Table of Content

10 September 2021, Volume 43 Issue 9

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Guideline·Standard·Consensus

Chinese expert consensus on the all-oral treatment of drug-resistant pulmonary tuberculosis (2021 Edition)

Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Chinese Antituberculosis Association, Editorial Board of Chinese Journal of Antituberculosis

Chinese Journal of Antituberculosis. 2021, 43(9):  859-866.  doi:10.3969/j.issn.1000-6621.2021.09.002

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In 2020, the World Health Organization (WHO) proposed the all-oral treatment for drug-resistant pulmonary tuberculosis. Analysis showed that the success rate of all-oral treatment is higher than that of the treatment regimen containing injection. Although WHO guidelines recommend all-oral treatment regimen for different drug-resistant pulmonary tuberculosis patients, some drugs or dosages are not suitable for Chinese patients. There is no consensus on all-oral treatment for drug-resistant pulmonary tuberculosis patients in China. In order to formulate all-oral treatment for drug-resistant pulmonary tuberculosis in China, the Chinese Antituberculosis Association, Beijing Chest Hospital Affiliated to Capital Medical University and the Editorial Board of Chinese Journal of Antituberculosis jointly organized experts to write the “Chinese expert consensus on the all-oral treatment of drug-resistant pulmonary tuberculosis (2021 Edition)” (referred to as “Consensus”). Based on the research progress of all-oral treatment for drug-resistant pulmonary tuberculosis at home and abroad in recent years, this consensus recommends suitable all-oral treatment for patients with drug-resistant pulmonary tuberculosis in China, including the types and dosages of drugs used, and the types of patients and their applications and exclusion criteria. In addition, the relevant questions that may be encountered in the treatment are answered, and the precautions for the use of the plan are also emphasized, in order to improve the diagnosis and treatment of drug-resistant pulmonary tuberculosis in China.

Expert consensus on the therapeutic drug monitoring of anti-tuberculosis drugs

Beijing Chest Hospital, Capital Medical University, Editorial Board of Chinese Journal of Antituberculosis

Chinese Journal of Antituberculosis. 2021, 43(9):  867-873.  doi:10.3969/j.issn.1000-6621.2021.09.003

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Therapeutic drug monitoring (TDM) is an individualized administration guided by determining the drug exposure, pharmacological markers or efficacy indicators in patients, by using quantitative pharmacological model and taking the drug treatment window as the benchmark. In the process of anti-tuberculosis treatment, there are many problems such as individual differences in drug concentration and various adverse effects, which may lead to treatment failure, drug resistance and recurrence. The use of anti-tuberculosis drugs TDM can optimize drug treatment, improve drug efficacy and reduce toxic and side effects. In order to promote the standardization of tuberculosis TDM in China, ensure the scientificity, ethics and legality of TDM, and maximize the benefits of patients, the Expert Consensus on the Therapeutic Drug Monitoring of Anti-Tuberculosis Drugs was composed. This consensus has been repeatedly discussed by experts in the fields of tuberculosis, including clinicians and pharmacologists. Based on the significance, indications, detection methods, implementation process and quality control of TDM, the experts generated the consensus.

Expert consensus on detection and preventive treatment of latent tuberculosis infection in high-risk population

Chinese Antituberculosis Association

Chinese Journal of Antituberculosis. 2021, 43(9):  874-878.  doi:10.3969/j.issn.1000-6621.2021.09.004

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Active discovery and preventive treatment is the core measure of tuberculosis control of the global strategy for ending tuberculosis epidemic. China is one of the countries with high burden of tuberculosis in the world. For the goal of ending tuberculosis in the world, strengthening the active discovery of latent tuberculosis infection (LTBI), screening the close contacts of tuberculosis patients, and preventive treatment for the newly infected and immunocompromised LTBI populations are important measures to reduce the incidence of LTBI. However, there are still many doubts and disputes about the applicable objects, regimes and effect of preventive treatment now. New diagnostic techniques and preventive treatment methods are constantly studied and applied. In view of this, experts from Chinese Antituberculosis Association have compiled the Expert consensus on detection and preventive treatment of latent tuberculosis infection in high-risk population, and reviewed the principle and detection of LTBI, and objects of prevention treatment, diagnostic methods, chemical prevention and immunization prevention, to provide reference for Chinese tuberculosis control workers.

Expert Note

Current status and prospect of all-oral treatment regimens for drug-resistant pulmonary tuberculosis

ZHOU Wen-qiang, ZHANG Shuang, CHU Nai-hui

Chinese Journal of Antituberculosis. 2021, 43(9):  879-882.  doi:10.3969/j.issn.1000-6621.2021.09.005

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Tuberculosis is a serious public health problem and one of the top 10 causes of death worldwide. The treatment success rate is high in sensitive tuberculosis, and low in drug-resistant tuberculosis, while the mortality rate of drug-resistant tuberculosis is high. In recent years, the all-oral regimens with new anti-tuberculosis drugs as the core are greatly successful in treatment, overcoming the high incidence of adverse reactions of second-line injections, poor treatment compliance of patients and other shortcomings, and increasing the treatment success rate of drug-resistant tuberculosis. However, how to select anti-tuberculosis drugs for safe and effective oral regimens, and how to carry out researches on treatment program are still problems. In this paper, by reviewing the transition from chemotherapy drugs and injection-containing regimens to all-oral regimens for drug-resistant tuberculosis, as well as relevant studies on short and ultra-short course all-oral regimens at home and abroad and the basis for the formulation, the author made comments and shared thoughts and inspiration in combination with conditions in China, in order to provide reference for clinical researchers to better understand and carry out related researches.

Host immune responses-based methods for laboratory diagnosis and clinical application of tuberculosis

PANG Yu, GAO Xing-hui, TANG Yi-wei, GAO Meng-qiu

Chinese Journal of Antituberculosis. 2021, 43(9):  883-892.  doi:10.3969/j.issn.1000-6621.2021.09.006

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Mycobacterium tuberculosis is the main pathogen causing tuberculosis in humans. As an intracellular pathogen, its interaction with host immune system determines occurrence, development and outcome of the disease; host responses against M.tuberculosis have potential value in early diagnosis and prognosis of tuberculosis. In this paper, starting with detection techniques based on host immune responses, we systematically reviewed basic research hot spots and clinical application cases in order to provide important and new strategies for early, precise diagnosis of tuberculosis.

Original Articles

Study on the early efficacy and safety of the regimen containing bedaquiline in the treatment of multidrug-resistant pulmonary tuberculosis

DING Cai-hong, XIONG Yu, WANG Qing, GAO Xu-sheng, HAO Yan

Chinese Journal of Antituberculosis. 2021, 43(9):  893-898.  doi:10.3969/j.issn.1000-6621.2021.09.007

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Objective To investigate the early efficacy and safety of the regimen containing bedaquiline in the treatment of multidrug-resistant pulmonary tuberculosis (MDR-PTB). Methods According to the inclusion criteria, 79 MDR-PTB patients diagnosed in Shandong chest hospital from September 2018 to December 2020 were prospectively studied, all of them completed 24-week anti-tuberculosis treatment containing bedaquiline. Basic characteristics (gender, age, residence, body mass index (BMI)) and clinical information (mycobacterium sputum smear and culture results, electrocardiogram, blood routine, liver and kidney function, chest CT, adverse drug reactions), etc.) were collected. To monitor the time of negative conversion of sputum culture, the occurrence of adverse drug reactions, and the treatment outcome during the treatment containing bedaquiline were monitored, and the factors affecting the treatment outcome were analyzed. Results Of the 79 cases, 72 (91.1%) had good outcomes and 7 (8.9%) had adverse outcomes after completing 24-week treatment. Multivariate logistic regression analysis showed that BMI <18.5 (20.8% (5/24)) and aged ≥45 years (27.8% (5/18)) were the risk factors for adverse outcomes (OR (95%CI) were 9.393 (1.443-61.125) and 7.769 (1.289-46.835), respectively. The median (quartile) of sputum culture negative conversion time was 4 (2, 8) weeks. The cumulative sputum culture negative conversion rate gradually increased with the extension of treatment time. The sputum culture negative conversion rates at 2, 4, 8, 12, 16, 20 and 24 weeks were 30.4% (24/79), 51.9% (41/79), 70.9% (56/79), 83.5% (66/79), 87.3% (69/79), 88.6% (70/79) and 91.1% (72/79), respectively. Fifty-three patients (67.1%) had adverse drug-resistant, of which one had serious gastrointestinal reactions, 30 (38.0%) had prolonged Q-Tc interval, and Q-Tc interval ≥500 ms was found in 15 (19.0%); the Q-Tc interval increased first and then decreased with the increase in usage time of bedaquiline, and the peak was at the 12th week ((436.10±27.97) ms). Conclusion The treatment containing bedaquiline showed good outcome for MDR-PTB, with a higher rate of negative conversion of sputum culture in the early stage; adverse outcomes were more likely to happen in malnutrition, middle-aged and elderly patients. The Q-Tc interval of patients during treatment should be monitored.

Short-term effectiveness and safety of a regimen containing bedaquiline in the treatment of multidrug-resistant/extensively drug-resistant tuberculosis

WU Guo-lan, GAO Jing-tao, CHEN Xiao-hong, CHEN Li-zhou, WENG Li-zhen, GUO Zhi-ping, CHEN Xiu-ping, LIN Jian-dong, CHEN Su-xia, GAO Meng-qiu, LIU Yu-hong

Chinese Journal of Antituberculosis. 2021, 43(9):  899-904.  doi:10.3969/j.issn.1000-6621.2021.09.008

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Objective To analyze the short-term effectiveness and safety of bedaquiline-containing regimen in 16 patients with multidrug-resistant tuberculosis (MDR-TB) or extensively drug-resistant tuberculosis(XDR-TB). Methods From September 2018 to January 2020, 16 patients treated with bedaquiline regimen and met the inclusion criteria in Fuzhou Pulmonary Hospital were selected, including 4 MDR-TB patients, 6 XDR-TB patients, and 6 pre-XDR-TB patients. The conversion of sputum culture for Mycobacterium tuberculosis at 24 weeks was analyzed. Changes of electro-cardiogram QTcF at 1, 2, 4, 8, 12, 16, 20, 24 weeks before enrollment and changes of chest lesions at 12 and 24 weeks after treatment were monitored, and adverse drug reactions and treatment for them were recorded. Results All of the 16 patients completed 24 weeks of intensive therapy, and the median time of sputum culture conversion was 8 (IQR:4,12) weeks. The time of conversion was 4 weeks in 2 patients, 8 weeks in 10 patients, and 12 weeks in 3 patients,1 patient was continuously positive in culture. Chest CT scan of lung lesions showed significant absorption in 7 cases, partial absorption in 7 cases, and no change in 2 cases. Adverse reactions mainly were prolonged QTcF (25.8%, 42/163), tolerable gastrointestinal reactions (22.1%, 36/163), abnormal liver function (3.7%, 6/163), hyperuricemia (36.8%, 60/163), and leukopenia (4.3%, 7/163), fatigue, joint muscle soreness (3.1%. 5/163), respiratory failure (0.6%, 1/163), and skin redness (3.7%, 6/163). The median ECG QTcF value at baseline time for those 16 patients was 412.50 (IQR: 398.25, 420.75) ms,while it changed to 414.00 (405.00, 426.75) ms at 2 weeks, 419.50 (402.00, 434.50) ms at 4 weeks, 410.50 (398.25, 421.25) ms at 8 weeks, 421.50 (409.50, 434.75) ms at 12 weeks, and 424.50 (413.75,432.25) ms at 16 weeks, 421.50 (409.50, 434.75) ms at 20 weeks and 424.00 (414.00, 435.25) ms at 24 weeks. There were statistically significant differences at 12, 16, 20 and 24 weeks comparing with the baseline (Z=-2.198,P=0.028;Z=-2.096,P=0.036;Z=-1.965,P=0.049;Z=-2.406,P=0.016). None of the 16 patients had QTcF>500ms. Conclusion The treatment regimen containing bedaquiline showed good clinical effectiveness and high safety in the treatment of MDR-TB patients, which can enrich the clinical drug selection for treating MDR-TB.

Resistance to fluoroquinolones and the influencing factors in patients with drug-resistant pulmonary tuberculosis

SHI Wen-hui, CHU Nai-hui

Chinese Journal of Antituberculosis. 2021, 43(9):  905-909.  doi:10.3969/j.issn.1000-6621.2021.09.009

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Objective To analyze the resistance to fluoroquinolones and the influencing factors in patients with drug-resistant pulmonary tuberculosis. Methods Retrospective analysis was conducted on 988 drug-resistant tuberculosis patients diagnosed and hospitalized in Beijing Chest Hospital, Capital Medical University from January 2015 to December 2020. All the subjects were positive in sputum mycobacterium culture and the strains were identified as Mycobacterium tuberculosis. All the patients were tested for drug sensitivity, and resistant to one or more of the following drugs: isoniazid, rifampicin, rifapentine, rifabutin, ethambutol, clofazimine, amikacin, prothiazide, clarithromycin, kanamycin, capreomycin, and streptomycin, etc. Proportional drug sensitivity test was used to detect the resistance of ofloxacin, levofloxacin, and moxifloxacin, etc. The drug resistance of subjects with different characteristics to fluoroquinolones was analyzed, and the influencing factors of fluoroquinolones resistance in patients with drug-resistant pulmonary tuberculosis were analyzed by multivariate logistic regression model. Results Among the 988 subjects, 431 were resistant to fluoroquinolones, and the resistance rate was 43.62%. Of the patients with fluoroquinolones resistant, 0.93% (4/431) were aged <18 years, 17.86% (77/431) were newly treated patients, and 14.62% (63/431) lived in Beijing, all the proportions were significantly higher than those of the patients sensitive to fluoroquinolones (3.05% (17/557), 36.98% (206/557) and 31.42% (175/557), respectively; χ ² were 6.154, 43.453 and 37.508, respectively, all P<0.05); the patients with rifampicin resistance accounted for 94.66% (408/431), significantly higher than that in the patients sensitive to fluoroquinolones (84.38%, 470/557; χ ²=25.968, P<0.01); 3.81% (15/431) had a history of fluoroquinolones, and there was no significant difference compared to those who were sensitive to fluoroquinolones (2.98%, 15/557; χ ²=0.465, P=0.495). Multivariate logistic regression analysis showed that rifampicin resistance (OR(95%CI)=2.704 (1.585-4.615)) and history of fluoroquinolones (OR(95%CI)=2.661 (1.210-5.854)) were the risk factors of fluoroquinolones resistance in patients with drug-resistant pulmonary tuberculosis; while initial treatment (OR (95%CI)=0.402 (0.283-0.571)) and living in Beijing (OR (95%CI)=0.411 (0.289-0.585)) were the protective factors. Conclusion Drug-resistant pulmonary tuberculosis patients had a higher rate of resistance to fluoroquinolone drugs. The risk of fluoroquinolone drug resistance increased in patients with retreatment, rifampicin resistance, fluoroquinolone history, and non-Beijing residents.

Analysis of direct medical costs and influencing factors of pulmonary tuberculosis patients in Chongqing

ZHANG Ting, SU Qian, WU Cheng-guo, WANG Qing-ya, LEI Rong-rong, CHEN Jian

Chinese Journal of Antituberculosis. 2021, 43(9):  910-915.  doi:10.3969/j.issn.1000-6621.2021.09.010

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Objective To investigate the direct medical expenses of active pulmonary tuberculosis (PTB) patients in Chongqing and analyze the influencing factors. Methods Clinical data of PTB patients (excluded patients with simple extra-pulmonary tuberculosis and rifampicin-resistant tuberculosis) registered in 41 district/county level TB hospitals in Chongqing from January to December in 2019 were collected from the subsystem (Tuberculosis Information Management System) of the China Information System for Disease Control and Prevention, and match with the diagnosis, treatment and cost information (such as outpatient and inpatient records, charging and reimbursements, etc.) of TB medical institutions at the municipal and district/county level in Chongqing from January 1, 2019 to May 31, 2020. Finally, 11745 patients who had been cured or had completed the treatment were included. Single-factor analysis and multi-factor generalized linear model analysis were used to investigate the direct medical expenses and influencing factors. Results The total direct medical expenses of 11745 cases were 83856000 yuan, of which 34009000 yuan (40.56%) for drugs, 32053000 yuan (38.22%) for examinations, and 17794000 yuan (21.22%) for others. The median (quartiles) of direct medical cost per case was 4517.0 (2144.0, 8903.0) yuan. Multifactorial generalized linear model analysis showed that secondary hospitals, tertiary hospitals, workers with urban health insurance, complications and hospitalization were the influential factors that increased the direct medical costs of general PTB patients. The medians (quartiles) of the direct medical costs of these five factors are: 4701.0 (2262.0, 9165.0), 5258.0 (2198.0, 11197.5), 6158.0 (2960.0, 11619.0), 6289.0 (2658.0, 11417.0) and 10858.0 (7544.0, 16390.0)yuan, respectively; OR (95%CI) values are: 1.299 (1.062-1.437), 1.123 (1.020-1.366), 1.240 (1.114-1.379), 1.149 (1.096-1.205) and 3.115 (3.012-3.226), respectively. Conclusion The direct medical expenses of PTB patients in Chongqing were high. High-level medical institutions, workers with health insurance, complications and hospitalization were the influential factors that increased the direct medical costs. We should proactively develop and implement the medical insurance policy of single-disease payment should be promoted, second- and third-level TB hospitals and the treatment of employees with medical insurance should be regulated.

Prevalence and correlated factors of drug-resistant pulmonary tuberculosis admitted to the designated medical institutions in Hainan Province from 2015 to 2019

ZHAO Xiu-juan, MO Jing-lian, SUN Tao, LIU Lin, ZHONG Ye-teng, PEI Hua, XIA Qian-feng

Chinese Journal of Antituberculosis. 2021, 43(9):  916-923.  doi:10.3969/j.issn.1000-6621.2021.09.011

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Objective To investigate the baseline and related factors of drug-resistant pulmonary tuberculosis who had admitted to the tuberculosis designated hospital in Hainan Province from 2015 to 2019, in order to provide scientific basis for the control and prevention of tuberculosis in Hainan. Methods One thousand two hundred and twenty-nine patients who were cultured positive of Mycobacterium, confirmed as Mycobacterium tuberculosis by Mycobacterium species identification testing and had anti-tuberculosis drug susceptibility testing (including rifampin, isoniazid, streptomycin and ethambutol) in the tuberculosis designated hospital of Hainan from January 2015 to December 2019 were enrolled. Patients’ information was collected retrospectively. Conditional logistic regression model was used to analysis the related factors of multidrug-resistance. Results The drug resistance rate of pulmonary tuberculosis patients was 41.66% (512/1229), of which in newly treated patients and retreated patients were 21.01% (137/652) and 64.99% (375/577), respectively, and the difference was statistically significant (χ²=243.600, P<0.001). The drug resistance rate was rifampicin (32.06%, 394/1229) >isoniazid (31.49%, 387/1229) >streptomycin (21.24%, 261/1229) >ethambutol (9.93%, 122/1229). From 2015 to 2019, the drug resistance rate of pulmonary tuberculosis patients decreased by 5.10% ((0.391/0.482) ^1/4-1) annually, and the multidrug-resistance rate decreased by 4.07% ((0.249/0.294)^1/4-1) annually, and the difference was statistically significant ({\chi }_{\mathrm{trend}}^2=8.837, P=0.003). Multivariate conditional logistic regression analysis showed that the risk of multidrug-resistance in patients with retreatment was 12.305 times of that in patients with initial treatment, with 95% confidence interval of (6.778-22.337); the multidrug-resistance risk of patients with hyperuricemia was 2.720 times of that in patients without hyperuricemia, with 95% confidence interval of (1.064-6.951); the rate of multidrug-resistance in pulmonary tuberculosis patients with pulmonary cavity was 2.017 times of that in patients without pulmonary cavity, with 95% confidence interval of (1.143-3.560). Conclusion The level of drug resistance of pulmonary tuberculosis patients is relatively high and severe in Hainan. Pulmonary tuberculosis patients with retreatment, hyperuricemia and pulmonary cavity are the high risk group of multi-drug resistant patients, and should be monitored.

Analysis of the drug resistance surveillance results of Mycobacterium tuberculosis in Fujian Province from 2016 to 2019

LIN Jian, LIN Shu-fang, DAI Zhi-song, ZHAO Yong, ZHOU Yin-fa, ZHANG Tian-lin, WEI Shu-zhen

Chinese Journal of Antituberculosis. 2021, 43(9):  924-928.  doi:10.3969/j.issn.1000-6621.2021.09.012

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Objective To understand the drug resistance of Mycobacterium tuberculosis complex isolates from the drug-resistant surveillance sites in Fujian province from 2016 to 2019, and to analyze the trend of change in drug resistance, in order to provide reference for tuberculosis control. Methods The culture positive isolates from 9 drug-resistant surveillance sites in Fujian province were identified by PNB and TCH, and the Mycobacterium tuberculosis complex (MTPC) strains were performed the drug susceptibility test by proportion method. The tested 9 drugs included INH, RFP, SM, EMB, Km, Ofx, Cm, Pto and PAS. The drug resistance spectrum and resistant level was described. Results Among the 1434 MTPC strains, 1261 strains were isolated from new cases and 173 were isolated from re-treated cases. The overall drug resistance rate was 19.04% (273/1434), the mono-resistance rate was 11.65% (167/1434), the poly-resistance rate was 3.56% (51/1434), and the MDR rate was 3.84% (55/1434). The overall drug resistance rate (28.90%, 50/173) and MDR rate (12.14%, 21/173) in the retreated cases were significantly higher than those (17.68% (223/1261), 2.70% (34/1261)) in the new cases (χ²=12.419, P=0.000;χ²=36.775, P=0.000).The spectrum consisted of 42 different typed of drug resistance. Resistance rate of 9 drugs were Sm (9.90%, 142/1434), INH (8.30%, 119/1434), RFP (5.93%, 85/1434), Ofx (3.63%, 52/1434), EMB (2.30%, 33/1434), Km (0.98%, 14/1434), Cm (0.77%, 11/1434), PAS (0.77%, 11/1434), Pto (0.63%, 9/1434). The overall drug resistance rates from 2016 to 2019 were 17.69% (66/373), 22.34% (63/282), 20.31% (78/384) and 16.71% (66/395) respectively, which showed no trend of change ({\chi }_{\mathrm{trend}}^2=0.248, P=0.619). Conclusion The drug resistance in Fujian province is at a low level and shows complex and diversity. It is necessary to pay attention to the screening of drug resistance and strengthen the treatment management of drug resistant patients.

The impact of the COVID-19 epidemic on tuberculosis notification in Sichuan Province

LI Ting, HE Jin-ge, XIA Lan, CHEN Chuang, XIAO Yue, LU Jia, WANG Dan-xia

Chinese Journal of Antituberculosis. 2021, 43(9):  929-938.  doi:10.3969/j.issn.1000-6621.2021.09.013

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Objective To analyze the impact of COVID-19 epidemic on tuberculosis (TB) case notification in Sichuan Province in 2020, and to provide experience for TB detection under the situation of normalized COVID-19 control. Methods Medical records of TB patients from TB Management Information System of Chinese Diseases Control Information System were divided into three phases (control phase, intensive intervention phase and normalized phase, each phase contain 11 weeks) in relation to two time point: national response to COVID-19 (January 25, 30 provinces launched public health emergency response level 1) and Wuhan reopen (April 8). Data from 2017-2019 were used as baseline. The changes of TB notification number and the percentage of bacteriologically confirmed cases in each phases were analyzed as well as the changes of spatial distribution and characteristics of notified TB patients before and after the epidemic. Results In the first quarter of 2020, the number of visitors in designated TB hospitals (22656 cases) in Sichuan Province decreased by 35.97% (12730/35386) year-on-year and 33.94% (11642/34298) quarter-on-quarter. The notification number of TB patients and the percentage of bacteriologically confirmed cases decreased sharply in the 1st week of the intensive intervention phase by 62.52% (452/723) and 5.10% (from 48.27% (349/723) 1 week before Sprint Festival to 43.17% (117/271) 1 week after), respectively. It took 8 weeks and 4 weeks for these two indicators rebounding to their pre-epidemic levels. Among all 183 counties in the province, 131 (71.58%) showed a year-on-year decline on notification number and 98 (53.55%) showed a quarter-on-quarter decline. The notification number of male, student, Han, inter-provincial migrants, patients from Hong Kong, Macao, Taiwan and foreign countries showed larger year-on-year decline rates (25.06% (1805/7203), 38.77% (352/908), 25.01% (2088/8348) and 38.46% (100/260) respectively). Also, the notification number among patients under 15, 15-24, 25-34, 35-44, 45-54, 55-64 and over 65 had declined 8.89% (16/180), 26.28% (488/1857), 4.52% (61/1350), 18.68% (203/1087), 24.83% (498/2006), 28.53% (432/1514) and 28.57% (558/1953), respectively, which showed an upward trend (Z=2.520, P<0.001). Conclusion The COVID-19 epidemic has caused a very significant impact on the notification level of TB patients in Sichuan in short term and the number of cases notified has been greatly reduced. We should establish an emergency mechanism for TB control program, and enhance the active case finding activities for students and elders when the situation becomes normalized.

Analysis of the composition and phenotypes of intestinal flora in primary bacteriologically-confirmed pulmonary tuberculosis patients based on high-throughput sequencing of 16S rRNA V4 region

YI Yi-hang, YU Rong, SHI Guo-min, MA Xiao-hua, XIAO Si-fang, SHUI Jian, FAN Ren-hua, XIANG Yan-gen

Chinese Journal of Antituberculosis. 2021, 43(9):  939-946.  doi:10.3969/j.issn.1000-6621.2021.09.014

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Objective To study the differences of composition and phenotypes of intestinal flora between diagnosed pulmonary tuberculosis(PTB) patients and healthy individuals by using high-throughput sequencing technology and bio-informatics analysis. Methods PE 150 (pair-end 2×150 bp) sequencing scheme was used to sequence flora 16S rRNA gene V4 region from fresh stool samples of 29 primary bacteriologically-confirmed PTB patients (PTB group)and 28 healthy volunteers (healthy controls) at Changsha Central Hospital,University of South China from April 14, to December 28, 2020. Operational taxonomic units (OTU) were annotated by aligning with Silva database (Silva 128). QIIME software was used to calculate OTU level, α diversity index, β diversity index and relative abundance at phylum and genus levels, and to generate OTU level abundance grade curve (Ranked abundance). R software package “VennDiagram” was used to generate VennDiagram. R order “ggplot” was used to draw a horizontal bubble diagram. BugBase software was used to classify and compare 7 phenotypes of intestinal flora. Results For the α diversity index, the Shannon index of intestinal flora in the PTB group and the health controls were 4.24±1.71 and 5.64±0.85 respectively (t=3.889, P<0.01), Simpson index were (0.89 (0.80,0.94)) and (0.94 (0.90,0.96)) (Z=-3.256, P<0.01), Chao1 index were 1085.35±659.99 and 1844.04±658.95 (t=4.378, P<0.01), ACE index were 1091.64±666.93 and 1857.34±657.90 (t=4.403, P<0.01). The difference of β diversity between the PTB group and the healthy control group was statistically significant (R²=0.253, P<0.01).Twelve bacterial genera with significant differences between groups were found, which were mainly concentrated in Firmicutes (PTB group: 35.44%, control group: 51.55%, Z=-3.290,P<0.01). Phenotypic analysis showed that the relative abundance of anaerobic gene, intestinal gram-positive bacteria in the intestinal flora of the PTB group were lower than that of the health controls (21.80% vs 26.50%, Z=-3.080, P<0.01; 13.86% vs 17.75%, Z=-2.283, P<0.05). The relative abundance of intestinal gram-negative bacteria, intestinal facultative bacteria, oxidative stress tolerance bacteria and the ability of biofilm formation in the intestinal flora of the PTB group was higher than the health controls (15.14% vs 10.25%, Z=-2.283, P<0.05; 5.00% vs 0.59%, Z=-3.240, P<0.01; 3.10% vs 0.35%, Z=-2.075, P<0.05; 4.94% vs 1.19%, Z=-2.267, P<0.05). Conclusion The PTB group got changes in the composition of intestinal flora and bacterial phenotypes, which were mainly manifested as decrease in the diversity of the intestinal flora. The phenotypic changes were mainly caused by changes in the intestinal oxygen environment.

Evaluation of in vitro antibacterial effects of 13 antibiotics against rapidly growing mycobacteria

YU Xia, REN Ru-yan, WEN Shu-an, LIANG Qian, DONG Ling-ling, HUANG Hai-rong

Chinese Journal of Antituberculosis. 2021, 43(9):  947-951.  doi:10.3969/j.issn.1000-6621.2021.09.015

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Objective To evaluate the susceptibility characteristics of clinical isolates of rapidly growing mycobacteria (RGM) to 13 antibiotics. Methods A total of 98 isolates of RGM recruited from Beijing Chest Hospital, Capital Medical University between January 2015 and December 2019 were collected, including 25 Mycobacterium (M.) fortuitum, 70 M.abscessus and 3 M.chelonae. Sensititre RAPMYCO MIC plate was used to determine 13 antibiotics (amikacin, tobramycin, amoxicillin-clavulanic acid, cefoxitin, imipenem, ciprofloxacin, moxifloxacin, clarithromycin, linezolid, minocycline, doxycycline, tigecycline, trimethoprim-sulfamethoxazole) in vitro antibacterial activity against the 98 RGM clinical isolates. Results Among the 13 tested antibiotics, amikacin had the best in vitro antibacterial activity against three RGM clinical isolates tested, the sensitivity rates to M.fortuitum and M.abscessus were 100.0% (25/25) and 90.0% (63/70), respectively. In vitro antibacterial effect of tigecycline on RGM clinical isolates was better than the effects of doxycycline and minocycline, and the sensitivity rates to M.fortuitum and M.abscessus were 100.0% (25/25) and 72.9% (51/70), respectively. Moxifloxacin and ciprofloxacin showed strong antibacterial activity against M.fortuitum, with sensitivity rates of 100.0% (25/25) and 92.0% (23/25), respectively; however, for M.abscessus branches, they had almost no antibacterial activity in vitro, and the drug resistance rate was 95.7% (67/70). In addition, almost all tested RGM clinical isolates were resistant to cefoxitin, doxycycline, linezolid, imipenem, and methoxazole-sulfamethoxazole. Conclusion Amikacin, tigecycline and clarithromycin had good in vitro antimicrobial activity against M.abscessus and M.fortuitum, but there were still differences among different strains. Separate drug sensitivity test is necessary to be carried out for each strain or clinical strain.

Analysis and comparative study on the virulence of several drug-resistant Mycobacterium tuberculosis

ZHOU Ying-yu, FU Lei, ZHANG Wei-yan, WANG Bin, CHEN Xi, LU Yu, CHEN Xiao-you

Chinese Journal of Antituberculosis. 2021, 43(9):  952-960.  doi:10.3969/j.issn.1000-6621.2021.09.016

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Objective To evaluate the virulence of clinical drug-resistant isolates and laboratory induced drug-resistant strains of Mycobacterium tuberculosis (MTB). Methods MTB standard strain H37Rv and attenuated strain H37Ra, four clinical drug-resistant isolates (15833, 16030, 17080 and 30744) and eight laboratory induced drug-resistant strains, including one pretomanid(PA-824)resistant strain (P1), one Lzd resistant strain (L1), three PBTZ-169 resistant strain (169-1, 169-2, 169-3), three PA-824 and Lzd dual resistant strains (PL1, PL2, PL3), were selected. The minimum inhibitory concentration (MIC) of clinical drug-resistant isolates against first-line and second-line anti-tuberculosis drugs and laboratory induced drug-resistant strains against Lzd, PA-824 and PBTZ-169 were measured. The in vitro growth curves of the studied strains and the intracellular colony forming units (CFU) of macrophages 2 days after infection were drawn, and the content of lactate dehydrogenase (LDH) released by macrophages 2 days after infection was measured.One hundred and sixty-eight BALB/c mice, 6-7 weeks old and 16-18 g/mouse, were randomly divided into 14 groups with 12 mice in each group. BALB/c mice were infected with drug-resistant strains by tail vein injection. The half survival time of mice was recorded and analyzed. Results In vitro experiments showed that the plateau phase of growth curve of MTB clinical drug-resistant isolate 30744 was earlier than that of the other drug-resistant strains, the adaptability of the strain in vitro was lower, and the growth curve trend of the other drug-resistant strains was basically identical. The intracellular CFU counts of clinical drug resistant isolates (15833, 16030, 30744, 17080) and laboratory induced drug resistant strains (PL1, PL2, PL3) resistant to Lzd and PA-824 were (5.180±0.074), (5.571±0.029), (5.550±0.073), (5.446±0.099), (5.763±0.197), (5.907±0.053), and (5.661±0.083) log₁₀ CFU/ml, which was significantly lower than that of standard strain H37Rv ((6.207 ± 0.028) log₁₀ CFU/ml), and the difference was statistically significant (t=17.932, 12.758, 12.034, 10.241, 4.796, 7.042, 9.113, Ps<0.05). In addition, the absorbance A₄₉₀ values of LDH release from macrophages infected by strains 15833, 16030, 30744, 1708, P1, L1, PL1, PL2, PL3, 169-1, 169-2 and 169-3 were 0.252±0.039, 0.412±0.078, 0.247±0.022, 0.358±0.054, 0.329±0.015, 0.483±0.017, 0.328±0.046, 0.455±0.075, 0.283±0.041, 0.258±0.044, 0.374±0.080, and 0.311±0.097, which was significantly lower than that of standard strain H37Rv (0.958±0.025), and the difference was statistically significant (t=27.269, 16.788, 38.244, 24.238, 44.005, 32.698, 27.713, 15.171, 31.798, 31.472, 16.515, 15.570, Ps<0.01). In vivo virulence test showed that: (1) The half surviors’ alive time (≥15 days) of all strains infected mice was significantly longer than that of H37Rv (12 days). (2) The survival curve of mice showed that the survival time of mice infected with pre-XDR strain was longer than that of MDR strains, namely 30744>17080>16030>15833; (3)The survival time of mice in the dual drug-resistant strain LPDR group>PBTZ-169 drug-resistant strain group=single Lzd resistant group>single PA-824 resistant strain group. Conclusion The virulence of MTB resistant strains was lower than that of wild-type standard strains, and the virulence might be negatively correlated with the number of drug-resistance.

Resistance of prothionamided and sodium aminosalicylate among isoniazid resistant pulmonary tuberculosis patients

MA Ting-ting, REN Fei, MA Jin-bao, YANG Han

Chinese Journal of Antituberculosis. 2021, 43(9):  961-964.  doi:10.3969/j.issn.1000-6621.2021.09.017

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Objective To analyze the resistance of prothionamide (Pto) and sodium phenyl aminosalicylate (PAS) in patients with isoniazid (IHN)-resistant pulmonary tuberculosis (PTB), and the correlation of inhA genes and Pto resistance. Methods We retrospectively collected data of 849 PTB patients diagnosed as INH resistant by 960 liquid drug susceptibility test (DST) in Xi’an Chest Hospital from Jan 1, 2018 to Dec 31, 2020. The DST results of rifampicin, Pto, PAS, and mutation of katG and inhA gene were analyzed. The correlation of inhA and Pto resistance was examined with Cohen’s Kappa test. Results In 849 cases of INH resistant patients, 33 cases were resistant to Pto, the drug resistance rate was 3.89% (33/849). One hundred and one patients were resistant to PAS, the drug resistance rate was 11.90%. Among 518 patients with INH resistance related gene detected by real-time PCR fusion curve test, the mutation rate of katG and inhA gene were 73.75% (382/518) and 15.83% (82/518) respectively, the drug resistance rate of Pto was 3.86% (20/518). Among 82 patients with inhA gene mutation,the drug resistance rate of Pto was 8.54% (7/82), while the inhA mutation rate among Pto resistant patients was 35.00% (7/20), their consistency was poor (Kappa=0.080). Conclusion The resistance rate of Pto among INH resistant patients was low, while resistance rate of PAS was high. The consistency of Pto resistance and inhA mutation was poor.

Review Articles

Pharmacodynamic characteristics and interaction of new antituberculosis drugs

QI Xue-ting, LU Yu, CHEN Xiao-you

Chinese Journal of Antituberculosis. 2021, 43(9):  965-969.  doi:10.3969/j.issn.1000-6621.2021.09.018

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Treatment of tuberculosis currently still relies on chemotherapy,however,there are multitude problems in the existing chemotherapy regimens, such as long treatment course, various adverse reactions, and suboptimal outcomes.There is an urgent need to exploit potent drug combinations to improve the treatment efficacy and shorten the course of treatment.Herein, the pharmacodynamic characteristics and interactions of novel anti-tuberculosis drugs launched in recent years,as well as those in the research stage, are briefly reviewed to provide reference for the research and development of anti-tuberculosis drugs and new drug combination regimens.

Research progress on recombinant protein subunit vaccine of tuberculosis

CAO Qian-qian, ZHU Bing-dong, NIU Hong-xia

Chinese Journal of Antituberculosis. 2021, 43(9):  970-974.  doi:10.3969/j.issn.1000-6621.2021.09.019

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Bacille Calmette-Guérin (BCG) is the only tuberculosis vaccine used clinically, but its protective effect against adult tuberculosis is still uncertain. Recombinant protein subunit vaccines can provide long-term immune protection, and have clear ingredients and good safety, so they have good prospects of application development. This article reviews the progress of the components of the tuberculosis recombinant protein subunit vaccine, including the protective antigens and adjuvants of Mycobacterium tuberculosis, the current status of clinical research, the application strategies and challenges faced by the research.

Research progress of tuberculosis patients self-efficacy assessing tools and related factors

CAO Xin-yu, LI Xiao-lin, XUE Miao, GE Ru-yu, TANG Li

Chinese Journal of Antituberculosis. 2021, 43(9):  975-978.  doi:10.3969/j.issn.1000-6621.2021.09.020

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Self-efficacy is the level of self-confidence in their ability to use skills they possess to accomplish a certain task or behavior. Self-efficacy assessment is increasingly important in studies of patients with chronic diseases, including hypertension, diabetes, stroke, and respiratory system chronic diseases, etc. The author summarized the significance, current status of studies about self-efficacy of tuberculosis patients, together with influencing factors of self-efficacy.

The diagnosis and treatment of non-tuberculous mycobacterium disease in children

ZHENG Hui-wen, SHEN A-dong

Chinese Journal of Antituberculosis. 2021, 43(9):  979-982.  doi:10.3969/j.issn.1000-6621.2021.09.021

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Compared with tuberculosis, nontuberculous mycobacterium (NTM) disease with various pathogenic bacteria infections has similar clinical symptoms, which increases the difficulties of differential diagnosis and treatment. In this study, the epidemiological features of NTM and clinical symptoms of NTM in children, as well as its diagnosis and treatment methods were reviewed.