A quarter of the world's population – that's two billion humans – is estimated to be latently infected with Mycobacterium tuberculosis. This staggering number is often presented in scientific publications, used by funding agencies for strategic planning, and taught to students (I've done this myself). If you consider that some ten percent of latently infected individuals will develop tuberculosis in their lifetime, the contribution of latency to the disease burden is enormous. But, where does this number of two billion latently infected individuals come from? In my mind, two factors are key to the estimate. First, there are well-documented cases where the very same bacterial strains isolated from patients in an initial infection are isolated from patients that develop the disease decades later. The bacteria can remain in a dormant state and then reactivated much later. As such, latently infected individuals are seen as "ticking timebombs" and much effort has been placed in understanding and developing approaches to curing latent infections. There is little doubt that very interesting biology must be behind such long term host-microbe interaction. So yes, there are prolonged latent infections. Second and most important for the large number estimate is that the evidence of prior exposure as determined by the tuberculin skin tests or interferon-γ release assays, that is immune memory, is equated with latent infection.
But a paper from 2018 by Behr, Edelstein and Ramakhrishnan questions some of the widely held views on latent tuberculosis infection. The authors did a thorough analyses of prior epidemiological and histopathological studies and came up with several eye-opening conclusions. For one, many studies (from both pre- and post-antibiotic times) all point to the fact that most active tuberculosis cases (~90%) appeared within 18-24 months of the primary infection. In their words: "The incubation period of tuberculosis is typically several months to two years, and after that, disease is relatively infrequent." That is, decades-long incubation periods are rare. Importantly, the authors also concluded that positive tuberculin test results do not necessarily mean latent infection. Among the take-home messages from these analyses is that latent infection followed by reactivation is most relevant in areas where there is very low disease prevalence. In contrast, in areas where the disease is prevalent, and these are usually in lower- and middle-income countries and represent the vast majority of cases worldwide, latent infections and later reactivations are much less numerous than transmissible active disease from recent infections. There are very important health policy implication from these analyses. In the authors' words, "classifying two billion people with evidence of immunoreactivity as having latent tuberculosis infection may divert fundamental research and public health interventions away from transmissible active TB disease and newly infected people at highest risk of progression to disease." I suspect their analyses were met with skepticism in some circles; the "quarter of the world population is latently infected" statement still abounds often in current papers. But I feel the conclusions presented in this paper are a very important message and serve as another reminder that some widely-held ideas in science are not as soundly supported by evidence as one would wish. An important lesson for all of us to learn and teach.