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 is a low-TB incidence setting 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 oflatent TB prevalence in migrant cohorts to quantifypost-migration reactivation rates. RESULTS: During the census years 3,246 TB cases occurred among an estimated 2,084,000 migrants with latent-TB. There were consistent trends in post-migration 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 twenty 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 five years of migration, annual reactivation rates were approximately 400 per 100,000 (uncertainty interval [UI]: 320-480), dropping to 170 (UI: 130-220) and 110 (UI: 70-160) from five-to-ten and ten-to-twenty, then sustaining at 60-70 per 100,000 up to sixty years from migration. Rates varied depending on age at migration. CONCLUSIONS: Post-migration reactivation rates appeared to show dependency on both time from migration and age. This approach to quantifying reactivation risk will enable evaluation of the potential impact of TB control and elimination strategies

Geospatial clustering and modelling provide policy guidance to distribute funding for active TB case finding in Ethiopia

Tuberculosis (TB) exhibits considerable spatial heterogeneity, occurring in clusters that may act as hubs of community transmission. We evaluated the impact of an intervention targeting spatial TB hotspots in a rural region of Ethiopia. To evaluate the impact of targeted active case finding (ACF), we used a spatially structured mathematical model that has previously been described. From model equilibrium, we simulated the impact of a hotspot-targeted strategy (HTS) on TB incidence ten years from intervention commencement and the associated cost-effectiveness. HTS was also compared with an untargeted strategy (UTS). We used logistic cost-coverage analysis to estimate cost-effectiveness of interventions. At a community screening coverage level of 95% in a hotspot region, which corresponds to screening 20% of the total population, HTS would reduce overall TB incidence by 52% compared with baseline. For UTS to achieve an equivalent effect, it would be necessary to screen more than 80% of the total population. Compared to the existing passive case detection strategy, the HTS at a CDR of 75 percent in hotspot regions is expected to avert 1,023 new TB cases over ten years saving USD 170 per averted case. Similarly, at the same CDR, the UTS will detect 1316 cases over the same period saving USD 3 per averted TB case. The incremental-cost effectiveness-ratio (ICER) of UTS compared with HTS is USD 582 per averted case corresponding to 293 more TB cases averted at an additional cost of USD 170,700. Where regional TB program spending was capped at current levels, maximum gains in incidence reduction were seen when the regional budget was shared between hotspots and non-hotspot regions in the ratio of 40% to 60%. Our analysis suggests that a spatially targeted strategy is efficient and cost-saving, with the potential for significant reduction in overall TB burden

Strategic investment in tuberculosis control in the Republic of Bulgaria

As Bulgaria transitions away from Global Fund grant, robust estimates of the comparative impact of the various response strategies under consideration are needed to ensure sustained effectiveness of the tuberculosis (TB) programme. We tailored an established mathematical model for TB control to the epidemic in Bulgaria to project the likely outcomes of seven intervention scenarios. Under existing programmatic conditions projected forward, the country's targets for achieving TB elimination in the coming decades will not be achieved. No interventions under consideration were predicted to accelerate the baseline projected reduction in epidemiological indicators significantly. Discontinuation of the 'Open Doors' program and activities of non-governmental organisations would result in a marked exacerbation of the epidemic (increasing incidence in 2035 by 6-8% relative to baseline conditions projected forward). Changing to a short course regimen for multidrug-resistant TB (MDR-TB) would substantially decrease MDR-TB mortality (by 21.6% in 2035 relative to baseline conditions projected forward). Changing to ambulatory care for eligible patients would not affect TB burden but would be markedly cost-saving. In conclusion, Bulgaria faces important challenges in transitioning to a primarily domestically-financed TB programme. The country should consider maintaining currently effective programs and shifting towards ambulatory care to ensure program sustainability

A multistate model of health transitions in older people: a secondary analysis of ASPREE clinical trial data

Background: Understanding the nature of transitions from a healthy state to chronic diseases and death is important for planning health-care system requirements and interventions. We aimed to quantify the trajectories of disease and disability in a population of healthy older people. Methods: We conducted a secondary analysis of data from the ASPREE trial, which was done in 50 sites in Australia and the USA and recruited community-dwelling, healthy individuals who were aged 70 years or older (≥65 years for Black and Hispanic people in the USA) between March 10, 2010, and Dec 24, 2014. Participants were followed up with annual face-to-face visits, biennial assessments of cognitive function, and biannual visits for physical function until death or June 12, 2017, whichever occurred first. We used multistate models to examine transitions from a healthy state to first intermediate disease events (ie, cancer events, stroke events, cardiac events, and physical disability or dementia) and, ultimately, to death. We also examined the effects of age and sex on transition rates using Cox proportional hazards regression models. Findings: 19 114 participants with a median age of 74·0 years (IQR 71·6–77·7) were included in our analyses. During a median follow-up of 4·7 years (IQR 3·6–5·7), 1933 (10·1%) of 19 114 participants had an incident cancer event, 487 (2·5%) had an incident cardiac event, 398 (2·1%) had an incident stroke event, 924 (4·8%) developed persistent physical disability or dementia, and 1052 (5·5%) died. 15 398 (80·6%) individuals did not have any of these events during follow-up. The highest proportion of deaths followed incident cancer (501 [47·6%] of 1052) and 129 (12·3%) participants transitioned from disability or dementia to death. Among 12 postulated transitions, transitions from the intermediate states to death had much higher rates than transitions from a healthy state to death. The progression rates to death were 158 events per 1000 person-years (95% CI 144–172) from cancer, 112 events per 1000 person-years (86–145) from stroke, 88 events per 1000 person-years (68–111) from cardiac disease, 69 events per 1000 person-years (58–82) from disability or dementia, and four events per 1000 person-years (4–5) from a healthy state. Age was significantly associated with an accelerated rate for most transitions. Male sex (vs female sex) was significantly associated with an accelerate rate for five of 12 transitions. Interpretation: We describe a multistate model in a healthy older population in whom the most common transition was from a healthy state to cancer. Our findings provide unique insights into the frequency of events, their transition rates, and the impact of age and sex. These results have implications for preventive health interventions and planning for appropriate levels of residential care in healthy ageing populations. Funding: The National Institutes of Health

The Importance of Heterogeneity to the Epidemiology of Tuberculosis

Although less well-recognised than for other infectious diseases, heterogeneity is a defining feature of 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 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

Risk factors for infectiousness of patients with tuberculosis: a systematic review and meta-analysis

We performed a systematic review and meta-analyses of studies assessing tuberculosis (TB) patient-related risk factors for transmission of Mycobacterium tuberculosis infection. Meta-analyses were conducted for sputum smear-positivity, lung cavitation and HIV seropositivity of index patients with both crude and adjusted odds ratios (AORs) pooled using random effect models. Thirty-seven studies were included in the review. We found that demographic characteristics such as age and sex were not significant risk factors, while behaviours such as smoking and alcohol intake were associated with infectiousness although inconsistently. Treatment delay of >28 days was a significant predictor of greater infectiousness. Contacts of sputum smear-positive index patients were found to be more likely to be infected than contacts of sputum smear-negative patients, with a pooled AOR of 2.15 (95% confidence interval (CI) 1.47-3.17, I-2 = 38%). Similarly, contacts of patients with the cavitary disease were around twice as likely to be infected as contacts of patients without cavitation (pooled AOR 1.9, 95% CI 1.26-2.84, I-2 = 63%). In contrast, HIV seropositive patients were associated with few contact infections than HIV seronegative patients (AOR 0.45, 95% CI 0.26-0.80, I-2 = 52%). In conclusion, behavioural and clinical characteristics of TB patients can be used to identify highly infectious patients for targeted interventions

Is IPT more effective in high-burden settings? Modelling the effect of tuberculosis incidence on IPT impact

Setting: Isoniazid preventive therapy (IPT) is effective for preventing active tuberculosis (TB), although its mechanism of action is poorly understood and the optimal disease burden for IPT use has not been defined. Objective: To describe the relationship between TB incidence and IPT effectiveness. Methods: We constructed a model of TB transmission dynamics to investigate IPT effectiveness under various epidemiological settings. The model structure was intended to be highly adaptable to uncertainty in both input parameters and the mechanism of action of IPT. To determine the optimal setting for IPT use, we identified the lowest number needed to treat (NNT) with IPT to prevent one case of active TB. Results: We found that the NNT as a function of TB incidence shows a ‘U-shape’, whereby IPT impact is greatest at an intermediate incidence and attenuated at both lower and higher incidence levels. This U-shape was observed over a broad range of parameter values; the optimal TB incidence was between 500 and 900 cases per 100 000 per year. Conclusions: TB burden is a critical factor to consider when making decisions about communitywide implementation of IPT. We believe that the total disease burden should not preclude programmatic application of IPT

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