Table of Content

10 March 2022, Volume 44 Issue 3

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Editorial

Clinical application of new anti-tuberculosis drugs:new hope and new challenge

AN Jun, PANG Yu

Chinese Journal of Antituberculosis. 2022, 44(3):  205-208.  doi:10.19982/j.issn.1000-6621.20220011

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Expert Note

To end tuberculosis epidemic needs strengthen the management of screening and preventive treatment of latent tuberculosis infection in high-risk groups

MA Yan, LU Wei, GAO Lei, CHU Nai-hui, ZHOU Lin, CHENG Shi-ming

Chinese Journal of Antituberculosis. 2022, 44(3):  209-214.  doi:10.19982/j.issn.1000-6621.20220008

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Currently, the slow decline of tuberculosis incidence rate becomes a huge challenge to the goal of ending tuberculosis. In 2020, the estimated global latent tuberculosis infection (LTBI) population was nearly 2 billion. With the condition of no preventive intervention, 5% to 10% of them will develop into active tuberculosis in the lifetime, and the incidence rate is higher in high-risk population. The World Health Organization has called for the promotion of the prevention of LTBI worldwide, so as to achieve the goal of a rapid decline in the incidence rate of tuberculosis. This paper reviews the current situation of LTBI epidemic and preventive treatment, the incidence risk of high-risk population, screening methods, intervention and management suggestions, etc., in order to provide reference for formulating LTBI intervention and management strategies and measures in China.

Build an intelligent network to promote tuberculosis prevention and treatment

XU Cai-hong, ZHAO Yan-lin

Chinese Journal of Antituberculosis. 2022, 44(3):  215-218.  doi:10.19982/j.issn.1000-6621.20210724

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A well-functioning tuberculosis control system is the premise and foundation of high-quality tuberculosis control services. Under the background of developing big data, artificial intelligence and other information technologies, it is crucial to ensure the healthy and sustainable development of tuberculosis prevention and control work by making overall planning and gradually building a service system for tuberculosis prevention and control that is scientifically managed and efficiently operated. Based on the current socio-economic development and the new situation of tuberculosis control in China, this study emphasized the necessity of building an intelligent tuberculosis control system, and described how to build an intelligent network and play the role in intelligent network effectively and comprehensively improve the efficiency and quality of tuberculosis control by taking three major actions as a practical case, to speed the achievement of the End-TB targets.

Original Articles

Changes of plasma concentration of bedaquiline during the treatment of drug-resistant pulmonary tuberculosis and its assocation with QTc interval prolongation

XIE Li, ZHU Hui, GAO Jing-tao, LIU Zhong-quan, MA Li-ping, ZHANG Li-qun, GE Qi-ping, NIE Li-hui, KONG Zhong-shun, WU Xiao-guang, LIU Rong-mei, CHEN Hong-mei, SONG Yan-hua, LI Qiang, LYU Zi-zheng, LIU Yu-hong, LU Yu, PANG Yu, GAO Meng-qiu

Chinese Journal of Antituberculosis. 2022, 44(3):  219-226.  doi:10.19982/j.issn.1000-6621.20210696

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Objective: To explore the changes of plasma concentration of bedaquiline during the treatment in patients with drug-resistant pulmonary tuberculosis and its association with QTc interval prolongation. Methods: All 119 patients with multidrug-resistant/rifampicin resistant pulmonary tuberculosis (MDR/RR-PTB) were enrolled prospectively according to the inclusion criteria in Beijing Chest Hospital from Feb. 2018 to Feb. 2020, provided with individualized bedaquiline-containing regimen by the expert group. Baseline information were collected before the first dose of bedaquiline and electrolyte (potassium, calcium and magnesium), blood routine, urine routine, hepatic and renal function, QTcF value and plasm drug concentration of bedaquiline were serially recorded at different time points post treatment initiation. Univariate and multivariate logistic regression analysis were performed to analyze the risk factors associated with QTc interval prolongation. Results: All 119 patients had completed full course of 72 week-treatment and were in period of post treatment follow-up. Out of them, 5 (4.2%) had QTcF >500ms within 24 weeks and bedaquiline was discontinued as per protocol; 114 patients completed full doses of bedaquiline, among which 53 took for 24 weeks and 61 took for 36 weeks. For the 114 patients who completed full administration of bedaquiline, their trough concentration was highest at the end of week 2 (1.753(1.365,2.412) μg/ml), significantly higher(Z=-9.222,P<0.001;Z=-7.798,P<0.001)than that at the end of week 4 (0.830(0.586,1.035) μg/ml) and week 24 (1.098(0.909,1.440) μg/ml) while it was higher at the end of week 24 than that at week 4 with significance(Z=-7.826,P<0.001). No matter patients with 24-week or 36-week bedaquiline exposure, the plasma concentration of it returned to the level at the end of week 4 (0.769(0.500,0.947) μg/ml and 0.824(0.642,1.023) μg/ml) respectively after bedaquiline was discontinued for 12 weeks. Furthermore, the plasma concentration of it was still close to the effective value (0.6 μg/ml) after bedaquiline was discontinued for 24 weeks. The trend for the QTcF value was basically consistent with that of bedaquiline plasma concentration which presented gradual increase with bedaquiline accumulated administration and hit the peak before and after its discontinuation, then decreased gradually. Eight cases (6.7%) had QTcF>500ms, 36 cases (30.3%) had QTcF>450ms and no serious ventricular arrhythmia was found in all patients during the above observation period. Multivariate analysis indicated that elder age (≥55 years), low body mass index (<18.5) and hypocalcemia (<2.3 mmol/L) were the risk factors for occurrence of QTc interval prolongation (OR (95%CI)=7.056 (1.841-27.043),3.850 (1.236-11.989), 2.786 (1.029-7.541)). Conclusion: Given the long half-life of bedaquiline, its effective plasma concentration could maintain until 24 weeks post its discontinuation. Moreover, extending bedaquiline exposure to 36 weeks presented safe and effective.During bedaquiline administration, the occurrence of QTc interval prolongation was relatively high but severity grade was mainly mild to moderate. ECG monitoring should be intensified for patients with elder age, low body mass index and hypocalcemia.

Study of expression and function of Mycobacterium tuberculosis membrane protein MmpL5-MmpS5

LI Dong-shuo, WANG Bin, LU Yu, XU Jian

Chinese Journal of Antituberculosis. 2022, 44(3):  227-233.  doi:10.19982/j.issn.1000-6621.20210587

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Objective: To express the Mycobacterium tuberculosis membrane protein MmpL5 and MmpS5-MmpL5 efflux pump system and explore its role in the drug resistance of bedaquiline. Methods: Induced expression of proteins MmpL5 and MmpS5-MmpL5 in Mycobacterium smegmatis were achieved based on the construction of acetamide-induced expression vector. The growth characteristics and efflux capacity of the expressed strains were measured, and the change of minimum inhibitory concentration (MIC) of bedaquiline on the expressed strain and its effect on the and content of adenosine triphosphate (ATP) were investigated. Results: MmpL5 and MmpS5-MmpL5 proteins of Mycobacterium tuberculosis were successfully expressed in Mycobacterium smegmatis. The growth of expressed strains was not affected by MmpL5 and MmpS5-MmpL5, but the efflux capacity of co-expressing MmpS5-MmpL5 strains increased. Compared with the MmpL5-expressing group (△Fluoresce intensity=655) and pMV261s carrying empty plasmid group (△Fluoresce intensity=642), the accumulation of ethidium bromide in co-expressing MmpS5-MmpL5 (△Fluoresce intensity=395) was reduced by 40%. The MIC of bedaquiline to MmpS5-MmpL5 recombinant strain was increased 8-fold than the control (2 μg/ml vs. 0.25 μg/ml). The content of ATP in MmpS5-MmpL5 recombinant Mycobacterium smegmatis ((0.197±0.018) μmol/L) decreased by 36.49% ((0.125±0.010) μmol/L) after bedaquiline treatment. Single expression of MmpL5 could not form efflux pump and had no effect on bedaquiline. Conclusion: Membrane protein MmpL5 and MmpS5 of Mycobacterium tuberculosis needed to be co-expressed to reduce the drug sensitivity of bedaquiline in Mycobacterium smegmatis. The establishment of the MmpS5-MmpL5 protein expression system laid the foundation for the study of the transport mechanism of bedaquiline.

In vitro synergistic activities of GSK656 with amikacin against Mycobacterium abscessus

CHEN Lei, GUO Hai-ping, PANG Yu, LIU Guang-fu, PAN Zhao-bao, HAN Shou-hua, CHENG Juan, LI Shan-shan

Chinese Journal of Antituberculosis. 2022, 44(3):  234-238.  doi:10.19982/j.issn.1000-6621.20210465

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Objective: To investigate the in vitro synergistic effect of GSK656, a novel member of 3-aminomethyl 4-halogen benzoxaboroles, with aminoglycoside-amikacin against Mycobacterium abscessus. Methods: Thirty clinical M.abscessus isolates were collected from the Biobank of Beijing Chest Hospital affiliated to Capital Medical University. Minimum inhibitory concentration (MIC) were determined using microdilution MABA assay. The checkerboard titration method was used to explore the in vitro synergistic effect between GSK656 and amikacin against M.abscessus isolates. Fractional inhibitory concentration index was calculated to determine the combined effects of these two compounds. Results: GSK656 and amikacin showed potent antibacterial activities against M.abscessus. The MIC of M.abscessus ranged from 0.063 to 4.000 mg/L for GSK656, the MIC₅₀ and MIC₉₀ of which were 0.250 and 2.000 mg/L, respectively. The MIC ranged from 4.000 to 16.000 mg/L for amikacin, the MIC₅₀ and MIC₉₀ of which were 8.000 and 16.000 mg/L, respectively. For GSK656-amikacin combination, only 1 strain (3.3%) had antagonistic effect. Synergy for GSK656-amikacin combination was observed in 5 isolates (16.7%); antagonism was observed in one isolate (3.3%); while the remaining isolates (80.0%) showed indifference. Conclusion: GSK656 and amikacin holds potent antibacterial activity against M.abscessus, which provids important clinical benefit for treatment of. M.abscessus infections.

Analysis of adverse reactions of bedaquiline containing regimen in the treatment of drug-resistant pulmonary tuberculosis

ZHANG Yu-xia, XIONG Yu, CHANG Ting-ting, LIU Feng-xia

Chinese Journal of Antituberculosis. 2022, 44(3):  239-245.  doi:10.19982/j.issn.1000-6621.20210702

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Objective: To analyze the adverse reactions of bedaquiline combined with conventional anti-tuberculosis drugs in the treatment of drug-resistant pulmonary tuberculosis, so as to provide basis for the safe use and monitoring of bedaquiline. Methods: A retrospective study was conducted in 127 patients with multidrug-resistant tuberculosis, pre-extensive drug-resistant pulmonary tuberculosis, extensively drug-resistant pulmonary tuberculosis and rifampicin-resistant pulmonary tuberculosis from the Drug-Resistant Tuberculosis Ward of Shandong Public Health Clinical Center. All of them completed 24-week treatment and follow-up from November 2018 to December 2020. And 66 patients treated with bedaquiline containing regimen were considered as the observation group, the other 61 patients treated without bedaquiline containing regimen were considered as the control group. Clinical data including age, gender, drug resistance type, whether or not complicated with diabetes mellitus, whether or not take other drugs that led to prolonged QTc interval, etc., were collected. The occurrence of adverse drug reactions in the treatment of the two groups was monitored, and the influencing factors of QTc interval prolongation (>450 ms) in the observation group were analyzed. Results: The incidence of QTc interval prolongation in the observation group was 48.5% (32/66), which was significantly higher than that in the control group (26.2% (16/61)) (χ²=6.678, P=0.001). There were 3 cases (4.5%) and 1 case (1.6%) with QTc interval >500 ms in the observation group and the control group, respectively. The difference was not statistically significant (Fisher exact probability method, P=0.143). There was no difference in the occurrence of other adverse drug reactions between the two groups. The QTc interval in the observation group gradually increased with the use time of the treatment regimen containing bedaquiline. At the end of the 4th week, the QTc interval was (435.1±28.8) ms, which was significantly higher than that in the baseline period ((419.0±23.2) ms) (t=3.477, P=0.001), and the peak appeared at the end of the 12th week ((439.5±30.7) ms). Multivariate analysis showed that, if treated with bedaquiline containing regimen, the risk of QTc interval prolongation in patients aged ≥45 years was 9.027 times (95%CI: 1.033-78.859) of that in patients aged 18-45 years; combined use of other drugs that can lead to QTc interval prolongation was also an independent risk factor for QTc interval prolongation (OR (95%CI)=9.033 (1.042-78.326)). Conclusion: The incidence of QTc interval prolongation increased in patients with drug-resistant pulmonary tuberculosis after treatment with bedaquiline containing regimen, but there was no serious adverse cardiac events. The incidence of adverse events in other systems did not increase. Elderly patients were at high risk of QTc interval prolongation.

Effect of Roast Radix Glycyrrhizae Decoction Granules on the prolongation of QT interval caused by bedaquiline in the treatment of multidrug-resistant pulmonary tuberculosis

QI Qi, CAI Qing-shan, CUI Yan-fei, CHEN Yuan-yuan, BAO Zhi-jian, QIU Mei-hua, GUO Yi-nan, MA Xiao-qing

Chinese Journal of Antituberculosis. 2022, 44(3):  246-251.  doi:10.19982/j.issn.1000-6621.20210687

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Objective: To explore the effect of Roast Radix Glycyrrhizae Decoction Granules (RRGDG) on the prolongation of QT interval caused by the regimen containing bedaquiline in the treatment of multidrug-resistant pulmonary tuberculosis. Methods: From September 2018 to October 2020,45 patients with pulmonary tuberculosis who were treated with bedaquiline-containing regimen and met the inclusion criteria in Hangzhou Chest Hospital Affiliated to School of Medicine of Zhejiang University were selected as the research objects. They were randomly allocated into Traditional Chinese Medicine (TCM) group (23 cases) and control group (22 cases) using random number table. Patients in the TCM group were treated with RRGDG during the first month of the bedaquiline-containing anti-tuberculosis therapy, while the control group did not take RRGDG. ECGs were performed and recorded before the treatment and at 2,4,8,12,16,20 and 24 weeks after the treatment started, and QTcF values were calculated (the corrected QT intervals were calculated according to Fridericia formula). Results: During 24 weeks of bedaquiline administration, the adverse events were as follows: QTcF>450 ms in 8 patients (8/23,34.8%) and QTcF prolongation >30 ms comparing with baseline (ΔQTcF) in 16 patients (16/23,69.6%) in TCM group; QTcF value >450 ms in 16 patients (16/22,72.7%) and ΔQTcF value ≥30 ms in 20 patients (20/22,90.9%) in the control group. The serious adverse events were as follows: QTcF value ≥500 ms in 1 case (1/23,4.3%), which occurred at the 8th week of treatment, and ΔQTcF ≥60 ms in 4 cases (4/23,17.4%) in the TCM group; QTcF value ≥500 ms in 4 cases (4/22,18.2%), occurred at 4th (1 case), 8th (1 case), and 24th (2 cases) week of treatment, respectively, and ΔQTcF ≥60 ms in 11 cases (11/22,50.0%) in the control group. There were significant differences between the TCM group and the control group in adverse event (QTcF>450 ms) incidence and serious adverse event (ΔQTcF ≥60 ms) incidence (χ² values were 6.505 and 5.380, P values were 0.011 and 0.020, respectively). Conclusion: The regimen containing bedaquiline in the treatment of multidrug-resistant tuberculosis could induce prolongation of QT intervals of patients. Combined use of RRGDG could reduce the incidence of QTcF>450 ms and ΔQTcF≥60 ms.

Congenital drug-resistant tuberculosis: a case report and literature review

YUE Ying, HUANG Ting-ting, REN Fei, MA Jin-bao, QI Yun

Chinese Journal of Antituberculosis. 2022, 44(3):  252-257.  doi:10.19982/j.issn.1000-6621.20210505

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Objective: To review the clinical characteristics, diagnosis and treatment of congenital tuberculosis combined with the literature, in order to accumulate clinical experience for clinicians. Methods: The clinical data of a child with congenital drug-resistant tuberculosis and its mother admitted to Xi’an Chest Hospital in October 2020 were retrospectively analyzed. Taking “congenital tuberculosis” as the keyword, the literature was searched through the CNKI, Wanfang, PubMed and CJFD, and a total of 24 related literatures were searched out, and 2 cases of them were drug-resistant tuberculosis. Combined with this case, the clinical characteristics, diagnosis and treatment of 17 congenital tuberculosis children whose mothers underwent in vitro fertilization-embryo transfer were analyzed, and the 17 children were selected from 11 literatures. Results: In this study, there were 18 children, including 2 pairs of twins; 12 children’mothers had a history of tuberculosis or close contact to tuberculosis, 4 cases had no history of tuberculosis or close contact to tuberculosis; 5 cases were screened for tuberculosis infection before pregnancy, and 11 cases without screening. Sixteen cases were screened for tuberculosis after ineffective anti-infective treatment of “neonatal pneumonia, sepsis, fever”, and the time from onset to diagnosis was 3-44 days. The clinical manifestation is fever, cough, dyspnea, hepatomegaly, jaundice, apnea, diarrhea, and ear pus. Chest CT showed diffuse miliary nodular shadow, mediastinal and hilar lymph node enlargement, and a small amount of pleural effusion. In this study, of the 15 cases treated with the first-line anti-tuberculosis regimen, 11 had good prognosis, and 4 cases were found to be critically ill and died. Three cases were congenital drug-resistant tuberculosis, one was found “rifampicin” drug resistance and one showed “isoniazid” drug resistance through gastric juice test, and the case in our hospital was founde “isoniazid, rifampicin, rifampicin, and Isoniazid Aminosalicylate” drug resistance. Three cases were given second-line anti-tuberculosis treatment, no obvious adverse drug reactions were found, and the prognosis was good. Conclusion: The clinical manifestations of congenital drug-resistant tuberculosis were not specific, but the clinical symptoms were more serious. The second-line anti tuberculosis drugs had less adverse reactions and were relatively safe.

Study of MRI characteristics of spinal tuberculous meningitis and the change after anti-tuberculosis treatment

LI Duo, LYU Yan, LYU Ping-xin

Chinese Journal of Antituberculosis. 2022, 44(3):  258-263.  doi:10.19982/j.issn.1000-6621.20210711

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Objective: To describe MRI characteristics of spinal tuberculous meningitis, the changes after anti-tuberculosis treatment and the prognosis of patients. Methods: Using the electronic medical record management system of Beijing Chest Hospital Affiliated to Capital Medical University and Picture Archiving and Communication System (PACS), 31 patients whose complete MRI data were maintained and diagnosed as tuberculous spinal meningitis from 2012 to 2016 were selected as study objects. Two radiologists reviewed MRI retrospectively and the changes of spinal meninges, subarachnoid space and spinal cord were recorded. Results: The MRI showed that 96.8% (30/31) patients had thickened and enhanced meninges, 48.4% (15/31) had irregular or narrow subarachnoid space, 12.9% (4/31) had obliteration of the subarachnoid space, and 6.5% (2/31) had intradural extramedullary tuberculomas. Myelitis was detected in 51.6% (16/31) patients, while intramedullary tuberculoma was detected in 9.7% (3/31) patients. Furthermore, 58.3% (7/12) patients showed remission in the follow-up MRI, 25.0% (3/12) patients had progression; and 16.7% (2/12) patients showed no change in MRI. 71.0% patients (22/31) had a poor prognosis, including 13 deaths and 9 disability cases. Conclusion: Enhanced MRI can show the thickened and enhanced meninges, change in the subarachnoid space and in the spinal cord. MRI can also reflect the changes after anti-tuberculosis treatment. Enhanced MRI should be the first choice of imaging examination for patients with tuberculous spinal meningitis.

Diagnostic performance of differentially expressed miRNA identified by gene chip in discriminating tuberculous meningitis from viral meningitis

CHEN Meng-meng, DONG Jing, SUN Qi, HUANG Mai-ling, DING Ze-yu, SHI Yu-ting, JIA Hong-yan, DU Bo-ping, WEI Rong-rong, XING Ai-ying, ZHANG Zong-de, PAN Li-ping

Chinese Journal of Antituberculosis. 2022, 44(3):  264-272.  doi:10.19982/j.issn.1000-6621.20210699

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Objective: To evaluate the diagnostic performance of differentially expressed miRNA identified by gene chip in discriminating tuberculous meningitis (TBM) from viral meningitis (VM). Methods: A total of 28 TBM patients and 27 VM patients who were treated in Beijing Chest Hospital and Beijing Tiantan Hospital affiliated to Capital Medical University from Dec 2017 to Sep 2019 were recruited for validation using Real-time Quantitative PCR (qRT-PCR). Of 8 TBM patients and 5 VM patients who were recruited earlier were selected for genome-wide miRNA analysis by gene chip. The top 10 miRNA hub genes were screened by predicting the target genes of differentially expressed miRNAs, gene ontology (GO) enrichment analysis, Kyoto encyclopedia of genes and genomes (KEGG) signaling pathway analysis, and protein-protein interaction (PPI) network. qRT-PCR was used for further validation of the expression level of hsa-miR-21-5p between two groups, and the diagnostic value of miRNA was analyzed by area under receiver operating characteristic curve (AUC). Results: Totally 26 differentially expressed miRNAs (14 were up-regulated and 12 were down-regulated) were identified by miRNA microarray analysis, and further 3217 corresponding target genes were screened out by miRTarBase database. Through GO enrichment analysis and KEGG signal pathway analysis, 190 related target genes were screened out. The top 10 target genes as core target genes were defined by PPI. qRT-PCR verification of the relative expression of hsa-miR-21-5p based on gene chip samples showed that the expression level of has-miR-21-5p in TBM patients was significantly up-regulated than that in VM patients (15.890 (3.423, 25.581) vs. 0.807(0.614,0.955); Z=-2.355, P=0.019). The fold change (TBM/VM) in gene chip and qRT-PCR were 4.817 and 4.660, respectively, which was consistent between these two techniques. qRT-PCR analysis of hsa-miR-21-5p was further performed in 28 TBM patients and 27 VM patients. The results showed that the relative expression level of hsa-miR-21-5p in TBM patients was significantly higher than that in VM patients (4.825 (2.433, 21.362) vs. 0.204 (0.112, 0.711); Z=-5.000, P=0.000). The AUC for distinguishing TBM patients from VM patients was 0.893 (0.806-0.980), with a sensitivity of 85.7% and a specificity of 88.9%. Conclusion: As a significantly differentially expressed miRNA in gene chip analysis, has-miR-21-5p is significantly up-regulated in patients with TBM than VM patients, which can be used as a potential biomarker to differentiate TBM from VM.

Mechanism of traditional Chinese medicine “Qinbudan” in the treatment of pulmonary tuberculosis based on network pharmacology

ZHUANG Li, MA Zi-feng, JIANG Yu-wei, HUANG Xing, ZHANG Hui-yong, LU Zhen-hui, WU Xian-wei

Chinese Journal of Antituberculosis. 2022, 44(3):  273-283.  doi:10.19982/j.issn.1000-6621.20210572

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Objective: To explore the mechanism of “Qinbudan” in the treatment of pulmonary tuberculosis using the network pharmacology method. Methods: The effective components and potential targets of Radix Scutellariae, Radix Stemonae radix and Radix salvia were retrieved through TCMSP database. GeneCards, OMIM, TTD, and DrugBank databases were used to obtain targets of pulmonary tuberculosis. The gene name of those targets was standardized based on Unipront, and the protein interaction network of “Qinbudan” in treating pulmonary tuberculosis was generated based on STRING 11.0. The DAVID 6.8 platform was used for functional enrichment and pathway analysis. Cytoscape 3.7.1 software was used to analyze and construct the network of components, targets and pathways of “Qinbudan” in treating pulmonary tuberculosis. Results: Finally, 116 effective chemical components and 199 targets of “Qinbudan” were screened out. The core effective components of “Qinbudan” in treating pulmonary tuberculosis included luteolin, wogonin, baicalein, acacetin, formononetin, β-sitosterol and 7-methoxy-3-methyl-2,5-dihydroxy-9,10-dihydrophenanthrene. And 82 potential targets were involved, and the key targets were TP53, IL6, AKT1, VEGFA, EGFR, PTGS2, JUNP3, STAT3, TNF. A total of 373 biological process terms, 66 molecular function terms and 39 cell composition terms were found by GO enrichment analysis; 108 pathways were found by KEGG pathway analysis, TNF signaling pathway (P<0.001) and apoptosis (P<0.001) were the major pathways, T cell receptor signaling pathway (P<0.001), PI3K-Akt signaling pathway (P<0.001) and tuberculosis (P<0.001) were also included. Conclusion: Multi-component, multi-target and multi-pathway of the mechanism of “Qinbudan” in treating pulmonary tuberculosis were explored based on network pharmacology, which provided some theoretical support for later clinical and basic researches.

The value of the ratio of tuberculosis specific antigen to CD4⁺ T cell count in the auxiliary diagnosis of AIDS complicated with pulmonary tuberculosis

ZHANG Li-juan, ZHANG Hua, WANG Xia-fang, SHI Mei-hua, FENG Yan-jun, ZHANG Jian-ping, TANG Pei-jun

Chinese Journal of Antituberculosis. 2022, 44(3):  284-288.  doi:10.19982/j.issn.1000-6621.20210560

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Objective: To evaluate the value of the ratio of tuberculosis specific antigen (TBAg) to CD4⁺ T lymphocyte (CD4) count (TBAg/CD4) in the auxiliary diagnosis of AIDS complicated with active pulmonary tuberculosis (PTB). Methods: Basing on the inclusion criteria, a prospective study was conducted in 262 AIDS patients complicated with active PTB from the Fifth People’s Hospital of Suzhou from January 2018 to December 2020.The patients were divided into AIDS+PTB group (n=152) and AIDS group (n=110). The venous blood of patients in the morning of the next day after admission was collected for interferon in vitro release enzyme-linked immunosorbent assay (TB-IGRA), blood routine examination and CD4 detection. The differences of TBAg level and TBAg/CD4 ratio between the two groups were compared. Based on the clinical diagnosis, the efficacy of TB-IGRA in detecting AIDS complicated with PTB was evaluated, and the area under the receiver operating curve (ROC curve) (AUC) was used to determine the best detection index of diagnostic efficacy. Results: Based on the clinical diagnosis, the sensitivity and specificity of TB-IGRA in detecting AIDS complicated with active PTB were 53.95% (82/152) and 75.45% (83/110), respectively. TBAg and TBAg/CD4 levels in the AIDS+PTB group (92.51 (-68.20, 906.10) pg/ml and 1.01 (0.00, 10.12)) were significantly higher than those in the AIDS group (85.20 (-33.80, 801.30) pg/ml and 0.11(0.00, 2.07), respectively), and the antigen concentrations of control culture tube (529.50 (12.50, 1160.50) pg/ml) was significantly lower than that of AIDS group (694.50 (29.90, 990.00) pg/ml)(Z=-3.481, -9.557, 3.289, all P<0.001). ROC curve analysis showed that the AUC values of TBAg and TBAg/CD4 for the diagnosis of AIDS complicated with active PTB were 0.718, 0.637 and 0.842, respectively; when the critical value of TBAg/CD4 was 0.592, the Youden index was the largest, with a sensitivity of 88.10% and a specificity of 77.10%. Conclusion: Compared with AIDS patients, the levels of TBAg and TBAg/CD4 in AIDS patients complicate with PTB were significantly increased, and the diagnostic value of TBAg/CD4 was especially high. Combined with the influence of patients’ immune status, it was considered that TBAg/CD4 had certain auxiliary diagnostic value for AIDS patients with PTB.

Clinical Case Discussion

Analysis of diagnosis and treatment for a pulmonary lymphangitic carcinomatosis misdiagnosed as pulmonary tuberculosis caused by false positive molecular biological test

YANG Cheng-qing, MEI Chun-lin, DU Rong-hui, LEI Mei, QIN Li-xin

Chinese Journal of Antituberculosis. 2022, 44(3):  289-293.  doi:10.19982/j.issn.1000-6621.20210561

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On April 17, 2019, a 69-year-old male patient with pulmonary lymphangitic carcinomatosis was admitted to the Respiratory Department of Wuhan Pulmonary Hospital,and diagnosed as pulmonary tuberculosis due to the positive tuberculosis molecular biological result in other hospital. The patient was hospitalized because of “pulmonary shadow for 3 months and intermittent cough for 2 months”. He had previously been diagnosed with colon cancer. Chest CT scan revealed diffusing nodules along bronchovascular bundles with ground glass shadows, interlobular septal thickening, bilateral hilar and mediastinal lymph node enlargement and bilateral pleural effusion. In bronchoalveolar lavage fluid (BALF), MTB (extremely low) was detected by GeneXpert MTB/RIF (referred to as “GeneXpert”) and MTB was detected by TB-PCR in previous hospital. Therefore, he was diagnosed as tuberculosis, then transferred to Wuhan Pulmonary Hospital. After admission, relevant examinations were completed. PPD skin test and interferon gamma release test was negative, and chest CT imaging features were not consistent with pulmonary tuberculosis. We suspected it was a false positive molecular biological result. Therefore, GeneXpert and tracheal endoscopic ultrasound-guided needle aspiration biopsy (EBUS-TBNA) were recommended. However, the patient refused. The doctor performed a pleural puncture for diagnosis, and 20 ml pleural effusion was extracted. The examination showed that the carcinoembryonic antigen (118.4 μg/L) was significantly elevated, indicating malignant pleural effusion. Finally, medical thoracoscopic pleural biopsy revealed metastatic poorly differentiated adenocarcinoma. Combined with chest CT findings, the patient was diagnosed as pulmonary lymphangitic carcinomatosis who later died due to deterioration of his condition. Therefore, the authors suggest that radiographic findings of nodules along the bronchovascular bundle with thickening of interlobular septa and mediastinal lymph node enlargement should be considered as pulmonary lymphangitic carcinomatosis for differential diagnosis. When imaging findings are not consistent with tuberculosis and molecular biological test is positive, we should be cautious about diagnosing tuberculosis to avoid misdiagnosis and mistreatment.

Review Articles

Research progress of molecular biology detection technology for tuberculosis

FAN Ru, LI Xiao-fei

Chinese Journal of Antituberculosis. 2022, 44(3):  294-298.  doi:10.19982/j.issn.1000-6621.20210646

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With the continuous development of medical science and technology, especially the advent of the era of precise diagnosis and treatment, molecular biology detection technology has been widely valued and applied in the early diagnosis of tuberculosis. Molecular biological detection technology has the advantages of accuracy, high efficiency and high throughput, which brings a new dawn for the diagnosis and treatment of tuberculosis and the prevention and control of the epidemic. Researches at home and abroad were summarized to expound the application status and the latest research progress based on nucleic acid amplification test technology, gene sequencing tuberculosis detection and drug sensitivity analysis technology and other new tuberculosis detection technology, in order to provide reference for the auxiliary diagnosis of tuberculosis.