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Background: Community active case finding (ACF) for tuberculosis was widely implemented in Europe and North America between 1940 and 1970, when incidence was comparable to many present-day high-burden countries. Using an interrupted time series analysis, we analysed the effect of the 1957 Glasgow mass chest X-ray campaign to inform contemporary approaches to screening., Methods and Findings: Case notifications for 1950 to 1963 were extracted from public health records and linked to demographic data. We fitted Bayesian multilevel regression models to estimate annual relative case notification rates (CNRs) during and after a mass screening intervention implemented over 5 weeks in 1957 compared to the counterfactual scenario where the intervention had not occurred. We additionally estimated case detection ratios and incidence. From 11 March 1957 to 12 April 1957, 714,915 people (622,349 of 819,301 [76.0%] resident adults ≥15 years) were screened with miniature chest X-ray; 2,369 (0.4%) were diagnosed with tuberculosis. Pre-intervention (1950 to 1956), pulmonary CNRs were declining at 2.3% per year from a CNR of 222/100,000 in 1950. With the intervention in 1957, there was a doubling in the pulmonary CNR (RR: 1.95, 95% uncertainty interval [UI] [1.81, 2.11]) and 35% decline in the year after (RR: 0.65, 95% UI [0.59, 0.71]). Post-intervention (1958 to 1963) annual rates of decline (5.4% per year) were greater (RR: 0.77, 95% UI [0.69, 0.85]), and there were an estimated 4,599 (95% UI [3,641, 5,683]) pulmonary case notifications averted due to the intervention. Effects were consistent across all city wards and notifications declined in young children (0 to 5 years) with the intervention. Limitations include the lack of data in historical reports on microbiological testing for tuberculosis, and uncertainty in contributory effects of other contemporaneous interventions including slum clearances, introduction of BCG vaccination programmes, and the ending of postwar food rationing., Conclusions: A single, rapid round of mass screening with chest X-ray (probably the largest ever conducted) likely resulted in a major and sustained reduction in tuberculosis case notifications. Synthesis of evidence from other historical tuberculosis screening programmes is needed to confirm findings from Glasgow and to provide insights into ongoing efforts to successfully implement ACF interventions in today's high tuberculosis burden countries and with new screening tools and technologies., Competing Interests: PM is an PLOS Medicine Academic Editor., (Copyright: © 2024 MacPherson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Competing Interests: This work was supported by the National Institutes of Health (grant number R-202309-71190 to AS, LG, and RMGJH). The funders had no role in the writing of the manuscript or the decision to submit the paper for publication. All authors declare no competing interests.

Tuberculosis is a leading cause of death from an infectious agent globally. Infectious subclinical tuberculosis accounts for almost half of all tuberculosis cases in national tuberculosis prevalence surveys, and possibly contributes to transmission and might be associated with morbidity. Modelling studies suggest that new tuberculosis vaccines could have substantial health and economic effects, partly based on the assumptions made regarding subclinical tuberculosis. Evaluating the efficacy of prevention of disease tuberculosis vaccines intended for preventing both clinical and subclinical tuberculosis is a priority. Incorporation of subclinical tuberculosis as a composite endpoint in tuberculosis vaccine trials can help to reduce the sample size and duration of follow-up and to evaluate the efficacy of tuberculosis vaccines in preventing clinical and subclinical tuberculosis. Several design options with various benefits, limitations, and ethical considerations are possible in this regard, which would allow for the generation of the evidence needed to estimate the positive global effects of tuberculosis vaccine trials, in addition to informing policy and vaccination strategies., Competing Interests: Declaration of interests The following authors declare grants to their respective institutions. GJC: Division of AIDS/NIH. ALF-G: Bill & Melinda Gates Foundation, US NIH for HIV Vaccine Trials Network Statistical Center. ALG-B: Barcelona Institute for Global Health tenure track associate research professorship. EBW: Burroughs Wellcome Fund, 1022002; Bill & Melinda Gates Foundation, INV-046520; NIH/National Institute of Allergy and Infectious Diseases, AI201700104 and AI147321. FC: Bill & Melinda Gates Foundation, EDCTP. HE: Canadian Institutes for Health Research, Tier 1 Canada Research Chair. VM: NIH, Centers for Disease Control and Prevention. MH: NIH, EDCTP, Gates Medical Research Institute. RMGJH: European Research Council. RGW: Wellcome Trust (218261/Z/19/Z), NIH (1R01AI147321-01, G-202303-69963), EDCTP (RIA208D-2505B), UK Medical Research Council (CCF17-7779 Bloomsbury), Economic and Social Research Council (ES/P008011/1), Bill & Melinda Gates Foundation (INV-004737, INV-035506), WHO (2020/985800-0). ADG, WAH, MB, ACS, KF, AFD, and MXR declare no competing interests. The following authors declare royalties. ALG-B: Royalties for the patent Molecular differences between species of the Mycobacterium tuberculosis complex in November, 2020 and November, 2021. HE: Royalties to Stanford University for the patent Molecular differences between species of the Mycobacterium tuberculosis complex in November, 2020 and November, 2021., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Global tuberculosis (TB) burden estimates are aggregated at the national level, despite the likelihood of uneven distribution across and within regions in the same country. Subnational estimates are crucial to producing informed policies and informing budget allocation at more granular levels. In collaboration with the National TB Programme (NTP), we applied a simple and transparent tool to estimate the subnational TB burden in Pakistan. We tailored the SUBnational Burden Estimation for TB (SUBsET) tool to account for the district-level hierarchy of Pakistan. Districts were assigned weighted scores based on population size, level of urbanisation, households with one room, and food insecurity levels. Using the 2022 national TB incidence estimate, we first allocated the burden across administrative units based on data from the 2010-11 TB prevalence survey and subsequently refined this distribution to reflect weighted scores specific to each district. The estimated TB incidence was compared with pulmonary TB notifications to calculate the case detection rate (CDR) for each district. Utilising the updated SUBsET model, we assigned weight scores to 150 districts spanning seven provinces/regions in Pakistan. The estimated TB incidence varied significantly, ranging from 110 (95%CI: 80-145) to 462 (95%CI: 337-607) per 100,000 inhabitants per year. The provinces bearing the highest burden was Sindh (292; 95%CI: 213-384), followed by Khyber Pakhtunkhwa (269; 95%CI: 196-354) and Punjab (243; 95%CI: 177-320). The CDR was below 70% in three-quarters of the districts and over-reporting (>100%) was observed in 10 districts, primarily within Punjab, which suggests that individuals with TB may be crossing district lines to access care. The application of the SUBsET tool through active collaboration with the NTP revealed high heterogeneity in subnational TB incidence in Pakistan, urging a more granular and tailored approach to TB prevention and care. This approach ensured transparency and acceptance of the findings for wider in-country dissemination., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Schwalb et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

We read with great interest the recent paper by Lo et al., who argue that there is an urgent need to ensure the quality of modelling evidence used to support international and national guideline development. Here we outline efforts by the Tuberculosis Modelling and Analysis Consortium, together with the World Health Organization Global Task Force on Tuberculosis Impact Measurement, to develop material to improve the quality and transparency of country-level tuberculosis modelling to inform decision-making., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Current passive case-finding policies have not resulted in the expected decline in tuberculosis incidence. Recognition of the variety of disease pathways experienced by individuals with tuberculosis highlights how many are not served by the current prevention and care system, and how much transmission is missed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

In recent years, there has been increasing recognition of the public health significance of the spectrum of TB disease presentation, and the existing classification systems of asymptomatic infection and symptomatic TB have been limited in terms of explanatory power. Accordingly, in 2022-2023, a new International Consensus framework for Early TB (ICE-TB) was developed, categorising the spectrum of TB infection and disease into five states based on the presence or absence of macroscopic pathology, host infectiousness, and symptoms and signs.We used the ICE-TB framework to re-analyse existing notification data for 2022 within a low-incidence setting to explore the potential utility and future challenges for its public health application.Existing notification data were sufficient to allow substantial reclassification of currently recognised active disease states, but did not systematically capture Mycobacterium tuberculosis infection or subclinical TB. Fifty percent of existing TB notifications would be classified as 'Clinical, infectious', with the potential need to consider further subclassification.Our exploration highlighted limitations in existing classification systems and diagnostic approaches and should encourage researchers and programmatic implementers to emphasise person-centred and programmatic needs in the development of new tools for TB management..

The provision of tuberculosis preventive treatment is one of the critical interventions to reduce tuberculosis incidence and ultimately eliminate the disease, yet we still miss appropriate tools for an impactful intervention and treatment coverage remains low. We used recent data, epidemiological estimates, and research findings to analyze the challenges of each step of the cascade of tuberculosis prevention that currently delay the strategy implementation. We addressed research gaps and implementation bottlenecks that withhold key actions in tuberculosis case finding, testing for tuberculosis infection, provision of preventive treatment with safer, shorter regimens and supporting people to complete their treatment. Empowering communities to generate demand for preventive therapy and other prevention services in a holistic manner and providing adequate financial support to sustain implementation are essential requirements. The adoption of an effective, universal monitoring and evaluation system is a prerequisite to provide general and granular insight, and to steer progress of the tuberculosis infection strategy at global and local level., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Matteelli et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Tuberculosis (TB) disproportionally affects poor people, leading to income and non-income losses. Measures of socioeconomic impact of TB, e.g. impoverishment and patient costs are inadequate to capture non-income losses. We applied impoverishment and a multidimensional measure on TB and non-TB affected households in Zimbabwe. We conducted a cross-sectional study in 270 households: 90 non-TB; 90 drug-susceptible TB (DS-TB), 90 drug-resistant TB (DR-TB) during the COVID-19 pandemic (2020-2021). Household data included ownership of assets, number of household members, income and indicators on five capital assets: financial, human, social, natural and physical. Households with incomes per capita below US$1.90/day were considered impoverished. We used principal component analysis on five capital asset indicators to create a binary outcome variable indicating loss of livelihood. Log-binomial regression was used to determine associations between loss of livelihood and type of household. TB-affected households were more likely to report episodes of TB and household members requiring care than non-TB households. The proportions of impoverished households were 81% (non-TB), 88% (DS-TB) and 94% (DR-TB) by the time of interview. Overall, 56% (152/270) of households sold assets: 44% (40/90) non-TB, 58% (52/90) DS-TB and 67% (60/90) DR-TB. Children's education was affected in 33% (55/168) of TB-affected compared to 14% (12/88) non-TB households. Overall, 133 (50%) households experienced loss of livelihood, with TB-affected households almost twice as likely to experience loss of livelihood; adjusted prevalence ratio (aPR = 1.78 [95%CI:1.09-2.89]). The effect of TB on livelihood was most pronounced in poorest households (aPR = 2.61, [95%CI:1.47-4.61]). TB-affected households experienced greater socioeconomic losses compared to non-TB households. Multisectoral social protection is crucial to mitigate impacts of TB and other shocks, especially targeting poorest households., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Timire et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The current active-latent paradigm of tuberculosis largely neglects the documented spectrum of disease. Inconsistency with regard to definitions, terminology, and diagnostic criteria for different tuberculosis states has limited the progress in research and product development that are needed to achieve tuberculosis elimination. We aimed to develop a new framework of classification for tuberculosis that accommodates key disease states but is sufficiently simple to support pragmatic research and implementation. Through an international Delphi exercise that involved 71 participants representing a wide range of disciplines, sectors, income settings, and geographies, consensus was reached on a set of conceptual states, related terminology, and research gaps. The International Consensus for Early TB (ICE-TB) framework distinguishes disease from infection by the presence of macroscopic pathology and defines two subclinical and two clinical tuberculosis states on the basis of reported symptoms or signs of tuberculosis, further differentiated by likely infectiousness. The presence of viable Mycobacterium tuberculosis and an associated host response are prerequisites for all states of infection and disease. Our framework provides a clear direction for tuberculosis research, which will, in time, improve tuberculosis clinical care and elimination policies., Competing Interests: Declaration of interests AKC reports a grant (GNT2020750) from the Australian National Health and Medical Research Council. SMAZ reports personal support from the Commonwealth Scholarship Commission studentship. BWA reports funding for research, including salaries for group members, from the German Federal Ministry for Research and Education (BMBF). LM reports grant funding from the US National Institutes of Health (NIH). DFW reports grants to his institution from NIH, the US National Institute of Allergy and Infectious Diseases, the South African Medical Research Council, the Bill & Melinda Gates Foundation, and the Research Council of Norway. RJW reports a grant to his institution from Wellcome. HE reports a grant (MR/V00476X/1) from the UK Medical Research Council and participation on a data safety monitoring board for the StatinTB trial. RMGJH reports a European Research Council Starting Grant (action number 757699). PKD, GG, MK, TK, BJM, GBM, MR, TJS, JAS, and PT declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Tuberculosis (TB) incidence rates among migrants are higher than those in low-incidence countries. We evaluated smear-positive, pulmonary TB notifications of foreign-born individuals, comparing time since arrival and time since last return travel to the country of origin. TB incidence suggests a time course consistent with recent infection during travel., Competing Interests: Potential conflicts of interest. G. H. B. reports support for attending meetings and/or travel from European Respiratory Society, Milan 2023 (600 Euros a speaker as a contribution to expenses incurred (flights and accommodation) re “Lungs on Fire”—clinical cases expert review as one of 3 experts); an unpaid role on Steering Committee Tbnet. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Individuals with bacteriologically confirmed pulmonary tuberculosis (TB) disease who do not report symptoms (subclinical TB) represent around half of all prevalent cases of TB, yet their contribution to Mycobacterium tuberculosis ( Mtb ) transmission is unknown, especially compared to individuals who report symptoms at the time of diagnosis (clinical TB). Relative infectiousness can be approximated by cumulative infections in household contacts, but such data are rare., Methods: We reviewed the literature to identify studies where surveys of Mtb infection were linked to population surveys of TB disease. We collated individual-level data on representative populations for analysis and used literature on the relative durations of subclinical and clinical TB to estimate relative infectiousness through a cumulative hazard model, accounting for sputum-smear status. Relative prevalence of subclinical and clinical disease in high-burden settings was used to estimate the contribution of subclinical TB to global Mtb transmission., Results: We collated data on 414 index cases and 789 household contacts from three prevalence surveys (Bangladesh, the Philippines, and Viet Nam) and one case-finding trial in Viet Nam. The odds ratio for infection in a household with a clinical versus subclinical index case (irrespective of sputum smear status) was 1.2 (0.6-2.3, 95% confidence interval). Adjusting for duration of disease, we found a per-unit-time infectiousness of subclinical TB relative to clinical TB of 1.93 (0.62-6.18, 95% prediction interval [PrI]). Fourteen countries across Asia and Africa provided data on relative prevalence of subclinical and clinical TB, suggesting an estimated 68% (27-92%, 95% PrI) of global transmission is from subclinical TB., Conclusions: Our results suggest that subclinical TB contributes substantially to transmission and needs to be diagnosed and treated for effective progress towards TB elimination., Funding: JCE, KCH, ASR, NS, and RH have received funding from the European Research Council (ERC) under the Horizon 2020 research and innovation programme (ERC Starting Grant No. 757699) KCH is also supported by UK FCDO (Leaving no-one behind: transforming gendered pathways to health for TB). This research has been partially funded by UK aid from the UK government (to KCH); however, the views expressed do not necessarily reflect the UK government's official policies. PJD was supported by a fellowship from the UK Medical Research Council (MR/P022081/1); this UK-funded award is part of the EDCTP2 programme supported by the European Union. RGW is funded by the Wellcome Trust (218261/Z/19/Z), NIH (1R01AI147321-01), EDTCP (RIA208D-2505B), UK MRC (CCF17-7779 via SET Bloomsbury), ESRC (ES/P008011/1), BMGF (OPP1084276, OPP1135288 and INV-001754), and the WHO (2020/985800-0)., Competing Interests: JE, SB, BF, FG, KH, SH, IL, Fv, HN, HN, MQ, AR, ET, RW, KZ, FC, RH No competing interests declared, PD has received consultancy fees from WHO (TB burden estimation) and participates as chair of SAB for NIHR grant on TBI screening. The author has no other competing interests to declare, GM acts as President of the International Union Against TB & Lung Disease. The author has no other competing interests to declare, IO has received grants from National TB Program Cambodia, WHO and DFAT (Australia) and has received consulting fees from WHO Myanmar Office. The author is on the Board of the Directors, UNION IUATLD and WHO’s Global Task Force on TB Impact Measurement. The author has no other competing interests to declare, NS received a grant from the Bill and Melinda Gates Foundation and owns stock/stock options in Sanofi Aventis Pharma LTD. The author has no other competing interests to declare, (© 2023, Emery et al.)

Background: The prevalence of tuberculosis infection is critical to the design of tuberculosis prevention strategies, yet is unknown in Canada. We estimated the prevalence of tuberculosis infection among Canadian residents born abroad., Methods: We estimated the prevalence of tuberculosis infection by age and year of migration to Canada for people from each of 168 countries by constructing country-specific and calendar year-specific trends for annual risk of infection using a previously developed model. We combined country-specific prevalence estimates with Canadian Census data from 2001, 2006, 2011, 2016 and 2021 to estimate the overall prevalence of tuberculosis infection among foreign-born Canadian residents., Results: The estimated overall prevalence of tuberculosis infection among foreign-born people in Canada was 25% (95% uncertainty interval [UI] 20%-35%) for census year 2001, 24% (95% UI 20%-33%) for 2006, 23% (95% UI 19%-30%) for 2011, 22% (95% UI 19%-28%) for 2016 and 22% (95% UI 19%-27%) for 2021. The prevalence increased with age at migration and incidence of tuberculosis in the country of origin. In 2021, the estimated prevalence of infection among foreign-born residents was lowest in Quebec (19%, 95% UI 16%-24%) and highest in Alberta (24%, 95% UI 21%-28%) and British Columbia (24%, 95% UI 20%-30%). Among all foreign-born Canadian residents with tuberculosis infection in 2021, we estimated that only 1 in 488 (95% UI 185-1039) had become infected within the 2 preceding years., Interpretation: About 1 in 4 foreign-born Canadian residents has tuberculosis infection, but very few were infected within the 2 preceding years (the highest risk period for progression to tuberculosis disease). These data may inform future tuberculosis infection screening policies., Competing Interests: Competing interests: James Johnston reports support from the Michael Smith Foundation for Health Research BC. Faiz Ahmad Khan reports support from the Canadian Institutes of Health Research, the National Research Council of Canada, Fonds de Recherche du Québec – Santé, Fonds de Recherche du Québec – Nature et technologies, Fonds de recherche du Québec – Société et culture, and Institut nordique du Québec. Delft and qure.ai have provided Faiz Ahmad Khan’s laboratory with use of their software for chest radiography analysis at academic-use pricing. Contractual agreements are in place to ensure the companies do not have input in any aspect of research design, conduct or reporting. Kevin Schwartzman reports support from the Bill and Melinda Gates Foundation and participation on a data safety monitoring board for Laurent Pharmaceuticals. He is a volunteer board member and executive committee member with the International Union Against Tuberculosis and Lung Disease. No other competing interests were declared., (© 2023 CMA Impact Inc. or its licensors.)

Traditional understanding of the risk of progression from Mycobacterium tuberculosis ( Mtb ) infection to tuberculosis (TB) overlooks diverse presentations across a spectrum of disease. We developed a deterministic model of Mtb infection and minimal (pathological damage but not infectious), subclinical (infectious but no reported symptoms), and clinical (infectious and symptomatic) TB, informed by a rigorous evaluation of data from a systematic review of TB natural history. Using a Bayesian approach, we calibrated the model to data from historical cohorts that followed tuberculin-negative individuals to tuberculin conversion and TB, as well as data from cohorts that followed progression and regression between disease states, disease state prevalence ratios, disease duration, and mortality. We estimated incidence, pathways, and 10-y outcomes following Mtb infection for a simulated cohort. Then, 92.0% (95% uncertainty interval, UI, 91.4 to 92.5) of individuals self-cleared within 10 y of infection, while 7.9% (95% UI 7.4 to 8.5) progressed to TB. Of those, 68.6% (95% UI 65.4 to 72.0) developed infectious disease, and 33.2% (95% UI 29.9 to 36.4) progressed to clinical disease. While 98% of progression to minimal disease occurred within 2 y of infection, only 71% and 44% of subclinical and clinical disease, respectively, occurred within this period. Multiple progression pathways from infection were necessary to calibrate the model and 49.5% (95% UI 45.6 to 53.7) of those who developed infectious disease undulated between disease states. We identified heterogeneous pathways across disease states after Mtb infection, highlighting the need for clearly defined disease thresholds to inform more effective prevention and treatment efforts to end TB.

There is growing recognition that tuberculosis (TB) infection and disease exists as a spectrum of states beyond the current binary classification of latent and active TB. Our aim was to systematically map and synthesize published conceptual frameworks for TB states. We searched MEDLINE, Embase and EMcare for review articles from 1946 to September 2023. We included 40 articles that explicitly described greater than two states for TB. We identified that terminology, definitions and diagnostic criteria for additional TB states within these articles were inconsistent. Eight broad conceptual themes were identified that were used to categorize TB states: State 0: Mycobacterium tuberculosis ( Mtb ) elimination with innate immune response (n = 25/40, 63%); State I: Mtb elimination by acquired immune response (n = 31/40, 78%); State II: Mtb infection not eliminated but controlled (n = 37/40, 93%); State III: Mtb infection not controlled (n = 24/40, 60%); State IV: bacteriologically positive without symptoms (n = 26/40, 65%); State V: signs or symptoms associated with TB (n = 39/40, 98%); State VI: severe or disseminated TB disease (n = 11/40, 28%); and State VII: previous history of TB (n = 5/40, 13%). Consensus on a non-binary framework that includes additional TB states is required to standardize scientific communication and to inform advancements in research, clinical and public health practice., Competing Interests: AKC received funding from the Center for Infectious Diseases Research in Africa (CIDRI-Africa), National Institutes of Health and the Bill and Melinda Gates Foundation to support the 1st International Symposium on New Concepts in Early TB. DW has received funding from National Institutes of Health, South African Medical Research Council, Bill & Melinda Gates Foundation and Research Council of Norway. HE is a Data Safety Monitoring Board member for the StatinTB Trial., (© 2023 The Author(s).)

Background: People with radiographic evidence for pulmonary tuberculosis (TB), but negative sputum cultures, have increased risk of developing culture-positive TB. Recent expansion of X-ray screening is leading to increased identification of this group. We set out to synthesise the evidence for treatment to prevent progression to culture-positive disease., Methods: We conducted a systematic review and meta-analysis. We searched for prospective trials evaluating the efficacy of TB regimens against placebo, observation, or alternative regimens, for the treatment of adults and children with radiographic evidence of TB but culture-negative respiratory samples. Databases were searched up to 18 Oct 2022. Study quality was assessed using ROB 2·0 and ROBINS-I. The primary outcome was progression to culture-positive TB. Meta-analysis with a random effects model was conducted to estimate pooled efficacy. This study was registered with PROSPERO (CRD42021248486)., Findings: We included 13 trials (32,568 individuals) conducted between 1955 and 2018. Radiographic and bacteriological criteria for inclusion varied. 19·1% to 57·9% of participants with active x-ray changes and no treatment progressed to culture-positive disease. Progression was reduced with any treatment (6 studies, risk ratio [RR] 0·27, 95%CI 0·13-0·56), although multi-drug TB treatment (RR 0·11, 95%CI 0·05-0·23) was significantly more effective than isoniazid treatment (RR 0·63, 95%CI 0·35-1·13) (p = 0·0002)., Interpretation: Multi-drug regimens were associated with significantly reduced risk of progression to TB disease for individuals with radiographically apparent, but culture-negative TB. However, most studies were old, conducted prior to the HIV epidemic and with outdated regimens. New clinical trials are required to identify the optimal treatment approach., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Gray et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

A key metric in tuberculosis epidemiology is the annual risk of infection (ARI), which is usually derived from tuberculin skin test (TST) and interferon-γ release assay (IGRA) prevalence surveys carried out in children. Derivation of the ARI assumes that immunoreactivity is persistent over time; however, reversion of immunoreactivity has long been documented. We used a deterministic, compartmental model of Mycobacterium tuberculosis (Mtb) infection to explore the impact of reversion on ARI estimation using age-specific reversion probabilities for the TST and IGRA. Using empirical data on TST reversion (22.2%/year for persons aged ≤19 years), the true ARI was 2-5 times higher than that estimated from immunoreactivity studies in children aged 8-12 years. Applying empirical reversion probabilities for the IGRA (9.9%/year for youths aged 12-18 years) showed a 1.5- to 2-fold underestimation. ARIs are increasingly underestimated in older populations, due to the cumulative impact of reversion on population reactivity over time. Declines in annual risk did not largely affect the results. Ignoring reversion leads to a stark underestimation of the true ARI in populations and our interpretation of Mtb transmission intensity. In future surveys, researchers should adjust for the reversion probability and its cumulative effect with increasing age to obtain a more accurate reflection of the burden and dynamics of Mtb infection., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

In 2020, almost half a million individuals developed rifampicin-resistant tuberculosis (RR-TB). We estimated the global burden of RR-TB over the lifetime of affected individuals. We synthesized data on incidence, case detection, and treatment outcomes in 192 countries (99.99% of global tuberculosis). Using a mathematical model, we projected disability-adjusted life years (DALYs) over the lifetime for individuals developing tuberculosis in 2020 stratified by country, age, sex, HIV, and rifampicin resistance. Here we show that incident RR-TB in 2020 was responsible for an estimated 6.9 (95% uncertainty interval: 5.5, 8.5) million DALYs, 44% (31, 54) of which accrued among TB survivors. We estimated an average of 17 (14, 21) DALYs per person developing RR-TB, 34% (12, 56) greater than for rifampicin-susceptible tuberculosis. RR-TB burden per 100,000 was highest in former Soviet Union countries and southern African countries. While RR-TB causes substantial short-term morbidity and mortality, nearly half of the overall disease burden of RR-TB accrues among tuberculosis survivors. The substantial long-term health impacts among those surviving RR-TB disease suggest the need for improved post-treatment care and further justify increased health expenditures to prevent RR-TB transmission., (© 2023. Springer Nature Limited.)

Tuberculosis (TB) disproportionally affects impoverished members of society. The adverse socioeconomic impact of TB on households is mostly measured using money-centric approaches, which have been criticized as one-dimensional and risk either overestimating or underestimating the true socioeconomic impacts of TB. We propose the use of the sustainable livelihood framework, which includes 5 household capital assets (human, financial, physical, natural, and social) and conceptualizes that households employ accumulative strategies in times of plenty and coping (survival) strategies in response to shocks such as TB. The proposed measure ascertains to what extent the 5 capital assets are available to households affected by TB as well as the coping costs (reversible and nonreversible) that are incurred by households at different time points (intensive, continuation, and post-TB treatment phase). We assert that our approach is holistic and multidimensional and draws attention to multisectoral responses to mitigate the socioeconomic impact of TB on households., Competing Interests: Potential conflicts of interest. K. K. reports grants or contracts from the European and Developing Countries Clinical Trials Partnership (ERASE-TB and VITALITY), the Wellcome Trust (impact of the typhoid conjugate vaccine), the Bill & Melinda Gates Foundation, and the China Center for Disease Control and Prevention (investigating COVID-19 vaccine effectiveness). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Throughout 2020, COVID-19 interventions prioritised symptomatic individuals despite growing evidence of pre-symptomatic and asymptomatic transmission. From the pandemic we have learned that global health is slow to quantify asymptomatic disease transmission and slow to implement relevant interventions. While asymptomatic infectious periods exist for nearly all pathogens, it is frequently ignored during case finding, and there are limited research efforts to understand its potential to drive small scale outbreaks, epidemics and pandemics. We conducted a pragmatic review on 15 key pathogens including SARS-CoV-2 and Ebola to demonstrate substantial variation in terminology around asymptomatic infectious individuals, and varying proportions of asymptomatic amongst prevalent infectious cases (0-99 %) and their contribution to transmission (0-96 %). While no pattern was discernible by pathogen type (virus, bacteria, parasite) or mode of transmission (direct, indirect or mixed), there are multiple lessons to learn from previous and current control programmes. As found during the COVID-19 pandemic, overlooking asymptomatic infectious individuals can impede disease control. Improving our understanding of how asymptomatic individuals can drive epidemics can strengthen our efforts to control current pathogens, and improve our preparedness for when the next new pathogen emerges.., Competing Interests: Declaration of Competing Interest N.S. reports current employment at Sanofi Pasteur, her Sanofi employment includes work on COVID-19, but does not benefit from the research conducted in this study. The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

Background: Mathematical modelling has been used extensively to estimate the potential impact of new tuberculosis vaccines, with the majority of existing models assuming that individuals with Mycobacterium tuberculosis (Mtb) infection remain at lifelong risk of tuberculosis disease. Recent research provides evidence that self-clearance of Mtb infection may be common, which may affect the potential impact of new vaccines that only take in infected or uninfected individuals. We explored how the inclusion of self-clearance in models of tuberculosis affects the estimates of vaccine impact in China and India., Methods: For both countries, we calibrated a tuberculosis model to a scenario without self-clearance and to various scenarios with self-clearance. To account for the current uncertainty in self-clearance properties, we varied the rate of self-clearance, and the level of protection against reinfection in self-cleared individuals. We introduced potential new vaccines in 2025, exploring vaccines that work in uninfected or infected individuals only, or that are effective regardless of infection status, and modelling scenarios with different levels of vaccine efficacy in self-cleared individuals. We then estimated the relative disease incidence reduction in 2050 for each vaccine compared with the no vaccination scenario., Findings: The inclusion of self-clearance increased the estimated relative reductions in incidence in 2050 for vaccines effective only in uninfected individuals, by a maximum of 12% in China and 8% in India. The inclusion of self-clearance increased the estimated impact of vaccines only effective in infected individuals in some scenarios and decreased it in others, by a maximum of 14% in China and 15% in India. As would be expected, the inclusion of self-clearance had minimal impact on estimated reductions in incidence for vaccines that work regardless of infection status., Interpretations: Our work suggests that the neglect of self-clearance in mathematical models of tuberculosis vaccines does not result in substantially biased estimates of tuberculosis vaccine impact. It may, however, mean that we are slightly underestimating the relative advantages of vaccines that work in uninfected individuals only compared with those that work in infected individuals., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Macronutrient and micronutrient deficiencies are associated with tuberculosis (TB) incidence. However, evidence is limited on the impact of micronutrient (vitamins and minerals) supplementation among underweight individuals. We conducted a secondary data analysis of a randomised controlled trial of lipid nutritional supplements with and without high-dose vitamin and mineral supplementation (LNS-VM vs LNS) for underweight (Body Mass Index [BMI] <18.5 kg/m2) adults with human immunodeficiency virus (HIV) initiating antiretroviral therapy (ART) in Tanzania and Zambia (2011-2013). Incident TB disease diagnoses were extracted from trial records. We used multivariable Cox regression to estimate hazard ratios (HR) for the impact of receiving LNS-VM on TB incidence, and the dose-response relationship between baseline BMI and TB incidence. Overall, 263 (17%) of 1506 participants developed TB disease. After adjusting for age, sex, CD4 count, haemoglobin, and C-reactive protein, receiving LNS-VM was not associated with TB incidence (aHR [95%CI] = 0.93 [0.72-1.20]; p = 0.57) compared to LNS alone. There was strong evidence for an association between lower BMI and incident TB (aHR [95%CI]: 16-16.9kg/m2 = 1.15 [0.82-1.62] and <16kg/m2 = 1.70 [1.26-2.30] compared to 17-18.5kg/m2; linear trend p<0.01). There was strong evidence that the rate of developing TB was lower after initiating ART (p<0.01). In conclusion, the addition of micronutrient supplementation to LNS was not associated with lower TB incidence in this underweight ART-naive population., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Schwalb et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Prevalence surveys show a substantial burden of subclinical (asymptomatic but infectious) tuberculosis, from which individuals can progress, regress, or even persist in a chronic disease state. We aimed to quantify these pathways across the spectrum of tuberculosis disease., Methods: We created a deterministic framework of untreated tuberculosis disease with progression and regression between three states of pulmonary tuberculosis disease: minimal (non-infectious), subclinical (asymptomatic but infectious), and clinical (symptomatic and infectious). We obtained data from a previous systematic review of prospective and retrospective studies that followed and recorded the disease state of individuals with tuberculosis in a cohort without treatment. These data were considered in a Bayesian framework, enabling quantitative estimation of tuberculosis disease pathways with rates of transition between states and 95% uncertainty intervals (UIs)., Findings: We included 22 studies with data from 5942 individuals in our analysis. Our model showed that after 5 years, 40% (95% UI 31·3-48·0) of individuals with prevalent subclinical disease at baseline recover and 18% (13·3-24·0) die from tuberculosis, with 14% (9·9-19·2) still having infectious disease, and the remainder with minimal disease at risk of re-progression. Over 5 years, 50% (40·0-59·1) of individuals with subclinical disease at baseline never develop symptoms. For those with clinical disease at baseline, 46% (38·3-52·2) die and 20% (15·2-25·8) recover from tuberculosis, with the remainder being in or transitioning between the three disease states after 5 years. We estimated the 10-year mortality of people with untreated prevalent infectious tuberculosis to be 37% (30·5-45·4)., Interpretation: For people with subclinical tuberculosis, classic clinical disease is neither an inevitable nor an irreversible outcome. As such, reliance on symptom-based screening means a large proportion of people with infectious disease might never be detected., Funding: TB Modelling and Analysis Consortium and European Research Council., Competing Interests: Declaration of interests FC coordinates a research project that received Xpert HR cartridges from Cepheid for evaluation of their utility for incipient tuberculosis. HE has participated on an advisory board for Cepheid concerning novel diagnostics with no payment or any other form of compensation received. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Tuberculosis remains a leading infectious cause of death in resource-limited settings. Effective treatment is the cornerstone of tuberculosis control, reducing mortality, recurrence and transmission. Supporting treatment adherence through facility-based observations of medication taking can be costly to providers and patients. Digital adherence technologies (DATs) may facilitate treatment monitoring and differentiated care. The ASCENT-Ethiopia study is a three-arm cluster randomised trial assessing two DATs with differentiated care for supporting tuberculosis treatment adherence in Ethiopia. This study is part of the ASCENT consortium, assessing DATs in South Africa, the Philippines, Ukraine, Tanzania and Ethiopia. The aim of this study is to determine the costs, cost-effectiveness and equity impact of implementing DATs in Ethiopia., Methods and Design: A total of 78 health facilities have been randomised (1:1:1) into one of two intervention arms or a standard-of-care arm. Approximately 50 participants from each health facility will be enrolled on the trial. Participants in facilities randomised to the intervention arms are offered a DAT linked to the ASCENT adherence platform for daily adherence monitoring and differentiated response for those who have missed doses. Participants at standard-of-care facilities receive routine care. Treatment outcomes and resource utilisation will be measured for each participant. The primary effectiveness outcome is a composite index of unfavourable end-of-treatment outcomes (lost to follow-up, death or treatment failure) or treatment recurrence within 6 months of end-of-treatment. For the cost-effectiveness analysis, end-of-treatment outcomes will be used to estimate disability-adjusted life years (DALYs) averted. Provider and patient cost data will be collected from a subsample of 5 health facilities per study arm, 10 participants per facility (n = 150). We will conduct a societal cost-effectiveness analysis using Bayesian hierarchical models that account for the individual-level correlation between costs and outcomes as well as intra-cluster correlation. An equity impact analysis will be conducted to summarise equity efficiency trade-offs., Discussion: Trial enrolment is ongoing. This paper follows the published trial protocol and describes the protocol and analysis plan for the health economics work package of the ASCENT-Ethiopia trial. This analysis will generate economic evidence to inform the implementation of DATs in Ethiopia and globally., Trial Registration: Pan African Clinical Trial Registry (PACTR) PACTR202008776694999. Registered on 11 August 2020,  https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=12241 ., (© 2023. The Author(s).)

Stages of tuberculosis disease can be delineated by radiology, microbiology, and symptoms, but transitions between these stages remain unclear. In a systematic review and meta-analysis of studies of individuals with untreated tuberculosis who underwent follow-up (34 cohorts from 24 studies, with a combined sample of 139 063), we aimed to quantify progression and regression across the tuberculosis disease spectrum by extracting summary estimates to align with disease transitions in a conceptual framework of the natural history of tuberculosis. Progression from microbiologically negative to positive disease (based on smear or culture tests) in participants with baseline radiographic evidence of tuberculosis occurred at an annualised rate of 10% (95% CI 6·2-13·3) in those with chest x-rays suggestive of active tuberculosis, and at a rate of 1% (0·3-1·8) in those with chest x-ray changes suggestive of inactive tuberculosis. Reversion from microbiologically positive to undetectable disease in prospective cohorts occurred at an annualised rate of 12% (6·8-18·0). A better understanding of the natural history of pulmonary tuberculosis, including the risk of progression in relation to radiological findings, could improve estimates of the global disease burden and inform the development of clinical guidelines and policies for treatment and prevention., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Competing Interests: CFM is funded by the Bill & Melinda Gates Foundation (TB MAC OPP1135288) and the Unitaid Adherence Support Coalition to End TB project (20193–3-ASCENT). PS is supported by Burroughs Wellcome Fund/American Society of Tropical Medicine and Hygiene postdoctoral fellowship, the Warren Alpert Foundation, the Government of India's Department of Biotechnology, the Indian Council of Medical Research, the US National Institute of Allergy and Infectious Diseases, the National Institutes of Health Office of AIDS Research, and distributed in part by US Civilian Research & Development Foundation Global. RMGJH is funded by a European Research Council Starting Grant (action number 757699). The other authors declare no competing interests.

Background: The importance of remote infection with M.tuberculosis as a cause of tuberculosis disease (TB) is unclear, with limited evidence of impact on TB rates beyond 10 years. Our objective was to assess rates of tuberculosis over 30 years by M.tuberculosis infection status at baseline in Karonga District, Northern Malawi., Materials and Methods: Population-based surveys of tuberculin skin testing (TST) from the 1980s were linked with follow-up and TB surveillance in Karonga district. We compared rates of microbiologically-confirmed TB by baseline TST induration <5mm (no evidence of M.tuberculosis infection) and those with baseline TST >17mm (evidence of M.tuberculosis infection), using hazard ratios by time since baseline and attributable risk percent. The attributable risk percent was calculated to estimate the proportion of TB in those infected that can be attributed to that prior infection. We analysed whole genome sequences of M.tuberculosis strains to identify recent transmission., Results: Over 412,959 person-years, 208 incident TB episodes were recorded. Compared to the small induration group, rates of TB were much higher in the first two years in the large induration group, and remained higher to 20 years: age, sex and area-adjusted hazard ratios (HR) 2-9 years post-TST 4.27 (95%CI 2.56-7.11); 10-19 years after TST 2.15 (1.10-4.21); ≥20 years post-TST 1.88 (0.76-4.65). The attributable risk percent of remote infection was 76.6% (60.9-85.9) 2-9 years post-TST, and 53.5% (9.1-76.2) 10-19 years post-TST. Individuals with large TST indurations had higher rates of unique-strain TB (HR adjusted for age, sex and area = HR 6.56 (95% CI 1.96-22.99)), suggesting disease following remote infection, but not of linked-strain TB (recent transmission)., Conclusions: M.tuberculosis infection can increase the risk of TB far beyond 10 years, accounting for a substantial proportion of TB occurring among those remotely infected., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Glynn et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The End TB strategy recommends social protection to mitigate socio-economic impacts of tuberculosis. Zimbabwe started implementing a conditional cash transfer (CCT) programme for people on drug resistant tuberculosis (DR-TB) treatment in 2013. We aimed to determine the proportion of people receiving CCT and effectiveness of CCT in improving treatment outcomes, explore their experiences with registering for CCT and understand the impact of CCT from the perspective of beneficiaries. Data from 2014-2021 were extracted from TB registers and CCT payment records within the National TB Programme. Sixteen in-depth interviews were conducted with people who were completing treatment or had completed treatment within two months. Poisson regression, adjusted for province, year of treatment, age and sex was used to investigate associations between receiving CCT and successful treatment outcomes among people who were in DR-TB care for ≥3 months after treatment initiation. Qualitative data were analyzed using thematic analysis. A total of 481 people were included in the quantitative study. Of these, 53% (254/481) received CCT at some point during treatment. People who exited DR-TB care within three months were 73% less likely to receive CCT than those who did not (prevalence ratio (PR) = 0.27 [95%CI: 0.18-0.41]). Among those who were alive and in care three months after treatment initiation, CCT recipients were 32% more likely to have successful outcomes than those who did not (adjusted PR = 1.32, [95%CI: 1.00-1.75]). Qualitative results revealed lack of knowledge about availability of CCT among people with DR-TB and missed opportunities by healthcare providers to provide information about availability of CCT. Delays and inconsistencies in disbursements of CCT were frequent themes. CCT were associated with successful treatment outcomes. Improvements in coverage, timeliness and predictability of disbursements are recommended., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Timire et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Tuberculosis (TB) still causes 1.5 million deaths globally each year. Over recent decades, slow and uneven declines in TB incidence have resulted in a falling prevalence of TB disease, which increasingly concentrates in vulnerable populations. Falling prevalence, while welcome, poses new challenges for TB surveillance. Cross-sectional disease surveys require very large sample sizes to accurately estimate disease burden, and even more participants to detect trends over time or identify high-risk areas or populations, making them prohibitively resource-intensive. In the past, tuberculin skin surveys measuring Mycobacterium tuberculosis (Mtb) immunoreactivity were widely used to monitor TB epidemiology in high-incidence settings, but were limited by challenges with both delivering and interpreting the test. Here we argue that the shifting epidemiology of tuberculosis, and the development of new tests for Mtb infection, make it timely and important to revisit the strategy of TB surveillance based on infection or immunoreactivity. Mtb infection surveys carry their own operational challenges and fundamental questions, for example: around survey design and frequency; which groups should be included; how the prevalence of immunoreactivity in a population should be used to estimate force of infection; how individual results should be interpreted and managed; and how surveillance can be delivered efficiently and ethically. However, if these knowledge gaps are addressed, the relative feasibility and lower costs of Mtb infection surveillance offer a powerful and affordable opportunity to better "know your TB epidemic", understand trends, identify high-risk and underserved communities, and tailor public health responses to dynamic epidemiology., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Rickman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)