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Objectives: Limited information is currently available on the prevalence of and risk factors for tuberculosis infection (TBI) among close contacts of patients with pulmonary TB (PTB) in China. In this study, we estimated the burden of TBI among close contacts using QuantiFERON-TB Gold In-Tube assay (QFT) and identified factors associated with TB transmission among this high-risk population., Methods: From January 1, 2018 to August 31, 2020, we identified laboratory-confirmed patients with PTB from a population-based, multicentered, cluster-randomized control trial for tuberculosis preventive treatment. Close contacts of these patients were identified, interviewed, and tested using the QFT assay. We estimated TBI prevalence and calculated ORs and 95% CIs for TBI risk factors., Results: A total of 3138 index cases and 8117 close contacts were identified. Of these contacts, 36 had PTB (a prevalence of 443.51 cases/100 000 population). Among the remaining 7986 close contacts; 3124 (39.12%) reported a positive QFT result. QFT positivity was significantly associated with older age (adjusted OR, 1.77; [95% CI, 1.27-2.47], 2.20; [95% CI, 1.59-3.05], and 2.74; [95% CI, 1.96-3.82]) for age groups: 35-44, 45-54, and 55-64, respectively) when compared with a younger age group: 5-14; longer contact duration (adjusted OR, 1.44; 95% CI, 1.22-1.69); and sharing of a bedroom (adjusted OR, 1.39; 95% CI, 1.18-1.65)., Discussion: Our findings indicate a high TBI burden among the close contacts of PTB. The results also highlighted that contact tracing and investigation for TBI are necessary and beneficial, particularly for those who are older, have had a longer contact duration, and share a bedroom., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: China has the third largest number of TB cases in the world, and the average annual floating population in China is more than 200 million, the increasing floating population across regions has a tremendous potential for spreading infectious diseases, however, the role of increasing massive floating population in tuberculosis transmission is yet unclear in China., Methods: 29,667 tuberculosis flow data were derived from the new smear-positive pulmonary tuberculosis cases in China. Spatial variation of TB transmission was measured by geodetector q-statistic and spatial interaction model was used to model the tuberculosis flow and the regional socioeconomic factors., Results: Tuberculosis transmission flow presented spatial heterogeneity. The Pearl River Delta in southern China and the Yangtze River Delta along China's east coast presented as the largest destination and concentration areas of tuberculosis inflows. Socioeconomic factors were determinants of tuberculosis flow. Some impact factors showed different spatial associations with tuberculosis transmission flow. A 10% increase in per capita GDP was associated with 10.2% in 2010 or 2.1% in 2012 decrease in tuberculosis outflows from the provinces of origin, and 1.2% in 2010 or 0.5% increase in tuberculosis inflows to the destinations and 18.9% increase in intraprovincial flow in 2012. Per capita net income of rural households and per capita disposable income of urban households were positively associated with tuberculosis flows. A 10% increase in per capita net income corresponded to 14.0% in 2010 or 3.6% in 2012 increase in outflows from the origin, 44.2% in 2010 or 12.8% increase in inflows to the destinations and 47.9% increase in intraprovincial flows in 2012. Tuberculosis incidence had positive impacts on tuberculosis flows. A 10% increase in the number of tuberculosis cases corresponded to 2.2% in 2010 or 1.1% in 2012 increase in tuberculosis inflows to the destinations, 5.2% in 2010 or 2.0% in 2012 increase in outflows from the origins, 11.5% in 2010 or 2.2% in 2012 increase in intraprovincial flows., Conclusions: Tuberculosis flows had clear spatial stratified heterogeneity and spatial autocorrelation, regional socio-economic characteristics had diverse and statistically significant effects on tuberculosis flows in the origin and destination, and income factor played an important role among the determinants., (© 2024. The Author(s).)

Background: Despite current guidelines for tuberculosis (TB) control in health care settings, which focused on smear-positive cases, prevention of nosocomial TB transmission continues to be a challenge. Here, we report the results of the first hospital-wide prospective study applying interferon-gamma release assay to investigate the role of smear-negative, culture-positive index cases in nosocomial TB transmission., Methods: We prospectively identified cases of culture-confirmed smear-negative pulmonary TB receiving aerosol-generating procedures (AGPs) and cases of culture-confirmed smear-positive pulmonary TB admitted at a medical center. Nosocomial transmission was evaluated by screening their close contacts for latent TB infection (LTBI) using an interferon-gamma release assay., Results: A total of 93 smear-negative index receiving AGP and 122 smear-positive index were enrolled. Among them, 13 (14.0%) and 43 (35.2%) index cases, respectively, had secondary cases of LTBI (P < .001). Sputum smear negativity (adjusted odds ratio: 0.20 [0.08-0.48]) and AGP (sputum suction; adjusted odds ratio: 3.48 [1.34-9.05]) are independent factors of transmission. A similar proportion in the close contacts of the 2 index groups had LTBI (17 [15.3%] and 63 [16.0%], respectively), and the former index group contributed to 21.3% of the nosocomial transmission., Conclusions: Smear-negative, culture-positive index cases receiving AGPs could be as infectious as smear-positive index cases. Hospital TB control policy should also focus on the former group., (Copyright © 2024 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Xinjiang has been one of the high incidence areas of pulmonary tuberculosis (PTB) in China. Besides being infected by direct contacting with active PTB individuals (direct infection), the susceptible would be infected because of the exposure to the environment contaminated by Mycobacterium tuberculosis (indirect infection). Active PTB individuals include not only the smear-positive PTB (PTB+) but also the smear-negative PTB (PTB-) who are infectious due to their ability to release tiny Mycobacterium tuberculosis particles even in the absence of visible Mycobacterium tuberculosis in sputum. By taking account of direct/indirect infection and the difference between PTB+ and PTB- individuals in transmission capability, a periodic dynamical PTB transmission model is proposed. The model is fitted to the newly monthly PTB+ and PTB- cases in Xinjiang from 2008 to 2017 by Markov Chain Monte Carlo algorithm. Moreover, global sensitivity analysis is constructed to address the uncertainty of some key parameters by using Latin hypercube sampling and partial rank correlation coefficient methods. Basic reproduction number R 0 for PTB transmission in Xinjiang is estimated to be 2.447 (95% CrI:(1.203, 3.844)), indicating that PTB has been prevalent in Xinjiang over the study period. Our results suggest that reducing the direct/indirect transmission rates, early screening, isolating and treating the latent, PTB+ and PTB- individuals, and enhancing the clearance of Mycobacterium tuberculosis in the environment could more effectively control PTB transmission in Xinjiang. The model fits the reported PTB data well and achieves acceptable prediction accuracy. We believe that our model can provide heuristic support for controlling PTB transmission in Xinjiang., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Mechanisms underlying variability in transmission of Mycobacterium tuberculosis strains remain undefined. By characterizing high and low transmission strains of M.tuberculosis in mice, we show here that high transmission M.tuberculosis strain induce rapid IL-1R-dependent alveolar macrophage migration from the alveolar space into the interstitium and that this action is key to subsequent temporal events of early dissemination of bacteria to the lymph nodes, Th1 priming, granulomatous response and bacterial control. In contrast, IL-1R-dependent alveolar macrophage migration and early dissemination of bacteria to lymph nodes is significantly impeded in infection with low transmission M.tuberculosis strain; these events promote the development of Th17 immunity, fostering neutrophilic inflammation and increased bacterial replication. Our results suggest that by inducing granulomas with the potential to develop into cavitary lesions that aids bacterial escape into the airways, high transmission M.tuberculosis strain is poised for greater transmissibility. These findings implicate bacterial heterogeneity as an important modifier of TB disease manifestations and transmission., (© 2022. The Author(s).)

Introduction: Understanding the epidemiology of tuberculosis is limited by lack of genotyping data. We sought to characterize the drug susceptibility testing patterns and genetic diversity of M. tuberculosis isolates in southern Ethiopia., Methodology: A cross-sectional study was conducted among newly diagnosed sputum smear positive patients with tuberculosis visiting nine health facilities in southern Ethiopia from June 2015 to May 2016. Three consecutive sputum samples (spot-morning-spot) per patient were examined using acid-fast bacilli smear microscopy with all smear positive specimens having acid-fast bacilli cultures performed. M. tuberculosis isolates had drug susceptibility testing performed using indirect proportion method and were genotyped with RD9 deletion analysis and spoligotyping. Mapping of strain was made using geographic information system., Results: Among 250 newly diagnosed patients with tuberculosis, 4% were HIV co-infected. All 230 isolates tested were M. tuberculosis strains belonging to three lineages: Euro-American, 187 (81%), East-African-Indian, 31 (14%), and Lineage 7 (Ethiopian lineage), 8 (4%); categorized into 63 different spoligotype patterns, of which 85% fell into 28 clusters. M. tuberculosis strains were clustered by geographic localities. The dominant spoligotypes were SIT149 (21%) and SIT53 (19%). Drug susceptibility testing found that 14% of isolates tested were resistant to > 1 first line anti- tuberculosis drugs and 11% to INH. SIT 149 was dominant among drug resistant isolates., Conclusions: The study revealed several clusters and drug resistant strains of M. tuberculosis in the study area, suggesting recent transmission including of drug resistant tuberculosis. Wider monitoring of drug susceptibility testing and geospatial analysis of transmission trends is required to control tuberculosis in southern Ethiopia., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2021 Yared Merid, Elena Hailu, Getnet Habtamu, Melaku Tilahun, Markos Abebe, Mesay Hailu, Tsegaye Hailu, Daniel Gemechu Datiko, Yimtubezinash Woldeamanuel, Abraham Aseffa.)

Introduction: Tuberculosis is a disease of public health concern. It can be treated effectively with good knowledge about the disease and complete adherence to the recommended treatment regime. This study is intended to assess the level of knowledge and perception of treatment among tuberculosis patients attending primary care clinics., Methodology: We conducted a cross-sectional study using a validated self-administered questionnaire among tuberculosis patients attending primary care clinics in Johor Bahru district. A total of 208 tuberculosis patients were enrolled in this study through convenience sampling. We assessed the general knowledge, transmission, causes, and prevention of tuberculosis, where higher scores indicated better knowledge. For the perception of treatment, a higher mean score indicated a more negative perception., Results: The mean score for knowledge on tuberculosis was 54.33 ± 12.78, ranging from 25 to 88.9%. The mean score for perception was 2.75±0.52, ranging from 2.15-3.39. We found that although 88.9% of respondents knew a person could be infected with TB through inhalation of tuberculosis bacilli, a majority believed that smoking (68.2%), sharing food (69.2%), and eating from the same plate (66.8%) are causes of tuberculosis. Moreover, there was still a negative perception regarding the treatment of tuberculosis with the highest mean score for the statement 'I am afraid if I am told I am tuberculosis positive'., Conclusions: We found that there were gaps in knowledge among tuberculosis patients. Intermittent counseling during the treatment re-enforces the knowledge of tuberculosis. An updated standardized counseling sheet of tuberculosis Health Education should be included along with staff training to update their knowledge as part of their important role in health education in tuberculosis prevention., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2021 Nesamalar Balakrishnan, Ezura Madiana Md Monoto, Noorlaili Mohd Tohit, Asrul Abdul Wahab.)

Abstract: Smear-positive pulmonary tuberculosis (SPPTB) is the major contributor to the spread of tuberculosis (TB) infection, and it creates high morbidity and mortality worldwide. The objective of this study was to determine the predictors of delayed sputum smear conversion at the end of the intensive phase of TB treatment in Kota Kinabalu, Malaysia.This retrospective study was conducted utilising data of SPPTB patients treated in 5 TB treatment centres located in Kota Kinabalu, Malaysia from 2013 to 2018. Pulmonary TB (PTB) patients included in the study were those who had at least completed the intensive phase of anti-TB treatment with sputum smear results at the end of the 2nd month of treatment. The factors associated with delayed sputum smear conversion were analyzed using multiple logistic regression analysis. Predictors of sputum smear conversion at the end of intensive phase were evaluated.A total of 2641 patients from the 2013 to 2018 periods were included in this study. One hundred eighty nine (7.2%) patients were identified as having delayed sputum smear conversion at the end of the intensive phase treatment. Factors of moderate (advanced odd ratio [aOR]: 1.7) and advanced (aOR: 2.7) chest X-ray findings at diagnosis, age range of >60 (aOR: 2.1), year of enrolment 2016 (aOR: 2.8), 2017 (aOR: 3.9), and 2018 (aOR: 2.8), smokers (aOR: 1.5), no directly observed treatment short-course (DOTS) supervisor (aOR: 6.9), non-Malaysian citizens (aOR: 1.5), and suburban home locations (aOR: 1.6) were associated with delayed sputum smear conversion at the end of the intensive phase of the treatment.To improve sputum smear conversion success rate, the early detection of PTB cases has to be fine-tuned so as to reduce late or severe case presentation during diagnosis. Efforts must also be in place to encourage PTB patients to quit smoking. The percentage of patients assigned with DOTS supervisors should be increased while at the same time ensuring that vulnerable groups such as those residing in suburban localities, the elderly and migrant TB patients are provided with proper follow-up treatment and management., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Pakistan implemented initiatives to detect tuberculosis (TB) patients through extended contact screening (ECS); it improved case detection but treatment outcomes need assessment., Objectives: To compare treatment outcomes of pulmonary TB (PTB) patients detected by ECS with those detected by routine passive case finding (PCF)., Methods: A cohort study using secondary program data conducted in Lahore, Faisalabad and Rawalpindi districts and Islamabad in 2013-15. We used log binomial regression models to assess if ECS was associated with unfavorable treatment outcomes (death, loss-to-follow-up, failure, not evaluated) after adjusting for potential confounders., Results: We included 79,431 people with PTB; 4604 (5.8%) were detected by ECS with 4052 (88%) bacteriologically confirmed. In all PTB patients the proportion with unfavorable outcomes was not significantly different in ECS group (9.6%) compared to PCF (9.9%), however, among bacteriologically confirmed patients unfavorable outcomes were significantly lower in ECS (9.9%) than PCF group (11.6%, P = 0.001). ECS was associated with a lower risk of unfavorable outcomes (adjusted relative risk (aRR) 0.90; 95% CI 0.82-0.99) among 'all PTB' patients and bacteriologically confirmed PTB patients (aRR 0.91; 95% CI 0.82-1.00)., Conclusion: In PTB patients detected by ECS the treatment outcomes were not inferior to those detected by PCF., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Mycobacterium tuberculosis ( Mtb ), the causative organism of pulmonary tuberculosis (PTB) now infects more than half of the world population. The efficient transmission strategy of the pathogen includes first remaining dormant inside the infected host, next undergoing reactivation to cause post-primary tuberculosis of the lungs (PPTBL) and then transmit via aerosol to the community. In this review, we are exploring recent findings on the role of bone marrow (BM) stem cell niche in Mtb dormancy and reactivation that may underlie the mechanisms of PPTBL development. We suggest that pathogen's interaction with the stem cell niche may be relevant in potential inflammation induced PPTBL reactivation, which need significant research attention for the future development of novel preventive and therapeutic strategies for PPTBL, especially in a post COVID-19 pandemic world. Finally, we put forward potential animal models to study the stem cell basis of Mtb dormancy and reactivation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pathak and Das.)

Background: Symptoms of infectious respiratory illnesses are often assumed to drive transmission. However, production and release of Mycobacterium tuberculosis (Mtb) bioaerosols is poorly understood. We report quantitation of Mtb exhaled during specific respiratory manoeuvres., Methods: Direct capture of nascent bioaerosol particles and indirect collection of aged particles was performed in 10 healthy subjects. Indirect and direct capture of exhaled viable Mtb bacilli was compared in 38 PTB patients and directly captured viable Mtb during cough and bronchiole-burst manoeuvres in 27 of the PTB patients., Results: Direct sampling of healthy subjects captured larger bioaerosol volumes with higher proportions of 2-5 μm particles than indirect sampling. Indirect sampling identified viable Mtb in 92.1% (35 of 38) of PTB patients during 60-min relaxed breathing, median bacillary count 7.5 (IQR: 3.25-19). Direct sampling for 10-min identified Mtb in 97.4% (37 of 38) of PTB patients with higher bacilli counts (p < 0.001), median 24.5 (IQR:11.25-37.5). A short 5-min sampling regimen of 10 coughs or 10 bronchiole-burst manoeuvres yielded a median of 11 (IQR: 4-17) and 11 (IQR: 7-17.5) Mtb bacilli, respectively (p = 0.53)., Conclusions: Peripheral lung bioaerosol released through deep exhalations alone contained viable Mtb suggesting non-cough transmission is possible in PTB., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Cost functions linked to transmission dynamic models are commonly used to estimate the resources required for infectious disease policies. We present a conceptual and empirical approach for estimating these functions, allowing for nonconstant marginal costs. We aim to expand on the current approach which commonly assumes linearity of cost over scale., Methods: We propose a theoretical framework adapted from the field of transport economics. We specify joint functions of production of services within a disease-specific program. We expand these functions to include qualitative insights of program expansion patterns. We present the difference in incremental total costs between an approach assuming constant unit costs and alternative approaches that assume economies of scale, scope and homogeneous or heterogeneous facility recruitment into the programme during scale-up. We illustrate the framework's application in tuberculosis, using secondary data from the literature and routine reporting systems in South Africa., Results: Economies of capacity and scope substantially change cost estimates over time. Cost data requirements for the proposed approach included standardized and disaggregated unit costs (for a limited number of outputs) and information on the facilities network available to the program., Conclusions: The defined functional form will determine the magnitude and shape of costs when outputs and coverage are increasing. This in turn will impact resource allocation decisions. Infectious diseases modelers and economists should use transparent and empirically based cost models for analyses that inform resource allocation decisions. This framework describes a general approach for developing these models., (Copyright © 2020 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

The COVID-19 pandemic and phased nationwide lockdown have impacted negatively on individuals with tuberculosis (TB) and routine TB services. Through a literature review and the perspective of members of a national TB Think Tank task team, we describe the impact of the pandemic and lockdown on TB patients and services as well as the potential long-term setback to TB control in South Africa (SA). Strategies to mitigate risk and impact are explored, together with opportunities to leverage synergies from both diseases to the benefit of the National TB Programme (NTP). With the emergence of COVID-19, activities to address this new pandemic have been prioritised across all sectors. Within the health system, the health workforce and resources have been redirected away from routine services towards the new disease priority. The social determinants of health have deteriorated during the lockdown, potentially increasing progression to TB disease and impacting negatively on people with TB and their households, resulting in additional barriers to accessing TB care, with early reports of a decline in TB testing rates. Fewer TB diagnoses, less attention to adherence and support during TB treatment, poorer treatment outcomes and consequent increased transmission will increase the TB burden and TB-related mortality. People with TB or a history of TB are likely to be vulnerable to COVID-19. Modifications to current treatment practices are suggested to reduce visits to health facilities and minimise the risks of COVID-19 exposure. The COVID-19 pandemic has the potential to negatively impact on TB control in TB-endemic settings such as SA. However, there are COVID-19-related health systems-strengthening developments that may help the NTP mitigate the impact of the pandemic on TB control. By integrating TB case finding into the advanced screening, testing, tracing and monitoring systems established for COVID-19, TB case finding and linkage to care could increase, with many more TB patients starting treatment. Similarly, integrating knowledge and awareness of TB into the increased healthcare worker and community education on infectious respiratory diseases, behavioural practices around infection prevention and control, and cough etiquette, including destigmatisation of mask use, may contribute to reducing TB transmission. However, these potential gains could be overwhelmed by the impact of increasing poverty and other social determinants of health on the burden of TB.

Outbreaks of tuberculosis (TB) - such as the large isoniazid-resistant outbreak centred on London, UK, which originated in 1995 - provide excellent opportunities to model transmission of this devastating disease. Transmission chains for TB are notoriously difficult to ascertain, but mathematical modelling approaches, combined with whole-genome sequencing data, have strong potential to contribute to transmission analyses. Using such data, we aimed to reconstruct transmission histories for the outbreak using a Bayesian approach, and to use machine-learning techniques with patient-level data to identify the key covariates associated with transmission. By using our transmission reconstruction method that accounts for phylogenetic uncertainty, we are able to identify 21 transmission events with reasonable confidence, 9 of which have zero SNP distance, and a maximum distance of 3. Patient age, alcohol abuse and history of homelessness were found to be the most important predictors of being credible TB transmitters.

Background: Household contacts (HHC) of tuberculosis (TB) patients are at risk of TB infection and disease. The study assessed the utility of "Household contact card and register" for screening of HHC of pulmonary TB (PTB) patients for TB and explored the reasons for HHC not being screened and followed-up., Methods: The "Household contact card and register" was implemented by the Health Care Workers (HCW) of the TB Control Programme in Chennai District for screening HHC of index PTB patients initiated on treatment between June and August, 2018. Contacts were required to be screened within 2 months of treatment initiation of the index patient. Details collected included age, gender, smoking, alcohol use, immunosuppressive conditions and TB treatment. Symptom screening along with chest radiograph and or sputum examination was attempted. Follow-up TB screening at 6 and 12 months were performed. Screening of HHC was compared pre and post implementation phase. Proportions were computed for the data analysed., Results: HHC information was documented for 93% (1268/1364) of Index PTB patients. The main reasons of non-listing of HHC in 96 PTB patients were HCW non-availability or non-co-operation of the HHC. There were 2150 (80%) contacts who were screened for TB. Inconvenient time, feeling healthy, stigma, out-station visit were the main reasons for 537 contacts not undergoing TB screening. Anti-TB treatment was initiated in 21 (1%) of contacts diagnosed with TB. Preventive therapy was initiated in 59% (81/138) of contacts aged <6 years. The screening of HHC improved from 36% to 80% during the implementation phase. Follow-up TB screening at 12 months was performed in 50% of HHC and 2 incident TB cases were identified., Conclusion: "Household contact card and register" is a useful tool for HCWs for TB screening in HHC of PTB patients. Reasons for non-adherence to contact screening needs to be addressed., Competing Interests: The authors have declared that no competing interests exist.

Objectives: 1. To estimate the prevalence of latent tuberculosis infection among household contacts of sputum positive pulmonary tuberculosis patient receiving DOTS chemotherapy. 2. To evaluate the risk factors among household contacts of sputum positive pulmonary tuberculosis patient receiving DOTS chemotherapy. 3. To evaluate the degree of exposure among household contacts of sputum positive pulmonary tuberculosis patient receiving DOTS chemotherapy., Methods: This study was a cross sectional done among 220 household contacts of age 12 years and above (male and female) of the index sputum positive patients receiving DOTS. Mantoux skin test (Tuberculin Skin Test - TST) was administered by the principal investigator along with TST reading & final diagnosis. Chi-square test was done to find out the association., Results: Out of 220 household contacts tested, 43.6% (96) tested positive for latent TB (induration ≥10mm) with 95% CI ranging from 37% to 50%. The prevalence of latent TB among men and women are 35.6% and 49.2% respectively the difference between which is found to be statistically significant (p = 0.04). Odds Ratio of 5.5 was noted among study subjects who were diabetic (p = 0.018). Household contacts of index patients taking CAT II were at a higher risk than that of CAT I., Conclusion: This study clearly shows the high prevalence of latent TB infection among household contacts of sputum positive patients receiving DOTS and so RNTCP should include them in IPT along with under 6 children. The household contacts who spend most time with the index case, who sleep close to them within 5 feet, female household contacts, students, diabetic household contacts are at a significantly higher risk than others., Competing Interests: Conflicts of interest The author has none to declare., (Copyright © 2020. Published by Elsevier B.V.)

Introduction: Household Contacts (HHCs) of Pulmonary Tuberculosis (PTB) patients have a higher risk of latent tuberculosis infection (LTBI). However, its prevalence and risk factors among adults living with PTB patients are poorly documented in Kenya., Objective: to determine the prevalence and risk factors for LTBI among adult HHCs of PTB patients in Kenya., Methods: this was an analytical cross-sectional study of HHCs of PTB patients in Nairobi, Kenya. Socio-demographic data was captured on questionnaires and blood samples drawn for Interferon gamma (IFN-γ) quantification. Univariate and multivariate analyses using the Statistical Package for Social Scientists (SPSS) was used to determine the prevalence of LTBI and risk factors at 95% Confidence Interval (CI)., Results: a total of 166 PTB patients yielded 175 HHCs of whom 29.7% (52/125) were males and 70.3% (123/125) were females. A majority of HHCs [65.7% (115/175)] lived in a single-room house with the patient and [37.7% (66/175)] were in the age group 30-39-years. The overall prevalence of LTBI was 55.7%, peaking among spouses of the patients [70.0% (14/20) and the 30-39 year age group [63.5% (42/66)]. Potential risk factors for LTBI included cohabiting with a PTB patient for 8 to 12 weeks [OR = 3.6 (0.70-18.5), p = 0.107], being a spouse of the patient [OR = 2.0 (0.72-5.47), p = 0.173] and sharing a single room with the patient [OR = 1.58 (0.84 - 2.97), p = 0.158]., Conclusion: the high prevalence of LTBI among adult HHCs of PTB patients in this population demonstrates the need for targeted contact-screening programs in high TB transmission settings., Competing Interests: The authors declare no competing interests., (Copyright: Susan Odera et al.)

Tuberculosis (TB) is a serious global public health threat, and school-clustered outbreaks are common. Here, we report a TB outbreak in a high school in southern China, which was confirmed and characterized by traditional epidemiological methods and whole-genome sequencing (WGS) of Mycobacterium tuberculosis isolates. All students and faculty (n = 287) were screened by chest X-ray for active TB. TB was diagnosed in 28 patients, according to laboratory confirmation (n = 11) of Mycobacterium tuberculosis, sputum/bronchoalveolar fluid culture, smear, or TB-Xpert. Clinically diagnosed TB cases (n = 17) were further defined by the interferon-γ releasing assay or clinical and radiological findings. Twenty-five of the affected individuals were 12th grade students aged 16 to 19 years; among them, 24 patients were male and 21 had visited the internet café near the school. WGS and phylogenetics analysis confirmed that the outbreak was mainly caused by a super transmission strain of lineage 4.2, which was susceptible to all tested antibiotics. After a treatment regimen of 9 to12 months, all 28 patients were cured. This study highlights the key factors contributing to school-clustered TB outbreaks mainly derived from a single super transmission strain, along with effective interventional measures to prevent a larger scale outbreak., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020. Published by Elsevier B.V.)

Introduction: Recent respiratory infectious disease (RID) outbreaks of influenza and the novel coronavirus have resulted in global pandemics. RIDs can trigger nosocomial infections if not adequately prevented., Objective: The objective of this study was to rate the adequacy of healthcare workers (HCWs) and hospital settings on RID prevention using unannounced standardized patients (USP) in clinical settings of hospital gateways., Methods: Trained USPs visited 5 clinical settings: information desks, registration desks, two outpatient departments and the emergency departments in 10 hospitals across 3 cities of Inner Mongolia, China. USPs observed the hospital air ventilation and distance from the nearest hand-washing facilities to each clinical setting, then mimicked symptoms of either tuberculosis or influenza before observing the HCW's behavior. A total of 480 clinical-setting assessments were made by 19 USPs., Results: The overall adequacy of triage services was 86.7% and for prevention of the spread of airborne droplets was 83.5%. Almost all hospitals offered adequate air ventilation. Compared to the information desk, adequacy of triage and preventing the spread of airborne droplets by physicians in the three clinical departments was less likely to be adequate. Triage services for USPs simulating symptoms of influenza were 2.6 times more likely to be adequate than for those simulating symptoms of tuberculosis but there was no significant difference in the prevention of the spread of airborne droplets., Conclusions: There is a need to improve respiratory infectious disease procedures in our study hospitals, especially in outpatient and emergency departments.

A burgeoning epidemic of drug-resistant tuberculosis (TB) threatens to derail global control efforts. Although the mechanisms remain poorly clarified, drug-resistant strains are widely believed to be less infectious than drug-susceptible strains. Consequently, we hypothesized that lower proportions of patients with drug-resistant TB would have culturable Mycobacterium tuberculosis from respirable, cough-generated aerosols compared to patients with drug-susceptible TB, and that multiple factors, including mycobacterial genomic variation, would predict culturable cough aerosol production. We enumerated the colony forming units in aerosols (≤10 µm) from 452 patients with TB (227 with drug resistance), compared clinical characteristics, and performed mycobacterial whole-genome sequencing, dormancy phenotyping and drug-susceptibility analyses on M. tuberculosis from sputum. After considering treatment duration, we found that almost half of the patients with drug-resistant TB were cough aerosol culture-positive. Surprisingly, neither mycobacterial genomic variants, lineage, nor dormancy status predicted cough aerosol culture positivity. However, mycobacterial sputum bacillary load and clinical characteristics, including a lower symptom score and stronger cough, were strongly predictive, thereby supporting targeted transmission-limiting interventions. Effective treatment largely abrogated cough aerosol culture positivity; however, this was not always rapid. These data question current paradigms, inform public health strategies and suggest the need to redirect TB transmission-associated research efforts toward host-pathogen interactions.

An HIV-positive mother infected her daughter with extensively drug-resistant Mycobacterium tuberculosis. Despite adhering to the then current guidelines for prevention, the infant was diagnosed with extensively drug-resistant pulmonary tuberculosis at the age of 4 months and developed tuberculous meningitis. After a short delay, appropriate treatment was initiated, followed by an inhospital stay at a specialised hospital. The infant became generally well, but had delayed neurological development. Secondary hydrocephalus due to tuberculous meningitis required a ventriculoperitoneal shunt. After 2 years of microbiologically and clinically effective tuberculosis treatment and several shunt complications, the HIV-negative child died at the age of 28 months ‒ with radiological signs of a shunt infection. The reason for the fatal outcome was probably related to inadequate risk reduction of airborne mother-to-child transmission, inappropriate chemoprophylaxis and delayed initiation of adequate treatment.

The World Health Organization (WHO) recently changed its guidance for tuberculosis (TB) preventive treatment (TPT) recommending TPT for all pulmonary TB (PTB) exposed household contacts (HHC) to prevent incident TB disease (iTBD), regardless of TB infection (TBI) status. However, this recommendation was conditional as the strength of evidence was not strong. We assessed risk factors for iTBD in recently-exposed adult and pediatric Indian HHC, to determine which HHC subgroups might benefit most from TPT. We prospectively enrolled consenting HHC of adult PTB patients in Pune and Chennai, India. They underwent clinical, microbiologic and radiologic screening for TB disease (TBD) and TBI, at enrollment, 4-6, 12 and 24 months. TBI testing was performed by tuberculin skin test (TST) and Quantiferon®- Gold-in-Tube (QGIT) assay. HHC without baseline TBD were followed for development of iTBI and iTBD. Using mixed-effect Poisson regression, we assessed baseline characteristics including TBI status, and incident TBI (iTBI) using several TST and/or QGIT cut-offs, as potential risk factors for iTBD. Of 1051 HHC enrolled, 42 (4%) with baseline TBD and 12 (1%) with no baseline TBI test available, were excluded. Of the remaining 997 HHC, 707 (71%) had baseline TBI (TST #x2265; 5 mm or QGIT #x2265; 0.35 IU/ml). Overall, 20 HHC (2%) developed iTBD (12 cases/1000 person-years, 95%CI: 8-19). HIV infection (aIRR = 29.08, 95% CI: 2.38-355.77, p = 0.01) and undernutrition (aIRR = 6.16, 95% CI: 1.89-20.03, p = 0.003) were independently associated with iTBD. iTBD was not associated with age, diabetes mellitus, smoking, alcohol, and baseline TBI, or iTBI, regardless of TST (#x2265; 5 mm, #x2265; 10 mm, #x2265; 6 mm increase) or QGIT (#x2265; 0.35 IU/ml, #x2265; 0.7 IU/ml) cut-offs. Given the high overall risk of iTBD among recently exposed HHCs, and the lack of association between TBI status and iTBD, our findings support the new WHO recommendation to offer TPT to all HHC of PTB patients residing in a high TB burden country such as India, and do not suggest any benefit of TBI testing at baseline or during follow-up to risk stratify recently-exposed HHC for TPT., Competing Interests: The authors have declared that no competing interests exist.

Background: Health-care workers (HCWs) are an epidemiological group with increased exposure to tuberculosis (TB), especially at health-care facilities (HCFs) with poor TB infection control in high-TB-burden settings. China is a high-TB-burden country, and the comprehensive measures for stopping TB transmission at some HCFs were not implemented well owing to limited resources and other factors. The purpose of this study was to review risk of occupational exposure to TB among HCWs and its change trend, and identify epidemiological characteristics of pulmonary tuberculosis (PTB) among HCWs in Henan, central part of China., Methods: A retrospective cohort study was conducted from 2010 to 2017. All HCWs and teachers in Henan were enrolled to the study as exposed group and non-exposed control group, respectively. Relative risk (RR), attributable risk (AR) and AR percent (AR%) were used to measure the association between the occupational exposure and PTB, and estimated with Poisson regression., Results: The study results showed a total of 1663 cases of PTB were reported among the HCWs in Henan, accounting for 3.2‰ of all PTB cases reported in the whole population, and annual incidence rate of PTB among HCWs declined by 34% from 2010 to 2017. Over the eight years, the incidence rate of PTB among HCWs was 43.7 cases per 100,000 person-years (PYs), significantly higher than that among teachers (18.8 cases/100,000 PYs), and RR, AR and AR% were estimated to 2.3, 24.9 cases per 100,000 PYs and 57%, respectively. Among HCWs, males were more likely to suffer from PTB than females (adjusted RR: 1.3; 95%CI: 1.2-1.4), and HCWs aged under 25 years had the highest relative risk over all age groups with adjusted RR equaling to 8.3 (95%CI: 6.9-9.9) calculated with those aged 45-54 years as the reference., Conclusions: Although overall incidence rate of PTB among HCWs showed decreasing temporal trends over the period of 2010-2017, attributable risk of occupational exposure to TB among HCWs did not decrease in Henan, and TB infection at HCFs for males, young or senior HCWs, especially for young HCWs is of much concern.

Background: At present, there are few studies on polymorphism of Mycobacterium tuberculosis (Mtb) gene and how it affects the TB epidemic. This study aimed to document the differences of polymorphisms between tuberculosis hot and cold spot areas of Guangxi Zhuang Autonomous Region, China., Methods: The cold and hot spot areas, each with 3 counties, had been pre-identified by TB incidence for 5 years from the surveillance database. Whole genome sequencing analysis was performed on all sputum Mtb isolates from the detected cases during January and June 2018. Single nucleotide polymorphism (SNP) of each isolate compared to the H37Rv strain were called and used for lineage and sub-lineage identification. Pairwise SNP differences between every pair of isolates were computed. Analyses of Molecular Variance (AMOVA) across counties of the same hot or cold spot area and between the two areas were performed., Results: As a whole, 59.8% (57.7% sub-lineage 2.2 and 2.1% sub-lineage 2.1) and 39.8% (17.8% sub-lineage 4.4, 6.5% sub-lineage 4.2 and 15.5% sub-lineage 4.5) of the Mtb strains were Lineage 2 and Lineage 4 respectively. The percentages of sub-lineage 2.2 (Beijing family strains) are significantly higher in hot spots. Through the MDS dimension reduction, the genomic population structure in the three hot spot counties is significantly different from those three cold spot counties (T-test p = 0.05). The median of SNPs distances among Mtb isolates in cold spots was greater than that in hot spots (897 vs 746, Rank-sum test p < 0.001). Three genomic clusters, each with genomic distance ≤12 SNPs, were identified with 2, 3 and 4 consanguineous strains. Two clusters were from hot spots and one was from cold spots., Conclusion: Narrower genotype diversity in the hot area may indicate higher transmissibility of the Mtb strains in the area compared to those in the cold spot area.

Introduction: Resource constraints in Low and Middle-Income Countries (LMICs) limit tuberculosis (TB) contact investigation despite evidence its benefits could outweigh costs, with increased efficiency when compared with intensified case finding (ICF). However, there is limited data on yield and cost per TB case identified. We compared yield and cost per TB case identified for ICF and Tuberculosis-Contact Investigation (TB-CI) in Uganda., Methods: A retrospective cohort study based on data from 12 Ugandan hospitals was done between April and September 2017. Two methods of TB case finding (i.e. ICF and TB-CI) were compared. Regarding ICF, patients either self-reported their signs and symptoms or were prompted by health care workers, while TB-CI was done by home-visiting and screening contacts of TB patients. Patients who were presumed to have tuberculosis were requested to produce a sample for examination. TB yield was defined as a ratio of diagnoses to tests, and this was computed per method of diagnosis. The cost per TB case identified (medical, personnel, transportation and training) for each diagnosis method were computed using the activity-based approach, from the health care perspective. Cost data were analyzed using Windows Excel., Results: 454 index TB cases and 2,707 of their household contacts were investigated. Thirty-one per cent of contacts (840/2707) were found to be presumptive TB cases. A total of 7,685 tests were done, 6,967 for ICF and 718 for TB-CI. The yields were 18.62% (1297/6967) and 5.29% (38/718) for ICF and TB-CI, respectively. It cost US$ 120.60 to diagnose a case of TB using ICF compared to US$ 877.57 for TB-CI., Conclusion: The yield of TB-CI was found to be four-times lower and seven-times costlier compared to ICF. These findings suggest that ICF can improve TB case detection at a low cost, particularly in high TB prevalent settings., Competing Interests: The authors declare no competing interests exist.

Tuberculosis continues to be a major threat to global health. Cavitation is a dangerous consequence of pulmonary tuberculosis associated with poor outcomes, treatment relapse, higher transmission rates, and development of drug resistance. However, in the antibiotic era, cavities are often identified as the most extreme outcome of treatment failure and are one of the least-studied aspects of tuberculosis. We review the epidemiology, clinical features, and concurrent standards of care for individuals with cavitary tuberculosis. We also discuss developments in the understanding of tuberculosis cavities as dynamic physical and biochemical structures that interface the host response with a unique mycobacterial niche to drive tuberculosis-associated morbidity and transmission. Advances in preclinical models and non-invasive imaging can provide valuable insights into the drivers of cavitation. These insights will guide the development of specific pharmacological interventions to prevent cavitation and improve lung function for individuals with tuberculosis., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Household Contacts (HHCs) of patients with pulmonary tuberculosis (PTB) have a higher risk of developing TB. Contact investigation is recommended to reach this group and identify undiagnosed cases. In this study, we have determined the yield of contact investigation among HHCs of patients with smear-positive PTB, and estimated TB burden., Methods: We conducted retrospective record review for the occurrence of TB among HHCs of Index PTB+ cases treated between November 2010 and April 2013 in 12 public health facilities in Boricha district. HHCs were followed up monthly and revisited between March and June 2015. Information on additional TB cases diagnosed and treated among HHCs were documented. HHCs who were diagnosed as having TB after the index cases were diagnosed and treated were considered as 'incident cases'. Presumptive TB case was defined as those having cough for ≥2 weeks or enlarged lymph node. Diagnosis of TB among HHCs were made using smear-microscopy and/or X-rays, and clinically for Extra-pulmonary TB (EPTB)., Results: One thousand five hundred and seventeenth HHCs of 344 index cases were visited and screened for TB and followed up for a median of 37 months. 77 (5.1% - 72 with PTB and 5 with EPTB) HHCs developed TB during 4713 person-years of follow-up with an estimated incidence of 1634 (95% CI: 1370-2043) per 100,000 person-years follow-up which is much higher than the estimated TB incidence for the general population in Ethiopia of 210/100,000. Half (41/77) of incident TB cases were diagnosed within the first year of diagnosis of the index cases and 88% (68/77) were adults (Hazard Ratio: 4.03; 95% CI: 2.00-8.12)., Conclusion: HHCs of index PTB+ cases have high risk of developing active TB. Long term follow-up of HHCs could help improve TB case finding depending on country contexts. Further studies on effectiveness and feasibility of the approach and integration in routine settings are needed.

The local situation with tuberculosis (TB) is shaped by the complex interplay of multiple factors related to both human host and Mycobacterium tuberculosis. We hypothesized that TB epidemiology in the rural regions in the Soviet Union was impacted by construction of the Gulag camps and significant incoming migration. This molecular M. tuberculosis study was conducted in 2017 in the Komi Republic in northern Russia, a region with high rate (26%) of primary multidrug-resistant (MDR) TB. MDR was detected in 30.8% (40/130) isolates; eight were extensively drug resistant. The Beijing genotype was predominant (56.2%). The main Beijing subtypes B0/W148 and 94-32 differed in the MDR rate, 83.3% and 27.2%, respectively. The non-Beijing isolates represented five genotypes (LAM, Ural, Haarlem, X, T). The proportion of Beijing B0/W148 in the "camp" cities (originated from Gulag camps) was twice as large as in other districts of the Komi Republic. To conclude, сirculation of the MDR-associated Beijing B0/W148 cluster critically influences the current situation with MDR-TB in this Russian region. The increased prevalence of B0/W148 in the urban setting on the whole, and in the "camp cities", in particular, indirectly points to the increased transmission capacity of this successful Russian strain of M. tuberculosis., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

More than one in two healthcare workers (HCWs) in developing countries have latent tuberculosis infection (LTBI), an asymptomatic condition signifying persistent tubercular infection in absence of disease., Objective: to evaluate the physician attitude towards LTBI preventive therapy and their perspectives regarding the potential expansion of latent TB management under the RNTCP., Material and Methods: We conducted a cross-sectional analysis among 60 participants of a continuing medical education program during October' 2019 in a medical college in Delhi, India., Results: We enrolled a total of 30 medical officers, 15 resident doctors and 15 medical interns, comprising 27 (45%) males and 33 (55%) females. Only 9 (15%) participants were aware of existing RNTCP guidelines for programmatic management of LTBI. The median (IQR) self-rated willingness of the participants in receiving treatment for LTBI after confirmation of diagnosis on a 10 point continuous rating scale was 6 (5.8). The principal reason attributed to the treatment hesitancy were concerns over drug side effects 19 (31.7%), emergence of drug resistance 11 (18.3%) and the likelihood of reinfection 4 (6.7%). Support for expansion of preventive therapy among household TB contacts was varied, with maximum (41.2%) participants wanting it only for the comorbid patients., Conclusion: LTBI preventive treatment is associated with considerable side effects and lack of long-term benefits by a majority of Indian physicians despite significant personal health concerns in treating pulmonary TB cases., Competing Interests: Conflicts of interest All authors have none to declare., (Copyright © 2020 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.)

Background: Tens of millions of children are exposed to Mycobacterium tuberculosis globally every year; however, there are no contemporary estimates of the risk of developing tuberculosis in exposed children. The effectiveness of contact investigations and preventive therapy remains poorly understood., Methods: In this systematic review and meta-analysis, we investigated the development of tuberculosis in children closely exposed to a tuberculosis case and followed for incident disease. We restricted our search to cohort studies published between Jan 1, 1998, and April 6, 2018, in MEDLINE, Web of Science, BIOSIS, and Embase electronic databases. Individual-participant data and a pre-specified list of variables were requested from authors of all eligible studies. These included characteristics of the exposed child, the index case, and environmental characteristics. To be eligible for inclusion in the final analysis, a dataset needed to include: (1) individuals below 19 years of age; (2) follow-up for tuberculosis for a minimum of 6 months; (3) individuals with household or close exposure to an individual with tuberculosis; (4) information on the age and sex of the child; and (5) start and end follow-up dates. Studies assessing incident tuberculosis but without dates or time of follow-up were excluded. Our analysis had two primary aims: (1) estimating the risk of developing tuberculosis by time-period of follow-up, demographics (age, region), and clinical attributes (HIV, tuberculosis infection status, previous tuberculosis); and (2) estimating the effectiveness of preventive therapy and BCG vaccination on the risk of developing tuberculosis. We estimated the odds of prevalent tuberculosis with mixed-effects logistic models and estimated adjusted hazard ratios (HRs) for incident tuberculosis with mixed-effects Poisson regression models. The effectiveness of preventive therapy against incident tuberculosis was estimated through propensity score matching. The study protocol is registered with PROSPERO (CRD42018087022)., Findings: In total, study groups from 46 cohort studies in 34 countries-29 (63%) prospective studies and 17 (37%) retrospective-agreed to share their data and were included in the final analysis. 137 647 tuberculosis-exposed children were evaluated at baseline and 130 512 children were followed for 429 538 person-years, during which 1299 prevalent and 999 incident tuberculosis cases were diagnosed. Children not receiving preventive therapy with a positive result for tuberculosis infection had significantly higher 2-year cumulative tuberculosis incidence than children with a negative result for tuberculosis infection, and this incidence was greatest among children below 5 years of age (19·0% [95% CI 8·4-37·4]). The effectiveness of preventive therapy was 63% (adjusted HR 0·37 [95% CI 0·30-0·47]) among all exposed children, and 91% (adjusted HR 0·09 [0·05-0·15]) among those with a positive result for tuberculosis infection. Among all children <5 years of age who developed tuberculosis, 83% were diagnosed within 90 days of the baseline visit., Interpretation: The risk of developing tuberculosis among exposed infants and young children is very high. Most cases occurred within weeks of contact investigation initiation and might not be preventable through prophylaxis. This suggests that alternative strategies for prevention are needed, such as earlier initiation of preventive therapy through rapid diagnosis of adult cases or community-wide screening approaches., Funding: National Institutes of Health., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Household contacts of patients with active pulmonary tuberculosis (TB) often have latent TB infection, and are at risk of progression to disease. We set out to investigate whether index TB case HIV status was linked to a higher probability of latent TB infection among household contacts., Materials and Methods: Data were collected prospectively from participants in the intervention arm of a household cluster-randomised trial in two South Africa provinces (Mangaung, Free State, and Capricorn, Limpopo). In intervention group households, TB contacts underwent HIV testing and tuberculin skin testing (TST). TST induration was estimated at two cut-offs (≥5mm, ≥10mm). Multilevel Bayesian regression models estimated posterior distributions of the percentage of household contacts with TST induration ≥5mm and ≥10mm by age group, and compared the odds of latent TB infection by key risk factors including HIV status index case age and study province., Results: A total of 2,985 household contacts of 924 index cases were assessed, with most 2,725 (91.3%) undergoing TST. HIV prevalence in household contacts was 14% and 10% in Mangaung and Capricorn respectively. Overall, 16.8% (458/2,725) had TST induration of ≥5mm and 13.1% (359/2,725) ≥10mm. In Mangaung, children aged 0-4 years had a high TST positivity prevalence compared to their peers in Capricorn (22.0% vs. 7.6%, and 20.5% vs. 2.3%, using TST thresholds of ≥5mm and ≥10mm respectively). Compared to contacts from Capricorn, household contacts living in Mangaung were more likely to have TST induration ≥5mm (odds ratio [OR]: 3.08, 95% credibility interval [CI]: 2.13-4.58) and ≥10mm (OR: 4.52, 95% CI: 3.03-6.97). There was a 90% and 92% posterior probability that the odds of TST induration ≥5mm (OR: 0.79, 95% CI: 0.56-1.14) and ≥10mm (OR: 0.77, 95% CI: 0.53-1.10) respectively were lower in household contacts of HIV-positive compared to HIV-negative index cases., Conclusions: High TST induration positivity, especially among young children and people living in Mangaung indicates considerable TB transmission despite high antiretroviral therapy coverage. Household contact of HIV-positive index TB cases were less likely to have evidence of latent TB infection than contacts of HIV-negative index cases., Competing Interests: The authors have declared that no competing interests exist

Few studies have prospectively compared the relative transmissibility and propensity to cause disease of Mycobacterium tuberculosis Beijing strains with other human-adapted strains of the M. tuberculosis complex. We assessed the effect of Beijing strains on the risk for M. tuberculosis infection and disease progression in 9,151 household contacts of 2,223 culture-positive pulmonary tuberculosis (TB) patients in Lima, Peru. Child contacts exposed to Beijing strains were more likely than child contacts exposed to non-Beijing strains to be infected at baseline, by 12 months of follow-up, and during follow-up. We noted an increased but nonsignificant tendency for child contacts to develop TB. Beijing strains were not associated with TB in adult contacts. These findings suggest that Beijing strains are more transmissible in children than are non-Beijing strains.

Background: Host genetic polymorphisms may be important in determining susceptibility to Mycobacterium tuberculosis (Mtb) infection, but their role is not fully understood. Detection of microbial DNA and activation of type I interferon (IFN) pathways regulate macrophage responses to Mtb infection., Methods: We examined whether seven candidate gene SNPs were associated with tuberculin skin test (TST) positivity in close contacts of microbiologically confirmed pulmonary TB patients in Brazil. Independent associations with TST positivity were tested using multivariable logistic regression (using genotypes and clinical variables) and genetic models., Results: Among 482 contacts of 145 TB index cases, 296 contacts were TST positive. Multivariable regression analysis adjusted for population admixture, age, family relatedness, sex and clinical variables related to increased TB risk demonstrated that SNPs in PYHIN1-IFI16-AIM2 rs1101998 (adjusted OR [aOR]: 3.72; 95%CI=1.15-12.0; p=0.028) and in PYHIN1-IFI16-AIM2 rs1633256 (aOR=24.84; 95%CI=2.26-272.95; p=0.009) were associated with TST positivity in a recessive model. Furthermore, an IRF7 polymorphism (rs11246213) was associated with reduced odds of TST positivity in a dominant model (aOR: 0.50, 95%CI: 0.26-0.93; p=0.029)., Conclusions: Polymorphisms in PYHIN1-IFI16-AIM2 rs1633256, rs1101998 and in IRF7 rs11246213 were associated with altered susceptibility to Mtb infection in this Brazilian cohort., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Tuberculosis (TB) is generally considered a disease that principally afflicts the low-income segments of a population. In the Nanshan District of Shenzhen, China, with the economic transformation and a new Headquarters Economy (HE) emerging, there are now more cases in office workers than in manufacturing workers. To illustrate this trend, we describe a small TB outbreak in an office building located in the centre of the rapidly growing HE district. Two active pulmonary tuberculosis cases were found in workers who shared an office, and whole genome sequencing showed that the genetic distance between the strains of the two cases was just one single nucleotide polymorphism, consistent with intra-office transmission. Investigation of 30 other workers in the same or adjacent offices with interviews, interferon-gamma release assays (IGRAs) and chest X-rays, identified one new TB case and latent tuberculosis infection (LTBI) in 40.0% (12/30) of the contacts. The offices were under-ventilated. None of the IGRA positive, asymptomatic contacts agreed to receive treatment for LTBI, presumably due to TB stigma, and over the next 2 years 69.0% (20/29) of the contacts were lost to follow-up. Treatment for LTBI and stigma of TB remain challenges here. Office workers in the HE of rapidly economic developing areas should be targeted with increased vigilance by TB control programmes.

It is relevant to evaluate MDR-tuberculosis in prisons and its impact on the global epidemiology of this disease. However, systematic molecular epidemiology programs in prisons are lacking. A health-screening program performed on arrival for inmates transferred from Peruvian prisons to Spain led to the diagnosis of five MDR-TB cases from one of the biggest prisons in Latin America. They grouped into two MIRU-VNTR-clusters (Callao-1 and Callao-2), suggesting a reservoir of two prevalent MDR strains. A high-rate of overexposure was deduced because one of the five cases was coinfected by a pansusceptible strain. Callao-1 strain was also identified in 2018 in a community case in Spain who had been in the same Peruvian prison in 2002-5. A strain-specific-PCR tailored from WGS data was implemented in Peru, allowing the confirmation that these strains were currently responsible for the majority of the MDR cases in that prison, including a new mixed infection.

Background: The goal of tuberculosis elimination put forward in the End TB Strategy prioritizes diagnosis and treatment of incipient and subclinical TB, recently defined by key stakeholders as "asymptomatic, early pre-clinical disease during which pathology evolves". Regarded as indicative of a high risk of TB progression, considerable efforts have been made to identify these cases through exploration of biomarkers. The present study aimed to evaluate simple scoring systems for TB exposure as screening tools for subclinical TB, the only identifiable of the incipient and subclinical disease states, in a contact investigation (CI) setting of low HIV-prevalence., Methods: Nested within a large prospective study in household contacts (HHCs) of smear positive pulmonary TB cases in South-India conducted 2010-2012, we assessed 1) the association between the Tuberculosis Contact Score (TCS) and the Infectivity Score, with established tools for Mycobacterium tuberculosis (Mtb) infection, corrected for established TB risk factors, and 2) the capability of the TB exposure scores to identify subclinical TB defined by Mtb-culture positivity in sputum or gastric aspirate (subjects < 5 years) specimen., Results: Of 525 HHCs, 29 were Mtb-culture positive and 96.6% of these asymptomatic. The TCS and the Infectivity Score associated with positive Tuberculin Skin Test and QuantiFeron TB-Gold In-tube assay (QFT) results in multivariate analyses (TCS: OR TST 1.16, 95% CI: 1.01, 1.33; OR QFT 1.33 95% CI: 1.16, 1.51. Infectivity Score: OR TST 1.39, 95% CI: 1.10, 1.76; OR QFT 1.41 95% CI: 1.16, 1.71). The Infectivity Score showed a moderate capability to identify subclinical TB (AUC of 0.61, 95% CI: 0.52, 0.70)., Conclusions: Although our results did not identify an easily applicable screening tool for subclinical TB, the present study indicates that focusing on TB-related symptoms in CI settings may be of limited value for early identification of HHCs with high risk for TB progression.

Tuberculosis (TB) infects about 25% of the world population and claims more human lives than any other infectious disease. TB is spread by inhalation of aerosols containing viable Mycobacterium tuberculosis expectorated or exhaled by patients with active pulmonary disease. Air-sampling technology could play an important role in TB control by enabling the detection of airborne M. tuberculosis, but tools that are easy to use and scalable in TB hotspots are lacking. We developed an electrostatic air sampler termed the TB Hotspot DetectOR (THOR) and investigated its performance in laboratory aerosol experiments and in a prison hotspot of TB transmission. We show that THOR collects aerosols carrying microspheres, Bacillus globigii spores and M. bovis BCG, concentrating these microparticles onto a collector piece designed for subsequent detection analysis. The unit was also successfully operated in the complex setting of a prison hotspot, enabling detection of a molecular signature for M. tuberculosis in the cough of inmates. Future deployment of this device may lead to a measurable impact on TB case-finding by screening individuals through the aerosols they generate., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The goal of this study was to identify individuals at risk of progression and reactivation among household contacts (HHC) of pulmonary TB cases in Vitoria, Brazil. We first evaluated the predictive performance of six published signatures on the transcriptional dataset obtained from peripheral blood mononuclear cell samples from HHC that either progressed to TB disease or not (non-progressors) during a five-year follow-up. The area under the curve (AUC) values for the six signatures ranged from 0.670 to 0.461, and the PPVs did not reach the WHO published target product profiles (TPPs). We therefore used as training cohort the earliest time-point samples from the African cohort of adolescents (GSE79362) and applied an ensemble feature selection pipeline to derive a novel 29-gene signature (PREDICT29). PREDICT29 was tested on 16 progressors and 21 non-progressors. PREDICT29 performed better in segregating progressors from non-progressors in the Brazil cohort with the area under the curve (AUC) value of 0.911 and PPV of 20%. This proof of concept study demonstrates that PREDICT29 can predict risk of progression/reactivation to clinical TB disease in recently exposed individuals at least 5 years prior to disease development. Upon validation in larger and geographically diverse cohorts, PREDICT29 can be used to risk-stratify recently infected for targeted therapy., Competing Interests: Declaration of competing interest The authors have declared that no conflict of interest exists., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aim: To assess the risk of tuberculosis (infection and disease) in children less than 15 years' old who are household contacts of pulmonary tuberculosis patients in three Colombian cities (Medellín, Cali, and Popayán)., Methods: A cohort of 1,040 children household contacts of 380 adults with smear-positive pulmonary tuberculosis was followed up for 24 months. Study period 2005-2009., Results: Tuberculin skin test was positive (≥10 mm) in 43.7% (95% CI: 39.2-48.2). Tuberculin skin test positivity was associated with age 10-14 years (Prevalence Ratio -PR= 1.43, 95% CI: 1.1-1.9), having a BCG vaccine scar (PR= 1.52, 95% CI: 1.1-2.1), underweight, closer proximity to the index case and exposure time >3 months. The annual risk of infection (tuberculin skin test induration increase of 6 mm or more per year) was 17% (95% CI: 11.8-22.2) and was associated with a bacillary load of the adult index case (Relative Risk -RR= 2.12, 95% CI: 1.0-4.3). The incidence rate of active tuberculosis was 12.4 cases per 1,000 persons-year. Children <5 years without BCG vaccine scar had a greater risk of developing active disease (Hazard Ratio -HR= 6.00, 95% CI: 1.3-28.3) than those with scar (HR= 1.33, 95% CI: 0.5-3.4). The risk of developing active tuberculosis augmented along with the increase from initial tuberculin skin test (tuberculin skin test 5-9 mm HR= 8.55, 95% CI: 2.5-29.2; tuberculin skin test ≥10 mm HR= 8.16, 95% CI: 2.0-32.9)., Conclusions: There is a need for prompt interruption of adult-to-children tuberculosis transmission within households. Conducting proper contact investigation and offering chemoprophylaxis to infected children could reduce tuberculosis transmission., Competing Interests: Conflict of Interest: None of the authors have conflicts of interest relevant to this article to disclose., (Copyright © 2019 Universidad del Valle.)

BACKGROUND: Mycobacterium tuberculosis complex (MTBC) and its human host are the most competent organisms with co-evolutionary trajectory. This review determined the phylogeography, clinical phenotype-related genotype and transmission dynamics of MTBC in Africa. METHODS: Spoligotyping and mycobacterial interspersed repetitive units-variable number tandem repeats (MIRU-VNTR) based articles from Africa published in the English language were included. Articles were retrieved from PubMed and Scopus on 12 May 2018. RESULTS: In Africa, respectively 92% and 7% of tuberculosis (TB) cases were caused by M. tuberculosis and M. africanum . Among M. tuberculosis lineages (L), L4 was the predominant, at 67%, followed by L3/Central Asian (CAS; 10%). L7/ETH1 and L5/6/ Maf were restricted to the Horn and Western Africa, respectively. L4.6/SIT37, H37Rv like, L4.1.2/Haarlem and H3-Ural were proportionally more frequent among tuberculous lymphadenitis (TBLN) than among pulmonary tuberculosis (PTB) cases. On 24-locus MIRU-VNTR, clustering rate was 31%; the secondary case rate from a single primary source case was 20%. CONCLUSION: Africa in general, and the east-west pole of Africa in particular, harboured a genetically diverse population of MTBC, with characteristics of geographic segregation. Both generalist and specialist genotypes are circulating in the region. L4 is dominant across the continent, while M. bovis is rarely detected as a cause for human TB. The clinical significance of genetic diversity of MTBC in the different geographic and population groups of Africa is not fully understood. Both person-to-person transmission and reactivation mode of TB is significant in Africa. Prevention and control strategies should therefore envisage these two scenarios.

BACKGROUND: It is very difficult to observe tuberculosis (TB) transmission chains and thus, identify superspreaders. We investigate cough duration as a proxy measure of transmission to assess the presence of potential TB superspreaders. DESIGN: We analyzed six studies from China, Peru, The Gambia and Uganda, and determined the distribution of cough duration and compared it with several theoretical distributions. To determine factors associated with cough duration, we used linear regression and boosted regression trees to examine the predictive power of patient, clinical and environmental characteristics. RESULTS: We found within-study heterogeneity in cough duration and strong similarities across studies. Approximately 20% of patients contributed 50% of total cough days, and around 50% of patients contributed 80% of total cough days. The cough duration distribution suggested an initially increasing, and subsequently, decreasing hazard of diagnosis. While some of the exposure variables showed statistically significant associations with cough duration, none of them had a strong effect. Multivariate analyses of different model types did not produce a model that had good predictive power. CONCLUSION: We found consistent evidence for the presence of supercoughers, but no characteristics predictive of such individuals.

Background: Delays in isolating patients admitted to hospital with active pulmonary tuberculosis (PTB) can contribute to nosocomial transmission; however, in Korea, patients with clinically diagnosed PTB are not routinely isolated while awaiting microbiological confirmation of the diagnosis. We aimed to assess the extent of delays in isolating patients admitted with PTB and to identify the factors associated with delayed isolation., Methods: We retrospectively reviewed the electronic medical records of patients aged ≥ 18 years with active PTB, between January 2008 and December 2017, from two Korean hospitals., Results: Among 1,062 patients, 612 (57.6%) were not isolated on admission day. The median time from admission to isolation was 1 day (interquartile range: 0-2 days). The independent risk factor most strongly associated with delayed isolation was admission to departments other than pulmonology or infectious diseases departments (adjusted odds ratio [aOR], 5.302; 95% confidence interval [CI], 3.177-8.847; P < 0.001). Factors associated with isolation on admission day were a past history of tuberculosis (TB) (aOR, 0.669; 95% CI, 0.494-0.906; P = 0.009), night sweats (aOR, 0.530; 95% CI, 0.330-0.851; P = 0.009), and apical infiltrates on chest radiographs (aOR, 0.452; 95% CI, 0.276-0.740; P = 0.002)., Conclusion: Concerning patients subsequently diagnosed with active PTB, > 50% were not isolated on admission day. We suggest that the patients with clinically suspected PTB including the elderly who have a past history of TB, night sweats, or apical infiltration on chest radiographs, be presumptively isolated on admission, without waiting for microbiological confirmation of the diagnosis., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2019 The Korean Academy of Medical Sciences.)

Background: Delay in diagnosis and treatment of pulmonary tuberculosis (PTB) leads to severe disease, adverse outcomes and increased transmission. Assessing the extent of delay and its effect on disease progression in TB affected settings has clinical and programmatic importance. Hence, the aim of this study was to investigate the possible effect of delay on infectiousness (cavitation and smear positivity) of patients at diagnosis in Somali pastoralist area, Ethiopia., Methods: A cross-sectional study was conducted between December 2017 and October 2018, and 434 newly coming and confirmed PTB patients aged ≥15 years were recruited in five facilities. Data were collected using interview, record-review, anthropometry, Acid-fast bacilli and chest radiography techniques. Log-binomial regression models were used to reveal the association of delay and other factors associated with cavitation and smear positivity, and ROC Curve was used to determine discriminative ability and threshold delays., Results: Median age of patients was 30 years. Of all, 62.9% were males, and 46.5% were pastoralists. Median diagnosis delay was 49 days (IQR = 33-70). Cavitation was significantly associated with diagnosis delay [P < 0.001]; 22.2% among patients diagnosed within 30 days of illness and 51.7% if delay was over 30 days. The threshold delay that optimizes cavitation was 43 days [AUC (95% CI) = 0.67(0.62-0.72)]. Smear positivity was significantly increased in patients delayed over 49 days [p = 0.02]. Other factors associated with cavitation were age ≤ 35 years [APR (95% CI) =1.3(1.01-1.6)], chronic diseases [APR (95% CI) = 1.8(1.2-2.6)] and low MUAC* female [APR (95% CI) = 1.8(1.2-2.8)]. Smear positivity was also associated with age ≤ 35 years [APR (95% CI) =1.4(1.1-1.8)], low BMI [APR (95% CI) =1.3(1.01-1.7)] and low MUAC [APR (95% CI) =1.5(1.2-1.9)]., Conclusion: This study highlights delay in diagnosis of pulmonary TB remained high and increased infectiousness of patients in pastoral settings of Ethiopia. Hence, delay should be targeted to improve patient outcomes and reduce transmission in such settings.

Background: Whole genome sequencing provides better delineation of transmission clusters in Mycobacterium tuberculosis than traditional methods. However, its ability to reveal individual transmission links within clusters is limited. Here, we used a 2-step approach based on Bayesian transmission reconstruction to (1) identify likely index and missing cases, (2) determine risk factors associated with transmitters, and (3) estimate when transmission happened., Methods and Findings: We developed our transmission reconstruction method using genomic and epidemiological data from a population-based study from Valencia Region, Spain. Tuberculosis (TB) incidence during the study period was 8.4 cases per 100,000 people. While the study is ongoing, the sampling frame for this work includes notified TB cases between 1 January 2014 and 31 December 2016. We identified a total of 21 transmission clusters that fulfilled the criteria for analysis. These contained a total of 117 individuals diagnosed with active TB (109 with epidemiological data). Demographic characteristics of the study population were as follows: 80/109 (73%) individuals were Spanish-born, 76/109 (70%) individuals were men, and the mean age was 42.51 years (SD 18.46). We found that 66/109 (61%) TB patients were sputum positive at diagnosis, and 10/109 (9%) were HIV positive. We used the data to reveal individual transmission links, and to identify index cases, missing cases, likely transmitters, and associated transmission risk factors. Our Bayesian inference approach suggests that at least 60% of index cases are likely misidentified by local public health. Our data also suggest that factors associated with likely transmitters are different to those of simply being in a transmission cluster, highlighting the importance of differentiating between these 2 phenomena. Our data suggest that type 2 diabetes mellitus is a risk factor associated with being a transmitter (odds ratio 0.19 [95% CI 0.02-1.10], p < 0.003). Finally, we used the most likely timing for transmission events to study when TB transmission occurred; we identified that 5/14 (35.7%) cases likely transmitted TB well before symptom onset, and these were largely sputum negative at diagnosis. Limited within-cluster diversity does not allow us to extrapolate our findings to the whole TB population in Valencia Region., Conclusions: In this study, we found that index cases are often misidentified, with downstream consequences for epidemiological investigations because likely transmitters can be missed. Our findings regarding inferred transmission timing suggest that TB transmission can occur before patient symptom onset, suggesting also that TB transmits during sub-clinical disease. This result has direct implications for diagnosing TB and reducing transmission. Overall, we show that a transition to individual-based genomic epidemiology will likely close some of the knowledge gaps in TB transmission and may redirect efforts towards cost-effective contact investigations for improved TB control., Competing Interests: The authors have declared that no competing interests exist.

Background: Household contacts (HHCs) of TB patients are at high risk of developing evidence of latent TB infection (LTBI) and active disease from the index patient. We estimated the age-specific prevalence of LTBI and the force of infection (FI), as a measure of recent transmission, among HHCs of active TB patients., Methods: A cross-sectional analysis of HHCs of pulmonary TB patients enrolled in a prospective study, 'CTRIUMPh', was conducted at two sites in India. LTBI was defined as either a positive tuberculin skin test (induration ≥5 mm) or QuantiFERON-Gold in tube test (value ≥0.35 IU/ml) and was stratified by age. FI, which is a measure of recent transmission of infection and calculated using changes in age-specific prevalence rates at specific ages, was calculated. Factors associated with LTBI were determined by logistic regression models., Results: Of 1020 HHCs of 441 adult pulmonary TB cases, there were 566 (55%) females and 289 (28%) children aged ≤15 y. While screening for the study 3% of HHC were diagnosed with active TB. LTBI prevalence among HHCs of pulmonary TB was 47% at <6 y, 53% between 6-14 y and 78% between 15-45 y. FI increased significantly with age, from 0.4 to 1.15 in the HHCs cohort (p=0.05)., Conclusion: This study observed an increased prevalence of LTBI and FI among older children and young adults recently exposed to infectious TB in the household. In addition to awareness of coughing etiquette and general hygiene, expanding access to TB preventive therapy to all HHCs, including older children, may be beneficial to achieve TB elimination by 2035., (© The Author(s) 2019. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)