Estimating the annual risk of tuberculosis infection in Japan from interferon-gamma release assay data

To assess tuberculosis transmission frequency at a population level, the age-dependent Mantoux test has been used widely to estimate the annual risk of infection (ARI) with Mycobacterium tuberculosis. However, the widespread Bacille Calmette-Guerin (BCG) immunization program implemented in Japan in the 20th century has made natural infections with M. tuberculosis difficult to distinguish from immune responses against this vaccine. Consequently, a recognized alternative method for measuring the frequency of primary infections, the interferon-gamma release assay (IGRA), which partially decays as a function of time after infection, is used. We aimed to estimate the ARI in Japan from IGRA data along with its response decay information using mathematical modeling. Devising a partial differential equation system, we computed the probability of IGRA positivity as a function of time and age, accounting for the time-varying force of infection and decay function of the IGRA response. Jointly estimating the force of infection and the parameters governing the decay function of the IGRA response, we found that the age-dependent increasing pattern of the IGRA response was captured by the proposed simple model, yielding estimates of the time-dependent force of infection. ARI decreased as a function of time in the study subjects for all geographic locations. By the year 2030, our model showed that the median age of infection is predicted to be delayed by 40-50 years compared with that in 1940. The geographic variations in the ARI were striking, ranging from under 0.1% to 0.6% in 2018, which echoes the longstanding notion of highly heterogeneous geographical tuberculosis transmission in Japan.