Impact of fine particulate matter on latent tuberculosis infection and active tuberculosis in older adults: a population-based multicentre cohort study.

Evidence showed that air pollution was associated with an increased risk of tuberculosis (TB). This study aimed to study the impact of long-term exposure to ambient particulate matter with an aerodynamic diameter less than 2.5 µm (PM2.5) on the acquisition of LTBI and on the risk of subsequent active disease development among rural older adults from a multicentre cohort, which have not yet been investigated to date. A total of 4790 older adults were included in a population-based, multicentre, prospective cohort study (LATENTTB-NSTM) from 2013 to 2018. The level of long-term exposure to PM2.5 for each participant was assessed by aggregating satellite-based estimates. Logistic regression and time-varying Cox proportional hazards models with province-level random intercepts were employed to assess associations of long-term exposures to PM2.5 with the risk of LTBI and subsequent development of active TB, respectively. Out of 4790 participants, 3284 were LTBI-free at baseline, among whom 2806 completed the one-year follow-up and 127 developed newly identified LTBI. No significant associations were identified between PM2.5 and the risk of LTBI. And among 1506 participants with LTBI at baseline, 30 active TB cases were recorded during the 5-year follow-up. Particularly, an increment of 5 µg/m3 in 2-year moving averaged PM2.5 was associated with a 50.6% increased risk of active TB (HR = 1.506, 95% CI: 1.161-1.955). Long-term air pollution might be a neglected risk factor for active TB development from LTBI, especially for those living in developing or less-developed areas where the air quality is poor.

Tuberculosis preventive treatment among individuals with inactive tuberculosis suggested by untreated radiographic abnormalities: a community-based randomized controlled trial.

Epidemiological and interventional studies have been rarely conducted among those with positive interferon-γ release assay (IGRA) results and radiologically inactive tuberculosis (TB) lesions on chest radiograph. This study aimed to estimate the effectiveness and safety of a six-week twice-weekly regimen (rifapentine plus isoniazid) among this key population in rural China. First, chest digital radiography was conducted to screen individuals with inactive TB lesions. Then, the identified participants were further evaluated and eligible participants with IGRA-positive results were included in subsequent randomized controlled trial (RCT). Of 44,500 recruited residents, 2,988 presented with radiographically inactive TB among 43,670 with complete results of chest radiography and questionnaire, and 28.61% (855/2,988) tested IGRA positive. Subsequently, 677 eligible participants were included in this RCT (345 in the preventive treatment group and 332 in the untreated control group). The treatment completion rate was 80.00% (276/345), and 11.88% (41/345) participants reported side-effects including two cases of hepatotoxicity (0.58%, 2/345). In the intention-to-treat analysis, the cumulative incidence rate of microbiologically confirmed active TB during a two-year follow-up was 1.16 (95% confidence interval [CI]: 0.03-2.29) in the preventive treatment group and 1.51 (95% CI: 0.20-2.82) in the control group (p = .485). Subgroup analyses showed that the protective rates were 55.42% (95% CI: 10.33-93.07%) and 80.17% (95% CI: 25.36-97.96%) for participants with fibrosis and for those aged ≥60 years, respectively. The expected treatment effect was not observed for the six-week regimen in this study. Future studies with sufficient sample size are needed to verify our findings.

Serial testing of latent tuberculosis infection in patients with diabetes mellitus using interferon-gamma release assay, tuberculin skin test, and creation tuberculin skin test.

Background: Diabetes mellitus (DM) patients with latent tuberculosis infection (LTBI) have an increased risk of developing active tuberculosis (TB) due to impaired immunity. The performance of currently available immune response-based assays for identification of TB infection had been rarely evaluated in patients with type 2 DM (T2DM) in China. Methods: A prospective study was conducted to investigate the status of LTBI in patients with confirmed T2DM. At the baseline survey, the prevalence of LTBI was tested using interferon-gamma release assay (IGRA), tuberculin skin test (TST) and creation tuberculin skin test (C-TST) in parallel. After a 3-month interval, the participants were retested by the three assays to estimate their performance in the serial testing. Results: A total of 404 participants with T2DM were included in the study. At baseline, after excluding active TB, the prevalence of LTBI identified by TST (≥ 10 mm), C-TST (≥ 5 mm) and IGRA (≥ 0.35 IU/ml) were 9.65% (39/404), 10.40% (42/404) and 14.85% (60/404), respectively. The concordance of TST and C-TST results with IGRA results was 86.39% (349/404) and 92.08% (372/404) with a Kappa coefficient of 0.37 [95% confidence interval (CI): 0.24- 0.50] and 0.64 (95% CI: 0.53- 0.76), respectively. After a 3-month interval, the continuous results of TST, C-TST and IGRA were observed to be increased with testing conversion for 50, 26 and 27 patients, respectively. For TST and C-TST conversions, the distribution of their quantitative results in serial tests varied significantly when further classified by baseline IGRA dichotomous results. Conclusion: In studied patients with T2DM, C-TST showed higher consistency with IGRA as compared to TST. The present of conversion observed in serial testing suggested that boosting effect of skin testing should be considered for identify of LTBI in patients with T2DM.

Algorithms for Screening for Active Tuberculosis among Individuals with Latent Tuberculosis Infection in a Rural Community in China.

Screening for active tuberculosis (TB) among individuals with latent tuberculosis infection (LTBI) is important for the initiation and evaluation of TB preventive treatment. The performances of different tools and their combinations had rarely been studied in community-level screening among individuals with LTBI in China. This study aimed to explore appropriate algorithms for screening for active TB among individuals with LTBI in rural China. Three sputum samples were collected from each participant for smear microscopy, culture, and an Xpert MTB/RIF assay. Chest digital radiography and TB symptoms were investigated as well. The performances of different testing algorithms were compared with that of sputum culture as the gold standard. Overall, 1,564 study participants with LTBI were investigated, with a final diagnosis of 20 TB cases by sputum culture. Compared with other tests, the Xpert MTB/RIF assay detected 80.00% (95% confidence interval [CI], 58.40% to 91.93%) of culture-positive cases, with the highest sensitivity. When tests were combined using "or," "and," or "step" algorithms, the highest sensitivity reached 90.00% (95% CI, 69.90% to 97.21%) for the combination of the Xpert MTB/RIF assay and chest radiography, but the positive predictive value (PPV) decreased to 22.22% (95% CI, 14.54% to 32.41%). The Xpert MTB/RIF assay alone showed the best agreement with sputum culture, with a kappa value of 0.840. Pathogen molecular detection alone showed good performance compared to the other algorithms, for ruling out active TB in general LTBI, but the high cost might be a challenge for scaling it up. Identifying those with a high risk for progression to TB more precisely and establishing a cost-effective screening algorithm deserve further exploration. IMPORTANCE Enhancing community-wide active case screening in target LTBI populations is important for achieving the early treatment of active TB, and ruling active TB out is a prerequisite for initiating preventive treatment. The current study evaluated the performances of multiple tests and their combinations in screening for active TB among individuals with LTBI at the community level. Compared with the classical "TB symptoms and chest radiography" algorithm, the application of Xpert MTB/RIF improved the sensitivity from 45% to 80%. When the Xpert MTB/RIF assay was combined with chest radiography, the sensitivity was further improved to 90.00%, which achieved the World Health Organization (WHO) target product profiles. However, the algorithm requires caution as the PPV decreased from 88.89% for Xpert MTB/RIF alone to 22.22% for the combination. Xpert MTB/RIF alone offered remarkable sensitivity without compromising the PPV but would have major resource implications. Thus, identifying target populations for LTBI treatment more precisely and developing cost-effective and high-throughput screening tools and algorithms deserve further efforts.

Whole transcriptome sequencing reveals neutrophils' transcriptional landscape associated with active tuberculosis.

Neutrophils have been recognized to play an important role in the pathogenesis of tuberculosis in recent years. Interferon-induced blood transcriptional signatures in ATB are predominantly driven by neutrophils. In this study, we performed global RNA-seq on peripheral blood neutrophils from active tuberculosis patients (ATB, n=15); latent tuberculosis infections (LTBI, n=22); and healthy controls (HC, n=21). The results showed that greater perturbations of gene expression patterns happened in neutrophils from ATB individuals than HC or those with LTBI, and a total of 344 differentially expressed genes (DEGs) were observed. Functional enrichment analysis showed that besides the interferon signaling pathway, multiple pattern recognition receptor pathways were significantly activated in ATB, such as NOD-like receptors and Toll-like receptors. Meanwhile, we also observed that the expression of genes related to endocytosis, secretory granules, and neutrophils degranulation were downregulated. Our data also showed that the NF-κB signaling pathway might be inhibited in patients with ATB, which could increase Mycobacterium tuberculosis survival and lead to active tuberculosis status. Furthermore, we validated the accuracy of some differentially expressed genes in an independent cohort using quantitative PCR, and obtained three novel genes (RBM3, CSRNP1, SRSF5) with the ability to discriminate active tuberculosis from LTBI and HC.

Association Between Plasma Exosomes S100A9/C4BPA and Latent Tuberculosis Infection Treatment: Proteomic Analysis Based on a Randomized Controlled Study.

Background: Identifying host plasma exosome proteins associated with host response to latent tuberculosis infection (LTBI) treatment might promote our understanding of tuberculosis (TB) pathogenesis and provide useful tools for implementing the precise intervention. Methods: Based on an open-label randomized controlled trial (RCT) aiming to evaluate the short-course regimens for LTBI treatment, plasma exosomes from pre- and post-LTBI treatment were retrospectively detected by label-free quantitative protein mass spectrometry and validated by a parallel reaction monitoring method for participants with changed or not changed infection testing results after LTBI treatment. Eligible participants for both screening and verification sets were randomly selected from the based-RCT in a 1:1 ratio by age and gender. Reversion was defined as a decrease in IFN-γ levels from >0.70 IU/ml prior to treatment to 0.20 IU/ml within 1 week of treatment. The predictive ability of the candidate proteins was evaluated by receiver operating characteristic (ROC) analysis. Results: Totally, two sample sets for screening (n = 40) and validation (n = 60) were included. Each of them included an equal number of subjects with persistent positive or reversed QuantiFERON-TB Gold In-Tube (QFT) results after LTBI. A total of 2,321 exosome proteins were detected and 102 differentially expressed proteins were identified to be associated with QFT reversion. Proteins with high confidence and original values intact were selected to be further verified. Totally, 9 downregulated proteins met the criteria and were validated. After verification, C4BPA and S100A9 were confirmed to be still significantly downregulated (fold change <0.67, p < 0.05). The respective areas under the ROC curve were 0.73 (95% CI: 0.57-0.89) and 0.69 (95% CI: 0.52-0.86) for C4BPA and S100A9, with a combined value of 0.78 (95% CI: 0.63-0.93). The positive and negative predictive values for combined markers were 70.10% (95% CI: 50.22-86.30%) and 55.63% (95% CI: 29.17-61.00%). Conclusion: Our findings suggest that downregulated C4BPA and S100A9 in plasma exosomes might be associated with a host positive response to LTBI treatment. Further studies are warranted to verify the findings and potential underlying mechanisms in varied populations with a larger sample size.

The Association between Circulating microRNAs and the Risk of Active Disease Development from Latent Tuberculosis Infection: a Nested Case-Control Study.

Tuberculosis (TB) remains one of the deadliest communicable diseases. Biomarkers predicting the risk of active disease development from latent tuberculosis infection (LTBI) are urgently needed for precise intervention. This study aimed to identify potential circulating microRNAs (miRNAs) playing such a role in Chinese population. Based on a prospective study aiming to track the development of active TB among rural residents with LTBI, the baseline levels of circulating miRNAs were retrospectively compared between those who developed TB (case group) and those age-gender matched controls remain free of TB (contraol group) during the follow-up. Agilent human miRNA microarray were used to select differently expressed circulating miRNAs and verified by subsequent real-time quantitative PCR (RT-qPCR). Six candidate miRNAs were expressed at statistically significant levels between the two groups at the baseline, as determined by microarray. Following verification among 150 study participants by RT-qPCR, the levels of hsa-miR-16-5p (P < 0.001) and hsa-miR-451a (P < 0.001) were found to be significantly lower in case group compared to control group. The combined areas under curves (AUCs) and precision-recall curves (PRCs) were 0.84, 0.86 and 0.85, 0.87 for hsa-miR-16-5p and hsa-miR-451a, respectively. hsa-miR-451a combined with body mass index (BMI) and prior history of TB presented the best performance, with a sensitivity of 80.82% and an acceptable specificity of 79.22%. After adjusting the two co-variables, the AUC of hsa-miR-451a was 0.78. Circulating levels of hsa-miR-451a showed potential to predict development of active TB from LTBI in a Chinese population. Further studies are warranted to verify these findings in varied study settings. IMPORTANCE Approximately a quarter of the world population are infected with M. tuberculosis and about 5% to 10% of these might develop active disease in their lifetime. Preventive treatment could effectively protect individuals at a high risk of developing active disease from LTBI, and is regarded as a critical component of End TB Strategies. Biomarkers which could accurately identify high-risk population and predict the risk of disease development are urgently needed for developing local guidelines of LTBI management and precise intervention. A nested case-control study was designed to explore possible microRNAs related with TB occurrence based on a previous prospective study, which aimed to track the development of active TB among rural residents with LTBI. The baseline circulating levels of hsa-miR-16-5p and hsa-miR-451a were significantly lower in TB cases compared to those in LTBI controls. Further receiver operator characteristic (ROC) curve analysis found that hsa-miR-451a showed considerable potential to predict the development of active TB from LTBI.

Protective efficacy of 6-week regimen for latent tuberculosis infection treatment in rural China: 5-year follow-up of a randomised controlled trial.

BACKGROUND: Enlarging tuberculosis (TB) preventive treatment among at-risk populations is a critical component of the End TB Strategy. There is an urgent need to develop suitable latent tuberculosis infection (LTBI) testing and treatment tools according to the local TB epidemic and available resources worldwide. METHODS: Based on an open-label randomised controlled trial conducted since 2015 in China among rural residents aged 50-70 years with LTBI, the protective efficacy of a 6-week twice-weekly regimen of rifapentine plus isoniazid was further evaluated in a 5-year follow-up survey. RESULTS: 1298 treated participants and 1151 untreated controls were included in the 5-year protective efficacy analysis. In the per-protocol analysis, the incidence rate was 0.49 (95% CI 0.30-0.67) per 100 person-years in the untreated control group and 0.19 (95% CI 0.07-0.32) per 100 person-years in the treated group; the protection rate was 61.22%. Subgroup analysis showed that the protection rate was 76.82% in the per-protocol analysis among participants with baseline interferon (IFN)-γ levels in the highest quartile (≥3.25 IU·mL-1). Multiple logistic regression analysis indicated that participants with baseline body mass index <18.5 kg·m-2 and with pulmonary fibrotic lesions had increased hazard of developing active disease with an adjusted hazard ratio (aHR) of 3.64 (95% CI 1.20-11.00) and 5.99 (95% CI 2.20-16.27), respectively. In addition, individuals with higher baseline IFN-γ levels showed an increased risk of TB occurrence (aHR 2.27, 95% CI 1.13-4.58). CONCLUSIONS: Our findings suggest the 6-week twice-weekly regimen of rifapentine plus isoniazid for LTBI treatment might be an optional tool for TB control in the Chinese population.

Radiological and functional evidence of the bronchial spread of tuberculosis: an observational analysis.

BACKGROUND: Direct bronchial spread of tuberculosis was extensively described in pre-antibiotic human pathology literature but this description has been overlooked in the post-antibiotic era, in which most pathology data come from animal models that emphasise the granuloma. Modern techniques, such as [18F]2-fluoro-2-deoxy-D-glucose (FDG) PET-CT scans, might provide further insight. Our aim was to understand normal early tuberculosis resolution patterns on pulmonary PET-CT scans in treated patients with tuberculosis who were subsequently cured. METHODS: In this observational analysis, we analysed data from PredictTB, an ongoing, prospective, randomised clinical trial that examined sequential baseline and week 4 FDG-PET-CT scans from participants successfully treated (sputum culture negative 18 months after enrolment) for drug-susceptible pulmonary tuberculosis in South Africa and China. Participants who were aged 18-75 years, GeneXpert MTB/RIF positive for tuberculosis and negative for rifampicin resistance, had not yet started tuberculosis treatment, had not been treated for active tuberculosis within the previous 3 years, and met basic safety laboratory criteria were included and participants with diabetes, HIV infection, or with extrapulmonary tuberculosis including pleural tuberculosis were excluded. Scans were assessed by two readers for the location of tuberculosis lesions (eg, cavities and consolidations), bronchial thickening patterns, and changes from baseline to week 4 of treatment. FINDINGS: Among the first 124 participants (enrolled from June 22, 2017, to Sept 27, 2018) who were successfully treated, 161 primarily apical cavitary lesions were identified at baseline. Bronchial thickening and inflammation linking non-cavitary consolidative lesions to cavities were observed in 121 (98%) of 124 participants' baseline PET-CT scans. After 4 weeks of treatment, 21 (17%) of 124 participants had new or expanding lesions linked to cavities via bronchial inflammation that were not present at baseline, particularly participants with two or more cavities at baseline and participants from South Africa. INTERPRETATION: In participants with pulmonary tuberculosis who were subsequently cured, the location of cavitary and non-cavitary lesions at baseline and new lesions at week 4 of treatment suggest a cavitary origin of disease and bronchial spread through the lungs. Bronchial spread from cavities might play a larger role in the spread of pulmonary tuberculosis than has been appreciated. Elucidating cavity lesion dynamics and Mycobacterium tuberculosis viability within cavities might better explain treatment outcomes and why some patients are cured and others relapse. FUNDING: Bill & Melinda Gates Foundation, European and Developing Countries Clinical Trials Partnership, China Ministry of Science and Technology, National Natural Science Foundation of China, and National Institutes of Health. TRANSLATIONS: For the Chinese, Afrikaans and Xhosa translations of the abstract see Supplementary Materials section.

The Association Between Mycobacteria-Specific Antigen-Induced Cytokines and Host Response to Latent Tuberculosis Infection Treatment in a Chinese Population.

OBJECTIVES: Exploring biomarkers monitoring latent tuberculosis infection (LTBI) treatment effectiveness would benefit optimizing the therapeutic regimen. This study aims to identify potential mycobacteria-specific antigen-induced cytokines associated with host responses to preventive treatment. METHODS: Based on a randomized controlled trial on LTBI treatment among individuals with chest radiography abnormalities suggestive of prior tuberculosis (TB), the dynamically changed cytokine levels in QuantiFERON-TB Gold In-Tube (QFT) supernatants were estimated during the treatment by bead-based multiplex assays and enzyme-linked immunosorbent assay. RESULTS: In total, 63 treated participants and 32 untreated controls were included in the study. The levels of 13 background-corrected mycobacteria-specific antigen-stimulated cytokines [basic fibroblast growth factor (FGF), growth-regulated oncogene (GRO)-α, interleukin (IL)-1α, IL-1ra, IL-12 (p70), stem cell factor (SCF), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), IL-8, interferon (IFN)-α2, IL-5, IL-12 (p40), leukemia inhibitory factor (LIF), and IL-17A] were found to be statistically different between before and after treatment in treated participants, while no statistically differences were observed in untreated controls. Among these 13 cytokines, the level of IL-8 was significantly lower in the QFT reversed group than that in the non-reversed group (p = 0.028) among treated participants, while such a difference was not found for untreated controls (p = 0.292). CONCLUSION: Our results suggested that the lower level of mycobacteria-specific antigen-induced IL-8 might be associated with the host's positive response to LTBI treatment.

The effect of WeChat-based training on improving the knowledge of tuberculosis management of rural doctors.

BACKGROUND: In China, rural doctors played a crucial role in TB cases referral and management. The current study aimed to evaluate the effect of WeChat-based training program on improving the rural doctors' knowledge on TB management. METHODS: A One-year WeChat-based training was conducted among registered rural doctors from Zhongmu County, located in middle China, by means of releasing original contents (in forms of text, poster, video or cartoon) through WeChat subscription account (WeChat SA) once a week. Pre-and-post-training offline tests were hold using the same self-administered questionnaire to evaluate the training effect. RESULTS: A total of 467 rural doctor were included in the study. During the training, 60 original articles were posted through WeChat SA. With respect to the two tests, the median score increased from 50 (40.0-60.0) to 60 (53.0-70.0) (p < 0.001) after training. As compared with posters, the median readings were significantly higher for released contents in forms of text, video and cartoon (p < 0.001). Female's test performance improved better than male's. In addition, a positive relation was observed between education level and the test performance regardless of training. CONCLUSIONS: Our results indicated that WeChat-based training improved the knowledge of rural doctors on TB management to a certain extent. It is worthy to explore more effective new media-based training methods to promote TB control in rural China.

Urinary proteomic analysis to identify a potential protein biomarker panel for the diagnosis of tuberculosis.

Tuberculosis (TB) is caused by Mycobacterium tuberculosis and is one of the primary causes of death worldwide. Rapid and accurate diagnosis of TB is one of the most direct means to reduce the incidence of TB. In this study, urinary proteomic profiling of TB patients and non-TB individual controls (HCs) was performed, and differentially expressed urinary proteins between TB and HCs were compared and exclusively expressed proteins in TB patients were selected to establish a clinically useful disease marker panel. In total, these top 11 targeted proteins with 265 peptides were scheduled for multiple reaction monitoring validation analysis by using urine samples from 52 TB patients and 52 HCs. The result demonstrated that a three-protein combination out of the five-protein panel (namely P22352, Q9P121, P15151, Q13291, and Q8NDA2) exhibited sensitivity rate of 82.7% in the diagnosis of TB. Furthermore, the three-protein combination could differentiate TB from the latent tuberculosis (LTB) effectively, which exhibited specificity rate of 92.3% for the diagnosis of TB from the LTB category. Although more numbers of clinical samples are required for further verification, the results provided preliminary evidence that this "three-protein combination" out of the five-protein panel could probably be a novel TB diagnostic biomarker in clinical application.

Urinary metabolomic analysis to identify potential markers for the diagnosis of tuberculosis and latent tuberculosis.

Tuberculosis (TB) is a serious infectious disease with high infection and mortality rates. 5%-10% of the latent tuberculosis infections (LTBI) are likely to develop into active TB, and there are currently no clinical biomarkers that can distinguish between LTBI, active TB and other non-tuberculosis populations. Therefore, it is necessary to develop rapid diagnostic methods for active TB and LTBI. In this study, urinary metabolome of 30 active TB samples and the same number of LTBI and non-TB control samples were identified and analyzed by UPLC-Q Exactive MS. In total, 3744 metabolite components were obtained in ESI- mode and 4086 in ESI + mode. Orthogonal partial least square discriminant analysis (OPLS-DA) and hierarchical cluster analysis (HCA) showed that there were significant differences among LTBI, active TB and non-TB. Six differential metabolites were screened in positive and negative mode, 3-hexenoic acid, glutathione (GSH), glycochenodeoxycholate-3-sulfate, N-[4'-hydroxy-(E)-cinnamoyl]-l-aspartic acid, deoxyribose 5-phosphate and histamine. The overlapping pathways differential metabolites involved were mainly related to immune regulation and urea cycle. The results showed that the urine metabolism of TB patients was disordered and many metabolic pathways changed. Multivariate statistical analysis revealed that GSH and histamine were selected as potential molecular markers, with area under curve of receiver operating characteristic curve over 0.75. Among the multiple differential metabolites, GSH and histamine changed to varying degrees in active TB, LTBI and the non-TB control group. The levels of GSH and histamine in 48 urinary samples were measured by ELISA in validation phase, and the result in our study provided the potential for non-invasive biomarkers of TB.

Serum level of IL-1ra was associated with the treatment of latent tuberculosis infection in a Chinese population.

BACKGROUND: Dynamically changed levels of serum cytokines might predict the development of active TB from latent tuberculosis infection (LTBI) and monitor preventive treatment effectiveness. The aim of the study was to identify potential serum cytokines associated with LTBI treatment which might predict active disease development in a Chinese population. METHODS: Based on a randomized controlled trial aiming to explore short-course regimens for LTBI treatment, the dynamic changes of serum cytokines determined by bead-based multiplex assays were investigated for the participants who developed active TB during follow-up and age and gender matched controls stayed healthy. RESULTS: Totally, 21 patients diagnosed with active tuberculosis (TB) during the 2-year follow-up (12 from treated groups and 9 from untreated controls) and 42 age and gender matched healthy controls (24 from treated groups and 18 from untreated controls) were included in the study. Before treatment, serum IL-1ra was statistically higher among those who developed active disease during follow-up as compared with those stayed healthy. As for treated participants, the levels of IL-1ra were significantly lower after treatment in comparison with those before treatment both in active TB group (p = 0.002) and non-TB group (p = 0.009). For untreated participants, the levels of IL-1ra were not statistically different between different time points both in active TB group (p = 0.078) and non-TB group (p = 0.265). CONCLUSION: Our results suggested that declined serum level of IL-1ra was associated with LTBI treatment. Further studies are needed to verify whether it could be used to evaluate LTBI treatment and to predict active disease development.

Serial testing of Mycobacterium tuberculosis infection in Chinese village doctors by QuantiFERON-TB Gold Plus, QuantiFERON-TB Gold in-Tube and T-SPOT.TB.

OBJECTIVES: To evaluate the performance of QuantiFERON-TB Gold Plus (QFT-Plus) on Mycobacterium tuberculosis (MTB) infection test among registered village doctors from China. METHODS: MTB infection of the registered village doctors in Zhongmu County were tested using QFT-Plus and two other interferon-gamma release assays (IGRAs) in parallel: QuantiFERON-TB Gold In-Tube (QFT) and T-SPOT.TB (T-SPOT). Retests were carried out for baseline positives at 3 and 6 months later, respectively. RESULTS: A total of 616 village doctors were included in the baseline examination. The positivity of QFT, QFT-Plus and T-SPOT was 27.91% (168/602), 31.22% (187/599) and 27.70% (169/610), respectively. The concordance between QFT and QFT-Plus was 94.81% (Kappa coefficient: 0.87) and between T-SPOT and QFT-Plus was 88.93% (Kappa coefficient: 0.73). Reversions were frequently observed for all three assays. With respect to QFT-Plus, the quantitative results of reversions in the serial testing were mostly distributed in an "uncertain range" zone (0.2-0.7 IU/mL). Similar patterns of distribution were observed for QFT and T-SPOT as well. CONCLUSION: Village doctors should gain more attention as an at-risk group for TB infection control in rural China. Our results support, by means of serial testing, a good agreement between QFT-Plus and QFT in Chinese population.

Short-course regimens of rifapentine plus isoniazid to treat latent tuberculosis infection in older Chinese patients: a randomised controlled study.

Latent tuberculosis infection (LTBI) management is now a critical component of the World Health Organization's End TB Strategy.In this randomised controlled trial (Chinese Clinical Trial Registry identifier ChiCTR-IOR-15007202), two short-course regimens with rifapentine plus isoniazid (a 3-month once-weekly regimen and a 2-month twice-weekly regimen) were initially designed to be evaluated for rural residents aged 50-69 years with LTBI in China.Due to the increasingly rapid growth and unexpected high frequency of adverse effects, the treatments were terminated early (after 8 weeks for the once-weekly regimen and after 6 weeks for the twice-weekly regimen). In the modified intention-to-treat analysis on the completed doses, the cumulative rate of active disease during 2 years of follow-up was 1.21% (14 out of 1155) in the untreated controls, 0.78% (10 out of 1284) in the group that received the 8-week once-weekly regimen and 0.46% (six out of 1299) in the group that received the 6-week twice-weekly regimen. The risk of active disease was decreased, with an adjusted hazard ratio of 0.63 (95% CI 0.27-1.43) and 0.41 (95% CI 0.15-1.09) for the treatments, respectively. No significant difference was found in the occurrence of hepatotoxicity (1.02% (13 out of 1279) versus 1.17% (15 out of 1279); p=0.704).The short regimens tested must be used with caution among the elderly because of the high rates of adverse effects. Further work is necessary to test the ultrashort regimens in younger people with LTBI.

Incidence of active tuberculosis in individuals with latent tuberculosis infection in rural China: follow-up results of a population-based, multicentre, prospective cohort study.

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<0·0001), and 0·82 (0·60-1·04) per 100 person-years for those who tested positive with both tests. Male sex and a history of tuberculosis were significantly associated with increased risk of disease development with adjusted hazard ratios of 2·36 (95% CI 1·30-4·30) for male sex and 5·40 (3·34-8·71) for a history of tuberculosis. 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.

Using biomarkers to predict TB treatment duration (Predict TB): a prospective, randomized, noninferiority, treatment shortening clinical trial.

Background: By the early 1980s, tuberculosis treatment was shortened from 24 to 6 months, maintaining relapse rates of 1-2%. Subsequent trials attempting shorter durations have failed, with 4-month arms consistently having relapse rates of 15-20%. One trial shortened treatment only among those without baseline cavity on chest x-ray and whose month 2 sputum culture converted to negative. The 4-month arm relapse rate decreased to 7% but was still significantly worse than the 6-month arm (1.6%, P<0.01).  We hypothesize that PET/CT characteristics at baseline, PET/CT changes at one month, and markers of residual bacterial load will identify patients with tuberculosis who can be cured with 4 months (16 weeks) of standard treatment. Methods: This is a prospective, multicenter, randomized, phase 2b, noninferiority clinical trial of pulmonary tuberculosis participants. Those eligible start standard of care treatment. PET/CT scans are done at weeks 0, 4, and 16 or 24. Participants who do not meet early treatment completion criteria (baseline radiologic severity, radiologic response at one month, and GeneXpert-detectable bacilli at four months) are placed in Arm A (24 weeks of standard therapy). Those who meet the early treatment completion criteria are randomized at week 16 to continue treatment to week 24 (Arm B) or complete treatment at week 16 (Arm C). The primary endpoint compares the treatment success rate at 18 months between Arms B and C. Discussion: Multiple biomarkers have been assessed to predict TB treatment outcomes. This study uses PET/CT scans and GeneXpert (Xpert) cycle threshold to risk stratify participants. PET/CT scans are not applicable to global public health but could be used in clinical trials to stratify participants and possibly become a surrogate endpoint. If the Predict TB trial is successful, other immunological biomarkers or transcriptional signatures that correlate with treatment outcome may be identified. TRIAL REGISTRATION: NCT02821832.

Annual risk of tuberculosis infection in rural China: a population-based prospective study.

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 (<10 mm) or QuantiFERON-TB Gold In-Tube (QFT) (an interferon-γ release assay) negative from a baseline survey, were included in the first year's follow-up examination.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.

Latent tuberculosis infection in rural China: baseline results of a population-based, multicentre, prospective cohort study.

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 <0·0001). Rates of latent tuberculosis infection were higher for men than women (p<0·0001). Overall agreement between the tuberculin skin test and the QFT test was moderate (81·06%; kappa coefficient 0·485), with skin-test-only positive results associated with the presence of BCG scar, male sex, and ages of 60 years and older, and QFT-only positive results associated with male sex and ages of 60 years and older. 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.