Reevaluating progression and pathways following Mycobacterium tuberculosis infection within the spectrum of tuberculosis.

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.

Recent Travel and Tuberculosis in Migrants: Data From a Low-Incidence Country.

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.

Use of a Sustainable Livelihood Framework-Based Measure to Estimate Socioeconomic Impact of Tuberculosis on Households.

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.

Impact of Reversion of Mycobacterium tuberculosis Immunoreactivity Tests on the Estimated Annual Risk of Tuberculosis Infection.

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 prevalence of tuberculosis infection among foreign-born Canadians: a modelling study.

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.

Social determinants of the changing tuberculosis prevalence in Viet Nam: Analysis of population-level cross-sectional studies.

BACKGROUND: An ecological relationship between economic development and reduction in tuberculosis prevalence has been observed. Between 2007 and 2017, Viet Nam experienced rapid economic development with equitable distribution of resources and a 37% reduction in tuberculosis prevalence. Analysing consecutive prevalence surveys, we examined how the reduction in tuberculosis (and subclinical tuberculosis) prevalence was concentrated between socioeconomic groups. METHODS AND FINDINGS: We combined data from 2 nationally representative Viet Nam tuberculosis prevalence surveys with provincial-level measures of poverty. Data from 94,156 (2007) and 61,763 (2017) individuals were included. Of people with microbiologically confirmed tuberculosis, 21.6% (47/218) in 2007 and 29.0% (36/124) in 2017 had subclinical disease. We constructed an asset index using principal component analysis of consumption data. An illness concentration index was estimated to measure socioeconomic position inequality in tuberculosis prevalence. The illness concentration index changed from -0.10 (95% CI -0.08, -0.16; p = 0.003) in 2007 to 0.07 (95% CI 0.06, 0.18; p = 0.158) in 2017, indicating that tuberculosis was concentrated among the poorest households in 2007, with a shift towards more equal distribution between rich and poor households in 2017. This finding was similar for subclinical tuberculosis. We fitted multilevel models to investigate relationships between change in tuberculosis prevalence, individual risks, household socioeconomic position, and neighbourhood poverty. Controlling for provincial poverty level reduced the difference in prevalence, suggesting that changes in neighbourhood poverty contribute to the explanation of change in tuberculosis prevalence. A limitation of our study is that while tuberculosis prevalence surveys are valuable for understanding socioeconomic differences in tuberculosis prevalence in countries, given that tuberculosis is a relatively rare disease in the population studied, there is limited power to explore socioeconomic drivers. However, combining repeated cross-sectional surveys with provincial deprivation estimates during a period of remarkable economic growth provides valuable insights into the dynamics of the relationship between tuberculosis and economic development in Viet Nam. CONCLUSIONS: We found that with equitable economic growth and a reduction in tuberculosis burden, tuberculosis became less concentrated among the poor in Viet Nam.

Subclinical Tuberculosis Disease-A Review and Analysis of Prevalence Surveys to Inform Definitions, Burden, Associations, and Screening Methodology.

While it is known that a substantial proportion of individuals with tuberculosis disease (TB) present subclinically, usually defined as bacteriologically-confirmed but negative on symptom screening, considerable knowledge gaps remain. Our aim was to review data from TB prevalence population surveys and generate a consistent definition and framework for subclinical TB, enabling us to estimate the proportion of TB that is subclinical, explore associations with overall burden and program indicators, and evaluate the performance of screening strategies. We extracted data from all publicly available prevalence surveys conducted since 1990. Between 36.1% and 79.7% (median, 50.4%) of prevalent bacteriologically confirmed TB was subclinical. No association was found between prevalence of subclinical and all bacteriologically confirmed TB, patient diagnostic rate, or country-level HIV prevalence (P values, .32, .4, and .34, respectively). Chest Xray detected 89% (range, 73%-98%) of bacteriologically confirmed TB, highlighting the potential of optimizing current TB case-finding policies.

Ongoing challenges to understanding multidrug- and rifampicin-resistant tuberculosis in children versus adults.

Previous analyses suggest that children with tuberculosis (TB) are no more or no less likely to have multidrug (MDR)- or rifampicin-resistant (RR)-TB than adults. However, the availability of new data, particularly for high MDR/RR-TB burden countries, suggest updates of country-specific estimates are warranted.We used data from population-representative surveys and surveillance collected between 2000 and 2018 to compare the odds ratio of MDR/RR-TB among children (aged <15 years) with TB, compared to the odds of MDR/RR-TB among adults (aged ≥15 years) with TB.In most settings (45 out of 55 countries), and globally as a whole, there is no evidence that age is associated with odds of MDR/RR-TB. However, in some settings, such as former Soviet Union countries in general, and Georgia, Kazakhstan, Lithuania, Tajikistan and Uzbekistan in particular, as well as Peru, MDR/RR-TB is positively associated with age ≥15 years. Meanwhile, in Western Europe in general, and the United Kingdom, Poland, Finland and Luxembourg in particular, MDR/RR-TB is positively associated with age <15 years. 16 countries had sufficient data to compare over time between 2000-2011 and 2012-2018, with evidence for decreases in the odds ratio in children compared to adults in Germany, Kazakhstan and the United States of America.Our results support findings that in most settings a child with TB is as likely as an adult with TB to have MDR/RR-TB. However, setting-specific heterogeneity requires further investigation. Furthermore, the odds ratio for MDR/RR-TB in children compared to adults is generally either stable or decreasing. There are important gaps in detection, recording and reporting of drug resistance among paediatric TB cases, limiting our understanding of transmission risks and measures needed to combat the global TB epidemic.

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

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.

Estimating Long-term Tuberculosis Reactivation Rates in Australian Migrants.

BACKGROUND: The risk of progression to tuberculosis (TB) disease is greatest soon after infection, yet disease may occur many years or decades later. However, rates of TB reactivation long after infection remain poorly quantified. Australia has a low incidence of TB and most cases occur among migrants. We explored how TB rates in Australian migrants varied with time from migration, age, and gender. METHODS: We combined TB notifications in census years 2006, 2011, and 2016 with time- and country-specific estimates of latent TB prevalences in migrant cohorts to quantify postmigration reactivation rates. RESULTS: During the census years, 3246 TB cases occurred among an estimated 2 084 000 migrants with latent TB. There were consistent trends in postmigration reactivation rates, which appeared to be dependent on both time from migration and age. Rates were lower in cohorts with increasing time, until at least 20 years from migration, and on this background there also appeared to be increasing rates during youth (15-24 years of age) and in those aged 70 years and above. Within 5 years of migration, annual reactivation rates were approximately 400 per 100 000 (uncertainty interval [UI] 320-480), dropping to 170 (UI 130-220) from 5 to 10 years and 110 (UI 70-160) from 10 to 20 years, then sustaining at 60-70 per 100 000 up to 60 years from migration. Rates varied depending on age at migration. CONCLUSIONS: Postmigration reactivation rates appeared to show dependency on both time from migration and age. This approach to quantifying reactivation risks will enable evaluations of the potential impacts of TB control and elimination strategies.

What if They Don't Have Tuberculosis? The Consequences and Trade-offs Involved in False-positive Diagnoses of Tuberculosis.

To find the millions of missed tuberculosis (TB) cases, national TB programs are under pressure to expand TB disease screening and to target populations with lower disease prevalence. Together with imperfect performance and application of existing diagnostic tools, including empirical diagnosis, broader screening risks placing individuals without TB on prolonged treatment. These false-positive diagnoses have profound consequences for TB patients and prevention efforts, yet are usually overlooked in policy decision making. In this article we describe the pathways to a false-positive TB diagnosis, including trade-offs involved in the development and application of diagnostic algorithms. We then consider the wide range of potential consequences for individuals, households, health systems, and reliability of surveillance data. Finally, we suggest practical steps that the TB community can take to reduce the frequency and potential harms of false-positive TB diagnosis and to more explicitly assess the trade-offs involved in the screening and diagnostic process.

Chronic Respiratory Symptoms and Lung Abnormalities Among People With a History of Tuberculosis in Uganda: A National Survey.

BACKGROUND: People with pulmonary tuberculosis are at risk of developing chronic respiratory disorders due to residual lung damage. To date, the scope of the problem in high-burden tuberculosis countries is relatively unknown. METHODS: Chronic respiratory symptoms (cough and phlegm lasting >2 weeks) and radiological lung abnormalities were compared between adults with and without a history of tuberculosis among the general population of Uganda. Multivariable regression models were used to estimate odds ratios (ORs) with adjustment for age, gender, smoking, education, setting, and region. Random effects models accounted for village clustering effect. RESULTS: Of 45293 invited people from 70 villages, 41154 (90.9%) participated in the survey. A total of 798 had a history of tuberculosis and, among them, 16% had respiratory symptoms and 41% X-ray abnormalities. Adjusted ORs showed strong evidence for individuals with a history of tuberculosis having increased risk of respiratory symptoms (OR, 4.02; 95% confidence interval [CI], 3.25-4.96) and X-ray abnormalities (OR, 17.52; 95% CI, 14.76-20.79), attributing 6% and 24% of the respective population risks. CONCLUSIONS: In Uganda, a history of tuberculosis was a strong predictor of respiratory symptoms and lung abnormalities, before older age and smoking. Eliminating tuberculosis disease could reduce the prevalence of chronic respiratory symptoms as much as eliminating smoking.

The Importance of Heterogeneity to the Epidemiology of Tuberculosis.

Although less well-recognized than for other infectious diseases, heterogeneity is a defining feature of tuberculosis (TB) epidemiology. To advance toward TB elimination, this heterogeneity must be better understood and addressed. Drivers of heterogeneity in TB epidemiology act at the level of the infectious host, organism, susceptible host, environment, and distal determinants. These effects may be amplified by social mixing patterns, while the variable latent period between infection and disease may mask heterogeneity in transmission. Reliance on notified cases may lead to misidentification of the most affected groups, as case detection is often poorest where prevalence is highest. Assuming that average rates apply across diverse groups and ignoring the effects of cohort selection may result in misunderstanding of the epidemic and the anticipated effects of control measures. Given this substantial heterogeneity, interventions targeting high-risk groups based on location, social determinants, or comorbidities could improve efficiency, but raise ethical and equity considerations.

Identifying mixed Mycobacterium tuberculosis infections from whole genome sequence data.

BACKGROUND: Mixed, polyclonal Mycobacterium tuberculosis infection occurs in natural populations. Developing an effective method for detecting such cases is important in measuring the success of treatment and reconstruction of transmission between patients. Using whole genome sequence (WGS) data, we assess two methods for detecting mixed infection: (i) a combination of the number of heterozygous sites and the proportion of heterozygous sites to total SNPs, and (ii) Bayesian model-based clustering of allele frequencies from sequencing reads at heterozygous sites. RESULTS: In silico and in vitro artificially mixed and known pure M. tuberculosis samples were analysed to determine the specificity and sensitivity of each method. We found that both approaches were effective in distinguishing between pure strains and mixed infection where there was relatively high (> 10%) proportion of a minor strain in the mixture. A large dataset of clinical isolates (n = 1963) from the Karonga Prevention Study in Northern Malawi was tested to examine correlations with patient characteristics and outcomes with mixed infection. The frequency of mixed infection in the population was found to be around 10%, with an association with year of diagnosis, but no association with age, sex, HIV status or previous tuberculosis. CONCLUSIONS: Mixed Mycobacterium tuberculosis infection was identified in silico using whole genome sequence data. The methods presented here can be applied to population-wide analyses of tuberculosis to estimate the frequency of mixed infection, and to identify individual cases of mixed infections. These cases are important when considering the evolution and transmission of the disease, and in patient treatment.

A Bayesian Approach to Understanding Sex Differences in Tuberculosis Disease Burden.

Globally, men have a higher epidemiologic burden of tuberculosis (incidence, prevalence, mortality) than women do, possibly due to differences in disease incidence, treatment initiation, self-cure, and/or untreated-tuberculosis mortality rates. Using a simple, sex-stratified compartmental model, we employed a Bayesian approach to explore which factors most likely explain men's higher burden. We applied the model to smear-positive pulmonary tuberculosis in Vietnam (2006-2007) and Malawi (2013-2014). Posterior estimates were consistent with sex-specific prevalence and notifications in both countries. Results supported higher incidence in men and showed that both sexes faced longer durations of untreated disease than estimated by self-reports. Prior untreated disease durations were revised upward 8- to 24-fold, to 2.2 (95% credible interval: 1.7, 2.9) years for men in Vietnam and 2.8 (1.8, 4.1) years for men in Malawi, approximately a year longer than for women in each country. Results imply that substantial sex differences in tuberculosis burden are almost solely attributable to men's disadvantages in disease incidence and untreated disease duration. The latter, for which self-reports provide a poor proxy, implies inadequate coverage of case-finding strategies. These results highlight an urgent need for better understanding of gender-related barriers faced by men and support the systematic targeting of men for screening.

Estimating the prevalence of latent tuberculosis in a low-incidence setting: Australia.

Migration is a key driver of tuberculosis (TB) in many low-incidence settings, with the majority of TB cases attributed to reactivation of latent TB (LTBI) acquired overseas. A greater understanding of LTBI risk in heterogeneous migrant populations would aid health planning. We aimed to estimate the LTBI prevalence and distribution among locally born and overseas-born Australians.Annual risks of TB infection estimates were applied to population cohorts (by country of birth, year of arrival and age) in Australian census data in 2006, 2011 and 2016.Both the absolute number and proportion of Australian residents with LTBI increased from 4.6% (interquartile range (IQR) 4.2-5.2%) in 2006 to 5.1% (IQR 4.7-5.5%) in 2016, due to the increasing proportion of the population born overseas (23.8% in 2006 to 28.3% in 2016). Of all residents estimated to have LTBI in 2016; 93.2% were overseas born, 21.6% were aged <35 years and 34.4% had migrated to Australia since 2007.The overall prevalence of LTBI in Australia is low. Some residents, particularly migrants from high-incidence settings, may have considerably higher risk of LTBI, and these findings allow for tailored public health interventions to reduce the risk and impact of future TB disease.

Investigating the impact of TB case-detection strategies and the consequences of false positive diagnosis through mathematical modelling.

BACKGROUND: Increasing case notifications is one of the top programmatic priorities of National TB Control Programmes (NTPs). To find more cases, NTPs often need to consider expanding TB case-detection activities to populations with increasingly low prevalence of disease. Together with low-specificity diagnostic algorithms, these strategies can lead to an increasingly high number of false positive diagnoses, which has important adverse consequences. METHODS: We apply TIME, a widely-used country-level model, to quantify the expected impact of different case-finding strategies under two scenarios. In the first scenario, we compare the impact of implementing two different diagnostic algorithms (higher sensitivity only versus higher sensitivity and specificity) to reach programmatic screening targets. In the second scenario, we examine the impact of expanding coverage to a population with a lower prevalence of disease. Finally, we explore the implications of modelling without taking into consideration the screening of healthy individuals. Outcomes considered were changes in notifications, the ratio of additional false positive to true positive diagnoses, the positive predictive value (PPV), and incidence. RESULTS: In scenario 1, algorithm A of prolonged cough and GeneXpert yielded fewer additional notifications compared to algorithm B of any symptom and smear microscopy (n = 4.0 K vs 13.8 K), relative to baseline between 2017 and 2025. However, algorithm A resulted in an increase in PPV, averting 2.4 K false positive notifications thus resulting in a more efficient impact on incidence. Scenario 2 demonstrated an absolute decrease of 11% in the PPV as intensified case finding activities expanded into low-prevalence populations without improving diagnostic accuracy, yielding an additional 23 K false positive diagnoses for an additional 1.3 K true positive diagnoses between 2017 and 2025. Modelling the second scenario without taking into account screening amongst healthy individuals overestimated the impact on cases averted by a factor of 6. CONCLUSION: Our findings show that total notifications can be a misleading indicator for TB programme performance, and should be interpreted carefully. When evaluating potential case-finding strategies, NTPs should consider the specificity of diagnostic algorithms and the risk of increasing false-positive diagnoses. Similarly, modelling the impact of case-finding strategies without taking into account potential adverse consequences can overestimate impact and lead to poor strategic decision-making.

Ability of preventive therapy to cure latent Mycobacterium tuberculosis infection in HIV-infected individuals in high-burden settings.

Trials of isoniazid preventive therapy (IPT) for people living with HIV in southern Africa have shown high rates of tuberculosis disease immediately after cessation of therapy. This could be due to the lack of cure following preventive therapy or reinfection with rapid progression to disease. Using a model fitted to trial data, we estimate the degree to which preventive therapies cure latent Mycobacterium tuberculosis infection in HIV-infected individuals in high-tuberculosis-burden settings. We identified randomized controlled trials that compared IPT to placebo or alternative regimen in HIV-positive, tuberculin skin test positive individuals. A mathematical model describing tuberculosis transmission in a closed cohort of HIV-positive, M. tuberculosis infected, antiretroviral therapy naive individuals following completion of preventive therapy (or placebo) was fitted to posttherapy tuberculosis rates to estimate the annual risk of M. tuberculosis reinfection and the proportion of individuals whose latent infection was cured after therapy. Three trials met our inclusion criteria. Estimated annual risks of reinfection ranged between 3.7 and 4.9%. Our results suggest 6 mo of isoniazid cured in a small proportion [estimated proportion cured = 0% (interquartile range 0-30.9%)]. The proportion cured for 3-mo regimens containing rifampicin or rifapentine was 19-100%. IPT alone does not cure existing infections in the majority of HIV-infected individuals. In high-incidence settings, continuous IPT should be integrated with HIV care. Where the risk of reinfection is lower, preventive therapy with more curative drugs should be preferred for HIV-positive individuals to achieve durable patient benefit.