Effectiveness and safety of bedaquiline-containing regimens for treatment on patients with refractory RR/MDR/XDR-tuberculosis: a retrospective cohort study in East China.

OBJECTIVE: Refractory rifampicin-resistant/multidrug resistant/extensively-drug resistant tuberculosis (RR/MDR/XDR-TB) were defined as patients infected with Mycobacterium tuberculosis (MTB) resistant to rifampicin(RR-TB), or at least resistant to rifampicin and isoniazid (MDR-TB) or added resistant to fluoroquinolones (FQs) and one of second line injectable agents (XDR-TB), a patient for whom an effective regimen (fewer than 4 effective agents due to adverse events (AEs) or multiple drug resistances) cannot be developed. To compare the effectiveness and safety of bedaquiline (BDQ)-containing and BDQ-free regimens for treatment of patients with refractory RR/MDR/XDR-TB. METHODS: Patients with refractory RR/MDR/XDR-TB receiving BDQ-containing regimens (BDQ group, n = 102) and BDQ-free regimens (non-BDQ group, n = 100) satisfied with included criteria were strictly included in this retrospective historical control study across East China. Culture conversion, treatment outcome, cavity closing rate, and AEs were compared between two groups. RESULTS: The baseline characteristics involved all possible aspects of patients were well balanced between two groups (p > 0.05). Culture conversion rates in the BDQ group at month 3 (89.2% vs. 66.0%), month 6 (90.2% vs 72.0%), month 9 (91.2% vs. 66.0%), and month 12 (94.1% vs 65.0%) were all significantly higher than those in non-BDQ group (p < 0.001). Similar results were observed in the cavity closing rate at month 9 (19.6% vs 8.0%, p = 0.0) and month 12 (39.2% vs 15.0%, p < 0.001). Patients receiving BDQ-containing regimens had more treatment success than those receiving BDQ-free regimens (p < 0.001; cure rate, 69.6% vs. 45.0%; complete the treatment, 22.5% vs. 18.0%; treatment success, 92.2% vs. 63.0%); the use of BDQ and combined with Linezolid or Clofazimine or Cycloserine were identified as independent predictors of treatment success and no culture reversion (P < 0.05). AEs were similarly reported in 26.5% of patients in the BDQ group and 19.0% in the non-BDQ group (p = 0.2). CONCLUSIONS: BDQ-containing regimens resulted in better treatment outcomes and similar safety relative to BDQ-free regimens for patients with refractory pulmonary RR/MDR/XDR-TB.

Prevalence, risk factors, management, and treatment outcomes of first-line antituberculous drug-induced liver injury: a prospective cohort study.

PURPOSE: Antituberculosis drug-induced liver injury (ATDILI) is one of the most deleterious side effects associated with chemotherapy against tuberculosis (TB). In this study, our objective was to determine the incidence, risk factors, and management of ATDILI and analyze its impact on the treatment outcome in patients receiving standard anti-TB chemotherapy. METHODS: A prospective cohort study of ATDILI prevalence was conducted in 938 enrolled patients of the 1426 TB cases in Shanghai from March 2011 to September 2012. Patients were followed up until February 2014. Univariate and multivariate logistic regression analyses were used to determine the risk factors of ATDILI. Successful therapeutic outcome, rates of drug resistance conversion, sputum smear/culture conversion, and lung cavity closure were analyzed. RESULTS: Hepatitis B surface antigen/hepatitis B e antigen-positive hepatitis B carriers, complicated with systemic lupus erythematosus, albumin ≤ 25 g/L, and chronic alcoholism were independent risk factors for ATDILI. Of the 121 cases with ATDILI (incidence rate of 12.9%), 84 (69.4%) used modified anti-TB therapy after recovery of liver function. Compared with the non-ATDILI group, patients with ATDILI exhibited remarkably decreased lung cavity closure rate (84.6% vs. 93.0%, P < 0.001) along with significantly reduced sputum smear/culture conversion rate (85.4% vs. 94.0%, P < 0.001). CONCLUSIONS: Our findings indicated that 12.9% patients developed ATDILI during standard anti-TB therapy, resulting in poor therapeutic outcome. Hepatitis B carriers with systemic lupus erythematosus, albumin ≤ 25 g/L, and chronic alcoholism manifested increased risks for ATDILI. Copyright © 2016 John Wiley & Sons, Ltd.

Toll-like receptor polymorphisms and tuberculosis susceptibility: A comprehensive meta-analysis.

The polymorphisms of toll-like receptor (TLR) have been hypothesized to affect the tuberculosis susceptibility. However, the direct evidence remains controversial. Here we performed a comprehensive meta-analysis to summarize the associations between TLR polymorphisms and tuberculosis susceptibility. We systematically searched the PubMed, Embase, Cochrane library, and Chinese National Knowledge Infrastructure up to April 25, 2014. Case-control studies investigating TLR polymorphisms and tuberculosis susceptibility were included in the meta-analysis. Pooled odds ratios and corresponding 95% confidence intervals were calculated for cases and controls. Stata 11.0 and Review Manager 5.1 were adopted to conduct statistical analysis. We included 29 studies, involving 17 804 individuals. The results revealed an obvious increase of tuberculosis risk in TLR2 2258AA, and decreased risk in TLR6 745TT and TLR8 rs3761624 GA genotypes. Meanwhile, different genetic models were performed. TLR8 rs3764879C, TLR8 rs3761624A and TLR8 rs3764880A alleles were associated with high susceptibility, while TLR6 745T and TLR8 rs3788935C alleles were protective. Other polymorphisms, including TLR9 1486C/T, did not show significant associations with tuberculosis infection. Finally, subgroup analysis in TLR8 rs3764880 according to gender found a slight elevated effect of A allele in males. The meta-analysis suggests significant associations between several TLR polymorphisms and tuberculosis, including TLR2 2258G/A, TLR6 745C/T, TLR8 rs3761624, TLR8 rs3764879, TLR8 rs3761624 and TLR8 rs3764880. This study serves as the framework for additional studies to determine further the role of TLRs in tuberculosis infection.

Efficacy and Safety of Bufei Jiedu Granules in Treating Multidrug-Resistant Pulmonary Tuberculosis: A Multi-center, Double-Blinded and Randomized Controlled Trial.

OBJECTIVE: To assess the efficacy and safety of Bufei Jiedu (BFJD) ranules as adjuvant therapy for patients with multidrug-resistant pulmonary tuberculosis (MDR-PTB). METHODS: A large-scale, multi-center, double-blinded, and randomized controlled trial was conducted in 18 sentinel hospitals in China from December 2012 to December 2016. A total of 312 MDR-PTB patients were randomly assigned to BFJD Granules or placebo groups (1:1) using a stratified randomization method, which both received the long-course chemotherapy regimen for 18 months (6 Am-Lfx-P-Z-Pto, 12 Lfx-P-Z-Pto). Meanwhile, patients in both groups also received BFJD Granules or placebo twice a day for a total of 18 months, respectively. The primary outcome was cure rate. The secondary outcomes included time to sputum-culture conversion, changes in lung cavities and quality of life (QoL) of patients. Adverse reactions were monitored during and after the trial. RESULTS: A total of 216 cases completed the trial, 111 in the BFJD Granules group and 105 in the placebo group. BFJD Granules, as an adjuvant treatment, increased the cure rate by 13.6% at the end of treatment, compared with the placebo (58.4% vs. 44.8%, P=0.02), and accelerated the median time to sputum-culture conversion (5 months vs. 11 months). The cavity closure rate of the BFJD Granules group (50.6%, 43/85) was higher than that of the placebo group (32.1%, 26/81; P=0.02) in patients who completed the treatment. At the end of the intensive treatment, according to the 36-item Short Form, the BFJD Granules significantly improved physical functioning, general health, and vitality of patients relative to the placebo group (all P<0.01). Overall, the death rates in the two groups were not significantly different; 5.1% (8/156) in the BFJD Granules group and 2.6% (4/156) in the placebo group. CONCLUSIONS: Supplementing BFJD Granules with the long-course chemotherapy regimen significantly increased the cure rate and cavity closure rates, and rapidly improved QoL of patients with MDR-PTB (Registration No. ChiCTR-TRC-12002850).

[Cross-resistance between rifampin and rifabutin in multidrug resistant Mycobacterium tuberculosis complex strains].

OBJECTIVE: To study the cross-resistance between rifampin and rifabutin in multidrug resistant Mycobacterium tuberculosis complex strains, and therefore to provide laboratory data for using rifabutin in the treatment of multidrug resistant tuberculosis. METHODS: The MIC(90) of rifabutin and rifampin against 99 multidrug resistant Mycobacterium tuberculosis clinical strains were determined by microplate assays. Statistical analysis was performed by using the χ(2) test and the t test. RESULTS: The cross-resistance rate between rifampicin and rifabutin was 85.9% (85/99), but the MIC(90) of rifabutin (≤ 16 mg/L, median 2 mg/L) was significantly lower than that of rifampicin (≥ 2 mg/L, median > 32 mg/L). The cross-resistance rate increased with the resistance level of rifampicin. The cross-resistance strains in the lower and the medium groups were 0/9 and 5/9 respectively, while the strains of the high rifampicin-resistant group were almost all cross-resistant (98.8%, 80/81). CONCLUSION: Rifabutin had activities against rifampin resistant Mycobacterium tuberculosis complex strains in vitro, and therefore may be used as an alternative for the treatment of multidrug resistant tuberculosis.

[Comparative study of direct digital radiography and film-screen radiography in diagnosis of asbestosis].

OBJECTIVE: To evaluate the feasibility of direct digital radiography (DDR) in the diagnosis of asbestosis, and to analyze the difference and similarity between DDR and film-screen radiography (FSR) in terms of the radiographic features of asbestosis. METHODS: A total of 60 cases of asbestosis underwent FSR and DDR of the chest in the same day. The FSR and DDR findings were compared with respect to shapes and profusion of small opacities, pleural abnormality, and diagnostic stages. RESULTS: The patients showed "s", "t", and "p" small opacities on chest images, with irregular "s" and "t" ones predominating (FSR: 95.0%; DDR: 91.7%). The small opacities were widely distributed in six lung zones, especially in middle and lower zones. The shapes and distribution of small opacities did not differ significantly between FSR and DDR findings (P > 0.05). For all the 60 cases, the two radiographies demonstrated a concordance rate of 64.2% (231/360) for the profusion of small opacities in lung zones (κ = 0.62, 95%CI: 0.54 ∼ 0.69), and for the 43 cases (258 lung zones) who displayed identical small opacity shapes on the two radiographies, the concordance rate was 81.0% (209/258) (κ = 0.79, 95%CI: 0.72 ∼ 0.87). FSR revealed 10 cases (16.7%) of pleural thickening, compared to 12 cases (20.0%) on DDR (P > 0.05). FSR revealed 53 cases (88.3%) of stage I asbestosis and 7 cases (11.7%) of stage II asbestosis, compared to 51 cases (85.0%) and 9 cases (15.0%) on DDR (P > 0.05). There was no significant difference in diagnostic stages between the two radiographies (P > 0.05), demonstrating a concordance rate of 93.3% (56/60) (κ = 0.71, 95%CI: 0.45 ∼ 0.98). CONCLUSION: DDR is similar to FSR in determining the shapes, distribution, and profusion of small opacities, pleural abnormality, and diagnostic stages.

[Study of optimization of whole lung lavage applied to pneumoconiosis].

OBJECTIVE: To observe and evaluate the performances of intermittent positive pressure ventilation, beta-2 adrenergic receptor agonist, and pressure lavage in promoting residual fluid absorption and improving blood oxygen saturation during massive whole lung lavage (WLL). METHODS: A total of 155 patients were randomly divided into pressure ventilation (PV) group (n = 28), adrenaline (Ad) group (n = 31), PV plus Ad group (n = 29), pressure infusion bag (PIB) group (n = 30), and control group (n = 32). The patients underwent staged MWLL of bilateral lungs. The blood oxygen saturation (SpO2) of arterial blood of finger, chest X-ray findings, clinical symptoms, and lung functions were observed before and after MWLL. RESULTS: There were no significant differences in change in clinical symptoms among the five groups after MWLL (P > 0.05). The Ad group showed 6.3% increase in forced vital capacity (FVC) and 10.9% increase in forced expiratory flow at 25% of vital capacity (FEF(25%)) after MWLL (P < 0.05). The control group showed 5.7% decrease in FVC, 10.9% increase in forced expiratory volume in one second (FEV(1.0)), and 12.0% increase in FEF(25%) after MWLL (P < 0.05). No significant difference was found in other groups (P > 0.05). During and after MWLL, the incidence rates of hypoxemia in PV group, PV plus Ad group, and control group were 0, 0, and 12.5% (8/64), respectively (P < 0.01). There were no significant differences in total amount of lavage fluid and amount of residual fluid in the lung among all groups (P > 0.05). The smallest difference between the optical densities of the two lung fields on chest x-ray at 3 h after WLL was 0.152 ± 0.053 in the PV plus Ad group, compared to 0.194 ± 0.074 in the PV group, 0.197 ± 0.054 in the PIB group, 0.214 ± 0.054 in the Ad group, and 0.241 ± 0.109 in the control group, with significant differences between the saline group and other groups except Ad group (P < 0.05). CONCLUSION: Pressure ventilation, adrenaline, and pressure lavage can promote the transportation and absorption of residual fluid in the lung and decrease the incidence of hypoxemia during WLL.

[A scoring model for a differential diagnosis of tuberculous and non-tuberculous pleurisy].

OBJECTIVE: To evaluate various clinical features and laboratory biochemical markers so as to develop a predictive model for differentiating tuberculous pleurisy (TBP) from non-tuberculous pleurisy (non-TBP). METHODS: A total of 241 TBP patients and 212 non-TBP patients who were hospitalized between January 2007 and December 2009 at our hospital were studied retrospectively. Their symptoms and laboratory parameters were recorded. The statistically different variables were selected to undergo binary logistic regression to calculate a scoring system (range: 0 - 10) according to their ß coefficients. A receiver operating characteristic (ROC) curve was used to calculate the best cut-off value. The performance of the model was tested in a sample of 82 new cases with pleural exudates. RESULTS: Seven variables were selected in the present scoring model: temperature > 38°C (1.0 point), purified protein derivative testing positive (1.0 point), serum C-reactive protein ≥ 26 mg/L (1.5 points), pleural fluid lymphocyte percentage ≥ 85% (1.0 point), pleural fluid protein ≥ 49 g/L (1.0 point), pleural fluid adenosine deaminase ≥ 43 U/L (2.5 points) and serum and/or pleural fluid mycobacterium tuberculosis antibody positive (2.0 points). With a cut-off value of 6.0 points, the sensitivity, specificity and accuracy of differentiating TBP from non-TBP was 90.1%, 94.3% and 92.1% respectively. With the application of this model, 82 new pleural effusions showed a sensitivity of 94.1%, a specificity of 93.8% and an accuracy of 93.9%. CONCLUSION: The scoring model provided a simple and feasible way of facilitating a differential diagnosis of TBP and non-TBP patients.

[Changes and significance of peripheral blood T cell subsets, soluble interleukin-2 receptor and interferon-gamma in patients with retreatment pulmonary tuberculosis and initial treatment tuberculosis].

OBJECTIVE: The aim of this study was to compare the expression of peripheral blood T cell subsets, soluble interleukin-2 receptor (sIL-2R) and interferon-gamma (IFN-γ) in patients with retreatment pulmonary tuberculosis, initial treatment pulmonary and extra-pulmonary tuberculosis, and therefore to explore the cellular immune changes and the significance among different types and severity of tuberculosis. METHODS: A total of 170 patients with tuberculosis in Pulmonary Hospital of Shanghai from December 2009 to January 2011, including 98 males and 72 females, aged from 16 to 70 years (average 40 years), were included in this study. The patients were divided into retreatment pulmonary tuberculosis group (47 cases), initial treatment pulmonary tuberculosis group (62 cases) and initial treatment extra-pulmonary tuberculosis group (61 cases). Furthermore, the 109 patients with pulmonary tuberculosis were divided into different subgroups according to cavity formation and the lung fields involved: patients without lung cavity (52 cases) vs those with lung cavity (57 cases), patients with involvement of 1 - 2 lung fields (48 cases), vs 3 - 4 lung fields (26 cases) and 5 - 6 lung fields (35 cases). Peripheral blood T cell subsets (by flow cytometry doubled-labeled antibody), sIL-2R and IFN-γ (by ELISA) were determined in 170 patients. Differences between means of 2 groups were tested by t test, differences among multiple groups were tested by analysis of variance (ANOVA), and multiple comparisons among multiple groups were tested by LSD-t test or χ² test. Linear regression equation was used to analyze the correlations. RESULTS: The levels of peripheral blood CD4/CD8 in patients with retreatment pulmonary tuberculosis and initial treatment extra-pulmonary tuberculosis patients were significantly lower than that in initial treatment pulmonary tuberculosis patients, [(1.7 ± 0.7), (1.6 ± 0.7) and (2.0 ± 0.7) respectively (F = 4.380, P < 0.05)]. The levels of serum sIL-2R in patients with retreatment pulmonary tuberculosis and initial treatment extra-pulmonary tuberculosis were significantly higher than that in initial treatment pulmonary tuberculosis patients [(224 ± 89) pmol/L, (209 ± 98) pmol/L, (167 ± 73) pmol/L, (F = 6.402, P < 0.01)]. The levels of serum IFN-γ in patients with retreatment pulmonary tuberculosis and initial treatment extra-pulmonary tuberculosis were significantly higher than that in initial treatment pulmonary tuberculosis patients [(37 ± 23) ng/L, (37 ± 24) ng/L, (29 ± 16) ng/L, (F = 2.799, P < 0.05)]. The levels of peripheral blood CD4/CD8 in initial treatment and retreatment cavity pulmonary tuberculosis patients were lower than that in pulmonary tuberculosis patients without cavity, but the results of sIL-2R and IFN-γ were the opposite [(1.7 ± 0.6) vs (2.0 ± 0.8), (214 ± 93) pmol/L vs (167 ± 68) pmol/L and (38 ± 22) ng/L vs (27 ± 14) ng/L, t = -2.813 to 3.076, P < 0.05 or P < 0.01]. The level of serum sIL-2R was negatively correlated with peripheral blood CD4/CD8 level in all the patients (r = -0.380, P < 0.01). CONCLUSIONS: Patients with retreatment pulmonary tuberculosis and initial treatment extra-pulmonary tuberculosis had lower cellular immune function as compared to those with initial treatment pulmonary tuberculosis, and the cellular immune function was significantly correlated with the extent and cavity formation of pulmonary lesions.

[Changes of natural killer T cells in pulmonary tuberculosis patients complicated by diabetes mellitus].

OBJECTIVE: To investigate the changes of NKT cells in pulmonary tuberculosis patients (PTB) complicated by diabetes mellitus (DM). METHODS: From January 2008 to June 2010, 40 cases of PTB patients without DM hospitalized in Shanghai Pulmonary Hospital were selected. There were 26 males and 14 females, aged from 19 - 65 (mean, 42 ± 11) years, with an average BMI (20.6 ± 4.7) kg/m(2). Forty cases of PTB complicated with DM were included as patient controls which consisted of 25 males and 15 females, aged from 34 - 68 (mean, 47 ± 10)years, with an average BMI (21.3 ± 1.9) kg/m(2). Thirty-seven healthy controls and 38 cases of non-TB DM in the outpatient department for physical examination were enrolled at the same period. There were 25 male and 12 female healthy controls, aged from 21 - 60 (mean, 42 ± 12) years, with an average BMI (21.9 ± 5.4) kg/m(2). There were 23 males and 15 females in the non-TB DM volunteers, aged from 36 - 65 (mean, 44 ± 8) years, with an average BMI (20.5 ± 3.2) kg/m(2). The percentages of NKT cells with the phenotype of TCRVα24(+)Vß11(+) in peripheral blood and bronchial alveolar lavage fluid (BALF) were tested by flow cytometry for all the patients. Continuous data were analyzed by t test. Multiple comparisons were performed by SNK and LSD test. RESULTS: The percentages of NKT cells in peripheral blood from non-diabetic PTB [1.1% (0.8% - 1.3%)] and diabetic PTB patients [0.8% (0.5% - 1.0%)] were all significantly higher as compared with healthy controls [0.4% (0.3% - 0.7%)] and DM patients without TB [0.3%(0.2% - 0.5%)] (q = 3.258 - 7.074, respectively, all P < 0.01). The percentages of NKT cells in peripheral blood from non-diabetic PTB patients were also significantly higher as compared with diabetic PTB patients (q = 2.827, P < 0.01). The percentages of NKT cells in BALF from non-diabetic PTB patients [0.7%(0.3% - 1.0%)] were significantly higher as compared with diabetic PTB patients [0.3% (0.2% - 0.6%)] (t = 2.394, P < 0.05). The percentages of NKT cells from BALF in mild, moderate and severe PTB patients were [0.9% (0.3% - 1.3%)], [0.4% (0.3% - 0.9%)] and [0.3% (0.3% - 0.5%)], respectively, which were significantly different (F = 4.535, P < 0.05). The percentages of NKT cells from peripheral blood in mild, moderate and severe PTB patients were [1.0% (0.8% - 1.3%)], [1.0% (0.8% - 1.3%)] and [0.7% (0.5% - 1.1%)], respectively, which were also significantly different (F = 3.763, P < 0.05). The percentages of NKT cells from peripheral blood had a positive correlation with those from BALF (r = 0.709, P < 0.01). CONCLUSIONS: NKT cells play an important role in TB infection. The complicated milieus in PTB patients with DM have adverse effects on NKT cells, resulting in their dysfunction.

[The effect of the regimen containing cefoxitin on highly drug-resistant rapidly growing nontuberculous mycobacterial pulmonary disease].

OBJECTIVE: To evaluate the therapeutic effect and safety of the regimen containing cefoxitin on highly drug-resistant rapidly growing nontuberculous mycobacterial (RGM) pulmonary disease. METHODS: From January to December 2007, 16 patients with RGM pulmonary disease, who had been treated for 6-48 months, average (15 ± 11) months but still sputum positive, were included in the study and treated with a new regimen containing cefoxitin, fluoroquinolone, macrolide, and SMZco. Cefoxitin was used in the first 3 months and the total duration of therapy was 18 months. Sputum conversion rate, radiology change and side effects were observed before and after the therapy. RESULTS: Underlying chronic diseases including COPD (n = 2), tuberculosis (n = 3), bone-marrow transplantation due to chronic leukemia (n = 1) and bronchiectasis (n = 5), were present in 11 patients. Main symptoms before therapy were cough and expectoration. There were multi-focal patchy, small nodular shadows with cavities on CT scans. The 16 clinical strains were highly resistant to anti-tuberculous drugs: 15/16 to streptomycin, 16/16 to isoniazid, 14/16 to rifampin, 13/16 to ethambutol, 14/15 to amikacin, 15/15 to capreomycin and 14/15 to ofloxacin. After treatment, the clinical symptoms improved in all patients. Eight of the 16 patients became sputum negative by 6 months which lasted to the end of the therapy, while another 8 patients remained sputum positive. Six patients showed radiological improvement. No one experienced side effects induced by cefoxitin. The total cure rate was 8/16. CONCLUSION: The regimen containing cefoxitin has certain effect on highly drug-resistant nontuberculous mycobacterial pulmonary disease, especially for RGM.

[In vitro activities of clofazimine against different drug-resistant types of Mycobacterium tuberculosis].

OBJECTIVE: To study the in vitro antituberculous activities of clofazimine (CLF) to different drug-resistant types of Mycobacterium tuberculosis. METHODS: The minimal inhibitory concentration (MIC) of CLF and isoniazid (INH), rifampicin (RFP), ofloxacin (OFLX), amikacin (AK), and capreomycin (CPM) against sensitive, single-drug resistant (SDR), poly-drug resistant (PDR), multi-drug resistant (MDR), and extensive-drug resistant (XDR) Mycobacterium tuberculosis strains isolated clinically were determined by microplate assays. RESULTS: The MICs of CLF for sensitive, SDR, PDR, MDR and XDR strains of clinically isolated Mycobacterium tuberculosis were 0.06 - 4.00 mg/L, 0.03 - 4.00 mg/L, 0.06 - 8.00 mg/L, 0.06 - 8.00 mg/L, 0.03 - 8.00 mg/L. For the sensitive group, the MIC of CLF (0.06 - 4.00 mg/L) was higher than that of INH (0.06 - 0.25 mg/L) and RFP (0.06 - 0.25 mg/L), while there was no significant difference among OFLX (0.06 - 2.00 mg/L), AK (0.06 - 4.00 mg/L), and CPM (0.50 - 4.00 mg/L). For the single-drug resistant group, there was no significant difference among CLF (0.03 - 4.00 mg/L), INH (0.06 - 0.25 mg/L), and RFP (0.06 - 0.25 mg/L), but the MIC of CLF was lower than that of OFLX (0.25 - 8.00 mg/L), AK (0.06 - 4.00 mg/L), and CPM (0.50 - 8.00 mg/L). For the MDR group, there was no significant difference between CLF (0.06 - 8.00 mg/L) and AK (0.25 - 8.00 mg/L), but the MIC of CLF was lower than that of OFLX (0.125 - 8.00 mg/L) and CPM (0.50 - 8.00 mg/L). For the XDR group, the MIC of CLF (0.03 - 8.00 mg/L) was lower than that of others. CONCLUSION: CLF showed good in vitro activity against Mycobacterium tuberculosis, especially MDR and XDR strains.

[The correlation between polymorphisms of genes with susceptibility to tuberculosis and the clinical characteristics of tuberculosis in 459 Han patients].

OBJECTIVE: To study the correlation between polymorphisms of genes with susceptibility to tuberculosis and the clinical characteristics of tuberculosis in Han population. METHODS: Four hundred and fifty-nine tuberculosis inpatients of Han population in Shanghai Pulmonary Hospital from Jan 2007 to Dec 2008 were recruited. The clinical characteristics of tuberculosis (gender, fever, extent of lesions, cavity formation, hemoptysis, initial treatment and retreatment) were observed. The polymorphisms of VDR gene (variants in FokI and TaqI), NRAMP1 gene (variants in INT4, D543N and 3 UTR), MBL gene (variants in HL, YX and QP) and IFNG gene (variants in 874AT) were genotyped by a variety of SNP genotyping techniques. The correlation between polymorphisms of genes with susceptibility to tuberculosis and the clinical characteristics of the disease was analyzed by ANOVAs. RESULTS: The frequency of CC, CT and TT variants of FokI in VDR gene in cases with fever were 54.7% (29/53), 13.2% (7/53) and 32.1% (17/53), respectively, compared to 40.6% (52/128), 30.5% (39/128) and 28.9% (37/128) in cases without fever, the difference being significant (χ² = 6.183, P < 0.05). In patients with CT variants, 15.2% (7/46) had fever, while in patients with non-CT variants, 34.1% (46/135) had fever (χ² = 5.891, P < 0.05), suggesting that patients with CT variants were less likely to have fever. The frequencies of TT + TC and CC variants of QP in the MBL gene in initial treatment cases were 28.3% (60/212) and 71.7% (152/212), respectively, compared to 19.1% (41/215) and 80.9% (174/215) in retreatment cases, the difference being significant (χ² = 5.038, P < 0.05). No significant correlation was observed between the other variants and the clinical characteristics of tuberculosis (χ² = 0.001 - 2.732, P > 0.05). CONCLUSIONS: The polymorphisms of FokI in VDR gene was associated with fever among the clinical characteristics of tuberculosis, and patients with CT variants might be protected from fever. The polymorphisms of QP in MBL gene might be associated with recurrence of tuberculosis.

PCR-single-strand conformational polymorphism method for rapid detection of rifampin-resistant Mycobacterium tuberculosis: systematic review and meta-analysis.

The reference standard methods for drug susceptibility testing of Mycobacterium tuberculosis, such as culture on Lowenstein-Jensen or Middlebrook 7H10/11 medium, are very slow to give results; and due to the emergence of multidrug-resistant M. tuberculosis and extensively drug-resistant M. tuberculosis, there is an urgent demand for new, rapid, and accurate drug susceptibility testing methods. PCR-single-strand conformational polymorphism (PCR-SSCP) analysis has been proposed as a rapid method for the detection of resistance to rifampin, but its accuracy has not been systematically evaluated. We performed a systematic review and meta-analysis to evaluate the accuracy of PCR-SSCP analysis for the detection of rifampin-resistant tuberculosis. We searched the Medline, Embase, Web of Science, BIOSIS, and LILACS databases and contacted authors if additional information was required. Ten studies met our inclusion criteria for rifampin resistance detection. We applied the summary receiver operating characteristic (SROC) curve to perform the meta-analysis and to summarize diagnostic accuracy. The sensitivity of PCR-SSCP analysis for the rapid detection of rifampin-resistant tuberculosis was 0.79 (95% confidence interval [CI], 0.75 to 0.82), the specificity was 0.96 (95% CI, 0.94 to 0.98), the positive likelihood ratio was 16.10 (95% CI, 5.87 to 44.13), the negative likelihood ratio was 0.20 (95% CI, 0.10 to 0.40), and the diagnostic odds ratio was 100.93 (95% CI, 31.95 to 318.83). PCR-SSCP analysis is a sensitive and specific test for the rapid detection of rifampin-resistant M. tuberculosis. Additional studies in countries with a high prevalence of multidrug-resistant M. tuberculosis and also cost-effectiveness analysis are required in order to obtain a complete picture on the utility of this method for rapid drug resistance detection in M. tuberculosis.

[Associated factors for the infection of Beijing genotype Mycobacterium tuberculosis].

OBJECTIVE: to analyze the risk factors for the infection of Beijing genotype Mycobacterium tuberculosis (MTB) and the relationship to drug resistance and clinical symptoms. METHODS: sputum samples were collected from patients with pulmonary tuberculosis who were admitted to the hospital during July, 2007 to March, 2008. The sputum was cultured with L-J method, and then the bacterial DNA was isolated and genotyped with VNTR-7 (variable-number tandem repeats, VNTR) and RD105 deletion method respectively. The association between different genotypes and risk factors was analyzed. RESULTS: a hundred and sixteen clinical sputum isolates were obtained from 172 positive sputum cases. There were 112 isolates of MTB, and isolates of non-tuberculosis mycobacterium (NTM). Among the 97 isolates from Shanghai, Zhejiang and Jiangsu areas, Beijing genotype accounted for 86.6% (84/97), and non-Beijing genotype for 13.4% (13/97). The rates of MDR (multi-drug resistance), PDR (poly-drug resistance) and single drug resistance in Beijing genotype were not significantly higher than those in non-Beijing genotype. Among the risk factors, female gender, and CD(4)/CD(8)< 1 in patients with newly-treated tuberculosis, were associated with higher rate of Beijing genotype, chi(2) = 4.436, 4.494 and all P < 0.05, respectively. The Beijing genotype isolates were subdivided into 31 VNTR-7 types, and the distribution of quantity and resistance among different VNTR-7 genotypes was not even. A large number of MTB isolates (47.6%, 40/84) and drug resistant isolates (43.6%, 17/39) were among four VNTR-7 genotypes. CONCLUSION: Beijing genotype is the most prevalent MTB in Shanghai, Zhejian and Jiangsu areas. Female gender and low CD(4)/CD(8) ratio in patients with newly-treated TB are risk factors for infecting Beijing genotype MTB, which may have no relationship with drug resistance and clinical symptoms.

Genetic Polymorphisms in Antioxidant Enzymes Modulate the Susceptibility of Idiosyncratic Antituberculous Drug-Induced Liver Injury and Treatment Outcomes in Patients with Tuberculosis.

BACKGROUND: The pathogenic mechanism of antituberculous drug-induced liver injury (ATDILI) is associated with antioxidant enzymes. The objective of the present study was to investigate the associations of ATDILI susceptibility with genetic polymorphisms of antioxidant enzyme genes including nitric oxide synthase 2 (NOS2), thioredoxin reductase 1 (TXNRD1), superoxide dismutase 2 (SOD2), BTB domain and CNC homolog 1 (BACH1), and MAF bZIP transcription factor K (MAFK). METHODS: Thirty tag single nucleotide polymorphisms (tag-SNPs) from the all candidate genes were genotyped in a 2-stage cohort study including an initial discovery stage with 461 ATDILI patients and 466 controls and a replication stage with 216 ATDILI patients and 432 controls. The frequencies and distributions of genotypes and haplotypes were compared between the case and control groups. Three different genetic models including dominant, recessive, and additive models were used to determine the associations with susceptibility to ATDILI. RESULTS: The SNPs rs9906835, rs944725, and rs3794764 of the NOS2 gene were significantly associated with an increased risk of ATDILI. The MAFK rs3735656 SNP was significantly associated with a decreased risk for ATDILI. The AAA haplotype of the NOS2 gene was associated with susceptibility to ATDILI. The treatment outcomes of patients with tuberculosis were further affected by genetic variants of the NOS2 and MAFK genes. CONCLUSIONS: Genetic polymorphisms of NOS2 and MAFK are associated with ATDILI susceptibility in Chinese patients with tuberculosis. The variants in NOS2 and MAFK affect treatment outcomes of tuberculosis patients. Further studies are needed to better understand the molecular mechanisms of ATDILI susceptibility via regulation of the expression of ATDILI-susceptibility genes and proteins.

Improvement cues of lesion absorption using the adjuvant therapy of traditional Chinese medicine Qinbudan tablet for retreatment pulmonary tuberculosis with standard anti-tuberculosis regimen.

BACKGROUND: China is the second highest pulmonary tuberculosis (PTB) burden country worldwide. However, retreatment of PTB has often developed resistance to at least one of the four first-line anti-TB drugs. The cure rate (approximately 50.0-73.3%) and management of retreatment of PTB in China needs to be improved. Qinbudan decoction has been widely used to treat PTB in China since the 1960s. Previously clinical studies have shown that the Qinbudan tablet (QBDT) promoted sputum-culture negative conversion and lesion absorption. However, powerful evidence from a randomized controlled clinical trial is lacking. Therefore, the aim of this study was to compare the efficacy and safety of QBDT as an adjunct therapy for retreatment of PTB. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled clinical trial in China. People diagnosed with PTB were enrolled who received previous anti-TB treatment from April 2011 to March 2013. The treatment group received an anti-TB regimen and QBDT, and the control group was administered an anti-TB regimen plus placebo. Anti-TB treatment options included isoniazid, rifampicin, pyrazinamide, ethambutol, streptomycin for 2 months (2HRZES), followed by isoniazid, rifampicin, ethambutol for 6 months (6HRE), daily for 8 months. Primary outcome was sputum-culture conversion using the MGIT 960 liquid medium method. Secondary outcomes included lung lesion absorption and cavity closure. Adverse events and reactions were observed after treatment. A structured questionnaire was used to record demographic information and clinical symptoms of all subjects. Data analysis was performed by SPSS 25.0 software in the full analysis set (FAS) population. RESULTS: One hundred eighty-one cases of retreatment PTB were randomly divided into two groups: the placebo group (88 cases) and the QBDT group (93 cases). A total of 166 patients completed the trial and 15 patients lost to follow-up. The culture conversion rate of the QBDT group and placebo group did not show a noticeable improvement by using the covariate sites to correct the rate differences (79.6% vs 69.3%; rate difference = 0.10, 95% confidence interval (CI): - 0.02-0.23; F = 2.48, P = 0.12) after treatment. A significant 16.6% increase in lesion absorption was observed in the QBDT group when compared with the placebo group (67.7% vs 51.1%; rate difference = 0.17, 95% CI: 0.02-0.31; χ2 = 5.56, P = 0.02). The intervention and placebo group did not differ in terms of cavity closure (25.5% vs 21.1%; rate difference = 0.04, 95% CI: - 0.21-0.12; χ2 = 0.27, P = 0.60). Two patients who received chemotherapy and combined QBDT reported pruritus/nausea and vomiting. CONCLUSIONS: No significant improvement in culture conversion was observed for retreatment PTB with traditional Chinese medicine plus standard anti-TB regimen. However, QBDT as an adjunct therapy significantly promoted lesion absorption, thereby reducing lung injury due to Mycobacterium tuberculosis infection. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov, NCT02313610.

[Clinical, pathological and radiological characteristics of 83 cases of pleural tuberculoma].

OBJECTIVE: To investigate the clinical, pathological and radiological characteristics of pleural tuberculoma, so as to improve the understanding of this disease. METHODS: We retrospectively analyzed the clinical, laboratory, pathological and radiological data of 83 cases of pleural tuberculoma diagnosed by pathology and(or) bacteriology in Shanghai Pulmonary Hospital Affiliated to Tongji University. RESULTS: In the recruited 83 cases, there were 50 males and 33 females, aged from 7 to 85 years old, with a mean age of 37.8 years. Cough, fever and chest pain were common symptoms, but no significant symptoms were seen in 25 patients (31.3%). Some patients had positive physical signs, such as dullness to percussion and low breath sound. Pulmonary tuberculosis was also present in 36 patients (43.3%) with pleural tuberculoma. A history of tuberculous pleurisy was elicited in 80 patients, among whom 45 (56.3%) received delayed antituberculous treatment and 42 (52.5%) received nonstandard treatment. Forty-eight cases (60.0%) did not receive corticosteroids. Fifty-nine cases underwent CT-guided percutaneous biopsy, while 24 underwent thoracoscopic surgery, and tuberculosis was pathologically confirmed in 62 (74.7%). Pathological profiles included granuloma, coagulation or caseation necrosis, lymphocyte infiltration, epithelioid cells, inflammatory cells, histiocytes and scar tissue. Fifteen (18.1%) specimens from percutaneous biopsy were anti-fast smear positive, while Mycobacterium tuberculosis was obtained by culture in 21 (25.3%) cases. Chest X-ray showed that solitary lesions were seen in 68 cases, multiple foci in 15. The lesions of 46 cases (55.4%) occupied the lower right lobes. Round-like shadows were the most common signs, which were present in 63 cases (75.9%). CT examination demonstrated homogeneous density in 20, heterogeneous density in 40, calcification in 9, central attenuation in 34, and peripheral intensification in 28 cases. CONCLUSIONS: Pleural tuberculoma is an important sequelae of tuberculous pleurisy. Understanding its clinical, pathological and radiological characteristics is helpful for the differential diagnosis of pleural and lung diseases.