The Global Burden of Latent Tuberculosis Infection: A Re-estimation Using Mathematical Modelling

Abstract

Background: The existing estimate of the global burden of latent TB infection (LTBI) as "one-third" of the world population is nearly 20 y old. Given the importance of controlling LTBI as part of the End TB Strategy for eliminating TB by 2050, changes in demography and scientific understanding, and progress in TB control, it is important to re-assess the global burden of LTBI.

Methods and findings: We constructed trends in annual risk in infection (ARI) for countries between 1934 and 2014 using a combination of direct estimates of ARI from LTBI surveys (131 surveys from 1950 to 2011) and indirect estimates of ARI calculated from World Health Organisation (WHO) estimates of smear positive TB prevalence from 1990 to 2014. Gaussian process regression was used to generate ARIs for country-years without data and to represent uncertainty. Estimated ARI time-series were applied to the demography in each country to calculate the number and proportions of individuals infected, recently infected (infected within 2 y), and recently infected with isoniazid (INH)-resistant strains. Resulting estimates were aggregated by WHO region. We estimated the contribution of existing infections to TB incidence in 2035 and 2050. In 2014, the global burden of LTBI was 23.0% (95% uncertainty interval [UI]: 20.4%-26.4%), amounting to approximately 1.7 billion people. WHO South-East Asia, Western-Pacific, and Africa regions had the highest prevalence and accounted for around 80% of those with LTBI. Prevalence of recent infection was 0.8% (95% UI: 0.7%-0.9%) of the global population, amounting to 55.5 (95% UI: 48.2-63.8) million individuals currently at high risk of TB disease, of which 10.9% (95% UI:10.2%-11.8%) was isoniazid-resistant. Current LTBI alone, assuming no additional infections from 2015 onwards, would be expected to generate TB incidences in the region of 16.5 per 100,000 per year in 2035 and 8.3 per 100,000 per year in 2050. Limitations included the quantity and methodological heterogeneity of direct ARI data, and limited evidence to inform on potential clearance of LTBI.

Conclusions: We estimate that approximately 1.7 billion individuals were latently infected with Mycobacterium tuberculosis (M.tb) globally in 2014, just under a quarter of the global population. Investment in new tools to improve diagnosis and treatment of those with LTBI at risk of progressing to disease is urgently needed to address this latent reservoir if the 2050 target of eliminating TB is to be reached.

Fig 1. Fitted trends for annual risk of infection—Southeast Asia.

Fitted trends of annual risk of tuberculosis infection (ARI) for countries in the WHO Southeast Asia region (log scale). Points represent ARI data (black circles from WHO tuberculosis prevalence estimates, blue triangles from tuberculin skin test [TST] surveys); error bars represent measurement precision to +/- one standard deviation. Red lines show the mean (solid) and +/- one standard deviation (dashed lines) of Gaussian process regression with a linear trend. Similar plots for the other WHO regions are provided in S1 Text (Figures C-H).

Fig 2. Global map of prevalence of latent TB infection.

Median estimated population prevalence of latent Mycobacterium tuberculosis infection by country, 2014.

Fig 3. Prevalence of latent TB infection by age and WHO region.

Prevalence of latent Mycobacterium tuberculosis infection by age and World Health Organisation region, 2014. Red error bars indicate inter-quartile range. AFR = African Region; AMR = Region of the Americas; EMR = Eastern Mediterranean Region; EUR = European Region; SEA = Southeast Asia Region; WPR = Western Pacific Region.