Table of Content

10 February 2020, Volume 42 Issue 2

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Special Articles

Characteristics and points analysis of national Guidelines on chemotherapy of drug-resistant tuberculosis (2019) and associated consensus

FAN Lin,LIU Yi-dian,XIAO He-ping

Chinese Journal of Antituberculosis. 2020, 42(2):  91-94.  doi:10.3969/j.issn.1000-6621.2020.02.003

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Authors made analysis on the similarities and differences of Chinese Guidelines on chemotherapy of drug-resistant tuberculosis (2019) (abbreviated as “Guidelines 2019”) and Chinese consensus on multidrug-resistant tuberculosis and rifampin resistant tuberculosis treatment (2019 edition) and compared with WHO guidelines, provided the ideas from the elaboration on drug groups divided, implement approach of anti-TB treatment,the characteristics of Guidelines 2019 and future development direction of national drug-resistant treatment for clinical physicians.

Original Articles

Systematic evaluation and meta-analysis of integrated traditional Chinese and western medicine in the treatment of MDR-PTB

MA Gai-xia,TIAN Li-ming,WANG Yu,QIU Lei,XUE Ling-na,LU Zhen-hui,ZHANG Hui-yong,GUO Xiao-yan

Chinese Journal of Antituberculosis. 2020, 42(2):  95-100.  doi:10.3969/j.issn.1000-6621.2020.02.004

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Objective To reevaluate the qualities of literature methodology and report on systematic evaluation/meta-analysis of integrated traditional Chinese and western medicine in the treatment of multidrug-resistant pulmonary tuberculosis (MDR-TB). Methods The databases, including PubMed, EMbase, Cochrane Library, CBM, WanFang, CNKI and VIP databases, were searched by computer to collect systematic evaluation/meta-analysis literatures on the treatment of MDR-TB by integrated traditional Chinese and western medicine. The retrieval time was from the establishment of the database to August 2019. Based on the combination of subject words and free words, 30 literatures were initially screened out, and then 15 repeatedly published literatures and 10 literatures of non-MDR-TB were excluded, finally, 5 literatures were included for research. The methodological quality and report quality of the included literature were evaluated using AMSTAR scale and GRADE classification evaluation system. Results A total of 5 systematic evaluation/meta-analysis literatures were included, and 8 outcome indicators were obtained, including sputum negative conversion rate, lung lesion absorption rate, cavity closure rate, adverse reaction rate, improvement of traditional Chinese medicine (TCM) syndromes, cure rate, and relapse rate and treatment effective rate. All the included literatures compared the western medicine combined with TCM and western medicine alone. According to the AMSTAR scale score, the three literatures were 6 scores with the medium quality; as well as one literature was 7 scores and one was 9 scores with the high quality. GRADE classification showed that among the eight outcome indicators of 5 literatures, sputum negative conversion rate in 1 literature was very low quality, and the remaining 17 indicators were intermediate (3) or low (14) quality. The results of descriptive analysis showed that the combined treatment of traditional Chinese and western medicine for MDR-TB could elevate the sputum negative conversion rate and lung lesion absorption rate at the strengthening and consolidation stages, and improve the clinical symptoms of patients, meanwhile, the cavity closure rate and adverse reaction rate were relatively lower. Conclusion Integrated traditional Chinese and western medicine in the treatment of MDR-TB has synergistic effect, and the methodological quality of systematic evaluation/meta-analysis is medium and advanced, but the evidence strength of conclusion is low. Thus, the methodological quality and report quality of systematic evaluation should be strengthened.

Study of autophagy induced by myricetin in MTB infected macrophages through PI3K/Akt/mTOR signaling pathway

SUN Jin-xia,ZHANG Qing-wen,LI Yin-hong,JIANG Xin

Chinese Journal of Antituberculosis. 2020, 42(2):  101-107.  doi:10.3969/j.issn.1000-6621.2020.02.005

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Objective To explore the anti-tuberculosis mechanism of myricetin by studying the autophagy of MTB-infected macrophages induced by myricetin through PI3K/Akt/mTOR signaling pathway. Methods CCK8 method was used to detect the effect of myricetin on cell proliferation and determine the safe dosage range. Murine Raw 264.7 macrophages infected with H37Ra strain was used as the model group, meanwhile we set a blank group and a myricetin group. The cells were infected with MTB H37Ra (Multiplicity of infection=10). After 4 h of co-incubation, cells were washed three times with PBS to discard the MTB that did not enter the cells. In order to determine the optimal concentration of myricetin which promoted autophagy, the protein levels of LC3Ⅱ and p62 were detected by western blot in MTB-infected macrophages treated by different concentrations (12.5, 25, 50, 100 μmol/L) of myricetin for 24 h. The intracellular bacterial load of macrophages after treated with myricetin for 72 h were checked using colony-forming unit (CFU) method. Phosphorylations of Akt and mTOR in PI3K/Akt/mTOR signaling pathway were tested with western blot method for those infected macrophages treated with myricetin for 30, 60 and 180 min. Protein quantitative analysis was performed with Image J software. The results were analyzed using GraphPad Prism 7.0, one-way analysis of variance (ANOVA) was used for pairwise comparison of data, and P<0.05 was considered statistically significant. Results The survival rate of infected macrophages treated with myricetin below 100 μmol/L was about 90%, indicating minor toxic to cells. Western blot showed that compared with model group (0.52±0.01), LC3 Ⅱ expression (0.59±0.02, 0.65±0.01, 0.71±0.01, 0.83±0.01) were changed significantly with different concentrations of myricetin (12.5, 25, 50, 100 μmol/L). Differences were statistically significant (t=2.97,P=0.04,t=7.91,P=0.00,t=9.77,P=0.00,t=16.37,P=0.00); Comparing with the model group (0.86±0.02), different concentrations of myricetin treatment also inhibited the expression of p62 (0.72±0.01, 0.85±0.00, 0.60±0.02, 0.58±0.01). Differences were statistically significant (t=6.50, P=0.00,t=9.53, P=0.00,t=12.01, P=0.00) for concentrations of 12.5, 50, 100 μmol/L respectively, while the group treated with 25 μmol/L (t=0.81,P=0.46) was not statistically significant. The optimal drug concentration of myricetin to promote autophagy was 100 μmol/L. The inhibition rate of intracellular MTB was 21.02% when infected macrophages were treated with myricetin for 72 h. The phosphorylation of Akt in PI3K/Akt/mTOR pathway (1.23±0.01, 1.52±0.01, 0.74±0.02) was significantly increased in the model group at 30, 60, and 180 min after MTB infection, while the phosphorylation of Akt was significantly inhibited by myricetin at the same time (0.99±0.01, 0.96±0.01, 0.43±0.01), with statistically significant differences (t=27.60, P=0.00, t=30.06, P=0.00,t=18.60, P=0.00). However, the protein level of phosphorylated mTOR (p-mTOR) in the model group only increased significantly after MTB infection for 180 min (0.57±0.00), and myricetin also inhibited the phosphorylation of mTOR protein for 180 min (0.46±0.01), with a statistically significant difference (t=21.60, P=0.00). Conclusion Myricetin inhibited the PI3K/Akt/mTOR pathway by inhibiting the phosphorylation of Akt and mTOR proteins, thus inducing autophagy in MTB-infected macrophages to kill intracellular MTB.

Clinical value of chemotherapy regimen and Qinbudan tablet on the retreatment of retreated smear-positive pulmonary tuberculosis

QIU Lei,ZHANG Shao-yan,GUO Xiao-yan,FU Ji-you,TIAN Li-ming,ZHANG Hui-yong,LU Zhen-hui

Chinese Journal of Antituberculosis. 2020, 42(2):  108-114.  doi:10.3969/j.issn.1000-6621.2020.02.006

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Objective To observe the effect of chemotherapy regimen and Qinbudan Tablet on clinical symptoms and life quality of patients with retreated smear-positive pulmonary tuberculosis. Methods A total of 181 cases were collected from a multicenter, randomized, double-blind, placebo-controlled clinical trial of chemotherapy regimen and Qinbudan tablet on retreated pulmonary tuberculosis (Clinical trial registration number: NCT02313610) led by Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from April 2011 to March 2013. According to random number table, all cases were randomly divided into observation group (2H-R-Z-E-S/6H-R-E+Qinbudan tablets, 93 cases) and the control group (2H-R-Z-E-S/6H-R-E+placebo, 88 cases). Observe the differences in Traditional Chinese medicine (TCM) symptom score (including 8 single symptom scores of cough, expectoration, chest pain, hot flashes, cheeky red, night sweats, thirst and dry throat) and SF-36 scale (including physical function, role-physical, bodily pain, vitality, social functioning, role-emotional, mental health, general health and health transition) before and after treatment. Results At the end of treatment, the effective rate of TCM symptom improving for the observation group (91.4%, 85/93) was obviously higher than that in the control (78.4%, 69/88) group with a significant statistical difference (χ ²=6.010, P=0.012). The effective rate of 6 clinical symptom scores including hot flashes, cheeky red, night sweats, phlegm, thirst and dry throat for the observation group (83.9%,78/93;71.0%,66/93;86.0%,80/93;84.9%,79/93;80.6%,75/93;87.1%,81/93) were higher than those in the control group (68.2%,60/88;53.4%,47/88;73.9%,65/88;70.5%,62/88;54.5%,48/88;65.9%,58/88),and the differences were statistically significant (χ ²=6.415,P=0.013;χ ²=5.943,P=0.015;χ ²=4.195,P=0.041;χ ²=5.516,P=0.019;χ ²=14.144,P<0.001;χ ²=11.391,P=0.001). At the end of treatment, the mean rank of the four SF-36 scores including health transition, physical function, vitality and general health in the observation group were 98.58,99.03,102.27,100.47 which were higher than those in the control group (82.99,82.51,78.69,82.99), the differences statistically significant (U=3387.000, P=0.027;U=3345.000, P=0.028;U=3009.000, P=0.002; U=3211.000, P=0.012). Conclusion Qinbudan tablet can help improve the clinical symptoms and life quality of the retreated pulmonary tuberculosis.

Investigation of correlation between traditional Chinese medicine synbrome elements and clinical characteristics of patients with multidrug-resistant pulmonary tuberculosis

WANG Yu,FU Ji-you,ZHANG Shao-yan,QIU Lei,LU Zhen-hui,ZHANG Hui-yong,WU Ding-zhong

Chinese Journal of Antituberculosis. 2020, 42(2):  115-120.  doi:10.3969/j.issn.1000-6621.2020.02.007

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Objective To explore the correlation between the age, course of disease and pulmonary X-ray manifestation of multidrug-resistant pulmonary tuberculosis (MDR-PTB) patients and traditional Chinese medicine (TCM) syndrome elements, in order to guide TCM treatments. Methods All of 740 valid cases of MDR-PTB patients were surveyed ranging from 18 tuberculosis-designated hospitals, including Shanghai Pulmonary Hospital affiliated to Tongji University, Beijing Chest Hospital affiliated to Capital Medical University and the 8th Medical Center of Chinese PLA General Hospital, etc. Those patients were diagnosed between January, 2013 and December, 2015 and their course of diseases were all less than 6 months. As some patients’ clinical characteristics, such as age, course of disease, cavity and focal involvement, were insufficient, 615 cases were finally adopted. The survey questionnaire containing personal information of patients (name, gender, age, etc) was used, information also related to clinical treatments (previous symptoms, current symptoms, course of disease, cavity and focal involvement) and medical diagnosis. All the data was discussed and recognized by the panel participated in Drug-Resistant Tuberculosis of TCM Project during 12th-Five-Year Plan for Infectious Disease. One thousand pieces of questionnaire were offered, and 850 pieces returned back with information filled, while 740 pieces were eventually recognized as valid. The valid rate achieved 87.06%. SPSS 21.0 was used to analyze the data, in order to explored the correlation between different types of syndrome elements and these study objects mentioned above and their distribution. Results In this study, 5 types of TCM syndrome elements could be concluded according to their frequency: Yin deficiency (55.1% (339/615)), Qi deficiency (54.0% (332/615)), phlegm-turbidity (26.7% (164/615)), hyperactive fire (26.3% (162/615)), and Yang deficiency (15.0% (92/615)). The median age (M(Q₁,Q₃)) of patients developed with Qi deficiency, Yin deficiency and Yang deficiency were 40.0 (28.0,51.0), 40.0 (28.0,50.0) and 45.0 (28.0,53.0), respectively; all of them were significantly older than those of patients without the three TCM syndrome elements mentioned above (34.0 (25.0,47.0), 34.0 (26.0,48.0) and 36.0 (26.0,49.0), respectively) (Z=8.944, P=0.003; Z=8.043, P=0.005; Z=5.185, P=0.023). Furthermore, with their age grows, these patients were likely to suffer with severer Qi deficiency (lighter ones 38.0 (28.0, 51.0); severer ones 45.0 (29.0, 53.0)) (Z=6.350, P=0.042). Both the courses of disease of patients with Qi deficiency and Yang deficiency (averaged 24.0 (8.0, 60.0) and 28.0 (11.0,68.0) months, respectively) and their diameters of biggest cavity (averaged 1.5 (0.0, 3.0) and 1.5 (0.0, 3.0) cm, respectively) were significantly longer than those of patients without Qi and Yang deficiency (courses of disease: 18.0 (5.0, 39.8) and 18.0 (6.0, 48.0) months, respectively; diameters of biggest cavity: 1.3 (0.0,2.4) and 1.5 (0.0, 2.6) cm, respectively) (Z=8.642, P=0.003; Z=17.954, P<0.001; Z=4.191, P=0.041; Z=6.709, P=0.010). Additionally, patients with longer course of disease tend to suffer with severer Qi deficiency and hyperactive fire (lighter ones 27.0 (8.5, 59.0) months, severer ones 28.0 (11.0, 72.0) months; lighter ones 12.5 (5.3, 39.3) months, severer ones 26.0 (12.0, 60.0) months)(Z=12.725, P=0.002; Z=6.997, P=0.030). As to the rates of cavity, patients with hyperactive fire (79.6% (129/162)) were much higher than those without the syndrome elements (70.0% (317/453)) (Z=4.869, P=0.031). Conclusion MDR-PTB patients with Yin deficiency are the majority. It is helpful to guide TCM treatment by discerning and analyzing the correlation between clinical characteristics, such as age, course of disease and occurance rate of cavity as well as its biggest diameter, and the TCM syndrome elements.

Clinical effect analysis of Chaizhushigao Decoction in 29 recurrent fever tuberculosis patients complicated with other infections

LI Zhi-ming,YU Shan,WANG Tao.

Chinese Journal of Antituberculosis. 2020, 42(2):  121-125.  doi:10.3969/j.issn.1000-6621.2020.02.008

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Objective To observe the clinical effect of Chaizhushigao Decoction in recurrent fever tuberculosis complicated with other infections. Methods We collected the clinical data of 29 patients who were hospitalized in the tuberculosis department of institute for tuberculosis research, the 8th Medical Center of Chinese PLA General Hospital from March 2016 to March 2018 and were diagnosed as secondary tuberculosis complicated with other non-tuberculosis infections. These patients had clear evidence of bacteriological infection and still suffered from fever continuously or repeatedly after routine anti-tuberculosis and antiinfection treatment at different times. They were treated with Chaizhushigao Decoction (self-made prescription), and at same time the antibiotics against other bacterial infections were stopped with informed consent of all patients. The antipyretic effect of the treatment with Chaizhushigao Decoction afer 7 days and the long-term effect of 2 months after discharge were observed. These patients were treated with antituberculous drug for 1 to 6 months, with an average of (2.0±1.8) months; with anti-infection drug for 7 to 180 days, with an average of (43.3±36.6) days; and fever duration was 10 days to 6 months, with an average of (20.0±4.0) days. Results Of 29 tuberculosis patients treated with Chaizhushigao Decoction for 7 days, 20 (69.0%) patients were completely controlled, 6 (20.7%) patients were partially controlled, 2 (6.9%) patients were effective, 1 (3.4%) patient was ineffective, and the total effective rate was 96.6% (28/29). Among 26 (89.7%) patientswith complete and partial control, 12 (46.2%) patients recovered to normal temperature within 3 days, 8 (30.8%) patients recovered to normal temperature within 3 to 5 days, and 6 (23.1%) patients recovered to normal temperature within 5 to 7 days. And the temperature of these patients did not recur after one month of drug withdrawal. Among the 2 effective patients, their body temperature patient decreased to normal on the 9th and 10th day of taking medicine, respectively, but their body temperature fluctuated to about 37.5 ℃ after repeated observation, and the body temperature returned to normal after one month’s treatment with traditional Chinese medicine. After another antifungal treatment, the body temperature of one invalid patient gradually returned to normal 2 months later. Conclusion Chaizhushigao Decoction has a good clinical effect in the treatment of recurrent fever tuberculosis complicated with other infections. Its antipyretic mechanism needs further study in clinical practice.

Comparative analysis on drug-induced liver injury of the combination of traditional Chinese and Western medicine and single Western medicine in tuberculosis treatment (Literature review 2000-2019)

WANG Xue-di,JIANG Feng,DAI Qian-lan,WANG Jing,WANG Dong-mei.

Chinese Journal of Antituberculosis. 2020, 42(2):  126-132.  doi:10.3969/j.issn.1000-6621.2020.02.009

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Objective To analyze the occurrence of drug-induced liver injury of the combination of traditional Chinese and Western medicine in tuberculosis treatment through collecting literature provide the reference for rational drug use in clinic. Methods We determined literature on the combined treatment of traditional Chinese and Western medicine for tuberculosis published in domestic and foreign databases (CNKI, WanFang Data, VIP and PubMed databases) from January 2000 to July 2019, inclusion of primary disease for tuberculosis, and inclusion criteria were research papers that reported describing liver injury case report, primary disease with liver injury, drug method and dose. Treatment regimen with the combination of traditional Chinese and Western medicine was the experimental group, while regimen with Western medicine was the control group.Twenty-two full-text studies were included and analyzed through excluding unqualified literatures including content of studies was not meet the requirements (non-clinical trial studies, literature review, review, etc),describing the information was incomplete or inaccurate,and literature of low quality or low data reliability.SPSS 23.0 software was used for statistical analysis, frequency statistical analysis was used for measurement data, and rank sum test was used for comparison of counting data, P<0.05 was presented for statistically significant difference. Results Of the 22 articles, 2561 were tuberculosis patients. The incidence rate of liver injury in the experimental group (12.05%(156/1295)) was significantly lower than the control group (24.33%(308/1266))(χ ²=65.096, P<0.001). The incidence of liver injury in initial treatment regimen, retreatment regimen and drug-resistant tuberculosis treatment regimen in the experimental group (10.65%(23/216), 4.35%(3/69) and 10.86% (19/175) respectively) was significantly lower than the control group (25.12%(54/215), 13.04%(9/69) and 26.75% (42/157) respectively)(χ ²=15.371,P<0.001;χ ²=3.286,P=0.070;χ ²=13.940,P<0.001). Conclusion The combination of Chinese and Western medicine can reduce the incidence of anti-tuberculosis drug-induced liver injury compared with the anti-tuberculosis regimen of Western medicine.

Preliminary study on the gene function of a novel toxin-antitoxin system MSMEG_3435-3436 in Mycobacterium smegmatis

ZHANG Lan-yue,GENG Yi-man,JIA Hong-yan,XIAO Jing,LI Zi-hui,PAN Li-ping,SUN Yi-cheng,ZHANG Zong-de

Chinese Journal of Antituberculosis. 2020, 42(2):  133-142.  doi:10.3969/j.issn.1000-6621.2020.02.010

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Objective To investigate the function of the toxin-antitoxin (TA) systems in Mycobacterium smegmatis (M. smegmatis) and its role in bacterial drug tolerance. Methods Two toxin genes (MSMEG_3436 and MSMEG_6760) were constructed in anhydrous tetracycline (ATc)-induced shuttle plasmid, respectively, and then tested for repression of cell growth in M.smegmatis. The ΔMSMEG_3435-3436 and ΔMSMEG_6762-6760 mutants were constructed using CRISPR-Cas12a genome editing system to investigate the effect of TA system on cell growth. Wild type M.smegmatis and MSMEG_3435-3436 deletion mutant were treated with isoniazid (96 μg/ml) and rifampicin (40 μg/ml) and tested for drug tolerance by calculating survival rate. The TA genes (MSMEG_1277-1278, MSMEG_1283-1284, MSMEG_3435-3436, MSMEG_4447-4448, MSMEG_5635-5634) was replaced by LacZ reporter gene in M.smegmatis, resulting in promoter activity analysis stains SY3328, SY3309, SY6407, SY3310, and SY3311. The empty vector pMV261 and its derivatives expressing antitoxins were transformed into the aforementioned strains, respectively. The promoter activity of TA genes was then assessed by measurement of β-galactosidase. Results Highly expression of toxin gene MSMEG_3436 but not MSMEG_6760 in M.smegmatis repressed cell growth, while co-expression of anti-toxin gene MSMEG_3435 relieved the repression. The wild-type, ΔMSMEG_3435-3436 and ΔMSMEG_6762-6760 mutants showed similar growth phenotype in 7H9 liquid medium. Wild-type strain and ΔMSMEG_3435-3436 mutant treated with isoniazid and rifampicin had similar survival rate ((4.38±1.48) % and (3.49±0.66) %, (0.15±0.04) % and (0.03±0.02) %), which suggested that MSMEG_3435-3436 might not play an important role in drug tolerance of M.smegmatis (t=0.548, P=0.613; t=2.663, P=0.056). Promoter activity analysis showed that the β-galactosidase activities ((376.50±17.13) and (315.50±20.71) Miller units (MU), (189.00±12.24) and (160.70±9.89) MU, (225.20±9.95) and (211.70±2.57) MU, (221.40±12.07) and (186.60±13.17) MU, (179.10±5.87) and (127.70±19.21) MU) in the reporter strains harboring empty vector and antitoxin expressing plasmids were not significantly different (t=2.272, P=0.086; t=1.795, P=0.147; t=1.319, P=0.258; t=1.949, P=0.123; t=2.562, P=0.063). Conclusion The MSMEG_3435-3436 and MSMEG_6762-6760 induced expression systems and knockout strains are constructed in M.smegmatis. Further study shows that MSMEG_3435-3436 is a functional toxin-antitoxin system, but does not affect cell growth and might not affect the tolerance to isoniazid and rifampicin in M.smegmatis. Finally, the antitoxins of the known 5 TA systems are found not critical for auto-regulation of their promoter’s activity in M.smegmatis. These findings provide clues for further investigation of the roles of TA systems in M.tuberculosis.

Comparative study on detection rate and detection cost of Mycobacterium tuberculosis complex by three laboratory diagnostic techniques

LIU Bin-bin,GONG Dao-fang,CHEN Zhen-hua,GUO Jing-wei,YU Yan-yan,LIU Feng-ping,OU-Yang hui,TAN Yun-hong

Chinese Journal of Antituberculosis. 2020, 42(2):  143-148.  doi:10.3969/j.issn.1000-6621.2020.02.011

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Objective To evaluate the detection efficiency of Mycobacterium tuberculosis complex by liquid-based interlayer (using the method of collecting bacteria, referred to as “smear method”), L-J solid culture method (referred to as “L-J culture method”) and nucleic acid detection of Mycobacterium tuberculosis complex group (using constant temperature amplification method; referred to as “thermostatic amplification method”). +++ Methods--- Three hospitals were randomly selected as research sites from the 120 tuberculosis designated hospitals using random number table, including Liuyang People’s Hospital, Liling Xiangdong Hospital, and Taojiang County People’s Hospital. A total of 628 patients with suspected tuberculosis symptoms diagnosed in 3 hospitals from November 1 to December 31, 2018 were included as the research subjects. The same sputum specimens were tested by smear method, L-J culture method, and thermostatic amplification method, and then the difference of positive detection rate of Mycobacterium tuberculosis complex by 3 testing methods was analyzed. In addition, according to the diagnostic criteria of 《WS 288-2017 Pulmonary Tuberculosis Diagnosis》, the clinical diagnosis of tuberculosis was used as the reference standard, and the sensitivity, specificity, positive predictive value, negative predictive value and consistency of the 3 testing methods were calculated. Based on the actual expenditure of each test performed by the patient, the testing cost of each method was calculated. Comparison of detection rate of Mycobacterium tuberculosis complex among three methods was used by Chi square test, test level α=0.05/3=0.017. Results Among 628 patients with suspected pulmonary tuberculosis, there were 153 (24.4%) patients clinically diagnosed with pulmonary tuberculosis and 6 (1.0%) patients with non-tuberculous mycobacterium pulmonary disease. The results of 3 testing methods showed that the positive detection rates of Mycobacterium tuberculosis complex by smear method, L-J culture method, and thermostatic amplification method (excluding 6 patients with non-tuberculous mycobacterium pulmonary disease) were 13.5% (84/622), 14.0% (87/622), and 12.2% (76/622), respectively. The difference of positive rate of Mycobacterium tuberculosis complex among the three test methods was not statistically significant (smear method vs. L-J culture method: χ ²=1.32, P=0.359; L-J culture method vs. thermostatic amplification method: χ ²=5.83, P=0.024; smear method vs. thermostatic amplification method: χ ²=4.00, P=0.077). Based on the clinical diagnosis as the reference standard, for smear method, L-J culture method, and thermostatic amplification method (excluding 6 patients with non-tuberculous mycobacterium pulmonary disease and 32 patients with contaminated culture), the sensitivity was 55.2% (80/145), 57.9% (84/145) and 50.3% (73/145), respectively; the specificity was 99.6% (443/445), 99.3% (442/445) and 99.8% (444/445), respectively; the positive predictive value was 97.6% (80/82), 96.6% (84/87) and 98.6% (73/74), respectively; the negative predictive value was 87.2% (443/508), 87.9% (442/503) and 86.0% (444/516), respectively; and the coincidence rate was 88.6% (523/590), 89.2% (526/590) and 87.6% (517/590), respectively. The cost of three methods was calculated from low to high in order: L-J culture method: 317.2 yuan (29 500/93), smear method: 813.8 yuan (70800/87), and thermostatic amplification method: 1992.2 yuan (153400/77). Conclusion There is no difference among the three detection methods in terms of positive detection rate, sensitivity and specificity. When a patient with positive etiology is found, L-J culture method has the lowest cost, while thermostatic amplification method has the highest cost.

Analysis of risk factors for false-negative results with QuantiFERON-TB Gold In-Tube in the diagnosis of active pulmonary tuberculosis

GONG Dao-fang,LIU Bin-bin,WAN Xiao-jie,YU Yan-yan,TAN Yun-hong

Chinese Journal of Antituberculosis. 2020, 42(2):  149-153.  doi:10.3969/j.issn.1000-6621.2020.02.012

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Objective To investigate the influence factors of false-negative results of QuantiFERON-TB Gold In-Tube (QFT-GIT) in active pulmonary tuberculosis patients. Methods A total of 1287 patients with active pulmonary disease admitted to Hunan Chest Hospital from July to October 2018 were collected as study subjects, they were diagnosed individually or jointly based on medical history, clinical symptoms, signs, imaging, bacteriology, pathology and diagnostic treatment; 1072 patients were finally included according to inclusion and exclusion criteria. Multivariate logistic regression analysis was used to analyze independent risk factors for the false negative results of QFT-GIT in patients with active pulmonary tuberculosis patients. Results All the 1072 patients could be divided into 188 false-negative cases (17.5%) and 884 true positive cases (82.5%). Among the true positive cases, patients aged 40- and 60-92 years old were 32.1% (284/884) and 23.0% (203/884), respectively; 18.3% (162/884) were re-treated patients; 11.0% (97/884) were pulmonary tuberculosis with extra-pulmonary tuberculosis; 72.5% (641/884) were with negative mycobacterial cultures; 9.6% (85/884) with albumin <35 g/L; lymphocyte count <0.6×10 ⁹/L in 1.8% (16/884). Among the false-negative cases, 36.7% (69/188) and 38.8% (73/188) were aged 40- and 60-92 years old, respectively; 31.4% (59/188) were re-treated patients; 20.7% (39/188) were with pulmonary tuberculosis and extra-pulmonary tuberculosis; 86.2% (162/188) were negative in mycobacterial cultures; 19.1% (36/188) with albumin <35 g/L; 7.4% (14/188) with lymphocyte count <0.6×10 ⁹/L. All the differences were statistically significant (χ ² values were 31.819, 16.085, 13.574, 16.651, 14.072, and 18.109, respectively; P<0.05). According to multivariate analysis, patients aged 40- years old (OR=1.972, 95%CI=1.306-2.976,P=0.001), 60-92 years old (OR=2.782, 95%CI=1.832-4.224,P<0.001), re-treated tuberculosis (OR=1.741, 95%CI=1.174-2.581,P=0.006), pulmonary tuberculosis and extra-pulmonary tuberculosis (OR=2.043, 95%CI=1.314-3.176,P=0.002), negative mycobacterial culture (OR=3.354,95%CI=2.066-5.446,P<0.001), albumin <35 g/L (OR=2.777, 95%CI=1.721-4.481,P<0.001), lymphocyte count <0.6×10 ⁹/L (OR=3.662, 95%CI=1.679-7.987,P=0.001) were independent risk factors for false-negative result of QFT-GIT. Conclusion Aged 40- years old, re-treated tuberculosis, pulmonary tuberculosis with extra-pulmonary tuberculosis, culture-negative, albumin <35 g/L, and lymphocyte count <0.6×10 ⁹/L are independent risk factors for false-negative results of QFT-GIT in patients with active pulmonary tuberculosis.

The diagnostic value of MR diffusion-weighted imaging in cervical lymph node tuberculosis

LI Bao-xue,SHA Jin-lu,TIAN Kui,LI Zheng-min,YU Hui-shan,QIN Li-xin

Chinese Journal of Antituberculosis. 2020, 42(2):  154-158.  doi:10.3969/j.issn.1000-6621.2020.02.013

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Objective To evaluate the value of MR diffusion-weighted imaging (DWI) in the diagnosis of cervical lymph node tuberculosis. Methods From May 2016 to May 2018, a total of 132 patients with cervical lymph node tuberculosis diagnosed clinically in Wuhan Pulmonary Hospital were collected as the study object, including 33 males (25.0%) and 99 females (75.0%), with the age of 15 to 73 years old and the median age (M(Q₁,Q₃)) of 27 (22, 48) years. The course of disease was 14 days to 6 years, and the median (M(Q₁,Q₃)) was 60 (30, 180) days. The clinical information of the subjects, the size, quantity, distribution characteristics of lymph nodes, as well as MR imaging signal characteristics and apparent diffusion coefficient (ADC) value of cervical lymph node tuberculosis were collected, and the imaging characteristics were analyzed. Results DWI showed that among the 132 patients with cervical lymph node tuberculosis, there were 2032 abnormal lymph nodes, including 1127 on the right and 905 on the left, and the average diameter of lymph nodes was (21.32±6.50) mm. According to the imaging subarea, a total of 503 subarea were involved, which mainly distributed in Ⅱ areas (161 cases, 32.01%) and Ⅳ areas (113 cases, 22.47%). In accordance with the imaging morphology and pathology, four stages were divided and the total frequency of stage was 292 cases, including 100 cases (34.25%) in stage Ⅰ, 71 cases (24.32%) in stage Ⅱ, 71 cases (24.32%) in stage Ⅲ (24.32%), and 50 cases (17.12%) in stage Ⅳ. In stage Ⅰ of cervical lymph node tuberculosis, the signal intensity was slightly hypo-intensity in T₁WI sequence, high signal intensity in T₂WI and DWI sequence, and slit-shaped Hypo-intensity in some lymph nodes of DWI sequence; meanwhile, the low signal intensity in T₁WI sequence, as well as high signal intensity in T₂WI and DWI sequence were found in necrotic area of lymph nodes at stage Ⅱ, Ⅲ and Ⅳ. After the recovery of some cervical lymph node tuberculosis, the fibrosis nodules and calcification showed “four low” phenomena, that was, T₁WI, T₂WI, DWI, and ADC images all showed low signal intensity. The abscess area showed slightly hypo-intensity signal in T₁WI and T₂WI sequence, and significantly hyper-intensity in DWI, while annular hypo-intensity could be seen between parenchyma and necrotic region. Based on DWI scanning, when the diffusion sensitivity coefficients (b values) were 0, 200, 500, 1000, 2000 s/mm ², the corresponding ADC values (M(Q₁,Q₃)) were 0.935 (0.787, 1.504)×10 ^-3 mm ²/s, 1.254 (0.970, 1.565)×10 ^-3 mm ²/s, 1.039 (0.769, 1.290)×10 ^-3 mm ²/s, 0.842 (0.625, 1.193)×10 ^-3 mm ²/s, and 0.687 (0.337, 0.859)×10 ^-3 mm ²/s, respectively. There was significant difference in ADC values between 5 groups (H=34.16, P<0.01). Conclusion MR routine sequence combined with DWI and ADC value exhibits great value in the diagnosis and differential diagnosis of cervical lymph node tuberculosis.

The role of surgery in the treatment of non-tuberculous mycobacterium pulmonary disease

CHEN Pin-ru,TAN Shou-yong

Chinese Journal of Antituberculosis. 2020, 42(2):  159-163.  doi:10.3969/j.issn.1000-6621.2020.02.014

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Objective To investigate the role and efficacy of surgical treatment in patients with non-tuberculous mycobacterium (NTM) pulmonary disease. Methods Totally, 24 patients with NTM lung disease admitted to Guangzhou Chest Hospital from January 2009 to December 2017 were collected as subjects, including 9 males and 15 females, with the median age of 44.50 (30.75,55.00) years. The course of NTM pulmonary disease ranged from 0 to 6 years, with a median course of 1.0 (0.5,3.8) years. The medical records of the study subjects, including basic diseases, onset characteristics, clinical symptoms, mycobacterial culture and strain identification results, chest CT scan results, surgical conditions and treatment results, were retrospectively analyzed. Results Among the 24 patients, there were 11 (45.8%) cases with Mycobacterium avian-intracellular (MAC) pulmonary disease and 13 (54.2%) cases with Mycobacterium turtle-abscess pulmonary disease. The patients received preoperative chemotherapy for 3 to 18 months, among which, 1 patient (4.2%) experienced sputum negative conversion, and 23 patients (95.8%) experienced repeated positive sputum negative conversion. There were 13 cases (54.2%) of pulmonary lesions with recurrent progression and improvement or deterioration, 17 cases (70.8%) of pulmonary lesions with enlarged or unhealed cavities and accompanied by complex lesions, and 23 cases (95.8%) with the coexistence of cystic bronchiectasis in the tongue segment of the right middle lobe and the left upper lobe. The distribution of lesions that invaded the pulmonary lobe ranged from 1 to 6, with a median of 4.0 (3.3, 5.0) lesions. None of the patients died intraoperatively or postoperatively, including 1 case of total pneumonectomy (4.2%), 12 cases of single lobectomy (50.0%) and 11 cases of combined lobectomy (45.8%). Postoperative follow-up was conducted for 1 year, and 19 patients (79.2%) were cured and treated successfully, while treatment failed in 5 patients (20.8%) with lesion involvement in 5 or 6 lobes. The incidence of surgical complications was 33.3% (8/24), including 2 cases with residual granulation tissue hyperplasia and caseous necrosis, 5 cases with pleural hemorrhage and infection, and 1 case with poor wound healing. Among the 20 patients with excised lesions, 14 were positive for Mycobacterium culture and 6 were negative, while 11 cases experienced sputum negative conversion and 6 cases were cured after operation, with no significant difference (χ ²=0.30, P=0.585). MAC pulmonary disease and Mycobacterium turtle-abscess pulmonary disease were cured by surgery in 9 and 10 patients, respectively. Conclusion Surgery combined with chemotherapy can improve the rate of sputum negative conversion and treatment success rate for NTM pulmonary disease.

Short Articles

Incidence analysis of tuberculosis in household contacts of 635 new smear-positive pulmonary tuberculosis patients in Wuhan City

YAO Fang,YUAN Bao-dong,CHEN Guo-xi,LAN Xing,WANG Xiao-feng,LI Ming.

Chinese Journal of Antituberculosis. 2020, 42(2):  164-167.  doi:10.3969/j.issn.1000-6621.2020.02.015

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Clinical data of 635 new smear-positive pulmonary tuberculosis patients hospitalized in Wuhan Pulmonary Hospital from January 2015 to December 2017 were collected. All of 1242 household contacts of those patients were screened for active pulmonary tuberculosis. The detection rate of active pulmonary tuberculosis among those household contacts was 1.69% (21/1242). The detection rates of active pulmonary TB in spouses, parents, children/other relatives among those household contacts were 1.51% (7/464), 3.66% (9/246) and 0.94% (5/532) respectively, with parents having the highest detection rate,the difference was statistically significant(χ ²=7.036,P=0.008). The detection rates of household contacts of patients with different M. fluorescens results (positive,+,++,+++ and ++++) were 0.60% (2/334), 0.50% (2/401), 1.11% (3/271), 4.32% (6/139), and 8.25% (8/97) respectively,the difference was statistically significant(χ ²=37.232,P=0.000); The detection rate of active pulmonary tuberculosis in household contacts of new smear-positive patients with bronchial tuberculosis was 3.01% (10/332). Household contacts are more likely to be infected if the index case has high sputum bacilli counts or bronchial tuberculosis, or if contacts are parents of index case.

Review Articles

Research progress of immune regulatory mechanism of traditional Chinese medicine on tuberculosis

XIA Lu,LU Shui-hua,LIU Ping

Chinese Journal of Antituberculosis. 2020, 42(2):  168-172.  doi:10.3969/j.issn.1000-6621.2020.02.016

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The pathogenesis and prognosis of tuberculosis are closely related to the host’s immune status and the growth or inhibition of Mycobacterium tuberculosis. The research has shown that many traditional Chinese medicine ingredients or extracts, such as baicalin, saxifragifolin D, rhubarb extract, isoliquiritigenin, and astragalus polysaccharide, can play an adjuvant anti-tuberculosis role by inducing macrophage autophagy, strengthening the immune function of tuberculosis patients, inhibiting or destroying the production of Mycobacterium tuberculosis and other different ways. In this paper, the immune regulation mechanism of different small molecular chemicals of traditional Chinese medicine on tuberculosis was reviewed, which provided theoretical basis for the treatment of tuberculosis with traditional Chinese medicine.

Research progress on the mechanism of drug resistance of Mycobacterium tuberculosis to ethionamide/pthionamide and ethionamide boosters

SONG Yan-hua,GAO Meng-qiu,LI Qi

Chinese Journal of Antituberculosis. 2020, 42(2):  173-177.  doi:10.3969/j.issn.1000-6621.2020.02.017

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Ethionamide (ETH)/prothionamide (PTH) are analogues of isoniazid (INH). They are usually used as second-line anti-tuberculosis drugs on treatment of multidrug resistant tuberculosis(MDR-TB). The clinical usage of ETH/PTH is affected by their cross resistance with INH, weak bactericidal effect and adverse reactions of digestive system they may induce. In recent years, researches of ETH boosters based on molecular mechanism of ETH/PTH have also made significant progress. In this review, the mechanism of ETH/PTH resistance, the mechanism of INH cross resistance and studies of ETH boosters were summarized.

Tuberculosis in children:Current status and advances in laboratory diagnosis

LYU Chun-yang,LUO Jing-jing,SHI Hua,LI Ming-yuan,JIANG Yong-mei

Chinese Journal of Antituberculosis. 2020, 42(2):  178-184.  doi:10.3969/j.issn.1000-6621.2020.02.018

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Childhood tuberculosis is an important part of the global tuberculosis prevention and control work. The diagnosis of childhood tuberculosis mainly depends on the results of laboratory tests. However, due to the characteristics of disease and specimens, accurate and rapid diagnosis of tuberculosis in children is still challenging. Pathogenic diagnosis has poor sensitivity regarded as a gold standard for diagnosis, the new molecular biology tests represented by high sensitivity Mycobacterium tuberculosis and rifampin resistant gene detection (Xpert MTB/RIF Ultra) has its prospect due to higher sensitivity and shorter detection time. The tuberculin skin test (TST) is recommended by WHO for low-and middle-income countries. Direct antigen detecting technology has high sensitivity in paucibacillary and extrapulmonary specimens, possessing unique value in the detection of children tuberculosis. Other new immunological methods are important to the diagnosis of childhood tuberculosis when distinguishing latent from active infections. In addition, new methods for detecting the gene expression, protein production, and biomarkers changes after being infected with Mycobacterium tuberculosis have been developed. Retaining multiple specimens or joint testing of different specimen types and methods can help improve the detection rate of tuberculosis in children. Increasing the detection rate of tuberculosis in existing methods and non-invasive and accessible specimens, as well as assessing the applicability of new biomarkers and new technologies are the future direction of laboratory diagnosis in childhood tuberculosis.