Vitamin D and cathelicidin levels and susceptibility to Mycobacterium tuberculosis infection acquisition in household contacts / Niveles de vitamina D y catelicidina y susceptibilidad a la infección por Mycobacterium tuberculosis en contactos intradomiciliarios

Introduction Vitamin D deficiency has been proposed to confer susceptibility to acquiring tuberculosis infection by impairing the innate immune response. Methods In an exploratory study, we examined whether the levels of 25-hydroxyvitamin D3 (25(OH)D3) in serum, and cathelicidin – an antimicrobial peptide-induced under calcitriol – in the nasal fluid, would associate with the risk of acquiring tuberculosis infection. Results Within a prospective cohort of 231 tuberculosis household contacts tested with repeated interferon-gamma release assays, we serially analyzed all the uninfected contacts acquiring tuberculosis infection at follow-up (“converters”, n=18), and an age and sex-matched control group of contacts not acquiring tuberculosis infection (“non-converters”, n=36). The median levels of serum 25(OH)D3 did not differ between convertors and non-converters at baseline (14.9 vs. 13.2 ng/ml, p=0.41), nor at follow-up (19.0 vs 18.6ng/ml, p=0.83). Similarly, cathelicidin levels did not differ between both groups. Conclusion These data argue against a major role for hypovitaminosis D in tuberculosis infection susceptibility (AU)

Introducción Se ha propuesto que la deficiencia de vitamina D, al afectar la respuesta inmunitaria innata, aumentaría la susceptibilidad de adquirir una infección por Mycobacterium tuberculosis. Métodos En un estudio exploratorio, examinamos si los niveles de 25-hidroxivitamina D3 (25(OH)D3) y de catelicidina (péptido antimicrobiano inducido bajo calcitriol) en suero y fluido nasal, respectivamente, se asocian con el riesgo de contraer una infección tuberculosa. Resultados En una cohorte prospectiva de 231 contactos intradomiciliarios de tuberculosis en los que se realizaron ensayos de liberación de interferón-gamma en forma seriada, estudiamos a todos los contactos no infectados que adquirieron la infección al seguimiento («conversores», n=18), y a un grupo control pareado por edad y sexo que no adquirió la infección tuberculosa («no conversores», n=36). La mediana de los niveles séricos de 25(OH)D3 no difirió entre convestores y no conversores al inicio del estudio (14,9 vs. 13,2 ng/ml, p=0,41), ni al seguimiento (19,0 vs. 18,6 ng/ml, p=0,83). Igualmente, los niveles de catelicidina nasal no difirieron entre ambos grupos. Conclusión Estos resultados no apoyan la existencia de un papel significativo de la hipovitaminosis D en la susceptibilidad a la infección por tuberculosis (AU)

Genomic epidemiology sheds light on the emergence and spread of Mycobacterium bovis Eu2 Clonal Complex in Portugal.

ABSTRACTAnimal tuberculosis (TB) remains a serious concern for animal and human health. Mycobacterium bovis circulates in multi-host systems, dominated by the European 2 clonal complex (Eu2) in Iberia. In this work, we use genomic epidemiology to infer the emergence, spread, and spatiotemporal patterns of Eu2 in the official epidemiological risk area of animal TB in Portugal. Phylogenetic analysis of 144 M. bovis whole-genome sequences from cattle, wild boar, and red deer, representing the 2002-2021 period, distinguished three Eu2 clades that evolved independently. The major Eu2 clade underwent phylodynamic inferences to estimate the time and location of outbreaks, host transitions, and spatial diffusion as well. The origin of this Eu2 clade was attributed to the red deer population in the Castelo Branco district, near the border with Spain. Most host transitions were intraspecific (80%), while interspecific transmissions between wildlife species (wild boar-red deer), and between wild boar and cattle, were highly supported. Phylogeographic reconstruction evidenced that most transitions (82%) occur within municipalities, highlighting local transmission corridors.Our study indicates that M. bovis continues to spread at the cattle-wildlife interface within the animal TB hotspot area, possibly driven by the foraging behaviour of wild boar near agricultural lands. Red deer seems to be an important driver of TB within wildlife hosts, while the wild boar links the multi-host wildlife community and livestock. This work highlights the value of combining genomic epidemiology with phylodynamic inference to resolve host jumps and spatial patterns of M. bovis, providing real-time clues about points of intervention.

Comparing Mycobacterium tuberculosis transmission reconstruction models from whole genome sequence data.

Genomic epidemiology is routinely used worldwide to interrogate infectious disease dynamics. Multiple computational tools exist that reconstruct transmission networks by coupling genomic data with epidemiological models. Resulting inferences can improve our understanding of pathogen transmission dynamics, and yet the performance of these tools has not been evaluated for tuberculosis (TB), a disease process with complex epidemiology including variable latency and within-host heterogeneity. Here, we performed a systematic comparison of six publicly available transmission reconstruction models, evaluating their accuracy when predicting transmission events in simulated and real-world Mycobacterium tuberculosis outbreaks. We observed variability in the number of transmission links that were predicted with high probability (P ≥ 0.5) and low accuracy of these predictions against known transmission in simulated outbreaks. We also found a low proportion of epidemiologically supported case-contact pairs were identified in our real-world TB clusters. The specificity of all models was high, and a relatively high proportion of the total transmission events predicted by some models were true links, notably with TransPhylo, Outbreaker2, and Phybreak. Our findings may inform the choice of tools in TB transmission analyses and underscore the need for caution when interpreting transmission networks produced using probabilistic approaches.

Guia para Controle de Tuberculose em Instituições de Acolhimento para População em Situação de Rua / Guide to Tuberculosis Control in Reception Institutions for Population in Street Situation

Este guia se destina a profissionais que atuam, principalmente, nas Instituições de Acolhimento destinadas à População em Situação de Rua (PSR). Entretanto, vários conceitos e informações que serão apresentados aqui podem ser usados em outros espaços de acolhimento e de oferta de cuidados a esta população, como os de grupos informais e de organizações públicas, governamentais ou não-governamentais.

Perguntas e respostas sobre tuberculose para educadores comunitários - Elaboração participativa de material educativo / Questions and answers about tuberculosis for community educators - Participatory development of educational material

Esta cartilha é resultado de um processo de construção participativa de material educativo entre educadores e lideranças comunitárias do Fórum TB/RJ e profissionais de saúde.

Characterisation of drug-resistant Mycobacterium tuberculosis mutations and transmission in Pakistan.

Tuberculosis, caused by Mycobacterium tuberculosis, is a high-burden disease in Pakistan, with multi-drug (MDR) and extensive-drug (XDR) resistance, complicating infection control. Whole genome sequencing (WGS) of M. tuberculosis is being used to infer lineages (strain-types), drug resistance mutations, and transmission patterns-all informing infection control and clinical decision making. Here we analyse WGS data on 535 M. tuberculosis isolates sourced across Pakistan between years 2003 and 2020, to understand the circulating strain-types and mutations related to 12 anti-TB drugs, as well as identify transmission clusters. Most isolates belonged to lineage 3 (n = 397; 74.2%) strain-types, and were MDR (n = 328; 61.3%) and (pre-)XDR (n = 113; 21.1%). By inferring close genomic relatedness between isolates (< 10-SNPs difference), there was evidence of M. tuberculosis transmission, with 55 clusters formed consisting of a total of 169 isolates. Three clusters consist of M. tuberculosis that are similar to isolates found outside of Pakistan. A genome-wide association analysis comparing 'transmitted' and 'non-transmitted' isolate groups, revealed the nusG gene as most significantly associated with a potential transmissible phenotype (P = 5.8 × 10-10). Overall, our study provides important insights into M. tuberculosis genetic diversity and transmission in Pakistan, including providing information on circulating drug resistance mutations for monitoring activities and clinical decision making.

Detection of Mycobacterium tuberculosis complex DNA in oronasal swabs from infected African buffaloes (Syncerus caffer).

Mycobacterium bovis (M. bovis), a member of the Mycobacterium tuberculosis complex (MTBC), is the causative agent of bovine TB (bTB) in animals. Spread occurs through inhalation or ingestion of bacilli transmitted from infected individuals. Early and accurate detection of infected African buffaloes shedding M. bovis is essential for interrupting transmission. In this pilot study, we determined if MTBC DNA could be detected in M. bovis infected buffalo oronasal secretions using a molecular transport media (PrimeStore MTM) with oronasal swabs and a rapid qPCR assay (Xpert MTB/RIF Ultra). Bovine TB test-positive buffaloes were culled, then tissue samples and oronasal swabs collected post-mortem for mycobacterial culture and Ultra testing, respectively. The Ultra detected MTBC DNA in 5/12 swabs from M. bovis culture-confirmed buffaloes. Oronasal swabs from M. bovis negative buffaloes (n = 20) were negative on Ultra, indicating the high specificity of this test. This study showed that MTM can successfully preserve MTBC DNA in oronasal swabs. The proportion of MTBC positive oronasal swabs was higher than expected and suggests that the Ultra may be an additional method for identifying infected buffaloes. Further studies are needed to confirm the utility of the Ultra assay with oronasal swabs as an assay to evaluate possible MTBC shedding in buffaloes.

Drug-Resistant Characteristics, Genetic Diversity, and Transmission Dynamics of Rifampicin-Resistant Mycobacterium tuberculosis in Hunan, China, Revealed by Whole-Genome Sequencing.

To gain a deep insight into the additional drug-resistant profiles, genetic diversity, and transmission dynamics of rifampicin-resistant tuberculosis (RR-TB) circulating in Hunan province, drug susceptibility testing and whole-genome-sequencing were performed among RR-TB strains collected from Jan. 2013 to Jun. 2018 in Hunan province. A total of 124 RR-TB strains were recovered successfully and included into the final analysis. Lineage 2.2.1 was the dominant sublineage, accounting for 72.6% (90/124), followed by lineage 4.5 (11.3%, 14/124), lineage 4.4 (8.1%, 10/124), lineage 4.2 (6.5%, 8/124) and lineage 2.2.2 (1.6%, 2/124). Overall, 83.1% (103/124) and 3.2% (4/124) of RR-TB were MDR-TB and XDR-TB, respectively. Nearly 30% of RR-TB isolates were resistant to fluoroquinolones, and 26.6% (33/124) were pre-XDR-TB. Moreover, 30.6% (38/124) of RR-TB strains were identified as phenotypically resistance to pyrazinamide. Totally, 17 clusters containing 48 (38.7%, 48/124) RR-TB strains were identified, ranging in size from 2 to 10 isolates. No significant difference was detected in clustering rate between lineage 2 and lineage 4 (χ2 = 0.027, P = 0.870). Our study revealed the complexity of RR-TB strains circulating in Hunan province with complex additional drug-resistant profile and relatively higher clustering rates. Comprehensive information based on WGS should be used to guide the design of treatment regimens and tailor public interventions. IMPORTANCE Comprehensive information such as genetic background and drug-resistant profile of MTB strains could help to tailor public interventions. However, these data are limited in Hunan province, one of the provinces with high-TB burden in China. So, this study aimed to provide us with deep insight into the molecular epidemiology of RR-TB isolates circulating in Hunan province by combining phenotypic drug susceptibility testing and whole-genome sequencing. To our knowledge, this is the first study to use whole-genome sequencing data of RR-TB strains spanning more than 5 years for molecular epidemiology analysis in Hunan province, which allows us to identify genetic background information and clustered strains more accurately. Our study revealed the complexity of RR-TB strains circulating in Hunan province with complex additional drug-resistant profile and relatively higher clustering rates. Comprehensive information based on WGS should be used to guide the design of treatment regimens and tailor public interventions.

Transmission Of Tuberculosis Among illicit drug use Linkages (TOTAL): A cross-sectional observational study protocol using respondent driven sampling.

People who use illicit drugs (PWUDs) have been identified as a key at-risk group for tuberculosis (TB). Examination of illicit drug use networks has potential to assess the risk of TB exposure and disease progression. Research also is needed to assess mechanisms for accelerated TB transmission in this population. This study aims to 1) assess the rate of TB exposure, risk of disease progression, and disease burden among PWUD; 2) estimate the proportion of active TB cases resulting from recent transmission within this network; and 3) evaluate whether PWUD with TB disease have physiologic characteristics associated with more efficient TB transmission. Our cross-sectional, observational study aims to assess TB transmission through illicit drug use networks, focusing on methamphetamine and Mandrax (methaqualone) use, in a high TB burden setting and identify mechanisms underlying accelerated transmission. We will recruit and enroll 750 PWUD (living with and without HIV) through respondent driven sampling in Worcester, South Africa. Drug use will be measured through self-report and biological measures, with sputum specimens collected to identify TB disease by Xpert Ultra (Cepheid) and mycobacterial culture. We will co-enroll those with microbiologic evidence of TB disease in Aim 2 for molecular and social network study. Whole genome sequencing of Mycobacteria tuberculosis (Mtb) specimens and social contact surveys will be done for those diagnosed with TB. For Aim 3, aerosolized Mtb will be compared in individuals with newly diagnosed TB who do and do not smoke illicit drug. Knowledge from this study will provide the basis for a strategy to interrupt TB transmission in PWUD and provide insight into how this fuels overall community transmission. Results have potential for informing interventions to reduce TB spread applicable to high TB and HIV burden settings. Trial registration: Clinicaltrials.gov Registration Number: NCT041515602. Date of Registration: 5 November 2019.

Molecular Epidemiology and Genetic Diversity of Multidrug-Resistant Mycobacterium tuberculosis Isolates in Bangladesh.

Although the number of multidrug-resistant (MDR) tuberculosis (TB) cases is high overall, a major gap exists in our understanding of the molecular characteristics and transmission dynamics of the MDR Mycobacterium tuberculosis isolates circulating in Bangladesh. The present study aims to characterize the MDR-TB isolates of Bangladesh and to investigate the mode of transmission. A total of 544 MDR-TB isolates were obtained from a nationwide drug-resistant TB surveillance study conducted between October 2011 and March 2017 covering all geographic divisions of Bangladesh. The isolates were characterized using TbD1 deletion analysis, spoligotyping, and mycobacterial interspersed repetitive-unit-variable-number tandem-repeat (MIRU-VNTR) typing. Deletion analysis showed that 440 (80.9%) isolates were the modern type, while the remainder were the ancestral type. The largest circulating lineage was the Beijing type, comprising 208 isolates (38.2%), followed by T, EAI, and LAM with 93 (17.1%), 58 (10.7%), and 52 (9.5%) isolates, respectively. Combined MIRU-VNTR and spoligotyping analysis demonstrated that the majority of the clustered isolates were of the Beijing and T1 lineages. The overall rate of recent transmission was estimated at 33.8%. In conclusion, the MDR M. tuberculosis isolates circulating in Bangladesh are mostly of the modern virulent type. The Beijing and T lineages are the predominant types and most of the transmission of MDR-TB can be attributed to them. The findings also suggest that, along with the remarkable transmission, the emergence of MDR-TB in Bangladesh is largely due to acquired resistance. Rapid and accurate diagnosis and successful treatment will be crucial for controlling MDR-TB in Bangladesh. IMPORTANCE Multidrug-resistant TB is considered to be the major threat to tuberculosis control activities worldwide, including in Bangladesh. Despite the fact that the number of MDR-TB cases is high, a major gap exists in our understanding of the molecular epidemiology of the MDR-TB isolates in Bangladesh. In our study, we characterized and classified the MDR-TB isolates circulating in Bangladesh and investigated their mode of transmission. Our results demonstrated that the MDR M. tuberculosis isolates circulating in Bangladesh are mostly of the modern virulent type. The Beijing and T lineages are the predominant types and are implicated in the majority of MDR-TB transmission. Our findings reveal that, along with the remarkable transmission, the emergence of MDR-TB in Bangladesh is largely due to acquired resistance, which may be due to nonadherence to treatment or inadequate treatment of TB patients. Rapid diagnosis and adherence to an appropriate treatment regimen are therefore crucial to controlling MDR-TB in Bangladesh.

Insights into the Complexity of a Dormant Mycobacterium tuberculosis Cluster Once Transmission Is Resumed.

Genotyping tools help identify the complexity in Mycobacterium tuberculosis transmission clusters. We carried out a thorough analysis of the epidemiological and bacteriological complexity of a cluster in Almería, Spain. The cluster, initially associated with Moroccan migrants and with no secondary cases identified in 4 years, then reappeared in Spanish-born individuals. In one case, two Mycobacterium tuberculosis clonal variants were identified. We reanalyzed the cluster, supported by the characterization of multiple cultured isolates and respiratory specimens, whole-genome sequencing, and epidemiological case interviews. Our findings showed that the cluster, which was initially thought to have restarted activity with just a single case harboring a small degree of within-host diversity, was in fact currently growing due to coincidental reactivation of past exposures, with clonal diversity transmitted throughout the cluster. In one case, within-host diversity was amplified, probably due to prolonged diagnostic delay. IMPORTANCE The precise study of the dynamics of tuberculosis transmission in socio-epidemiologically complex scenarios may require more thorough analysis than the standard molecular epidemiology strategies. Our study illustrates the epidemiological and bacteriological complexity present in a transmission cluster in a challenging epidemiological setting with a high proportion of migrant cases. The combination of whole-genome sequencing, refined and refocused epidemiological interviews, and in-depth analysis of the bacterial composition of sputa and cultured isolates was crucial in order to correctly reinterpret the true nature of this cluster. Our global approach allowed us to reinterpret correctly the unnoticed epidemiological and bacteriological complexity involved in the Mycobacterium tuberculosis transmission event under study, which had been overlooked by the usual molecular epidemiology approaches.

Molecular Detection of Airborne Mycobacterium tuberculosis in South African High Schools.

Rationale: South African adolescents carry a high tuberculosis disease burden. It is not known if schools are high-risk settings for Mycobacterium tuberculosis (MTB) transmission. Objectives: To detect airborne MTB genomic DNA in classrooms. Methods: We studied 72 classrooms occupied by 2,262 students in two South African schools. High-volume air filtration was performed for median 40 (interquartile range [IQR], 35-54) minutes and assayed by droplet digital PCR (ddPCR)-targeting MTB region of difference 9 (RD9), with concurrent CO2 concentration measurement. Classroom data were benchmarked against public health clinics. Students who consented to individual tuberculosis screening completed a questionnaire and sputum collection (Xpert MTB/RIF Ultra) if symptom positive. Poisson statistics were used for MTB RD9 copy quantification. Measurements and Main Results: ddPCR assays were positive in 13/72 (18.1%) classrooms and 4/39 (10.3%) clinic measurements (P = 0.276). Median ambient CO2 concentration was 886 (IQR, 747-1223) ppm in classrooms versus 490 (IQR, 405-587) ppm in clinics (P < 0.001). Average airborne concentration of MTB RD9 was 3.61 copies per 180,000 liters in classrooms versus 1.74 copies per 180,000 liters in clinics (P = 0.280). Across all classrooms, the average risk of an occupant inhaling one MTB RD9 copy was estimated as 0.71% during one standard lesson of 35 minutes. Among 1,836/2,262 (81.2%) students who consented to screening, 21/90 (23.3%) symptomatic students produced a sputum sample, of which one was Xpert MTB/RIF Ultra positive. Conclusions: Airborne MTB genomic DNA was detected frequently in high school classrooms. Instantaneous risk of classroom exposure was similar to the risk in public health clinics.

Developing National Genotype-Independent Indicators for Recent Mycobacterium Tuberculosis Transmission Using Pediatric Cases-United States, 2011-2017.

INTRODUCTION: Pediatric tuberculosis (TB) cases are sentinel events for Mycobacterium tuberculosis transmission in communities because children, by definition, must have been infected relatively recently. However, these events are not consistently identified by genotype-dependent surveillance alerting methods because many pediatric TB cases are not culture-positive, a prerequisite for genotyping. METHODS: We developed 3 potential indicators of ongoing TB transmission based on identifying counties in the United States with relatively high pediatric (aged <15 years) TB incidence: (1) a case proportion indicator: an above-average proportion of pediatric TB cases among all TB cases; (2) a case rate indicator: an above-average pediatric TB case rate; and (3) a statistical model indicator: a statistical model based on a significant increase in pediatric TB cases from the previous 8-quarter moving average. RESULTS: Of the 249 US counties reporting ≥2 pediatric TB cases during 2009-2017, 240 and 249 counties were identified by the case proportion and case rate indicators, respectively. The statistical model indicator identified 40 counties with a significant increase in the number of pediatric TB cases. We compared results from the 3 indicators with an independently generated list of 91 likely transmission events involving ≥2 pediatric cases (ie, known TB outbreaks or case clusters with reported epidemiologic links). All counties with likely transmission events involving multiple pediatric cases were identified by ≥1 indicator; 23 were identified by all 3 indicators. PRACTICE IMPLICATIONS: This retrospective analysis demonstrates the feasibility of using routine TB surveillance data to identify counties where ongoing TB transmission might be occurring, even in the absence of available genotyping data.

Tuberculosis infantil en Chile: ¿de dónde provienen los casos? / Childhood tuberculosis in Chile: where do the cases come from?

La tuberculosis es la principal causa de muerte por un agente infeccioso a nivel mundial y se estima que un 6% de los casos nuevos corresponde a tuberculosis infantil. La presencia de tuberculosis en niños es una señal de la existencia de transmisión del agente en la comunidad. Esta investigación busca describir las características epidemiológicas de la tuberculosis infantil en Chile entre 2011 y 2020. METODOLOGÍA: estudio descriptivo de los casos de tuberculosis infantil registrados en Chile entre los años 2011 y 2020. RESULTADOS: se registraron 544 casos de tuberculosis en menores de 15 años en el período analizado, con una tasa de incidencia anual entre 1,1 y 2,2 casos por 100.000. Se observa un importante aumento de casos en los últimos tres años, especialmente en el grupo de menores de 5 años. 63,2% corresponden a tuberculosis pulmonar, y de ellos 62,3% fueron confirmados por bacteriología. La mayoría de los casos no presenta comorbilidades que impliquen inmunosupresión y la incidencia de meningitis tuberculosa en menores de 5 años es baja. La proporción de contactos es de 29% y la de extranjeros de 17%, ambas variables en aumento en los últimos años. CONCLUSIÓN: La tuberculosis en niños sigue siendo un problema de salud poco frecuente en Chile. Sin embargo, su aumento en los últimos años debe alertar sobre un incremento de la transmisión comunitaria de la enfermedad, por lo que se debe reforzar la detección oportuna de casos contagiantes, la investigación de contactos y el tratamiento preventivo.

Tuberculosis is the leading cause of death from a single infectious agent worldwide and it is estimated that 6% of new cases are children. Childhood tuberculosis reflects ongoing transmission within communities. This study aims to describe the epidemiological characteristics of childhood tuberculosis in Chile between 2011 and 2020. METHODOLOGY: descriptive study of the cases of tuberculosis under 15 years-old registered in Chile from 2011 to 2020. RESULTS: 544 cases were registered in the period analyzed, with an annual incidence rate between 1.1 and 2.2 cases per 100,000. A significant increase in cases is observed in the last three years, especially in the group under 5 years-old. 63.2% correspond to pulmonary tuberculosis, and among them 62.3% are confirmed by bacteriology. Most of the cases do not have comorbidities and the incidence of tuberculous meningitis in children under 5 years is low. Contacts are 29% of the cases and foreigners are 17%, both percentages are increasing in the last years. CONCLUSION: Childhood tuberculosis remains a low frequency health problem in Chile. However, its increase in recent years implies an increase in the community transmission. Active case finding, contact tracing and preventive treatment should be reinforced.

Prevention of Mycobacterium tuberculosis Transmission in Health Care Settings.

Patients with tuberculosis (TB) pose a risk to other patients and health care workers, and outbreaks in health care settings occur when appropriate infection control measures are not used. This article discusses strategies to prevent transmission of Mycobacterium tuberculosis within health care settings. All health care facilities should have an operational TB infection control plan that emphasizes the use of a hierarchy of controls (administrative, environmental, and personal respiratory protection). Resources available to clinicians who work in the prevention and investigation of nosocomial transmission of M tuberculosis also are discussed.

The impact of active case finding on transmission dynamics of tuberculosis: A modelling study.

BACKGROUND: In the last decade, active case finding (ACF) strategies for tuberculosis (TB) have been implemented in many diverse settings, with some showing large increases in case detection and reporting at the sub-national level. There have also been several studies which seek to provide evidence for the benefits of ACF to individuals and communities in the broader context. However, there remains no quantification of the impact of ACF with regards to reducing the burden of transmission. We sought to address this knowledge gap and quantify the potential impact of active case finding on reducing transmission of TB at the national scale and further, to determine the intensification of intervention efforts required to bring the reproduction number (R0) below 1 for TB. METHODS: We adopt a dynamic transmission model that incorporates heterogeneity in risk to TB to assess the impact of an ACF programme (IMPACT TB) on reducing TB incidence in Vietnam and Nepal. We fit the models to country-level incidence data using a Bayesian Markov Chain Monte Carlo approach. We assess the impact of ACF using a parameter in our model, which we term the treatment success rate. Using programmatic data, we estimate how much this parameter has increased as a result of IMPACT TB in the implementation districts of Vietnam and Nepal and quantify additional efforts needed to eliminate transmission of TB in these countries by 2035. RESULTS: Extending the IMPACT TB programme to national coverage would lead to moderate decreases in TB incidence and would not be enough to interrupt transmission by 2035. Decreasing transmission sufficiently to bring the reproduction number (R0) below 1, would require a further intensification of current efforts, even at the sub-national level. CONCLUSIONS: Active case finding programmes are effective in reducing TB in the short term. However, interruption of transmission in high-burden countries, like Vietnam and Nepal, will require comprehensive incremental efforts. Complementary measures to reduce progression from infection to disease, and reactivation of latent infection, are needed to meet the WHO End TB incidence targets.

Signature required: The transcriptional response to tuberculosis.

The majority of humans infected with Mycobacterium tuberculosis never experience clinical symptoms or signs, but predicting those who will remains out of reach. Here, we discuss recent studies that reveal patterns and pathways that determine who is at highest risk for progression.