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, thus enabling an estimate of the proportion of TB that is subclinical, explore associations with overall burden and programme indicators, and performance of screening strategies. We extracted data from all publicly available prevalence surveys conducted since 1990. Between 36.1–79.7% (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, 0.32, 0.4, 0.34, respectively). Chest X-ray detected 89% (range 73–98%) of bacteriologically-confirmed TB disease, highlighting the potential of optimizing current TB case-finding policies.
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.
Background: Prevalence surveys have found a substantial burden of subclinical (asymptomatic but infectious) TB, from which individuals can progress, regress or even persist in a chronic disease state. We aimed to quantify these pathways across the spectrum of TB disease. Methods: We created deterministic framework of TB disease with progression and regression between three states of pulmonary TB disease: minimal (non-infectious), subclinical, and clinical (symptomatic and infectious) disease. We estimated ranges for each parameter by considering all data from a systematic review in a Bayesian framework, enabling quantitative estimation of TB disease pathways. Findings: Twenty-four studies contributed data from 6030 individuals. Results suggested that, after five years, 24.7%(95% uncertainty interval, UI, 21.3%-28.6%) of individuals with prevalent subclinical disease at baseline had either progressed to clinical disease or died from TB, whereas 16.1%(95%UI, 13.8%-18.5%) had recovered after regressing to minimal disease. Over the course of five years 30% (95%UI, 27.2%-32.6%) of the subclinial cohort never developed symptoms. For those with clinical disease at baseline, 39%(95%UI, 35.8%-41.9%) and 10.3%(95%UI, 8.5%-12.4%) had died or recovered from TB, with the remainder in, or undulating between, the three disease states. The ten-year mortality of people with untreated prevalent infectious disease was 38%. Interpretation: Our results show that for people with subclinical disease, classic clinical disease is neither inevitable nor an irreversible outcome. As such, reliance on symptom- based screening means a large proportion of people with infectious disease may never be detected. Funding: TB Modelling and Analysis Consortium and European Research Council
BACKGROUNDKey stages in TB disease can be delineated by radiology, microbiology and symptoms, but transition between relevant stages remains unclear. We sought to quantify progression and regression across the spectrum of TB disease by systematically reviewing studies of individuals with untreated TB undergoing follow up.METHODSWe searched PubMED, EMBASE and Web of Science until December 31st 1960, the Index Medicus between 1895 and 1945, and extensive investigator collections without date restriction - in English and German. Eligible studies were observational cohorts and clinical trials, presenting adults/adolescents with TB or recent TB exposure, undergoing follow-up for at least 12 months without therapeutic intervention. Two authors independently reviewed titles/abstracts and full texts for inclusion. Quality was assessed with a modified Newcastle-Ottawa Score, excluding highly biased studies. Summary estimates were extracted to align with TB disease transitions in a conceptual model, and we used meta-analysis of proportions with random-effects to synthesise the extracted data. This study is registered with PROSPERO (CRD42019152585).FINDINGS10477 titles were screened and 1648 full texts reviewed. 223 met inclusion criteria. 109 were excluded for high risk of bias and 90 did not have extractable data. 24 studies (34 cohorts) were included. Progression from microbiologically negative to positive disease in those with radiographic TB evidence occurred at an annualized rate of 9.71% (95% CI:6.17-13.34) with “active” TB imaging, and 1.06% (95% CI:0.31-1.82) with “inactive” TB imaging. Reversion from microbiologically-positive to -undetectable in prospective cohorts occurred at an annualized rate of 12.40% (95% CI: 6.81-17.99). Studies reported symptoms poorly not allowing for direct estimation of transitions for subclinical (asymptomatic, culture positive) disease.INTERPRETATIONWe present the risk of progression in those with radiographic evidence of disease and the rate of self-cure for microbiologically positive disease to inform global disease burden estimates, clinical guidelines and policy decisions.
Background Individuals with bacteriologically confirmed pulmonary tuberculosis disease (TB) that 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 time of diagnosis (clinical TB). Relative infectiousness can be approximated by cumulative infections in household contacts, but such data are rare. Methods and Findings We reviewed the literature to identify studies where surveys of Mtb infection were linked to population surveys of TB disease. We collated individual population data 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. We collated data on 414 index cases and 789 household contacts from three prevalence surveys (Bangladesh, Philippines, Viet Nam) and one case-finding trial in Viet Nam. The odds ratio of household infection prevalence 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)). 14 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.
Background: Traditional understanding of the risk of progression fromMycobacterium tuberculosis(Mtb) infection to tuberculosis (TB) disease overlooks nuance across a spectrum of disease. Methods: We developed a deterministic model ofMtbinfection and minimal (pathological damage but not infectious), subclinical (infectious but no reported symptoms), and clinical (infectious and symptomatic) TB disease, 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 disease, 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 ten-year outcomes followingMtbinfection for a simulated cohort. Results: 90.8% (95% uncertainty interval, UI, 90.2-91.3) of individuals self-cleared within 10 years of infection, while 9.3% (95% UI 8.4-10.0) progressed to TB disease. Of those, 68.1% (95% UI 65.1-71.1) developed infectious disease, and 32.7% (95% UI 29.7-35.7) progressed to clinical disease. While 93% of progression to minimal disease occurred within two years of infection, only 63% and 38% of subclinical and clinical disease, respectively, occurred within this period. Multiple progression pathways from infection were necessary to calibrate the model, and 48.8% (95% UI 45.0-52.6) of those who developed infectious disease undulated between disease states. Conclusions: We identified highly heterogeneous pathways across disease states afterMtbinfection, highlighting the need for clearly defined disease thresholds to inform more effective prevention and treatment efforts to end TB.
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