IGRA or TST results or to a delay in conversion of IGRA to positivity compared to TST.

In this review, the authors elaborate on the definition, diagnosis, pathophysiology and natural history of LTBI, as well as promising methods for better stratifying risk of progression to TB. The review is centered on the human host and the clinical and epidemiologic features of LTBI that are relevant to the development of new and improved diagnostic tools.