Table of Content

10 November 2020, Volume 42 Issue 11

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Original Articles

Evaluation of the diagnosis value of nomogram based on the clinical and internal thoracoscopic features in pleural effusion patients complicated with tuberculous pleurisy

LIU Fang-chao, YANG Xin-ting, JIANG Hui, DUAN Hong-fei, LIANG Qing-tao, LI Hua, YANG Yang, GUO Chao, ZHANG Yun, SHAO Ling-ling, CHEN Xiao-you

Chinese Journal of Antituberculosis. 2020, 42(11):  1142-1152.  doi:10.3969/j.issn.1000-6621.2020.11.002

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Objective Constructing nomogram based on clinical and internal thoracoscopic features of pleural effusion patients, to explore its value of diagnosis of tuberculous pleurisy. Methods A total of 206 patients treated in 4 hospitals in Beijing from 2015 to 2018 were collected in this prospective study, and of them, 129 patients were tuberculous pleurisy patients (tuberculous pleurisy group), 77 patients were pleural effusion patients (pleural effusion group), including the patients of tuberculous pleurisy and patients with pleural effusion. All the patients were from Beijing Chest Hospital affiliated to Capital Medical University (n=99), Beijing Chaoyang Hospital affiliated to Capital Medical University (n=67), Beijing Jishuitan Hospital (n=16) and Beijing Hospital (n=24). The general information, results of pleural effusion, internal thoracoscopic and pathologic characteristics were collected. The 206 patients were randomly divided into the training set (n=162) and the validation set (n=44). The predictive factors of tuberculous pleurisy were screened by least absolute shrinkage and selection operator (LASSO), regression, and the predictive nomogram was constructed to verify its discrimination, calibration and benefits, comprehensively evaluating the diagnostic and predictive ability of the nomogram. Results Among the 162 pleural effusion patients, 104 (64.2%) were diagnosed with tuberculous pleurisy. By LASSO regression, 7 predictors of high diagnosis value were selected, which were caseous granulomas, necrotic manifestations, atypical granulomas, miliary nodules, pleural adhesions, isolated nodules with thoracoscopy and adenosine dehydrogenase level (an indicator in pleural effusion examination). The AUC, sensitivity and specificity in the training set were 0.97, 92.31% and 93.42%, respectively, while in the model of the verification set, those were 0.89, 80.44% and 100.00%, respectively. Conclusion The nomogram could effectively predict the diagnosis of tuberculous pleurisy in patients with pleural effusion, it had applied diagnosis value to some extent.

Analysis of MRI characteristics of pleural tuberculoma

YIN Qu-hua, JIANG Zhi-shan, NIE Gan-juan, YAO Qi-neng

Chinese Journal of Antituberculosis. 2020, 42(11):  1153-1157.  doi:10.3969/j.issn.1000-6621.2020.11.003

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Objective To explore the characteristics of MRI imaging of pleural tuberculoma, so as to improve the imaging diagnosis of this disease. Methods Clinical and imaging data of 87 patients diagnosed of pleural tuberculoma by pathology and/or bacteriology or clinically confirmed (based on clinical manifestations, immunological tests, response to diagnostic anti-TB treatment) in Hunan Chest Hospital from January 2018 to December 2019 were retrospectively analyzed. Among them, 60 patients (41 males, 19 females, 13-78 years old, median age 27 years) with complete information were selected, which included 8 cases confirmed by surgical pathology and 43 cases by percutaneous pleural puncture, 9 cases according to clinical diagnosis standard. They were all tested with tuberculosis related laboratory examinations, as well as CT scan, MRI scan and enhanced MRI examination. Results Among 60 patients, there were 47 (78.3%) with single lesions and 13 (21.7%) with multiple lesions; 37 lesions (37/74, 50.0%) occupied the lower right lobes. Rounded shadows were the most common signs, which were present in 34 lesions (45.9%).Most of lesions (68.9%) were close to the pleura with a wide base and smooth edges. Thirteen cases (21.7%) were immature tuberculomas, showed iso-intensity or slight hypo-intensity signal on T₁WI, DWI; slight hyper-intensity signal on T₂WI,ADC; nodular enhancement after contrast injection. Twenty-nine cases (48.3%) were mature tuberculomas with caseous necrosis, showed iso-intensity or slight hypo-intensity signal on T₁WI, DWI and variegated hyper-intensity signal on T₂WI,ADC,and nodular or annular enhancement. Eighteen cases (30.0%) were mature tuberculomas with liquefactive necrosis, showed hypo-intensity signal on T₁WI and high hyper-intensity signal on T₂WI,DWI,ADC,and annular enhancement after contrast injection. Multiple tuberculomas fused to form an abscess that ruptured into the extra-pleural fat gap and/or the chest wall in 2 cases (3.3%), showed high hyper-intensity signal on DWI and hypo-intensity signal ADC, and variegated-annular enhancement after contrast injection. Conclusion Pleural tuberculosis has certain characteristics of MRI which have advantages in determining the scope of pleural tuberculosis and its pathological stage.

The diagnostic value of pleural biopsy by medical thoracoscopy in tuberculous pleural effusions

ZHANG Yun, JIANG Guang-lu, WANG Chong, DUAN Hong-fei, LIANG Qing-tao, LI Hua, YANG Yang, GUO Chao, SHAO Ling-ling, CHEN Xiao-you, YANG Xin-ting*

Chinese Journal of Antituberculosis. 2020, 42(11):  1158-1164.  doi:10.3969/j.issn.1000-6621.2020.11.004

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Objective To evaluate the diagnostic value of pleural biopsy in tuberculous pleural effusions by medical thoracoscopy. Methods A total of 229 patients with undiagnosed pleural effusions in the four Beijing clinical centers including Beijing Chest Hospital, Beijing Chaoyang Hospital, Beijing Jishuitan Hospital and Beijing Hospital from Jun 2015 to Oct 2018 were enrolled as the subjects in this large sample and multi-central prospective clinical trial. All patients were given medical thoracoscopy and the pleural biopsy specimen were collected. A routine pathological examination of the pleural biopsy specimen was firstly conducted for each patient. Then, both GeneXpert MTB/RIF assay and BACTEC MGIT 960 liquid culture detentions were performed using the suspension of the other part of pleural specimen after grinding. Results Of the 229 patients, 129 patients (56.3%) were confirmed with tuberculous pleurisy, 77 patients (33.6%) were non-tuberculosis pleural effusion and 23 (10.0%) patients were still undiagnosed by the medical thoracoscopy. In comparison with the routine pathological examination (23.1%,53/229), there was no significant difference in the positive rate of Mycobacterim tuberculosis infection detected by GeneXpert MTB/RIF (27.9% (64/229)) or BACTEC MGIT 960 liquid culture (17.0% (39/229)) (χ ²=1.32,P=0.251;χ²=2.67,P=0.103). However, combined with the two detection methods, the positive rate of Mycobacterim tuberculosis infection (32.8% (75/229)) was significantly superior to the routine pathological examination (χ²=5.25,P=0.022). The appearances of fibrous adhesions (70.5%, 91/129), diffuse miliary nodules (41.1%, 53/129) and fibrinous exudate (40.3%, 52/129) under the medical thoracoscopy were showed significantly higher in tuberculous pleurisy than that (32.5% (25/77), 6.5% (5/77), 15.6% (12/77)) in non-tuberculosis pleural effusion. Moreover, the appearance of scattered multiple nodular lesions (26.4%, 34/129) were markedly lower than that in non-tuberculosis pleural effusion (53.2%(41/77)) (χ²=28.41,28.52,24.42,15.06;Ps=0.000). Of the 229 patients, no serious adverse events were found. The major complications after medical thoracoscopy were mild chest pain (97.8%,224/229), a small amount of bleeding (58.5%,134/229) and local subcutaneous emphysema (46.7%,107/229). Chest pain could be relieved 2-3 days after taking painkillers. Bleeding and local emphysema did not need special treatment and could be alleviated 2-3 days after drainage tube indwelling. Among them, only 2 patients had empyema and given the drainage tube indwelling for more than 14 days. Finally, the 2 patients were transferred to surgery for thoracoscopic pleural dissection and drainage tube have been safely extubated after follow-up 6 months. Conclusion Medical thoracoscopy and the pathological and Mycobacterium tuberculosis examination of pleural specimen taken under the medical thoracoscopy have important clinical values in the diagnosis of tuberculous pleurisy. Because of its clinical value and high safety, medical thoracoscopy is worthy of clinical application in the diagnosis of tuberculous pleurisy.

Analysis of risk factors of patients with initial treatment of secondary pulmonary tuberculosis complicated with cervical lymph node tuberculosis

REN Hang-kong, DUAN Li-ming, HUANG Da-ye, ZHANG Jian-hua, YAN Wen, ZHANG Cui-yun

Chinese Journal of Antituberculosis. 2020, 42(11):  1165-1170.  doi:10.3969/j.issn.1000-6621.2020.11.005

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Objective To investigate the risk factors of patients with initial treatment of secondary pulmonary tuberculosis complicated with cervical lymph node tuberculosis. Methods Three hundred and fifty-seven patients with initial treatment of secondary pulmonary tuberculosis admitted to Xi’an Chest Hospital from December 2018 to July 2020 were enrolled for analysis, including 57 patients complicated with cervical lymph node tuberculosis (concurrent group) and 300 patients without cervical lymph node tuberculosis (non-concurrent group). In the concurrent group, the median age (quartile: Q₁,Q₃) was 30 (26, 38) years old, with 40 patients aged 14-<44 years old and 17 patients ≥44 years old. In the non-concurrent group, the median age (quartile: Q₁,Q₃) was 39 (32, 48) years, with 198 patients aged 14-<44 years and 102 patients ≥44 years old. Seven related factors including patients’ age, gender, oral mucositis, upper respiratory tract infection, use of immunosuppressants, time of TB progression and sputum bacteria examination with cervical lymph node tuberculosis were respectively analyzed, using univariate analysis and multivariate logistic regression analysis, with P<0.05 as statistically significant differences. Results Univariate analysis of cervical lymph node tuberculosis in 357 newly treated secondary pulmonary tuberculosis patients showed that the proportions of patients aged ≥44 years old were 34.0% (102/300) and 29.8% (17/57) (χ²=0.376, P=0.540); males accounted for 45.7% (137/300) and 40.4% (23/57) (χ ²=0.547, P=0.459); the incidences of oral mucositis were 11.7% (35/300) and 45.6% (26/57) (χ ²=38.963, P=0.000); the incidences of upper respiratory infection were 16.3% (49/300) and 36.8% (21/57) (χ ²=12.781, P=0.000); the proportions of immunosuppressant users were 8.0% (24/300) and 10.5% (6/57) (χ ²=0.397, P=0.529); the proportions of patients with TB over 3 months were 41.0% (123/300) and 38.6% (22/57) (χ ²=0.115, P=0.735); the proportions of positive sputum bacteria were 19.3% (58/300) and 68.4% (39/57) (χ ²=58.326, P=0.000), respectively in the non-concurrent group and the concurrent group. Multivariate logistic regression results showed that oral mucositis (Wald χ ²=12.279, OR=3.564, 95%CI= 1.751-7.255, P=0.004), upper respiratory tract infection (Wald χ ²=9.987, OR=3.092, 95%CI=1.535-6.227, P=0.002) and sputum positive (Wald χ ²=26.320, OR=5.880, 95%CI=2.989-11.568, P=0.000) were risk factors for the occurrence of cervical lymph node tuberculosis in the course of tuberculosis treatment. Conclusion Among the initially treated patients with secondary pulmonary tuberculosis, patients with oral mucositis, upper respiratory tract infection and positive sputum bacteria are prone to complicated with cervical lymph node tuberculosis, which can be used as factors of concern for clinical prevention.

Correlation between traditional Chinese medicine syndromes of pulmonary tuberculosis and CT cavity characteristics

YANG Hong-mei1, CHEN Liang, PEI Ning, ZHONG Xiu-jun, ZOU Cheng-yun, JIANG Yan, WANG Hai-ying

Chinese Journal of Antituberculosis. 2020, 42(11):  1171-1176.  doi:10.3969/j.issn.1000-6621.2020.11.006

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Objective To explore the correlation between different TCM syndromes of pulmonary tuberculosis and chest CT cavity characteristics, to provide objective evidence for pulmonary tuberculosis TCM syndrome differentiation. Methods A total of 173 new tuberculosis patients diagnosed in the department of tuberculosis, Shanghai Public Health Clinical Center from January 2019 to August 2019 were included. TCM medical history, clinical manifestations, tongue pulse and other information of the patients were collected for TCM syndrome identifying. Senventy-one patients were proved to be having tuberculous cavities by chest CT. Correlation between TCM syndrome types and the characteristics of tuberculosis cavities was analyzed. Chi-square test or Fisher’s exact test were used for univariate analysis. Multi-nomial logistic regression analysis was used for multivariate analysis, P<0.05 was considered statistically significant. Results Among the 173 patients, 89 cases (51.45%) were diagnosed by TCM as having pulmonary Yin deficiency (PYD) syndrome, 38 cases (21.96%) having hyperactivity of fire due to Yin deficiency (HFYD) syndrome, 37 cases (21.39%) having deficiency of Qi and Yin (DQY) syndrome, and 9 cases (5.20%) having deficiency of Yin and Yang (DYY) syndrome. Senventy-one patients with tuberculous cavities included 31 cases (43.66%) with PYD, 22 cases (30.99%) with HFYD, 15 cases (21.13%) with DQY, and 3 cases (4.22%) with DYY; Univariate analysis showed that patients with DQY had the highest incidence of exudation around the cavity, significantly higher than that of patients with PYD (χ²=4.870 P=0.027); For patients with syndrome of PYD,HFYD and DQY: median numbers of cavities were 2.00 (1.00,5.00),4.50 (1.00,8.25), 3.50 (1.75,8.50),(Z=2.952,P=0.229);Median volume of cavities were 1884.00 (435.50,5569.50), 7969.50 (2958.25,29710.00) and 3250.00 (1162.00,8492.00)mm ³,(Z=10.534,P=0.005); Median areas of cavities were 420.50 (191.75,753.00),888.00 (487.00,2283.00),572.00 (190.50,1264.50)mm², (Z=6.822, P=0.033); Median thickness of cavity walls were 3.00 (1.25, 4.00), 4.00 (3.13, 5.88) and 3.50 (2.50, 5.00)mm respectively, (Z=10.436, P=0.005).The volume, area and wall thickness of cavities in patients with HFYD were significantly higher than those with FYD (Z values were -17.017,-13.792 and -16.695, respectively; P values are 0.004, 0.027 and 0.004, respectively). Comparing shapes of cavities in different patients, the incidence of thin-walled cavities in PYD patients (74.19%, 23/31) was significantly higher than that in HFYD patients (31.82%, 7/22) for which difference was statistically significant (χ²=9.407, P=0.004).Multivariate analysis showed that exudation around cavity was an independent factor affecting the TCM classification of pulmonary tuberculosis syndromes (OR=0.238, 95%CI:0.076-0.741; P=0.013). Conclusion There are differences in characteristics of CT cavities between different TCM syndromes of pulmonary tuberculosis. In the stage of PYD of pulmonary tuberculosis, cavities were mainly thin-walled cavities, when they progressed to HFYD, cavity areas appeared to expand, and cavity walls gradually thickened. Exudation is more likely to occur around the cavity in DQY patients.

Analysis of the drug sensitivity test results of the mycobacterium isolates from cerebrospinal fluid of 93 patients with tuberculous meningitis

FENG Ying, MA Jin-bao, YANG Han, YANG Yunan-li, REN Fei

Chinese Journal of Antituberculosis. 2020, 42(11):  1177-1182.  doi:10.3969/j.issn.1000-6621.2020.11.007

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Objective To analyze the drug resistance of mycobacteria isolated from the cerebrospinal fluid (CSF) in patients with tuberculous meningitis (TBM), to provide reference for the clinical management of TBM. Methods A total of 93 samples from 93 patients with positive CSF culture and bacterial strains identified as Mycobacterium tuberculosis were collected from December 2013 to December 2019 in Xi’an Chest Hospital, and a drug sensitivity test was conducted. Drug-resistance rates to isoniazid (INH), rifampicin (RFP), ethambutol (EMB), streptomycin (Sm), amikacin (Am), capreomycin (Cm), levofloxacin (Lfx), moxifloxacin (Mfx), prothionamide (Pto), and para-aminosalicylic acid (PAS) were collected and analyzed. The data was tested using chi-square test and Fisher’s exact test, and P<0.05 was considered statistically significant. Results (1) Of the 93 isolates, 56 (60.2%) were sensitive to all the anti-TB drugs, 37 (39.8%) were resistant to at least one anti-TB drug, and 19 (20.4%) were resistant to both INH and RFP (i.e. multidrug resistant, MDR).(2) The drug-resistance rates from high to low were INH(31.2%, 29/93)>Sm(25.8%, 24/93)>RFP(21.5%, 20/93)>Lfx(7.5%, 7/93)>EMB(5.4%, 5/93)=PAS(5.4%, 5/93)>Mfx(3.2%, 3/93)=Am(3.2%, 3/93)=Cm(3.2%, 3/93)>Pto(0.0%, 0/93). (3) Comparing the drug resistance rates of the newly-treated and retreated patients with tuberculosis showed that the drug-resistance rates to INH in the newly-treated group and retreated group(29.3% (22/75) and 38.9% (7/18) respectively)were not statistically different (χ ²=0.618, P=0.432); the drug-resistance rates to EMB in the newly-treated group and retreated group (4.0% (3/75) and 11.1% (2/18), respectively) were not statistically different (Fischer’s exact test, P=0.247); the drug resistance rates to Am in the newly-treated group and retreated group (2.7% (2/75) and 5.6% (1/18) respectively) were not statistically different (Fischer’s exact test, P=0.480); the drug resistance rates to Cm in the newly-treated group and retreated group (4.0% (3/75) and 0.0% (0/18) respectively) were not statistically different (Fischer’s exact test, P=1.000); the drug-resistance rates to Am in the newly-treated group and retreated group(respectively were 1.3% (1/75) and 11.1% (2/18)) were not statistically different (Fischer’s exact test, P=0.095); the drug resistance rate to RFP in the newly-treated group (17.3% (13/75)) was statistically lower than the retreated group (38.9% (7/18)) (χ ²=3.996, P=0.046); the drug resistance rate to Sm in the newly-treated group (20.0% (15/75)) was statistically significant lower than the retreated group (50.0% (9/18)) (χ ²=6.823, P=0.009); the drug resistance rate of Lfx in the newly-treated group (2.7% (2/75)) was statistically significant lower than the retreated group (27.8% (5/18))(Fischer’s exact test, P=0.003). Conclusion The clinical isolates of Mycobacterium tuberculosis from CSF of the TBM patients are more resistant to the first-line anti-tuberculosis drugs: INH, Sm and RFP. Among the second-line anti-tuberculosis drugs, the resistance to Lfx is the most serious, and the sensitivity to Am, Cm and Pto is better. In the treatment of TBM, the difference in drug resistance between the newly-treated and retreated patients should be considered, and a reasonable chemotherapy regimen should be formulated to improve the patient’s prognosis.

Clinical analysis of drug sensitivity tests of various drug-resistant MTB isolates against different combinations of anti-tuberculosis drugs in vitro

YING Ruo-yan, HUANG Xiao-chen, WANG Jie, LIU Yi-dian, SHA Wei, YANG Hua

Chinese Journal of Antituberculosis. 2020, 42(11):  1183-1182.  doi:10.3969/j.issn.1000-6621.2020.11.008

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Objective The results of in vitro drug sensitivity test (drug sensitivity test) of drug-resistant MTB isolates against different combinations of anti-tuberculosis drugs (different combinations of drugs) were analyzed to evaluate the minimum inhibitory concentration (MIC) of different combinations of drugs and the anti-MTB synergistic effect on drug-resistant strains. Methods One hundred and forty-eight first retreatment tuberculosis patients participating in the “twelfth five-year” national science and technology key projects undertaken by the Shanghai Pulmonary Hospital affiliated to Tongji University were collected, and 167 MTB isolates were obtained via culturing of sputum samples from patients by BACTEC MGIT 960 and modified Roche separation method. Ninety-two resistant strains (including 36 of MDR-MTB, 54 of XDR-MTB, and 2 of single H resistant strains) from 75 patients identified by the above two methods of drug susceptibility test were used to perform the in vitro susceptibility tests of 4 types of drug combinations, including H-R, Mfx-Pa, Mfx-Pa-Rfb and Mfx-Pa-Rft, respectively, through three-dimensional chessboard MIC detection, and the synergistic rates of different drug combinations were calculated. Results The median (quartile) (M(Q₁,Q₃)) of the MIC values of H, R, Rfb, Rft, and Pa before drug combination were 4 (1,8), 24 (2,64), 0.5 (0.125,1),4 (4,4), and 8 (4,8) mg/L, respectively, which were significantly higher than that of H (2 (1,4) mg/L), R (1 (0.25,16) mg/L), and Rfb (0.125 (0.03125,0.125) mg/L) after Mfx-Pa combination, Rft (1 (1,1) mg/L) after Mfx-Pa combination, Pa (0.0075 (0.0075, 0.875) mg/L, 0.0075 (0.0075, 0.125) mg/L, and 0.0225 (0.0075,0.5) mg/L) combined with Mfx/Mfx-Rfb/Mfx-Rft, respectively (Z=-4.855, -6.908, -8.386, -8.632, -8.094, -8.335, -7.771, all P values <0.001).The synergic rates of H-R, Mfx-Pa, Mfx-Pa-Rfb and Mfx-Pa-Rft were 12.0% (11/92), 5.4% (5/92), 17.4% (16/92) and 23.9% (22/92), respectively. The difference of the synergic rates between H-R and Mfx-Pa combination to Mfx-Pa-Rfb and Mfx-Pa-Rft combination, respectively, were statistically significant (χ ²=12.670, P=0.002;χ ²=19.420, P<0.001;χ ²=18.640, P<0.001;χ ²=28.500, P<0.001). Conclusion The MIC values of H, R, Rfb, Rft and Pa in the combined drugs are lower than those before combination, indicating that the sensitivities to the combined drugs of drug-resistant strains are enhanced. The synergy rates of the three drug combinations are better than that of the two drug combinations, and Mfx-Pa-Rft showed better synergy than Mfx-Pa-Rfb combination.

Evaluation of gene chips for the rapid diagnosis of drug-resistance genes in Mycobacterium tuberculosis

YANG Ying-hui, WU Ding-hui, SU Wei-ming, DONG Chun-ping, YAO Xiang-yang

Chinese Journal of Antituberculosis. 2020, 42(11):  1191-1195.  doi:10.3969/j.issn.1000-6621.2020.11.009

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Objective To evaluate the performance of gene chips in the detection of Mycobacterium tuberculosis (MTB) and determination of drug resistance. Methods Morning sputum specimens were collected from 933 suspected pulmonary tuberculosis patients at the First Affiliated Hospital of Xiamen University from June 2017 to June 2018. The sensitivity and specificity of gene chips was compared with that of GeneXpert MTB/RIF (GeneXpert) and BACTEC MGIT 960 liquid culture, and the Roche proportional drug sensitivity testing method (MGIT 960 culture+proportional method DST). Results Of 933 cases of sputum specimens, 484 sputum specimens were determined to be MTB positive using gene chips, 462 were detected as positive using GeneXpert, and 411 were detected as positive using MGIT 960. Three hundred and ninety-five samples were detected as MTB positive by all three methods, 232 cases were then selected randomly for evaluation of drug resistance, results from the Roche proportion method being used as a reference standard. For isoniazid resistance, gene chips had a sensitivity of 86.67% (26/30), and a specificity of 96.53% (195/202). Their consistency with the Roche proportion method was 95.26% (221/232), with a Kappa value of 0.798 (0.682-0.914). For rifampicin resistance, the sensitivity of gene chips was 93.75% (3032), specificity was 97.00% (194/200), consistency was 96.55% (224/232), and the Kappa value was 0.862 (0.768-0.956). For GeneXpert, the sensitivity of rifampicin resistance was 84.38% (27/32), specificity was 97.00% (194/200), consistency was 95.26% (221/232), and the Kappa value was 0.803 (0.691-0.915). The Kappa values obtained were all higher than 0.75 indicating that all three methods had good consistency. Conclusion We did not detect any significant difference between the gene chip, GeneXpert, and Roche proportional methods for the detection of rifampicin and isoniazid resistance in Mycobacterium tuberculosis.

Evaluation of the application value of the whole genome sequence analysis tools, TB Profiler v2.8.0, Mykrobe v0.7.0 and PhyResSE v1.0, in testing drug-resistant tuberculosis

LI Bing-ying, ZHENG Xu-bin, HU Yi, XU Biao

Chinese Journal of Antituberculosis. 2020, 42(11):  1196-1202.  doi:10.3969/j.issn.1000-6621.2020.11.010

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Objective To evaluate the application of three whole genome sequence (WGS) analysis tools developed for Mycobacterium tuberculosis (MTB), TB Profiler v2.8.0, Mykrobe v0.7.0 and PhyResSE v1.0, in testing drug-resistant of tuberculosis. Methods WGS data and drug susceptibility testing (DST) results of 534 MTB clinical isolates from two previous studies were collected from National Center for Biotechnology Information Sequence Read Archive (NCBI SRA) database. Of the 534 MTB clinical isolates, 457 were multi-resistant and 77 were susceptible. Using DST as reference, WGS data were analyzed by TB Profiler, Mykrobe and PhyResSE to access the performance on predicting resistance to first-line and second-line anti-tuberculosis drugs. Results Taking DST results as reference, the sensitivities of TB Profiler, Mykrobe and PhyResSE for rifampicin resistance were similar, which were 90.81% (415/457), 87.75% (401/457) and 90.81% (415/457), respectively. The sensitivities of Mykrobe and PhyResSE for isoniazid resistance were 76.42% (350/458) and 76.20% (349/458), slightly higher than that of TB Profiler (69.43%, 318/458). The sensitivities of the three tools for ethambutol and streptomycin resistance were similar, ranging from 76.00% to 81.61%. As to pyrazinamide, the sensitivity of TB Profiler (72.82%, 150/206) was higher than those of Mykrobe (61.65%, 127/206) and PhyResSE (50.97%, 105/206). For fluoroquinolones and amikacin, the sensitivities of PhyResSE were 88.27% (143/162) and 60.00% (27/45), higher than those of TB Profiler (81.48% (132/162) and 48.89% (22/45)) and Mykrobe (82.10% (133/162) and 55.56% (25/45). The specificities of the three tools for detecting drug resistance of anti-tuberculosis drugs were similar and high (higher than 90%), except for ethambutol which was 82.42%-83.88%. Conclusion All of the three bioinformatics tools have a good performance on rapid detection of drug-resistant tuberculosis with a promising prospect of future application. The relatively low sensitivity of the tools to pyrazinamide and some second-line anti-tuberculosis drugs suggests that studies on resistance mechanism of these drugs should be enhanced.

Application of next-generation sequencing technology in the diagnosis of drug-resistant tuberculosis

GU Ji-xiu, LI Qing, MA ling, LI Yin-hua, WANG Dong-dong, SI Hong-yan

Chinese Journal of Antituberculosis. 2020, 42(11):  1203-1208.  doi:10.3969/j.issn.1000-6621.2020.11.011

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Objective To explore the application value of next-generation sequencing (NGS) in the diagnosis of drug-resistant tuberculosis. Methods A total of 150 specimens of bacterial strain were selected from the Year 2016-2017 baseline survey on drug-resistant tuberculosis in Gansu Province, and tested by proportional drug sensitivity test (drug sensitivity test) and NGS of drug resistance-related genes (including katG, inhA, embB, rpoB, rpsL, rrs, gyrA, and gyrB). Two non-tuberculous mycobacteria (NTM) strains were excluded, 13 strains were failed to be sequenced, therefore, 135 strains were finally included. Results of drug sensitivity test were used as standard to evaluate the efficacy of NGS in the diagnosis of drug-resistant tuberculosis. Results Based on drug sensitivity results, sensitivities NGS in detecting isoniazid (INH), ethambutol (EMB), rifampicin (RFP), streptomycin (Sm), and ofloxacin (Ofx) were 88.75% (71/80), 85.71% (18/21), 84.72% (61/72), 73.91% (51/69) and 68.97% (20/29), respectively; and the specificities of the above drugs were 100.00% (55/55), 86.84% (99/114), 96.83% (61/63), 96.97% (64/66), and 99.06% (105/106), respectively; Kappa values were 0.87, 0.59, 0.81, 0.71, and 0.76, respectively. Gene mutations of INH-resistant were mainly in katG 315, with a mutation frequency of 97.18% (69/71); those in EMB) were in embB 306, with a mutation frequency of 88.89% (16/18); those in RFP were in the resistance-determining area, with a mutation frequency of 93.65% (59/63); those of Sm were in rpsL 43, with a mutation frequency of 79.25% (42/53); and those in Ofx were in gyrA 94, with a mutation frequency of 76.19% (16/21). Conclusion The efficacies of NGS in detecting RFP, INH and Ofx were high and could meet the needs of clinical diagnosis of tuberculosis; while the efficacies of NGS in detecting EMB and Sm were low, and further investigation of the mechanism of drug resistance of the two drugs was needed.

Analysis of drug-resistance to rifampin and isoniazid in 1307 patients with pulmonary tuberculosis in Kashi, Xinjiang

Maimaitiaili ·Aihemuti, HUANG Qiao-ling, Guerseman ·Abula, Renati ·Ailaiti

Chinese Journal of Antituberculosis. 2020, 42(11):  1209-1213.  doi:10.3969/j.issn.1000-6621.2020.11.012

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Objective To analyze the drug susceptible test results to rifampin and isoniazid among the patients with pulmonary tuberculosis (PTB) in Kashi, Xinjiang. Methods The sputum samples and patients’ information were collected from 1307 PTB patients, who were diagnosed from January 1, 2019 to June 30, 2019 in 11 cities/counties in Kashi, Xinjiang according to the Diagnosis standard of pulmonary tuberculosis (WS 288—2017). The drug susceptible test to rifampin and isoniazid were performed by using gene mutation detection kits for rifampin resistance and isoniazid resistance. The statistical analysis of drug resistance situation in patients with different age groups, different genders, different treatment histories and different regions was conducted. Chi-square test was used to compare the differences of drug resistance rate between different patient groups. A P-value <0.05 was considered as statistically significant. Results Among 1307 patients, 198 cases were resistant to rifampin and the drug resistance rate was 15.15%; 151 cases were resistant to isoniazid and the drug resistance rate was 11.55%; 63 cases were resistant to both rifampin and isoniazid and the multidrug-resistance (MDR) rate was 4.82%. There were no statistically significant differences of rifampin resistant rate, isoniazid resistant rate and MDR rate between male and female patient groups (rifampin, 15.71% (110/700) vs 14.57% (88/604), χ²=0.330, P=0.566; isoniazid, 10.71% (75/700) vs 12.42% (75/604), χ ²=0.924, P=0.337; MDR, 4.57% (32/700) vs 5.13% (31/604), χ ²=0.222, P=0.638). There were no statistically significant differences of rifampin resistant rate, isoniazid resistant rate and MDR rate between new and retreated patient groups (rifampin, 15.46% (160/1035) vs 16.32% (31/190), χ ²=0.090, P=0.765; isoniazid, 11.30% (117/1035) vs 14.74% (28/190), χ ²=1.812, P=0.178; MDR, 4.73% (49/1035) vs 6.32% (12/190), χ ²=0.849, P=0.357). The MDR rate was the highest among the patient group aging 60-70 (6.12%, 21/343). The highest rifampin resistance rate (21.32%, 29/136) and the highest isoniazid resistance rate (14.71%, 20/136) were found to be in the patient group aging 30-40. The highest rates of MDR (10.59%, 9/85), rifampin resistance (25.88%, 22/85) and isoniazid resistance (28.24%, 24/85) were found in Kashi City among the 11 cities/counties in Kashi area. Conclusion The situation of drug-resistant TB is relatively serious in Kashi. Drug-resistance screening should be strengthened to timely detect drug-resistant TB patients and effective chemotherapy regimens should be designed and provided.

Analysis of drug-resistance of 1719 mycobacterium strains in Nanjing from 2017 to 2019

SONG Ke-yu, ZHANG Qin, WANG Wen-jing, SHI Rui, WU Xu-ping

Chinese Journal of Antituberculosis. 2020, 42(11):  1214-1220.  doi:10.3969/j.issn.1000-6621.2020.11.013

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Objective To analyze the demographic characteristics, disease characteristics of patients infected with mycobacterium, and the drug resistance test results of clinical isolates in Nanjing. Methods A total of 1719 patients with positive mycobacterium treated in Nanjing Second Hospital from January 2017 to December 2019 were selected as the subjects, informations of age, gender, treatment history, whether concurrent AIDS and so on were collected. Of the 1719 strains of mycobacteria which were isolated and identified by PCR reverse dot blot hybridization, 308 (17.92%) were nontuberculous mycobacteria (NTM) and 1411 (82.08%) were Mycobacterium tuberculosis (MTB). Absolute concentration indirect method was used to test drug sensitivity of these strains with isoniazid (INH), rifampicin (RFP), streptomycin (Sm), ethambutol (EMB), kanamycin (Km), amikacin (Am), para-aminsalieylic acid (PAS), capreomycin (Cm) and levofloxacin (Lfx), etc., melting curve of fluorescence PCR was used to analyze the mutations of drug-resistant MTB strains. Results Of the 308 NTM isolates, the drug resistance rate of EMB was 40.58% (125/308), and the rates of other 8 drugs were all over 90.00%. In patients with MTB infection, the drug resistance rate and multidrug resistance rate were the highest in patients aged 35-<65-year group (36.01% (233/647) and 16.07% (104/647)); the drug-resistant rate, multidrug resistant rate and extensive drug resistant rate in retreated group were significantly higher than those in initial treatment group (34.17% (312/913) vs. 28.31% (141/498), χ ²=5.076, P=0.024; 14.13% (129/913) vs. 9.23% (46/498), χ ²=7.099, P=0.008; 2.63% (24/913) vs. 0.40% (2/498) χ ²=8.836, P=0.003). The order of drug resistance of the 1411 MTB isolates to 9 anti-tuberculosis drugs was: INH (17.65%, 249/1411) >Sm (17.15%, 242/1411) >RFP (13.39%, 189/1411) >Lfx (10.70%, 151/1411) >EMB (6.45%, 91/1411) >Am (4.39%, 62/1411) >Km (2.41%, 34/1411) >PAS (1.84%, 26/1411) >Cm (1.20%, 17/1411). The drug resistance rates of the isolates from retreated group to INH, Sm, RFP, EMB and Km were significantly higher than those from initial treatment group (19.39% (177/913) vs. 14.46% (72/498), χ ²=5.386, P=0.020; 18.51% (169/913) vs. 14.26% (71/498), χ ²=4.130, P=0.042; 14.90% (136/913) vs. 10.64% (53/498), χ ²=6.455, P=0.024; 8.00% (73/913) vs. 3.18% (29/913), χ ²=10.252, P=0.001; 3.61% (18/498) vs. 1.00% (5/498), χ ²=6.466, P=0.011). Drug resistance gene detection of drug-resistant MTB to INH, RFP, SM, EMB, fluoroquinolones and second-line anti-tuberculosis injection drugs showed that the main mutations were katG 315 (65.44%, 142/217), rpoB 529-533 (66.67%, 124/186), rpsL 43 (69.23%, 18/26), embB 306 (66.28%, 57/86), gyrA 88-94 (100.00%, 91/91) and rrs 1401 (100.00%, 26/26), respectively. The coincidence rates of genotype mutation and phenotype resistance were 87.15% (217/249), 98.41% (186/189), 86.67% (26/30), 94.51% (86/91), 100.00% (91/91) and 86.67% (26/30), respectively. Conclusion Mycobacterium infections in Nanjing were mainly occured in middle-aged and elderly population, and the drug resistance of mycobacteria was serious. The identification and baseline drug resistance test of mycobacteria should be popularized, the molecular biological examination of drug-resistant patients and the resistance of INH and quinolones should be paid more attention, the drug resistance monitoring in the treatment process should also be strengthened.

Analysis of diagnostic quality sampling survey results and influencing factors of smear negative pulmonary tuberculosis patients in hospitals at county level in Anhui province

BAO Fang-jin, MA Dong-chun, LIU Jie, LI Zi, LI Dong-fang, ZHANG Lei, LIU Hai-qing, WU Yue, YAO Song, WANG Qing, ZHU Qing-qing

Chinese Journal of Antituberculosis. 2020, 42(11):  1221-1226.  doi:10.3969/j.issn.1000-6621.2020.11.014

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Objective To understand the diagnosis status and influencing factors of smear negative pulmonary tuberculosis (PTB) in tuberculosis-designated hospitals at county level. Methods Convenient sampling method was used to select tuberculosis-designated hospitals at county level in Anhui province. A total of 6 counties (Qianshan city, Wangjiang county, Huoqiu county, Shucheng county, Taihe county and Linquan county) were selected (two counties in southern Anhui, central Anhui and northern Anhui respectively). Medical records, thoracic computed tomographic imaging and results of laboratory test of all smear negative PTB patients in the designated hospitals reported between 01 April and 31 May 2019 were retrospectively reviewed by an independent review board consisting of experts from provincial hospital. The consistency of diagnosis results was evaluated and the factors affecting the consistency of diagnosis were analyzed. Chi-square test was used to compare the categorical data, P<0.05 for the difference was statistically significant. Results A total of 280 patients were reviewed and the diagnoses of 237 cases (84.64%) were consistent with original diagnosis. Eight-one cases (28.93%) received biomolecular test. Univariate analysis showed that the diagnostic consistency rates of patients with qualified sputum specimens (92.31%, 72/78), initial treatment (87.40%, 215/246), pleural lesions (93.10%, 81/87), positive PPD (91.46%, 75/82), positive γ-interferon release test (100.00%, 46/46), and with local smear negative diagnosis team discussion (93.59%, 73/78) were significant high than those of the patients with unqualified sputum specimens (81.68%, 165/202), retreatment (64.70%, 22/34), without pleural lesions (80.83%, 156/193), negative PPD (70.83%, 17/24), negative γ-interferon release test (81.82%, 9/11) and without the smear negative diagnosis team discussion (81.19%,164/202), and χ² values were 4.887, 11.834, 6.951, 6.685, 9.987 and 6.658 respectively, and P values were all less than 0.05. Multivariate stepwise logistic regression analysis showed that the qualified sputum specimen (vs. unqualified, OR=2.944, 95%CI: 1.130-7.672, P=0.027), initial treatment (vs. retreatment, OR=2.465, 95%CI: 0.916-6.633, P=0.074), with pleural lesions (vs. without pleural lesions, OR=2.255, 95%CI: 0.924-5.499, P=0.074), PPD negative (vs. positive, OR=0.189, 95%CI: 0.052-0.692, P=0.012), with local diagnostic team discussion (without discussion, OR=2.244, 95%CI: 0.795-6.336, P=0.127) were the factors for the diagnosis consistency. Conclusion Diagnostic consistency for smear negative PTB between hospitals at county-level and provincial independent review board is not high, and the quality of sputum specimens, initial treatment, pleural lesions, PPD test result and local diagnostic team discussion are the main factors affecting the consistency of diagnosis results. The proportion of patients with molecular biological examination is low.

Correlation between health literacy of tuberculosis patients and core knowledge and social support of tuberculosis control

YU Qiao-lin, LEI Li-mei, WAN Bin, FU Li, ZHAO Xia, ZENG Qiong, WANG Yan

Chinese Journal of Antituberculosis. 2020, 42(11):  1227-1231.  doi:10.3969/j.issn.1000-6621.2020.11.015

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Objective To explore how tuberculosis (TB) patients’ health literacy plays a role in the correlation between the knowledge level on control and prevention of TB and the social support. Methods A total of 225 pulmonary tuberculosis patients hospitalized in the Public Health Clinical Center of Chengdu from May to June in 2019 were selected as study subjects with the median age (quartile, M(Q₁,Q₃)) of 45.0 (25.0, 60.0) (range, 18-84 years), 151 (67.1%) were male and 74 (32.9%) were female. Core knowledge of TB prevention and control (including main symptoms and severity, precautions, transmission routes, public policies), the health literacy (such as the ability of knowledge acquisition, communicative interaction, the willingness to improve health and provide economic support), and social support level (objective & subjective support and their availability) were investigated. Results The core knowledge score (M(Q₁,Q₃)) of the 225 subjects was 30.0 (20.0,40.0), and the awareness rate was 61.0% (686/1125). The health literacy score was 85.84±15.14, it showed that 26.2% (59/225) of TB patients had health literacy, while 73.8% (166/225) did not. The social support score (M(Q₁,Q₃)) was 36.0 (31.0, 43.0), with 52.4% (118/225) of the TB patients in the middle level and 47.6% (107/225) in the lower level. Using Spearman correlation analyses, the score of health literacy was positively correlated with the score of TB control core knowledge (r=0.947, t=38.818, P<0.01) and the social support score (r=0.485, t=23.027, P<0.01). There was a positive correlation between core knowledge of TB control and social support (r=0.469, t=19.890, P<0.01). Health literacy was the intermediary factor between core knowledge of TB control and social support (β(95%CI)=0.415 (0.282-0.550)). Conclusion Health literacy played a positive mediation role between the core knowledge of TB control and social support, indicating that when trying to improve the social support of TB patients with low level knowledge of TB prevention and control, improving the health literacy should also be enhanced.

Special Articles

Epidemiology and preventive intervention of inactive tuberculosis

DU Ying, ZHANG Bin, WANG Da-kuan, ZHANG Hao-ran, XIN He-nan, JIN Qi, GAO Lei

Chinese Journal of Antituberculosis. 2020, 42(11):  1232-1236.  doi:10.3969/j.issn.1000-6621.2020.11.016

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China is one of the countries with the highest burden of Mycobacterium tuberculosis (MTB) infection in worldwide with 350 million people were infected as estimated by Dr. Houben and colleagues using Gaussian process regression model. The guidelines on tuberculosis (TB) preventive treatment updated by the World Health Organization in 2020 recommended that “A history of prior TB or TB preventive treatment should not be a contraindication for preventive treatment in case of exposure, following the exclusion of reactivated disease. These individuals, including those with fibrotic radiological lesions, may be at increased risk of progression.” Individuals with chest radiography abnormalities suggestive of prior healed TB has been recommended as targets for latent tuberculosis infection (LTBI) testing and treatment in American and Canada. In countries and areas with high burden of TB,considering the potential high burden of inactive TB, enhancing active case finding and LTBI preventive treatment in this high-risk group might benefit TB incidence decline in a community level.

Review Articles

Research progress for delamanid resistance mechanism of Mycobacterium tuberculosis

LIU Yuan-yuan, CHU Ping, HAN Shu-jing, YANG Hui, LU Jie

Chinese Journal of Antituberculosis. 2020, 42(11):  1237-1242.  doi:10.3969/j.issn.1000-6621.2020.11.017

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At present, tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB) is still the leading cause of death for infectious diseases worldwide. The spread of drug-resistant strains has caused great difficulties in the treatment of TB. Delamanid (Dlm), a new anti-TB drug, is effective against multi-drug resistant (MDR) or extensively drug-resistant (XDR) tuberculosis. Accurate and timely detection of Dlm-resistant strains can maximize the effectiveness of clinical application for the drug and improve the cure rate of MDR-TB/XDR-TB. The acquired drug resistance in MTB is mainly caused by resistance associated gene mutations. This article reviews the resistance mechanism and resistance associated gene mutations of Dlm, to provide some reference for the early molecular diagnosis of Dlm-resistant strains.

Pathogenic mechanism of Ag85 complex and its application progress in the development of tuberculosis vaccine

LIANG Zheng-min, WANG Yuan-zhi, LIU Yi-duo, ZHOU Xiang-mei

Chinese Journal of Antituberculosis. 2020, 42(11):  1243-1249.  doi:10.3969/j.issn.1000-6621.2020.11.018

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Effective vaccines are urgently needed to control the transmission of Mycobacterium tuberculosis (MTB). A variety of MTB immunogenic molecules have been identified by now. And of them, the antigen 85 (Ag85) complex (Ag85A, Ag85B and Ag85C) is an important virulence factor, it could mediate the adhesion and invasion of MTB and the synthesis of the cell wall. Ag85 complex has been used in the construction of many new vaccines, such as recombinant attenuated vaccines, protein adjuvant vaccines and virus vector vaccines. In this paper, pathogenic mechanism of Ag85 complex and its application progress in the development of tuberculosis vaccine are reviewed, and the effects of Ag85 complex as antigens in developing different types of tuberculosis vaccines are also investigated.

Research progress of extracellular RNA of Mycobacterium tuberculosis

LI Ting, FAN Yun-fan, FU Ying-mei

Chinese Journal of Antituberculosis. 2020, 42(11):  1250-1253.  doi:10.3969/j.issn.1000-6621.2020.11.019

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Tuberculosis has become one of the ten leading causes of death in the world. For tuberculosis,we urgently need an earlier diagnosis and a more effective treatment. Extracellular RNA (exRNA) has great potential as a biomarker and treatment for many diseases. In order to follow up on the application of Mycobacterium tuberculosis exRNA in the diagnosis and treatment of tuberculosis,we summarize the current research progress of Mycobacterium tuberculosis exRNA and discusse the production mechanism of Mycobacterium tuberculosis exRNA,hopefully to provide a favorable understanding for the exploration of Mycobacterium tuberculosis exRNA.