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Background. Individuals infected with Mycobacterium tuberculosis (Mtb) may develop symptoms and signs of disease (tuberculosis disease) or may have no clinical evidence of disease (latent tuberculosis infection [LTBI]). Tuberculosis disease is a leading cause of infectious disease morbidity and mortality worldwide, yet many questions related to its diagnosis remain. Methods. A task force supported by the American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America searched, selected, and synthesized relevant evidence. The evidence was then used as the basis for recommendations about the diagnosis of tuberculosis disease and LTBI in adults and children. The recommendations were formulated, written, and graded using the Grading, Recommendations, Assessment, Development and Evaluation (GRADE) approach. Results. Twenty-three evidence-based recommendations about diagnostic testing for latent tuberculosis infection, pulmonary tuberculosis, and extrapulmonary tuberculosis are provided. Six of the recommendations are strong, whereas the remaining 17 are conditional. Conclusions. These guidelines are not intended to impose a standard of care. They provide the basis for rational decisions in the diagnosis of tuberculosis in the context of the existing evidence. No guidelines can take into account all of the often compelling unique individual clinical circumstances.

Individuals infected with Mycobacterium tuberculosis (Mtb) may develop symptoms and signs of disease (tuberculosis disease) or may have no clinical evidence of disease (latent tuberculosis infection [LTBI]). Tuberculosis disease is a leading cause of infectious disease morbidity and mortality worldwide, yet many questions related to its diagnosis remain. A task force supported by the American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America searched, selected, and synthesized relevant evidence. The evidence was then used as the basis for recommendations about the diagnosis of tuberculosis disease and LTBI in adults and children. The recommendations were formulated, written, and graded using the Grading, Recommendations, Assessment, Development and Evaluation (GRADE) approach. Twenty-three evidence-based recommendations about diagnostic testing for latent tuberculosis infection, pulmonary tuberculosis, and extrapulmonary tuberculosis are provided. Six of the recommendations are strong, whereas the remaining 17 are conditional. These guidelines are not intended to impose a standard of care. They provide the basis for rational decisions in the diagnosis of tuberculosis in the context of the existing evidence. No guidelines can take into account all of the often compelling unique individual clinical circumstances.

People with immunoreactivity to tuberculosis are thought to have lifelong asymptomatic infection and remain at risk for active tuberculosis. Marcel A Behr and colleagues argue that most of these people are no longer infected

The existing estimate of the global burden of latent TB infection (LTBI) as \"one-third\" of the world population is nearly 20 y old. Given the importance of controlling LTBI as part of the End TB Strategy for eliminating TB by 2050, changes in demography and scientific understanding, and progress in TB control, it is important to re-assess the global burden of LTBI. We constructed trends in annual risk in infection (ARI) for countries between 1934 and 2014 using a combination of direct estimates of ARI from LTBI surveys (131 surveys from 1950 to 2011) and indirect estimates of ARI calculated from World Health Organisation (WHO) estimates of smear positive TB prevalence from 1990 to 2014. Gaussian process regression was used to generate ARIs for country-years without data and to represent uncertainty. Estimated ARI time-series were applied to the demography in each country to calculate the number and proportions of individuals infected, recently infected (infected within 2 y), and recently infected with isoniazid (INH)-resistant strains. Resulting estimates were aggregated by WHO region. We estimated the contribution of existing infections to TB incidence in 2035 and 2050. In 2014, the global burden of LTBI was 23.0% (95% uncertainty interval [UI]: 20.4%-26.4%), amounting to approximately 1.7 billion people. WHO South-East Asia, Western-Pacific, and Africa regions had the highest prevalence and accounted for around 80% of those with LTBI. Prevalence of recent infection was 0.8% (95% UI: 0.7%-0.9%) of the global population, amounting to 55.5 (95% UI: 48.2-63.8) million individuals currently at high risk of TB disease, of which 10.9% (95% UI:10.2%-11.8%) was isoniazid-resistant. Current LTBI alone, assuming no additional infections from 2015 onwards, would be expected to generate TB incidences in the region of 16.5 per 100,000 per year in 2035 and 8.3 per 100,000 per year in 2050. Limitations included the quantity and methodological heterogeneity of direct ARI data, and limited evidence to inform on potential clearance of LTBI. We estimate that approximately 1.7 billion individuals were latently infected with Mycobacterium tuberculosis (M.tb) globally in 2014, just under a quarter of the global population. Investment in new tools to improve diagnosis and treatment of those with LTBI at risk of progressing to disease is urgently needed to address this latent reservoir if the 2050 target of eliminating TB is to be reached.

The risk of tuberculosis (TB) is variable among individuals with latent Mycobacterium tuberculosis infection (LTBI), but validated estimates of personalized risk are lacking. In pooled data from 18 systematically identified cohort studies from 20 countries, including 80,468 individuals tested for LTBI, 5-year cumulative incident TB risk among people with untreated LTBI was 15.6% (95% confidence interval (CI), 8.0–29.2%) among child contacts, 4.8% (95% CI, 3.0–7.7%) among adult contacts, 5.0% (95% CI, 1.6–14.5%) among migrants and 4.8% (95% CI, 1.5–14.3%) among immunocompromised groups. We confirmed highly variable estimates within risk groups, necessitating an individualized approach to risk stratification. Therefore, we developed a personalized risk predictor for incident TB (PERISKOPE-TB) that combines a quantitative measure of T cell sensitization and clinical covariates. Internal–external cross-validation of the model demonstrated a random effects meta-analysis C-statistic of 0.88 (95% CI, 0.82–0.93) for incident TB. In decision curve analysis, the model demonstrated clinical utility for targeting preventative treatment, compared to treating all, or no, people with LTBI. We challenge the current crude approach to TB risk estimation among people with LTBI in favor of our evidence-based and patient-centered method, in settings aiming for pre-elimination worldwide. The risk of developing active tuberculosis (TB) in individuals with latent TB infection is highly variable within and among different risk groups. A personalized risk predictor was developed to better target preventative treatment to individuals at greatest risk, supporting evidence-based clinical decision-making for latent TB.

Latent tuberculosis has been recognized for over a century, but discovery of new niches, where Mycobacterium tuberculosis resides, continues. We evaluated literature on M.tuberculosis locations during latency, highlighting that mesenchymal and hematopoietic stem cells harbor organisms in sensitized asymptomatic individuals.

Understanding how Mycobacterium tuberculosis is controlled by the body, leading to active disease in only a small fraction of infected individuals, is important for developing medical interventions to prevent and manage disease. Lin et al . now show that infected macaques with active tuberculosis have some sterile granulomas, suggesting immune-mediated control at certain sites of infection. Insight into the mechanisms underlying the heterogeneity of mycobacterial killing may inform vaccine development. Over 30% of the world's population is infected with Mycobacterium tuberculosis (Mtb), yet only ∼5–10% will develop clinical disease 1 . Despite considerable effort, researchers understand little about what distinguishes individuals whose infection progresses to active tuberculosis (TB) from those whose infection remains latent for decades. The variable course of disease is recapitulated in cynomolgus macaques infected with Mtb 2 . Active disease occurs in ∼45% of infected macaques and is defined by clinical, microbiologic and immunologic signs, whereas the remaining infected animals are clinically asymptomatic 2 , 3 . Here, we use individually marked Mtb isolates and quantitative measures of culturable and cumulative bacterial burden to show that most lung lesions are probably founded by a single bacterium and reach similar maximum burdens. Despite this observation, the fate of individual lesions varies substantially within the same host. Notably, in active disease, the host sterilizes some lesions even while others progress. Our data suggest that lesional heterogeneity arises, in part, through differential killing of bacteria after the onset of adaptive immunity. Thus, individual lesions follow diverse and overlapping trajectories, suggesting that critical responses occur at a lesional level to ultimately determine the clinical outcome of infection. Defining the local factors that dictate outcome will be useful in developing effective interventions to prevent active TB.

RNA sequencing and microarray analysis revealed transcriptional markers expressed in whole blood can differentiate active pulmonary TB (ATB) from other respiratory diseases (ORDs), and latent TB infection (LTBI) from healthy controls (HC). Here we describe a streamlined reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) assay that could be applied at near point-of-care for diagnosing and distinguishing ATB from ORDs and LTBI from HC. A literature review was undertaken to identify the most plausible host-gene markers (HGM) of TB infection. Primers, and dual labelled hydrolysis probes were designed and analytically evaluated for accuracy in an in-vitro model of infection using a lung fibroblast cell-line. Best performing genes were multiplexed into panels of 2–4 targets and taken forward for clinical evaluation. Mycobacteria Growth Indicator Tube and QuantiFERON-TB Gold Plus were used as reference tests for ATB and LTBI respectively. A total of 16 HGM were selected and incorporated into five multiplex RT-qPCR panels. PCR assay efficiency of all evaluated targets was ≥ 90% with a median analytical sensitivity of 292 copies/µl [IQR: 215.0-358.3 copies/µl], and a median limit of quantification of 61.7 copies/µl [IQR: 29.4-176.3 copies/µl]. Clinically, ATB was characterised by higher gene expression than ORDs, while LTBI was associated with lower gene expression than HC, Kruskal-Wallis p < 0.0001. Crucially, BATF2, CD64, GBP5, C1QB, GBP6, DUSP3, and GAS6 exhibited high differentiative ability for ATB from ORDs, LTBI or HC while KLF2, PTPRC, NEMF, ASUN, and ZNF296 independently discriminated LTBI from HC. Our results show that different HGM maybe required for ATB and LTBI differentiation from ORDs or HC respectively and demonstrate the feasibility of host gene-based RT-qPCR to diagnose ATB and LTBI at near point-of-care.

This study was conducted to investigate the role of iron deprivation in the persistence of Mycobacterium tuberculosis . We present evidence of iron restriction in human necrotic granulomas and demonstrate that under iron starvation M. tuberculosis persists, refractive to antibiotics and capable of restarting replication when iron is made available. Transcriptomics and metabolomic analyses indicated that the persistence of M. tuberculosis under iron starvation is dependent on strict control of endogenous Fe utilization and is associated with upregulation of pathogenicity and intrinsic antibiotic resistance determinants. M. tuberculosis mutants compromised in their ability to survive Fe starvation were identified. The findings of this study advance the understanding of the physiological settings that may underpin the chronicity of human tuberculosis (TB) and are relevant to the design of effective antitubercular therapies. IMPORTANCE One-third of the world population may harbor persistent M. tuberculosis , causing an asymptomatic infection that is refractory to treatment and can reactivate to become potentially lethal tuberculosis disease. However, little is known about the factors that trigger and maintain M. tuberculosis persistence in infected individuals. Iron is an essential nutrient for M. tuberculosis growth. In this study, we show, first, that in human granulomas the immune defense creates microenvironments in which M. tuberculosis likely experiences drastic Fe deprivation and, second, that Fe-starved M. tuberculosis is capable of long-term persistence without growth. Together, these observations suggest that Fe deprivation in the lung might trigger a state of persistence in M. tuberculosis and promote chronic TB. We also identified vulnerabilities of iron-restricted persistent M. tuberculosis , which can be exploited for the design of new antitubercular therapies. One-third of the world population may harbor persistent M. tuberculosis , causing an asymptomatic infection that is refractory to treatment and can reactivate to become potentially lethal tuberculosis disease. However, little is known about the factors that trigger and maintain M. tuberculosis persistence in infected individuals. Iron is an essential nutrient for M. tuberculosis growth. In this study, we show, first, that in human granulomas the immune defense creates microenvironments in which M. tuberculosis likely experiences drastic Fe deprivation and, second, that Fe-starved M. tuberculosis is capable of long-term persistence without growth. Together, these observations suggest that Fe deprivation in the lung might trigger a state of persistence in M. tuberculosis and promote chronic TB. We also identified vulnerabilities of iron-restricted persistent M. tuberculosis , which can be exploited for the design of new antitubercular therapies.

Infection with Mycobacterium tuberculosis causes a spectrum of outcomes; the majority of individuals contain but do not eliminate the infection, while a small subset present with primary active tuberculosis (TB) disease. This variability in infection outcomes is recapitulated at the granuloma level within each host, such that some sites of infection can be fully cleared while others progress. Understanding the spectrum of TB outcomes requires new tools to deconstruct the mechanisms underlying differences in granuloma fate. Here, we use novel genome-encoded barcodes to uniquely tag individual M. tuberculosis bacilli, enabling us to quantitatively track the trajectory of each infecting bacterium in a macaque model of TB. We also introduce a robust bioinformatics pipeline capable of identifying and counting barcode sequences within complex mixtures and at various read depths. By coupling this tagging strategy with serial positron emission tomography coregistered with computed tomography (PET/CT) imaging of lung pathology in macaques, we define a lesional map of M. tuberculosis infection dynamics. We find that there is no significant infection bottleneck, but there are significant constraints on productive bacterial trafficking out of primary granulomas. Our findings validate our barcoding approach and demonstrate its utility in probing lesion-specific biology and dissemination. This novel technology has the potential to greatly enhance our understanding of local dynamics in tuberculosis. IMPORTANCE Classically, M. tuberculosis infection was thought to result in either latent infection or active disease. More recently, the field has recognized that there is a spectrum of M. tuberculosis infection clinical outcomes. Within a single host, this spectrum is recapitulated at the granuloma level, where there can simultaneously be lesional sterilization and poorly contained disease. To better understand the lesional biology of TB infection, we digitally barcoded M. tuberculosis to quantitatively track the fate of each infecting bacterium. By combining this technology with serial PET-CT imaging, we can dynamically track both bacterial populations and granuloma trajectories. We demonstrate that there is little constraint on the bacterial population at the time of infection. However, the granuloma imposes a strong bottleneck on dissemination, and the subset of granulomas at risk of dissemination can be distinguished by physical features. Classically, M. tuberculosis infection was thought to result in either latent infection or active disease. More recently, the field has recognized that there is a spectrum of M. tuberculosis infection clinical outcomes. Within a single host, this spectrum is recapitulated at the granuloma level, where there can simultaneously be lesional sterilization and poorly contained disease. To better understand the lesional biology of TB infection, we digitally barcoded M. tuberculosis to quantitatively track the fate of each infecting bacterium. By combining this technology with serial PET-CT imaging, we can dynamically track both bacterial populations and granuloma trajectories. We demonstrate that there is little constraint on the bacterial population at the time of infection. However, the granuloma imposes a strong bottleneck on dissemination, and the subset of granulomas at risk of dissemination can be distinguished by physical features.