Self-clearance of Mycobacterium tuberculosis infection: implications for lifetime risk and population at-risk of tuberculosis disease

Abstract

Background: it is widely assumed that individuals with Mycobacterium tuberculosis (Mtb) infection remain at lifelong risk of tuberculosis (TB) disease. However, there is substantial evidence that self-clearance of Mtb infection can occur. We infer a curve of self-clearance by time since infection and explore its implications for TB epidemiology. Methods and findings: data for self-clearance were inferred using post-mortem and tuberculin-skin-test reversion studies. A cohort model allowing for self-clearance was fitted in a Bayesian framework before estimating the lifetime risk of TB disease and the population infected with Mtb in India, China and Japan in 2019. We estimated that 24.4% (17.8-32.6%, 95% uncertainty interval (UI)) of individuals self-clear within 10 years of infection, and 73.1% (64.6-81.7%) over a lifetime. The lifetime risk of TB disease was 17.0% (10.9-22.5%), compared to 12.6% (10.1-15.0%) assuming lifelong infection. The population at risk of TB disease in India, China and Japan was 35-80% (95% UI) smaller in the self-clearance scenario. Conclusions: the population with a viable Mtb infection may be markedly smaller than generally assumed, with such individuals at greater risk of TB disease. The ability to identify these individuals could dramatically improve the targeting of preventive programmes and inform TB vaccine development, bringing TB elimination within reach of feasibility.

Keywords: Mycobacterium tuberculosis; epidemiology; infection; mathematical modelling; self-clearance.

Figure 1.

Cohort model of TB natural history allowing for self-clearance of Mtb infection. A description of the model is provided in the main text and the parameters are detailed in table 1. Note that a_i can represent either the age at infection of the TST-reversion cohort (a_TST) or the autopsy cohort (a_AUT). Mtb, Mycobacterium tuberculosis; TST, tuberculin skin test.

Figure 2.

Cohort model results showing data for self-clearance of Mtb infection and progression to TB disease over time since infection. The figure shows the cohort model fitted to data on self-clearance of Mtb infection (a) and progression to TB disease (b) presented over time since infection. Data in (a) consist of TST studies (crosses) and autopsy studies (points). Uncertainty in the horizontal axis reflects the 95% uncertainty interval for the estimate for the age of infection. Uncertainty in the data in the vertical axes in both panels are the equal-tailed 95% confidence intervals. Model fits are median model output and equal-tailed 95% uncertainty intervals. Mtb, Mycobacterium tuberculosis; TB, tuberculosis; TST, tuberculin skin test. (Online version in colour.)

Figure 3.

Country-level model results for the number of people with a viable Mtb infection in the lifelong infection and self-clearance scenarios. (a–c) The estimated population at risk of TB disease in 2019 disaggregated by age in three epidemiologically distinct settings for the cases of lifelong Mtb infection (red outlined) and self-clearance (red filled). (d) The total population with a viable infection in each setting, assuming self-clearance, expressed as a percentage of the total population with a viable infection assuming lifelong infection. Point values and error bars show median and equal-tailed 95% uncertainty intervals from the model outputs. Note that median estimates for the historical ARI have been used, such that uncertainty presented in the results is associated with uncertainty in the natural history model parameters only (table 1). For clarity, uncertainty in the lifelong infection results is not shown because they are much smaller than in the self-clearance scenario. Mtb, Mycobacterium tuberculosis; ARI, annual risk of infection. (Online version in colour.)