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BackgroundTo verify the efficacy and safety of an inexpensive standardized regimen for multidrug-resistant tuberculosis (MDR-TB) with low resistance to isoniazid (INH), a multicenter prospective study was conducted in eastern China.MethodsPatients diagnosed as MDR-TB with low concentration INH resistance and rifampicin resistance, second-line/injectable agents sensitive were prospectively enrolled, given the regimen of Amikacin (Ak)–Fluoroquinolones (FQs)–Cycloserine (Cs)–Protionamide (Pto)–PasiniaZid (Pa)–Pyrazinamide (Z) for 6 months followed by 12 months of FQs–Cs–Pto–Pa–Z, and then followed up for treatment outcomes and adverse events (AEs).ResultsA total of 114 patients were enrolled into the study. The overall favorable treatment rate was 79.8% (91/114). Among 91 cases with favorable treatment, 75.4% (86/114) were cured and 4.4% (5/114) were completed treatment. Regarding to unfavorable outcomes, among 23 cases, 8.8% (10/114) had failures, 8.8% (10/114) losing follow up, 0.9% (1/114) had treatment terminated due to intolerance to drugs and 1.8% (2/114) died. Treatment favorable rate was significantly higher in newly treated MDR-TB (91.7%, 33/36) than that in retreated MDR-TB (74.4%, 58/78,p0.03). The investigators recorded 42 AEs occurrences in 30 of 114 patients (26.3%). Clinicians rated most AEs as mild or moderate (95.24%, 40/42).ConclusionsThe regimen was proved to be effective, safe and inexpensive. It is suitable for specific drug resistant population, especially for newly-treated patients, which could be expected to be developed into a short-course regimen.Clinical trials registrationChina Clinical Trial Registry ChiCTR-OPC-16009380

BackgroundThe management of latent tuberculosis infection (LTBI) is a key action for the realization of the “End tuberculosis (TB) Strategy” worldwide, and it is important to identify priority populations. In this prospective cohort study, we evaluated the prevalence of LTBI and incidence of active TB among close contacts and explored the suitable TB control strategy in schools.MethodsWe designed a cohort with 2 years of follow-up, recruiting freshman/sophomore TB patients’ close contacts from three administrative districts in Shanghai. These were chosen based on different levels of TB incidence reported in 2019. Questionnaires were included and all participants received both tuberculin skin test (TST) and QuantiFERON-TB Gold (QFT) at baseline, then tracked the outcomes of them during the follow-up period.ResultsThe prevalence of LTBI was 4.8% by QFT. Univariate analysis showed that the risk of LTBI was higher in those contacting bacteriologically confirmed patients or did not have BCG scars, including smokers. The risk increased with poor lighting and ventilation conditions at contact sites. Multivariate analysis showed that those contacting with bacteriologically confirmed patients (OR=4.180; 95%CI, 1.164-15.011) or who did not have BCG scars (OR=5.054; 95%CI, 2.278-11.214) had a higher risk of being LTBI, as did the current smokers (OR=3.916; 95%CI, 1.508-10.168) and those who had stopped smoking (OR=7.491; 95%CI, 2.222-25.249). During the 2-year follow-up period, three clinically diagnosed cases of TB were recorded, the 2-year cumulative incidence was 0.4% (95%CI 0.1-1.2), the median duration for TB occurrence was 1 year, the incidence rate of active TB was 2.0 per 1000 person-years with a total of 1497.3 observation person-years. For those LTBI, no one initiated preventive treatment, in the QFT (+) cohort, 1 TB case was observed, 71 person-years with an incidence rate of 14.1 14.1 (95%CI 2.5-75.6) per 1000 person-years, in the TST (+++) cohort, 2 TB cases were observed 91.5 person-years with an incidence rate of 21.9 (95%CI 6.0-76.3) per 1000 person-years.ConclusionsThe results suggest that school close contacts are one of the key populations for LTBI management. Measures should be taken to further reduce the prevalence of LTBI and the incidence of active TB among them.

Objectives Our aim was to assess the ability of the Whole-genome sequencing (WGS) in predicting drug resistance profile of multidrug-resistant mycobacterium tuberculosis (MDR-MTB) from newly diagnosed cases in China. Methods We validated the Phenotypic drug Sensitivity Test (pDST) for 12 anti-tuberculosis drugs using the Bactec MGIT 960 system. We described the characteristics of the isolates enrolled and compared the pDST results with resistance profiles predicted by WGS. Results The pDST showed that of the 43 isolates enrolled, 25.6% were sensitive to rifabutin (RFB); 97.7%、97.7%、93.0% and 93.0% were sensitive to cycloserine (Cs), amikacin/kanamycin (Ak/Km), para-aminosalicylic acid (Pas) and ethionamide Eto), respectively; 18.6% were resistant to fluoroquinolones (FQs) or second-line injections. Genotype DST determined by WGS of Ak/Km、Eto and RFP reached high consistency to 97.7% compared with pDST, followed by moxifloxacin (Mfx) 95.3%, levofloxaci (Lfx) and Pas 93%, streptomycin (Sm) 90.3%. The genotype DST of RFB and EMB showed low consistency with the pDST of 67.2 and 79.1%. WGS also detected 27.9% isolates of pyrazinamide(PZA)-related drug-resistant mutation. No mutations associated with linezolid (Lzd), bedaquiline (Bdq) and clofazimine (Cfz) were detectd. Conclusions WGS has the potential to infer resistance profiles without time-consuming phenotypic methods, which could be provide a basis to formulate reasonable treatment in high TB burden areas.

Our objective was to evaluate the performance of whole-genome sequencing (WGS) from early positive liquid cultures for predicting Mycobacterium tuberculosis complex (MTBC) drug resistance. Clinical isolates were obtained from tuberculosis patients at Shanghai Pulmonary Hospital (SPH). Antimicrobial susceptibility testing (AST) was performed, and WGS from early Bactec mycobacterial growth indicator tube (MGIT) 960-positive liquid cultures was performed to predict the drug resistance using the TB-Profiler informatics platform. A total of 182 clinical isolates were enrolled in this study. Using phenotypic AST as the gold standard, the overall sensitivity and specificity for WGS were, respectively, 97.1% (89.8 to 99.6%) and 90.4% (83.4 to 95.1%) for rifampin, 91.0% (82.4 to 96.3%) and 95.2% (89.1 to 98.4%) for isoniazid, 100.0% (89.4 to 100.0%) and 87.3% (80.8 to 92.1%) for ethambutol, 96.6% (88.3 to 99.6%) and 61.8% (52.6 to 70.4%) for streptomycin, 86.8% (71.9 to 95.6%) and 95.8% (91.2 to 98.5%) for moxifloxacin, 86.5% (71.2 to 91.5%) and 95.2% (90.3 to 98.0%) for ofloxacin, 100.0% (54.1 to 100.0%) and 67.6% (60.2 to 74.5%) for amikacin, 100.0% (63.1 to 100.0%) and 67.2% (59.7 to 74.2%) for kanamycin, 62.5% (24.5 to 91.5%) and 88.5% (82.8 to 92.8%) for ethionamide, 33.3% (4.3 to 77.7%) and 98.3% (95.1 to 99.7%) for para-aminosalicylic acid, and 0.0% (0.0 to 12.3%) and 100.0% (97.6 to 100.0%) for cycloserine. The concordances of WGS-based AST and phenotypic AST were as follows: rifampin (92.9%), isoniazid (93.4%), ethambutol (89.6%), streptomycin (73.1%), moxifloxacin (94.0%), ofloxacin (93.4%), amikacin (68.7%), kanamycin (68.7%), ethionamide (87.4%), para-aminosalicylic acid (96.2%) and cycloserine (84.6%). We conclude that WGS could be a promising approach to predict MTBC resistance from early positive liquid cultures.

Objective To evaluate the performance of whole-genome sequencing (WGS) for predicting Mycobacterium tuberculosis (MTB) drug resistance. Methods 276 rifampin-resistance tuberculosis (RR-TB) and 30 rifampicin-sensitive clinical isolates were randomly selected from patients with tuberculosis in Shanghai Pulmonary Hospital (SPH). Phenotypic drug susceptibility testing (DST) against six anti-TB drugs was performed, and WGS was used to predict the drug resistance using an online ‘TB-Profiler’ tool. Results Using phenotypic susceptibility as the gold standard, the overall sensitivities and specificities for WGS were 94.53% and 92.00% for isoniazid, 97.10% and 100.00% for rifampicin, 97.46% and 64.36% for ethambutol, 97.14% and 95.83% or streptomycin, 93.02% and 98.87% for ofloxacin, and 75.00% and 100.00% for amikacin, respectively. The concordances of WGS-based DST and phenotypic DST were: isoniazid (94.12%), rifampicin (97.39%), ethambutol (77.12%), streptomycin (96.73%), ofloxacin (96.41%) and amikacin (97.06%). Conclusions WGS could be a promising approach to predict resistance to isoniazid, rifampicin, ethambutol, streptomycin, ofloxacin, and amikacin.

To estimate the incidence of pulmonary tuberculosis (PTB) in Chinese diabetes patients and to evaluate the effect of blood glucose on PTB risk, a retrospective cohort study was built based on the diabetes management system in Shanghai and included 240,692 adults aged 35 or above. Incidences of PTB in all diabetes patients and by subgroups were calculated and compared. Multivariable Cox regression models with restricted cubic splines were used to evaluate the association of fasting plasma glucose (FPG) with the risk of PTB. A total of 439 incident PTB cases were identified in the cohort after an average of 3.83 years of follow-up. The overall PTB incidence rate was 51.3/100,000 in diabetes patients, and annual incidence remained higher than that in general population. The PTB incidence rate of diabetes patients was higher in men than in women (86.2 vs. 22.1 per 100,000) and was highest in patients with body mass index (BMI) 2 (215.2/100,000) or FPG ≥ 10 mmol/L (143.2/100,000). Our results suggest that the risk of tuberculosis may be greater at higher levels of FPG in diabetes patients of normal weight. Specific tuberculosis screening strategies for different characteristic diabetes population should be provided to prevent and control tuberculosis in China.

Background Xpert MTB/RIF (Xpert) is an automated molecular test recommended by World Health Organization (WHO) for diagnosis of tuberculosis (TB). This study evaluated the effect of Xpert implementation on the detection of pulmonary TB (PTB) and rifampicin-resistant TB (RR-TB) cases in Shanghai, China. Methods Xpert was routinely implemented in 2018 for all presumptive PTB patients. All PTB patients above 15 years-old identified within the Provincial TB Control Program during the first half of each of 2017 and 2018, were enrolled to compare the difference in proportions of bacteriological confirmation, patients with drug susceptibility test (DST) results for rifampicin (ie, DST coverage) and RR-TB detection before and after Xpert’s implementation. Results A total of 6047 PTB patients were included in the analysis with 1691 tested by Xpert in 2018. Percentages of bacteriological confirmation, DST coverage and RR-TB detection in 2017 and 2018 were 50% vs. 59%, 36% vs. 49% and 2% vs. 3%, respectively (all p-values Conclusions Integrating Xpert with smear, culture and culture-based DST in a routine setting significantly increased bacteriological confirmation, DST coverage and RR-TB detection with a dramatic reduction in the time to RR-TB diagnosis in Shanghai, China. Our findings can be useful for other regions that attempt to integrate Xpert into routine PTB and RR-TB case-finding cascade. Further study should focus on the identification and elimination of operational level challenges to fully utilize the benefit of rapid diagnosis by Xpert.

Background To assess the effect of a contact investigation strategy by assessing the incidence of tuberculosis and the case detection rate among contacts of tuberculosis patients. Methods The pulmonary tuberculosis incidence among contacts was determined retrospectively from a tuberculosis information management system. For each detection method (symptom examination only, symptom examination plus chest radiography or other alternatives), the detection rate of pulmonary tuberculosis patients among contacts was derived from contact investigation form records. Results Sixty-nine cases of pulmonary tuberculosis were identified among a total of 8137 contacts after an average follow-up of 2.6 years (range: 0.25–5.25) during the period from 2010 to 2014. The incidence density was 329/100,000 person-years (PYs), and the 95% confidence interval (CI) was 256–419/100,000 PYs, which was significantly higher than the notification rate during the same period in the general population (29–30/100,000 PYs). The incidence density was higher (p 0.05) between contacts whose index case was sputum smear positive and those whose index case was sputum smear negative. Contacts who were biologically related family of the index cases exhibited a higher (p

Aims To determine the prevalence of diabetes mellitus among pulmonary tuberculosis patients and the difference of clinical characteristics and outcomes between pulmonary tuberculosis patients with and without diabetes mellitus in an aging population in Shanghai, China. Methods This is a retrospective population-based study. 201 newly diagnosed pulmonary tuberculosis patients in Changning District, Shanghai during 2007–2008 were included. Clinical characteristics and outcomes were collected. Determination of diabetes mellitus was based on the medical records before pulmonary tuberculosis was diagnosed. Results The prevalence of diabetes mellitus among pulmonary tuberculosis patients was 19.9% (40/201). Pulmonary tuberculosis patients with diabetes mellitus were more likely to be old (≥ 50, OR = 5.23, 95% CI = 2.07–13.25), to have pulmonary cavities (OR = 3.02, 95% CI = 1.31–6.98), to be sputum smear positive (OR = 2.90, 95% CI = 1.12–7.51), and to have extension of anti-tuberculosis treatment duration (OR = 2.68, 95% CI 1.17–6.14). Besides, they had a higher 2nd month sputum smear positive proportion (OR = 2.97, 95% CI 1.22–7.22) and a higher 5-year recurrence rate (OR = 5.87, 95% CI 1.26–27.40). Conclusions High prevalence, severe clinical characteristics and poor outcomes of pulmonary tuberculosis patients with diabetes mellitus highlight the necessity of early bi-directional screening and co-management of these two diseases in Shanghai, China.

In high tuberculosis (TB)-burden countries such as China, the diagnosis of multidrug-resistant tuberculosis (MDR-TB) using conventional drug susceptibility testing (DST) takes months, making treatment delay inevitable. Poor outcomes of MDR-TB might be associated with delayed, even inappropriate, treatment. The purposes of this study were to investigate the time to MDR-TB treatment initiation and to assess the association between early treatment and treatment outcomes. Between April 2011 and December 2014, this population-based retrospective cohort study collected the demographic and clinical characteristics and the drug susceptibility profiles of all registered MDR-TB patients in Shanghai, China. The dates of TB and MDR-TB diagnoses, DST performance, and treatment initiation were extracted to calculate the times to treatment. In total, 284 of 346 MDR-TB patients were eligible for analysis, and 68.3% (194/284) had favored outcomes. The median time to treatment initiation from TB diagnosis was 172 days among those with favored outcomes and 190 days among those with poor outcomes. Treatments initiated within 60 days after performing DST (odds ratio [OR], 2.56; 95% confidence interval [CI], 1.22 to 5.36) and empirical treatments (OR, 2.09; 95% CI, 1.01 to 4.32) were positively associated with favored outcomes. Substantial delays to MDR-TB treatment were observed when conventional DST was used. Early treatment predicted favored outcomes. Rapid diagnostic methods should be scaled up and improvements should be made in patient management and information linkage to reduce treatment delay.

Recurrent tuberculosis is an important indicator of the effectiveness of tuberculosis control and can occur by relapse or exogenous reinfection. We conducted a retrospective cohort study on all bacteriologically confirmed tuberculosis cases that were successfully treated between 2000 and 2012 in Shanghai, an urban area with a high number but a low prevalence rate of tuberculosis cases and a low prevalence of HIV infection. Genotyping the Mycobacterium tuberculosis from clinical isolates was used to distinguish between relapse and reinfection. In total, 5.3% (710/13,417) of successfully treated cases had a recurrence, a rate of 7.55 (95% CI 7.01–8.13) episodes per 1000 person-years, more than 18 times the rate of tuberculosis in the general population. Patients who were male, age 30–59, retreatment cases, had cavitation, diabetes, drug-resistant or multidrug-resistant tuberculosis in their initial episode of tuberculosis, were at high risk for a recurrence. Among 141 recurrent cases that had paired isolates, 59 (41.8%) had different genotypes, indicating reinfection with a different strain. Patients who completed treatment were still at high risk of another episode of tuberculosis and exogenous reinfection contributed a significant proportion of the recurrent tuberculosis cases. Targeted control strategies are needed to prevent new tuberculosis infections in this setting.

Summary Background Multidrug-resistance is a substantial threat to global elimination of tuberculosis. Understanding transmission patterns is crucial for control of the disease. We used a genomic and epidemiological approach to assess recent transmission of multidrug-resistant (MDR) tuberculosis and identify potential risk factors for transmission. Methods We did a population-based, retrospective study of patients who tested positive for tuberculosis between Jan 1, 2009, and Dec 31, 2012, in Shanghai, China. We did variable-number-of-tandem-repeat genotyping and whole-genome sequencing of isolates. We measured strain diversity within and between genomically clustered isolates. Genomic and epidemiological data were combined to construct transmission networks. Findings 367 (5%) of 7982 patients with tuberculosis had MDR tuberculosis and 324 (88%) of these had isolates available for genomic analysis. 103 (32%) of the 324 MDR strains were in 38 genomic clusters that differed by 12 or fewer single nucleotide polymorphisms (SNPs), indicating recent transmission of MDR strains. Patients who had delayed diagnosis or were older than 45 years had high risk of recent transmission. 235 (73%) patients with MDR tuberculosis probably had transmission of MDR strains. Transmission network analysis showed that 33 (87%) of the 38 clusters accumulated additional drug-resistance mutations through emergence or fixation of mutations during transmission. 68 (66%) of 103 clustered MDR strains had compensatory mutations of rifampicin resistance. Interpretation Recent transmission of MDR tuberculosis strains, with increasing drug-resistance, drives the MDR tuberculosis epidemic in Shanghai, China. Whole-genome sequencing can measure of the heterogeneity of drug-resistant mutations within and between hosts and help to determine the transmission patterns of MDR tuberculosis. Funding National Science and Technology Major Project, National Natural Science Foundation of China, and US National Insitutes of Health.

The most reliable liver safety signal in a clinical trial is considered to be ‘Hy’s Law cases’ defined as subjects experiencing hepatocellular injury and serum bilirubin elevations with no more likely cause than study drug. However, there is little published data to support the current biochemical criteria for Hy’s Law cases or their use to estimate postmarketing risk of severe liver injury. The primary objective of this study was to identify and characterize Hy’s Law cases in patients treated for tuberculosis (TB). A secondary objective was to identify patient risk factors for drug-induced liver injuries. We utilized eDISH (evaluation of Drug-Induced Serious Hepatoxicity) to retrospectively analyze data from 517 patients treated for activeTB, a regimen well known to be capable of causing severe hepatotoxicity. We identified two Hy’s Law cases, which is consistent with the treatment’s known risk of liver failure. Despite monthly monitoring, neither Hy’s Law case experienced a documented elevation in serum alanine aminotransferase exceeding 10 × upper limits of normal. Hepatoprotectant use and infection with chronic hepatitis B were associated with increased risk of liver injury. Our observations support the current biochemical criteria for Hy’s Law cases and their use to estimate postmarketing risk.

Introduction. Second-line antituberculosis drugs (SLDs) are used for treating multidrug-resistant tuberculosis (MDR-TB). Prolonged delays before confirming MDR-TB with drug susceptibility testing (DST) could result in transmission of drug-resistant strains and inappropriate use of SLDs, thereby increasing the risk of resistance to SLDs. This study investigated the diagnostic delay in DST and prevalence of baseline SLD resistance in Shanghai and described the distribution of SLD resistance with varied delays to DST.Methods. All registered patients from 2011 to 2013 in Shanghai were enrolled. Susceptibility to ofloxacin, amikacin, kanamycin, and capreomycin was tested. Total delay in DST completion was measured from the onset of symptoms to reporting DST results.Results. Resistance to SLDs was tested in 217 of the 276 MDR-TB strains, with 118 (54.4%) being resistant to at least one of the four SLDs. The median total delay in DST was 136 days. Patients with delay longer than median days were roughly twice more likely to have resistance to at least one SLD (OR 2.22, 95% CI 1.19–4.11).Conclusions. During prolonged delay in DST, primary and acquired resistance to SLDs might occur more frequently. Rapid diagnosis of MDR-TB, improved nosocomial infection controls, and regulated treatment are imperative to prevent SLD resistance.