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Background: Ratios of bacteriologically positive tuberculosis (TB) prevalence to notification rates are used to characterise typical durations of TB disease. However, this ignores the clinical spectrum of tuberculosis disease and potentially long infectious periods with minimal or no symptoms prior to care-seeking., Methods: We developed novel statistical models to estimate progression from initial bacteriological positivity including smear conversion, symptom onset and initial care-seeking. Case-detection ratios, TB incidence, durations, and other parameters were estimated by fitting the model to tuberculosis prevalence survey and notification data (one subnational and 11 national datasets) within a Bayesian framework using Markov chain Monte Carlo methods., Results: Analysis across 11 national datasets found asymptomatic tuberculosis durations in the range 4-8 months for African countries; three countries in Asia (Cambodia, Lao PDR, and Philippines) showed longer durations of > 1 year. For the six countries with relevant data, care-seeking typically began half-way between symptom onset and notification. For Kenya and Blantyre, Malawi, individual-level data were available. The sex-specific durations of asymptomatic bacteriologically-positive tuberculosis were 9.0 months (95% credible interval [CrI]: 7.2-11.2) for men and 8.1 months (95% CrI: 6.2-10.3) for women in Kenya, and 4.9 months (95% CrI: 2.6-7.9) for men and 3.5 months (95% CrI: 1.3-6.2) for women in Blantyre. Age-stratified analysis of data for Kenya showed no strong age-dependence in durations. For Blantyre, HIV-stratified analysis estimated an asymptomatic duration of 1.3 months (95% CrI: 0.3-3.0) for HIV-positive people, shorter than the 8.5 months (95% CrI: 5.0-12.7) for HIV-negative people. Additionally, case-detection ratios were higher for people living with HIV than HIV-negative people (93% vs 71%)., Conclusion: Asymptomatic TB disease typically lasts around 6 months. We found no evidence of age-dependence, but much shorter durations among people living with HIV, and longer durations in some Asian settings. To eradicate TB transmission, greater gains may be achieved by proactively screening people without symptoms through active case finding interventions., (© 2021. The Author(s).)

Background: A sizeable fraction of tuberculosis (TB) cases go undiagnosed. By analysing data from enhanced demographic, microbiological and geospatial surveillance of TB registrations, we aimed to identify modifiable predictors of inequitable access to diagnosis and care., Methods: Governmental community health workers (CHW) enumerated all households in 315 catchment areas during October-December 2015. From January 2015, government TB Officers routinely implemented enhanced TB surveillance at all public and private TB treatment registration centres within Blantyre (18 clinics in total). This included collection from registering TB patients of demographic and clinical characteristics, a single sputum sample for TB microscopy and culture, and geolocation of place of residence using an electronic satellite map application. We estimated catchment area annual TB case notification rates (CNRs), stratified by microbiological status. To identify population and area-level factors predictive of CHW catchment area TB case notification rates, we constructed Bayesian spatially autocorrelated regression models with Poisson response distributions. Worldpop data were used to estimate poverty., Results: In total, the 315 CHW catchment areas comprised 753,489 people (range 162 to 13,066 people/catchment area). Between 2015 and 2017, 6077 TB cases (61% male; 99% HIV tested; 67% HIV positive; 55% culture confirmed) were geolocated, with 3723 (61%) resident within a CHW catchment area. In adjusted models, greater distance to the nearest TB registration clinic was negatively correlated with TB CNRs, which halved for every 3.2-fold (95% CI 2.24-5.21) increase in distance. Poverty, which increased with distance from clinics, was negatively correlated with TB CNRs; a 23% increase (95% CI 17-34%) in the mean percentage of the population living on less than US$2 per day corresponded to a halving of the TB case notification rates., Conclusions: Using enhanced surveillance of TB cases in Blantyre, we show an ecological relationship consistent with an 'inverse care law' whereby poorer neighbourhoods and those furthest from TB clinics have lower relative CNRs. If confirmed as low case detection, then pro-poor strategies to facilitate equitable access to TB diagnosis and treatment are required.

Background: The Bacillus Calmette-Guérin (BCG) vaccine is provided to over 100 million neonates annually to protect against childhood tuberculosis (TB). Recent BCG manufacturing interruptions highlight global supply risks. We estimated the potential impact of BCG shortfalls on global paediatric (<15 years) TB mortality., Methods: A static mathematical model was employed to estimate the number of paediatric TB deaths avoided by usual levels of BCG coverage, and potential additional TB deaths in the first 15 years of life due to 1-year BCG supply shortfalls of 6.3 % (as occurred in 2015) to 27.6 % (as anticipated without mitigating action in 2015) assuming no catch-up campaigns., Results: BCG coverage without shortfalls, estimated at 90 % globally, was estimated to avoid 117,132 (95 % uncertainty range (UR): 5049-306,911) TB deaths globally per birth cohort in the first 15 years of life. An estimated 11,713 (UR: 505-30,691) additional TB deaths would occur in the first 15 years of life per 10 % (26 million dose) annual supply shortfall. A 16.5 million dose (6.3 %) shortfall as reported at the close of 2015, reflecting 84 % global coverage, was estimated as associated with 7433 (95 % UR: 320-19,477) excess TB deaths in the affected cohort in the first 15 years. A possible 24,914 (UR: 1074-65,278) additional deaths were avoided due to prompt shortfall reduction measures in 2015., Conclusions: BCG shortages could greatly increase paediatric TB mortality. Although rapid action in 2015 minimised BCG shortfalls, avoiding a large number of potential additional deaths, the possible public health impact of even relatively small shortfalls highlights the critical importance of ensuring secure future manufacturing capacity and global BCG supply continuity.