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Background: Tracheobronchial stenosis due to tuberculosis (TSTB) seriously threatens the health of tuberculosis patients. The inflammation and autophagy of fibroblasts affect the development of TSTB. Triamcinolone acetonide (TA) can regulate the autophagy of fibroblasts. Nevertheless, the impact of TA on TSTB and underlying mechanism has remained unclear. Objective: To study the impact of TA on TSTB and underlying mechanism. Material and Methods: In order to simulate the TSTB-like model in vitro, WI-38 cells were exposed to Ag85B protein. In addition, the cell counting kit (CCK)-8 assay was applied to assess the function of TA in Ag85B-treated WI-38 cells. Quantitative real-time polymerase chain reaction was applied to detect the mRNA level of sirtuin 1 (SIRT1) and forkhead box O3 (FOXO3a), and autophagy-related proteins were evaluated by Western blot analysis. Vascular endothelial growth factor (VEGF) level was investigated by immunohistochemical staining. Enzyme-linked immunosorbent serologic assay was applied to detect the secretion of inflammatory cytokines. Furthermore, hematoxylin and eosin staining was applied to observe tissue injuries. Results: Ag85B affected WI-38 cell viability in a limited manner, while TA notably suppressed Ag85B-treated WI-38 cell viability. TA induced the apoptosis of Ag85B-treated WI-38 cells in a dose-dependent manner. In addition, Ag85B-treated WI-38 cells demonstrated the upregulation of interleukin (IL)-6, tumor necrosis factor-α (TNF-α), interferon gamma (IFN-γ), and fibrotic proteins (transforming growth factor-beta [TGF-β] and vascular endothelial growth factor [VEGF]), which can be significantly destroyed by the TA. Meanwhile, TA reversed Ag85-induced inhibition of cell autophagy by mediation of p62, LC3, and Beclin1. Furthermore, silencing of SIRT1/FOXO3a pathway could reverse the effect of TA on the autophagy of Ag85B-treated cells. Conclusion: TA significantly induced the autophagy of fibroblasts in Ag85B-treated cells by mediation of SIRT1/FOXO3 pathway. This study established a new theoretical basis for exploring strategies against TSTB.

Globally, China has the third highest number of tuberculosis (TB) cases despite high rates (85.6%) of effective treatment coverage. Identifying risk factors associated with unsuccessful treatment outcomes is an important component of maximising the efficacy of TB control programmes.Retrospective cohort study to evaluate the outcomes of 306,860 drug-susceptible TB patients who underwent treatment in Hunan Province, China between 2013 and 2018. Univariable and multivariable logistic regression models were used to identify factors associated with unsuccessful TB treatment outcomes.A successful treatment outcome was recorded for 98.6% of patients, defined as the sum of patients who were cured (36.2%) and completed treatment (62.4%). An unsuccessful treatment outcome was recorded for 1.8% of patients, defined as the sum of treatment failure (1.1%), deaths (0.5%) and lost to follow up (0.2%). The odds of an unsuccessful treatment outcome showed an increasing trend in more recent years of registration (2018 adjusted odds ratio (AOR): 1.43; 95% Confidence Interval (CI) 1.31, 1.57 relative to 2013). Other significant risk factors were male sex (AOR: 1.17; 95% CI 1.10, 1.25); increasing age (AOR:1.02 per year increase; 95% CI 1.02,1.02); being severely ill (AOR: 1.50; 95% CI 1.33, 1.70); having a history of TB treatment (AOR: 2.93; 95% CI 2.69, 3.20); not being under systematic management (AOR: 16.10 (14.49, 17.88) and treatment regimens that differed from full course management.The increasing likelihood of an unsuccessful treatment outcome over time necessitates the need for further research.

Tuberculosis (TB) is the leading cause of death from a bacterial pathogen worldwide. China has the third highest TB burden in the world, with a high reported burden in Hunan Province (amongst others). This study aimed to investigate the spatial distribution of TB and identify socioeconomic, demographic, and environmental drivers in Hunan Province, China. Numbers of reported cases of TB were obtained from the Tuberculosis Control Institute of Hunan Province, China. A wide range of covariates were collected from different sources, including from the Worldclim database, and the Hunan Bureau of Statistics. These variables were summarized at the county level and linked with TB notification data. Spatial clustering of TB was explored using Moran’s I statistic and the Getis–Ord statistic. Poisson regression models were developed with a conditional autoregressive (CAR) prior structure, and with posterior parameters estimated using a Bayesian approach with Markov chain Monte Carlo (MCMC) simulation. A total of 323,340 TB cases were reported to the Hunan TB Control Institute from 2013 to 2018. The mean age of patients was 51.7 years (SD + 17.6 years). The majority of the patients were male (72.6%, n = 234,682) and had pulmonary TB (97.5%, n = 315,350). Of 319,825 TB patients with registered treatment outcomes, 306,107 (95.7%) patients had a successful treatment outcome. The annual incidence of TB decreased over time from 85.5 per 100,000 population in 2013 to 76.9 per 100,000 population in 2018. TB case numbers have shown seasonal variation, with the highest number of cases reported during the end of spring and the beginning of summer. Spatial clustering of TB incidence was observed at the county level, with hotspot areas detected in the west part of Hunan Province. The spatial clustering of TB incidence was significantly associated with low sunshine exposure (RR: 0.86, 95% CrI: 0.74, 0.96) and a low prevalence of contraceptive use (RR: 0.88, 95% CrI: 0.79, 0.98). Substantial spatial clustering and seasonality of TB incidence were observed in Hunan Province, with spatial patterns associated with environmental and health care factors. This research suggests that interventions could be more efficiently targeted at locations and times of the year with the highest transmission risk.

ObjectiveThis study aimed to investigate the spatial distribution of drug-resistant tuberculosis (DR-TB) in Hunan province, China.MethodsAn ecological study was conducted using DR-TB data collected from the Tuberculosis Control Institute of Hunan Province between 2012 and 2018. Spatial clustering of DR-TB was explored using the Getis-Ord statistic. A Poisson regression model was fitted with a conditional autoregressive prior structure, and with posterior parameters estimated using a Bayesian Markov chain Monte Carlo simulation, to quantify associations with possible risk factors and identify clusters of high DR-TB risk.ResultsA total of 2649 DR-TB patients were reported to Hunan TB Control Institute between 2012 and 2018. The majority of the patients were male (74.8%, n=1983) and had a history of TB treatment (88.53%, n=2345). The proportion of extensively DR-TB among all DR-TB was 3.3% (95% CI 2.7% to 4.1%), which increased from 2.8% in 2012 to 4.4% in 2018. Of 1287 DR-TB patients with registered treatment outcomes, 434 (33.8%) were cured, 198 (15.3%) completed treatment, 92 (7.1%) died, 108 (8.3%) had treatment failure and 455 (35.3%) were lost to follow-up. Half (50.9%, n=655) had poor treatment outcomes. The annual cumulative incidence rate of notified DR-TB increased over time from 0.25 per 100 000 people in 2012 to 0.83 per 100 000 people in 2018. Substantial spatial heterogeneity was observed, and hotspots were detected in counties located in the North and East parts of Hunan province. The cumulative incidence of notified DR-TB was significantly associated with urban communities.ConclusionThe annual incidence of notified DR-TB increased over time in Hunan province. Spatial clustering of DR-TB was detected and significantly associated with urbanisation. This finding suggests that targeting interventions to the highest risk areas and population groups would be effective in reducing the burden and ongoing transmission of DR-TB.

It is crucial to maintain continuity of essential services for people affected by tuberculosis (TB). Efforts to deliver these essential services in many global settings have been complicated by the emergence and global spread of SARS-CoV-2 and the pandemic of COVID-19. Understanding how the COVID-19 pandemic has impacted the availability of TB diagnostic and treatment services is critical for identifying policies that can mitigate disruptions of these essential services. China has a dual burden of TB and COVID-19. We conducted a survey and collected data from 13 provinces in China to evaluate the early impact of COVID-19 on TB services and to document interventions that were adopted to maintain the continuity services for TB patients during the pandemic. We use these data to identify additional opportunities which will improve the ability of TB programs to maintain essential services during this crisis. While health systems and underlying epidemiology differ between countries, we believe that sharing China’s experience can inform the design of locally tailored strategies to maintain essential TB services during the COVID-19 pandemic.

Summary Background The management of latent Mycobacterium tuberculosis infection is a new priority action for the WHO End Tuberculosis (TB) Strategy. However, national guidelines on latent tuberculosis infection testing and treatment have not yet been developed in China. Here, we present the results from the 2-year follow-up of a study that aimed to track the development of active disease in individuals with latent tuberculosis infection, identify priority populations for latent infection management, and explore the most suitable latent infection diagnostic approach. Methods A population-based multicentre prospective study was done in four sites in rural China, between 2013 and 2015. The baseline survey in 2013 measured the prevalence of latent tuberculosis infection using QuantiFERON-TB Gold In-Tube (QFT) and tuberculin skin test (TST) in eligible participants. During the follow-up phase between 2014–15, we assessed individuals who had tuberculosis infection at baseline (QFT-positivity or TST tuberculin reaction size [induration] of ≥10 mm) for the development of active disease through active case finding. Eligible participants included in follow-up survey had a birth date before June 1, 2008 (5 years or older in 2013), and continuous residence at the study site for 6 months or longer in the past year. Participants with current active tuberculosis at baseline survey were excluded. Findings Between Sept 1, 2013, and Aug 31, 2015, 7505 eligible participants (aged 5 years or older) were included in tuberculosis infection test positive cohorts (4455 were QFT positive, 6404 had TST induration ≥10 mm, and 3354 were positive for both tests) after baseline examination. During the 2-year follow-up period, 84 incident cases of active tuberculosis were diagnosed. Of participants who developed active tuberculosis, 75 were diagnosed with latent infection by QFT, 62 were diagnosed by TST, and 53 were diagnosed by both tests. An incidence rate of 0·87 (95% CI 0·68–1·07) per 100 person-years was observed for individuals who tested positive with QFT, 0·50 (0·38–0·63) per 100 person-years for those who tested positive with TST (p Interpretation Our results suggest that high-risk populations in communities in rural China, such as individuals at a high risk of disease reactivation from previous tuberculosis, should be targeted for latent infection screening and treatment with an interferon-γ releasing assay rather than a TST. Funding National Science and Technology Major Project of China, Program for Changjiang Scholars and Innovative Research Team in University of China, CAMS Innovation Fund for Medical Sciences, and Sanming Project of Medicine in Shenzhen.

Background The worldwide emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) has posed additional challenges for global tuberculosis (TB) control efforts, as limited treatment options are available and treatment outcomes are often sub-optimal. This study determined treatment outcomes among a cohort of MDR-TB and XDR-TB patients in Hunan Province, China, and identified factors associated with poor treatment outcomes. Methods We conducted a retrospective study using data obtained from medical records of TB patients in Hunan Chest Hospital, and from the internet-based TB management information system managed by the Tuberculosis Control Institute of Hunan Province, for the period 2011 to 2014. Treatment outcomes were assessed for patients diagnosed with MDR-TB (TB resistant to at least isoniazid and rifampicin) and XDR-TB (MDR-TB plus resistance to any fluoroquinolone and at least 1 second-line injectable drug). Cumulative incidence functions were used to estimate time to events (i.e. poor treatment outcomes, loss to follow-up, and unfavourable treatment outcomes); and a competing-risks survival regression model was used to identify predictors of treatment outcomes. Result Of 481 bacteriologically-confirmed patients, with a mean age of 40 years (standard deviation SD ± 13 years), 10 (2%) had XDR-TB and the remainder (471; 98%) had MDR-TB. For the entire cohort, treatment success was 57% (n = 275); 58% (n = 272) for MDR-TB and 30% (n = 3) for XDR-TB. Overall, 27% were lost to follow-up (n = 130), 27% (n = 126) for MDR-TB and 40% (n = 4) for XDR-TB; and 16% had a poor treatment outcome (n = 76), 15% for MDR-TB and 30% (n = 3) for XDR-TB. Of the 10 XDR-TB patients, 3 (30%) completed treatment, 3 (30%) died and 4 (40%) were lost to follow-up. Of the 471 MDR-TB patients, 258 (57%) were cured, 16 (3%) completed treatment, 13 (3%) died, 60 (13%) experienced treatment failure, and 126 (27%) were lost to follow-up. Resistance to ofloxacin was an independent predictor of poor (AHR = 3.1; 95%CI = 1.5, 6.3), and unfavourable (AHR = 1.7; 95%CI = 1.07, 2.9) treatment outcomes. Patients who started treatment during 2011–2012 (AHR = 2.8; 95% CI = 1.5, 5.3) and 2013 (AHR = 2.1; 95% CI = 1.2, 3.9) had poorer treatment outcomes compared to patients who started treatment during 2014. Conclusion Patients with MDR-TB and XDR-TB had low rates of treatment success in Hunan Province, especially among patients who started treatment during 2011 to 2013, with evidence of improved treatment outcomes in 2014. Resistance to ofloxacin was an independent predictor of poor treatment outcomes.

A 5-year follow-up study found declining disease development rates from latent tuberculosis infection. In the latter 3 years, the incidence, per 100 person-years, was 0.26 for interferon-γ release assay positives and 0.19 for tuberculin skin test positives (P = .28). In addition, all round have been checked.

Concerns about the specificity of the Xpert MTB/RIF (Xpert) assay have arisen, as false-positive errors in the determination of Mycobacterium tuberculosis complex (MTBC) infection and rifampin (RIF) resistance in clinical practice have been reported. Here, we investigated 33 cases where patients were determined to be RIF susceptible using the Bactec MGIT 960 (MGIT) culture system but RIF resistant using the Xpert assay. Isolates from two of these patients were found not to have any mutations in the rifampin resistance determining region (RRDR) region of rpoB and had good treatment outcomes with first-line antituberculosis (anti-TB) drugs. The remaining 31 patients included 5 new cases and 26 previously treated patients. A large number of well-documented disputed mutations, including Leu511Pro, Asp516Tyr, His526Asn, His526Leu, His526Cys, and Leu533Pro, were detected, and mutations, including a 508 to 509 deletion and His526Gly, were described here as disputed mutations for the first time. Twenty-one (81%) of the 26 previously treated patients had poor treatment outcomes, and isolates from 19 (90%) of these 21 patients were resistant to isoniazid (INH) as determined using the MGIT culture system. Twenty-seven of the 31 isolates with disputed rpoB mutations were phenotypically resistant to INH, 21 (78%) being predicted by GenoType MTBDRplus to have a high level of INH resistance. Most (77.4%) of the isolates with disputed mutations were of the Beijing lineage. These findings have implications for the interpretation of false-positive and disputed rifampin resistance Xpert MTB/RIF results in clinical samples and provide guidance on how clinicians should manage patients carrying isolates with disputed rpoB mutations.

Summary Background Prophylactic treatment of individuals with latent Mycobacterium tuberculosis infection is an essential component of tuberculosis control in some settings. In China, the prevalence of latent tuberculosis infection, and preventive interventions against this disease, have not been systematically studied. We aimed to assess the prevalence of latent tuberculosis and its associated risk factors in rural populations in China. Methods Between July 1, and Sept 30, 2013, we undertook a baseline survey of a population-based, multicentre, prospective cohort study of registered residents (≥5 years old) at four study sites in rural China. Eligible participants were identified by door-to-door survey with a household sampling design. We screened participants for active tuberculosis and history of tuberculosis then used a tuberculin skin test and an interferon-γ release assay (QuantiFERON [QFT]) to test for latent infection. We used odds ratios (ORs) and 95% CIs to assess variables associated with positivity of QFT and tuberculin skin tests. Findings 21 022 (90%) of 23 483 eligible participants completed a baseline survey. Age-standardised and sex-standardised rates of skin-test positivity (≥10 mm) ranged from 15% to 42%, and QFT positivity rates ranged from 13% to 20%. Rates of positivity for the tuberculin skin test and the QFT test were low in study participants younger than 20 years and gradually increased with age (p for trend Interpretation On the basis of findings showing that the performance of the tuberculin skin test might be affected by various factors including BCG vaccination and age, our results suggest that the prevalence of latent tuberculosis in China might be overestimated by skin tests compared with interferon-γ release assays. Funding The National Science and Technology Major Project of China, the Program for Changjiang Scholars and Innovative Research Team in University of China.

Body mass index (BMI) has been shown to be associated with host susceptibility to several infections. However, the link between BMI and the risk of tuberculosis (TB) infection has been sparsely studied in China and in worldwide. Based on the baseline survey of a population-based, prospective study in rural China, the association between BMI and TB infection among adults was estimated by means of cross-sectional analysis. TB infection status was tested using QuantiFERON-TB Gold In-Tube (QFT), a commercial of interferon-γ release assay (IGRA). Totally, 17796 eligible participants aged ≥18 years from 4 study sites, were included in the analysis. 21.76% (3873/17796) were observed to be QFT positive. Age and gender standardized prevalence ranged from 16.49% to 23.81% across the study sites. 42.19% study participants were obese/overweight with BMI ≥ 24.0 kg/m2. BMI ≥ 28.0 kg/m2 was observed to be independently associated with QFT positivity (adjusted odds ratio: 1.17, 95% confidence interval: 1.04–1.33). The strength of the association was found to be geographically diversity, which might be explained, at least partly, by the varied local TB epidemic status. Our results suggest that individuals with obesity might be one important target population for TB infection control in rural China.

Objectives China has high burden on both of tuberculosis (TB) and tobacco use. This study aims to explore the potential link between smoking and TB infection using baseline survey data of a large-scale population-based prospective study in rural China Methods Between July 1 and Sept 30, 2013, based on the baseline survey of a population-based, prospective study in rural China, the relationship between smoking and TB infection, assessed by interferon-gamma release assays (IGRA), was investigated among the total study population and only among those smokers, respectively. Results A total of 21,008 eligible rural registered residents (≥ 5 years old) from 4 rural sites were included in the analysis. Ever-smokers were more likely to be QuantiFERON-TB Gold In-Tube (QFT) positive than never smokers with an adjusted odds ratio (OR) of 1.34 (95% confidence interval (CI): 1.21–1.49). Among ever smokers, a significant linear dose–response relation was observed between duration of smoking (by years) and QFT positivity (p < 0.001). Stratified analysis suggested that such an association was not influenced by gender and age. Evidence for interaction of smoking status with age was found. Conclusions Our results provide further evidence to support smoking might increase host susceptibility to TB infection. Populations under high risk of infection, such as elderly smokers, should be prior to TB infection controlling under a premise of community level intervention.

In 2015, only 49% of notified multi-drug resistant tuberculosis (MDR-TB) patients in China were estimated to have initiated treatment, compared with 90% of those worldwide. A case-control study was conducted to identify the reasons for non-enrollment in treatment among MDR-TB patients in Hunan province, China. All detected MDR-TB patients registered in designated MDR-TB hospitals in Hunan province from 2011 to 2014 were included and followed until June 2015 to determine their treatment status. Approximately 33.8% (482/1425) of patients were not enrolled in standardized treatment. Factors associated with lower enrollment rate were: age greater than 60 years, living in rural area, unemployed or occupation unreported. Of those who were not enrolled in MDR-TB treatment, the primary reasons for non-enrollment included economic hardship (23.0%), out-migration for work (18.0%), concerns about work and studies (13.7%), and the belief that they were cured after undergoing drug-sensitive TB treatment (12.4%). Therefore, comprehensive strategies targeting priority populations, especially those enhancing treatment affordability and availability, need to be implemented to improve MDR-TB control.

Prospective population data on the incidence of tuberculosis (TB) infection has been sparsely reported in the global literature.A population-based prospective study was conducted in rural China to investigate the annual risk of TB infection, and its persistence using serial tuberculin skin tests (TSTs) and an interferon-γ release assay. In total, 13 580 eligible participants from four rural sites, identified as TST negative (The annual conversion rate of QFT among the study sites ranged between 2.1% and 4.9% (average 3.1%), and the incidence of TST conversion ranged between 6.0% and 31.1% (average 14.5%). During the second year's follow-up, infection persistence was investigated using 390 subjects with QFT conversions. Among them, 49.7% (164 out of 330) were found to be consistently QFT positive. Both the conversion and the persistence of QFT positivity were found to be significantly increased with increasing age.In conclusion, the annual TB infection rate was suggested to be ∼1.5% based on persistent positive results after QFT conversion in rural China. Therefore, infection control among those high-risk populations, including the elderly, should be prioritised for TB control in China.

Background The World Health Organization (WHO) has conditionally recommended the use of sputum smear microscopy and culture examination for the monitoring of multidrug-resistant tuberculosis (MDR-TB) treatment. We aimed to assess and compare the validity of smear and culture conversion at different time points during treatment for MDR-TB, as a prognostic marker for end-of-treatment outcomes. Methods We undertook a retrospective observational cohort study using data obtained from Hunan Chest Hospital, China and Gondar University Hospital, Ethiopia. The sensitivity and specificity of culture and sputum smear conversion for predicting treatment outcomes were analysed using a random-effects generalized linear mixed model. Results A total of 429 bacteriologically confirmed MDR-TB patients with a culture and smear positive result were included. Overall, 345 (80%) patients had a successful treatment outcome, and 84 (20%) patients had poor treatment outcomes. The sensitivity of smear and culture conversion to predict a successful treatment outcome were: 77.9% and 68.9% at 2 months after starting treatment (difference between tests, p = 0.007); 95.9% and 92.7% at 4 months (p = 0.06); 97.4% and 96.2% at 6 months (p = 0.386); and 99.4% and 98.9% at 12 months (p = 0.412), respectively. The specificity of smear and culture non-conversion to predict a poor treatment outcome were: 41.6% and 60.7% at 2 months (p = 0.012); 23.8% and 48.8% at 4 months (p

Background Mobile text messaging and medication monitors (medication monitor boxes) have the potential to improve adherence to tuberculosis (TB) treatment and reduce the need for directly observed treatment (DOT), but to our knowledge they have not been properly evaluated in TB patients. We assessed the effectiveness of text messaging and medication monitors to improve medication adherence in TB patients. Methods and Findings In a pragmatic cluster-randomised trial, 36 districts/counties (each with at least 300 active pulmonary TB patients registered in 2009) within the provinces of Heilongjiang, Jiangsu, Hunan, and Chongqing, China, were randomised using stratification and restriction to one of four case-management approaches in which patients received reminders via text messages, a medication monitor, combined, or neither (control). Patients in the intervention arms received reminders to take their drugs and reminders for monthly follow-up visits, and the managing doctor was recommended to switch patients with adherence problems to more intensive management or DOT. In all arms, patients took medications out of a medication monitor box, which recorded when the box was opened, but the box gave reminders only in the medication monitor and combined arms. Patients were followed up for 6 mo. The primary endpoint was the percentage of patient-months on TB treatment where at least 20% of doses were missed as measured by pill count and failure to open the medication monitor box. Secondary endpoints included additional adherence and standard treatment outcome measures. Interventions were not masked to study staff and patients. From 1 June 2011 to 7 March 2012, 4,292 new pulmonary TB patients were enrolled across the 36 clusters. A total of 119 patients (by arm: 33 control, 33 text messaging, 23 medication monitor, 30 combined) withdrew from the study in the first month because they were reassessed as not having TB by their managing doctor (61 patients) or were switched to a different treatment model because of hospitalisation or travel (58 patients), leaving 4,173 TB patients (by arm: 1,104 control, 1,008 text messaging, 997 medication monitor, 1,064 combined). The cluster geometric mean of the percentage of patient-months on TB treatment where at least 20% of doses were missed was 29.9% in the control arm; in comparison, this percentage was 27.3% in the text messaging arm (adjusted mean ratio [aMR] 0.94, 95% CI 0.71, 1.24), 17.0% in the medication monitor arm (aMR 0.58, 95% CI 0.42, 0.79), and 13.9% in the combined arm (aMR 0.49, 95% CI 0.27, 0.88). Patient loss to follow-up was lower in the text messaging arm than the control arm (aMR 0.42, 95% CI 0.18–0.98). Equipment malfunction or operation error was reported in all study arms. Analyses separating patients with and without medication monitor problems did not change the results. Initiation of intensive management was underutilised. Conclusions This study is the first to our knowledge to utilise a randomised trial design to demonstrate the effectiveness of a medication monitor to improve medication adherence in TB patients. Reminders from medication monitors improved medication adherence in TB patients, but text messaging reminders did not. In a setting such as China where universal use of DOT is not feasible, innovative approaches to support patients in adhering to TB treatment, such as this, are needed. Trial Registration Current Controlled Trials, ISRCTN46846388, In a cluster-randomized controlled trial, Katherine Fielding and colleagues examine the effectiveness of electronic reminders for improving tuberculosis medication adherence., Editors' Summary Background Tuberculosis—a contagious bacterial disease that usually infects the lungs—is a major global public health problem. Every year, about 9 million people develop tuberculosis and at least 1.3 million people die as a result. Mycobacterium tuberculosis, the organism that causes tuberculosis, is spread in airborne droplets when people with tuberculosis cough or sneeze. The symptoms of tuberculosis include cough, weight loss, and fever. Diagnostic tests for tuberculosis include sputum smear microscopy (microscopic analysis of mucus coughed up from the lungs), the growth of M. tuberculosis from sputum samples, and chest X-rays. Tuberculosis can be cured by taking antibiotics daily for several months (usually isoniazid, rifampicin, ethambutol, and pyrazinamide for two months followed by isoniazid and rifampicin for a further four months), but the emergence of multidrug-resistant M. tuberculosis is making tuberculosis increasingly hard to treat. Why Was This Study Done? Because tuberculosis treatment is long and unpleasant, patients often fail to take all their drugs. To improve medication adherence, the World Health Organization recommends that health care workers supervise patients while they take their medication (directly observed treatment, DOT). However, DOT can be hard to implement. In China, for example, where 11% of tuberculosis cases occur, DOT cannot be implemented in many parts of the country, and the national tuberculosis control policy permits self-administered treatment and treatment monitored by family members. It is estimated that over half of individuals with tuberculosis in China self-administer their treatment, but, in 2010, 20% of patients treated using nationally recommended case-management approaches were lost to follow-up or failed to take their medications regularly. In this pragmatic cluster-randomized trial, the researchers investigate whether reminders delivered by mobile phone or by medication monitor boxes (which provide audio reminders to patients and record when the box is opened) might improve tuberculosis medication adherence in China. A pragmatic trial asks whether an intervention works under real-life conditions; a cluster-randomized trial randomly assigns groups of people (here, people living in different counties/districts) to receive alternative interventions and compares outcomes in the differently treated “clusters.” What Did the Researchers Do and Find? The researchers assigned people newly diagnosed with tuberculosis in counties/districts to receive reminders about taking their antibiotics and about monthly follow-up visits via text messaging, a medication monitor, or both text messaging and a medication monitor (the intervention arms), or to receive standard nationally recommended care without electronic reminders (the control arm). All the trial participants (about 1,000 per arm) took their drugs out of a medication monitor box, but the box’s audio reminder function was switched off in the text messaging only and control arms. In the intervention arms, doctors were advised to switch participants with poor medication adherence (evaluated at follow-up visits) to either more intensive management or DOT, depending on the level of missed treatment doses. Compared to the control arm, the percentage of patient-months with at least 20% of the drug doses missed (called “poor adherence” and measured by pill counts and data from the medication monitor) was not significantly reduced in the text messaging arm, whereas poor adherence was significantly reduced by 42% and 51% in the medication monitor and the combined arms, respectively (a significant reduction is unlikely to have happened by chance). Notably, fewer patients were switched to intensive management or DOT than expected based on medication adherence evaluations. What Do These Findings Mean? These findings show that, in China, the use of an electronic medication monitor box to remind patients to take their anti-tuberculosis drugs improved medication adherence. Interestingly, text messaging alone, which has been shown to improve adherence to antiretroviral therapy among HIV-positive individuals, did not improve medication adherence among patients with tuberculosis, possibly because the messages were too frequent or too impersonal, although this intervention (but none of the others) did reduce patient loss to follow-up. Battery problems with the medication monitor may have resulted in over-estimation of poor adherence to treatment. Moreover, the researchers’ assumption that opening the medication monitor box is synonymous with taking the medication may have introduced some inaccuracies into these findings. Despite these limitations and the underuse of more intensive case management in patients with poor adherence, these findings suggest that using medication monitors to deliver electronic drug reminders to patients might improve medication adherence among patients with tuberculosis in China and in other settings. Additional Information This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001876. This study is further discussed in a PLOS Medicine Perspective by John Metcalfe, Max R. O’Donnell, and David R. Bangsberg The World Health Organization provides information (in several languages) on tuberculosis and on its Directly Observed Treatment Short Course (DOTS) strategy; the Global Tuberculosis Report 2014 provides information about tuberculosis around the worldThe Stop TB Partnership is working towards tuberculosis elimination and provides personal stories about tuberculosis (in English and Spanish); the Tuberculosis Vaccine Initiative (a not-for-profit organization) also provides personal stories about tuberculosis The US Centers for Disease Control and Prevention provides information about tuberculosis and about treatment for tuberculosis (in English and Spanish)The US National Institute of Allergy and Infectious Diseases also has detailed information on all aspects of tuberculosis MedlinePlus has links to further information about tuberculosis (in English and Spanish)More information about this trial is available

The Xpert MTB/RIF showed high sensitivity and specificity in previous studies carried out in different epidemiological and geographical settings and patient populations in high-burden tuberculosis (TB) countries. However, there were little data obtained by validation or demonstration study of the assay in China. In this study, the performance of Xpert MTB/RIF was investigated in two county-level laboratories in Hunan Province, China.Consecutive patients with suspected pulmonary tuberculosis (PTB) and suspicion for multidrug-resistant tuberculosis (MDR-TB) were enrolled. For each patient suspected to have PTB, three sputum specimens (one spot sputum, one night sputum, and one morning sputum) were collected and each sputum was tested with smear microscopy, Löwenstein-Jensen (LJ) culture, and Xpert MTB/RIF test. For comparison across subgroups and testing methods, 95% confidence intervals were calculated. All analyses were done with SPSS 16.0, and P0.05 was regarded as significant.For case detection, the sensitivity of Xpert MTB/RIF was 100% for smear- and culture-positive TB and 88.6% for smear-negative and culture-positive TB; the overall sensitivity was 94.5% for all culture-positive patients. The specificity was 99.8%. The sensitivity of Xpert MTB/RIF assay was 22.0% in clinical TB patients and the specificity reached 100.0% in the group of patients who are infected with nontuberculous mycobacteria. For the detection of rifampin resistance, the sensitivity of MTB/RIF RIF-resistance detection was 92.9%, and the specificity was 98.7%. Of the 26 Xpert MTB/RIF-positive and RIF-resistant patients confirmed by LJ proportion tests, 20 (76.9%) patients were infected by MDR-TB.The Xpert MTB/RIF assay is a highly sensitive and specific method for diagnosis of TB and RIF resistance, which will enable it to have the potential to be used in county-level laboratories and lead to the reduction of the infectious pool and improvements in TB control in China. Further evaluations in county-level laboratories for implementing the assay are still required.

Background In the context of decreasing tuberculosis prevalence in China, we examined the effectiveness of screening household contacts of tuberculosis patients. Methods A tuberculosis survey was conducted in 2008. All 3,355 household contacts of notified tuberculosis cases were examined with a questionnaire interview, chest X-ray and three sputum smear tests. The effectiveness was examined by comparing the prevalence of pulmonary tuberculosis in household contacts with or without presenting clinical symptoms against the respective notification rates. Regression models were used to evaluate the factors associated with pulmonary tuberculosis. Results Of the 3,355 household contacts, 92 members (2.7%) had pulmonary tuberculosis, among which 46 cases were asymptomatic. The prevalence of pulmonary tuberculosis and smear positive cases in household contacts without symptoms were 20 and 7 times higher than the notification rates in 2008, while those in household contacts with symptoms were 247 and 108 times higher than notification rates, respectively. The patients detected were mainly Index Cases’ spouses, sisters/brothers and those who were in contact with female Index Cases. Conclusions The present study provides convincing evidence that household contacts of notified tuberculosis cases are at higher risk of developing tuberculosis. Routine screening for household contacts without any symptoms is recommended for sustained tuberculosis control in China as well as in the world.

Few studies have examined, in a prospective cohort study, factors causing delay of access to tuberculosis (TB) diagnosis among new, active TB patients. A prospective cohort study (2009-2011) was carried out among 408 889 Chinese. Data on known/potential influencing factors were obtained from baseline questionnaires. We used stepwise logistic regression models to analyze the association between several known/potential influencing factors and diagnosis delay, assessed the current situation, and explored determinants of diagnosis delay. During follow-up and final visits, 202 new, active TB patients were found. Median patient delay was 5.4 (quartile 2.7-26) weeks, health system delay was 0 (quartile 0-1.6) weeks, and diagnosis delay was 9.9 (quartile 3.1-28.1) weeks. The influencing factors on patient delay were age and duration of symptoms. Smoking and sputum smear status were influencing factors for health system delay, and duration of symptoms was one of the factors for diagnosis delay. These findings provide information on the current situation of diagnosis delay and evidence for specific strategy development for TB control in China.

The incidence of tuberculosis (TB) and its risk factors in China remains unclear. This study examined TB incidence and relative risk factors in rural areas of China. Participants (n = 177,529) were recruited in Xiangtan County (in the central area of China) and in Danyang County (in the eastern area of China) in 2009 and a followed-up study was conducted for one year. The incidence density of pulmonary TB and smear-positive TB were 91.6 (95% CI: 78.7, 106.0) per 100,000 person-year and 36.7 (95% CI: 33.1, 52.4) per 100,000 person-year respectively in Xiangtan, and 47.3 (95% CI: 38.2, 57.5) per 100,000 person-year and 22.7 (95% CI: 16.5, 30.8) per 100,000 person-year in Danyang. The medical history of TB was associated with TB, with the relative risk (RR) of 7.00 (95% CI: 2.76, 17.18) in Xiangtan and that of 31.08 (95% CI: 13.22, 73.10) in Danyang. The association between TB and per capita living space over median was found in Xiangtan, with the RR of 1.86 (95% CI: 1.15, 3.01). No association was found between TB and the insurance status, the contact history with TB, the history of diabetes, smoking, or per capita annual income. The host genetic susceptibility, and social factors such as education and income could be considered in future studies.

Background Acquisition and persistence of tuberculosis infection are important epidemiological measurements for evaluation of tuberculosis transmission in a community. However, prospective population data on the incidence of tuberculosis infection have been sparely reported in the global literature. Methods We conducted a population-based, multicentre, prospective study to investigate the annual risk of tuberculosis infection and its persistence in rural populations in China from July 2013 to June 2015, using yearly tests with tuberculin skin test (TST) and an interferon-γ release assay (IGRA). Findings 15 907 eligible participants from four rural sites (Xiangtan, Hunan province; Zhongmu, Henan Province; Longxi, Gansu Province; Danyang, Jiangsu Province) who were identified as TST-negative ( Interpretation Consistent with published cross-sectional data, the prospective results provide stronger evidence that close contacts, older people, and smokers are high-risk populations for tuberculosis infection in rural China. These groups should be prioritised for tuberculosis control in China and areas with a similar epidemiological profile. The unexpectedly high annual infection rates based on TST could not be explained by local epidemiology and were probably overestimated because of the boosting effect of serial TST testing, BCG vaccination, or environmental mycobacteria. Funding National Science and Technology Major Project of China (2013ZX10003004-002, 2014ZX10003001-001), and Program for Changjiang Scholars and Innovative Research Team in University of China (IRT13007).