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Development and Evaluation of a Promising Biomarker for Diagnosis of latent and Active tuberculosis infection

Infectious Diseases & Immunity 2024年第1期4卷 10-24页

作者： Cong Peng Fan Jiang Yinping Liu Yong Xue Peng Cheng Jie Wang Liang Wang Wenping Gong Hebei North University Zhangjiakou 075000Hebei ProvinceChina Beijing Key Laboratory of New Techniques of tuberculosis Diagnosis and Treatment Senior Department of TuberculosisEighth Medical Center of PLA General HospitalBeijing 100091China Department of Geriatrics Eighth Medical Center of PLA General HospitalBeijing 100091China Section of Health No.94804 Unit of the Chinese People's Liberation ArmyShanghai 200434China

Background:Diagnosing latent tuberculosis(TB)infection(LTBI)and active TB(ATB)is crucial for preventing disease progression and transmission.However,current diagnostic tests have limitations in terms of accuracy and sensitivity,making it challenging to diagnose these different infection states.Therefore,this study intends to develop a promising biomarker for LTBI and ATB diagnosis to overcome the limitations of the current diagnostic tests.Methods:We developed a novelmultiepitope-based diagnostic biomarker(MEBDB)fromLTBI region of differentiation antigens using bioinformatics and immunoinformatics.Immune responses induced byMEBDM were detected using enzyme-linked immunosorbent spot and cytometric bead assays.This study was conducted from April 2022 to December 2022 in the SeniorDepartment of tuberculosis at the 8thMedical Center of PLA General Hospital,China.Blood samples were collected from participants with ATB,individuals with LTBI,and healthy controls(HCs).The diagnostic efficacy of MEBDB was evaluated using receiver operating characteristic curves.Results:A novel MEBDB,designated as CP19128P,was generated.CP19128P comprises 19 helper T lymphocyte epitopes,12 cytotoxic T lymphocyte epitopes,and 8 B-cell epitopes.In silico simulations demonstrated that CP19128P possesses strong affinity for Toll-like receptors and elicits robust innate and adaptive immune responses.CP19128P generated significantly higher levels of tumor necrosis factor(TNF-α),interleukin 4(IL-4),and IL-10 in ATB patients(n=7)and LTBI(n=8)individuals compared with HCs(n=62)(P<0.001).Moreover,CP19128P-induced specific cytokines could be used to discriminate LTBI and ATB from healthy subjects with high sensitivity and specificity.Combining IL-2 with IL-4 or TNF-α could differentiate LTBI from HCs(the area under the receiver operating characteristic curve[AUC],0.976[95% confidence interval[CI],0.934-1.000]or 0.986[0.956-1.000]),whereas combining IL-4 with IL-17A or TNF-α could differentiate ATB from HCs(AUC,0.887[0.782-0.993]or 0.984[0.958-1.000])

关键词： tuberculosis latent tuberculosis infection Active tuberculosis Multiepitope-based diagnostic biomarker Bioinformatics:Immunoinformatics

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latent tuberculosis infection in health-care workers in the government sector in Brunei Darussalam:A cross-sectional study

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中西医结合护理杂志(英文) 2023年第3期5卷 197-202页

作者： Nurin Jazmina Muhammad SYAFIQ Ashishkumar Akshaykumar TRIVEDI Alice LAI Maria Pureza Aurelio FONTELERA Mei Ann LIM PAPRSB Institute of Health Sciences Universiti Brunei DarussalamBandar Seri BegawanBrunei Darussalam Occupational Health Division Ministry of HealthBandar Seri BegawanBrunei Darussalam

Objective:Health-care workers(HCWs)are known to be at high risk for occupational biological hazards,and this includes exposure to mycobacterium tuberculosis(TB)which can result in either active or latent TB infection(LTBI).This study aims to provide an overview of the incidence of LTBI among HCWs in Brunei Darussalam,to examine associated risk factors,and to evaluate LTBI treatment compliance.Materials and Methods:This is a retrospective cross-sectional study which was conducted using data from January 2018 to December 2021,on notified cases of LTBI in HCWs which identified 115 cases.Demographic data,underlying medical conditions,and compliance to treatment were assessed through reviews of their electronic health records.Results:The incidence of LBTI was 14.6/year/1000 HCWs.The incidence rate reached a high of 24.6/1000 in 2020,and majority of cases were in the older age groups.There was good treatment acceptance and compliance(82.6%),and this was observed to be significantly higher in females than males(P=0.02).Conclusion:This study showed an average incidence of LTBI of 14.6/1000 HCWs over 4 years and high LTBI treatment acceptance(82.6%)and compliance.Emphasis on infection prevention and control measures in health-care settings and actions to increase awareness of LTBI are crucial interventions toward reducing the burden of LTBI.

关键词： Health-care worker latent tuberculosis infection treatment latent tuberculosis infection tuberculin skin test

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Mycobacterium tuberculosis latency-associated antigen Rv1733c SLP improves the accuracy of differential diagnosis of active tuberculosis and latent tuberculosis infection

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Chinese Medical Journal 2022年第1期135卷 63-69页

作者： Lifan Zhang Huimin Ma Shijun Wan Yueqiu Zhang Mengqiu Gao Xiaoqing Liu Division of Infectious Diseases Department of Internal MedicineState Key Laboratory of Complex Severe and Rare DiseasePeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China Clinical Epidemiology Unit Peking Union Medical CollegeInternational Clinical Epidemiology NetworkBeijing 100730China Center for tuberculosis Research Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China Department of tuberculosis Beijing Chest HospitalCapital Medical University/Beijing Tuberculosis and Thoracic Tumor Research InstituteBeijing 101149China

Background: Differential diagnosis of active tuberculosis (ATB) and latent tuberculosis infection (LTBI) has been a challenge for clinicians in high TB burden countries. The purpose of this study was to improve the accuracy of differential diagnosis of ATB and LTBI by using fluorescent immunospot (FluoroSpot) assay to detect specific Th1 cell immune responses. The novelmycobacterium tuberculosis (MTB) latency-associated antigens Rv1733c and synthetic long peptides derived from Rv1733c (Rv1733c SLP) were used based on virulence factors early secreting antigen target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10).Methods: Fifty-seven ATB cases, including 20 pathogen-confirmed ATB and 37 clinically diagnosed ATB, and 36 LTBI cases, were enrolled between January and December 2017. FluoroSpot assay was used to detect the interferon γ (IFN-γ) and interleukin 2 (IL-2) secreted by the specific T cells after being stimulated with MTB virulence factors ESAT-6 and CFP-10, MTB latency-associated antigens Rv1733c and Rv1733c SLP. The receiver operating characteristic (ROC) curve was used to define the best cutoff value of latency-associated antigens in the use of differentiating ATB and LTBI. The sensitivity, specificity, predictive value, and likelihood ratio of ESAT-6 and CFP-10-FluoroSpot combined with latency-associated antigen in the differential diagnosis of ATB and LTBI were also calculated.Results: Following the stimulation with Rv1733c and Rv1733c SLP, the frequency of single IL-2-secreting T cells stimulated by Rv1733c SLP had the largest area under the ROC curve, which was 0.766. With a cutoff value of 1 (spot-forming cells [SFCs]/2.5 × 105 peripheral blood mononuclear cells) for frequency, the sensitivity and specificity of distinguishing ATB from LTBI were 72.2% and 73.7%, respectively. ESAT-6 and CFP-10-FluoroSpot detected the frequency and proportion of single IFN-γ-secreting T cells;the sensitivity and specificity of distinguishing ATB from LTBI were 82.5% and 66.7%, respectively. Combined with the freque

关键词： Mycobacterium tuberculosis latency-associated antigens Active tuberculosis latent tuberculosis infection Differential diagnosis

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Evaluation of IFIT3 and ORM1 as Biomarkers for Discriminating Active tuberculosis from latent infection

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Current Medical Science 2022年第6期42卷 1201-1212页

作者： Bing-fen YANG Fei ZHAI Shan YU Hong-juan AN Zhi-hong CAO Yan-hua LIU Ruo WANG Xiao-xing CHENG tuberculosis Prevention and Control Key Laboratory Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and TreatmentInstitute of Senior Department of Tuberculosisthe Eighth Medical Center of Chinese PLA General HospitalBeijing100091China Fourth Division Senior Department of Tuberculosisthe Eighth Medical Center of PLA General HospitalBeijing100091China Department of tuberculosis Prevention and Control Senior Department of Tuberculosisthe Eighth Medical Center of PLA General HospitalBeijing100091China

Objective Current commercially available immunological tests cannot be used for discriminating active tuberculosis(TB)from latent TB infection.To evaluate the value of biomarker candidates in the diagnosis of active TB,this study aimed to identify differentially expressed genes in peripheral blood mononuclear cells(PBMCs)between patients with active TB and individuals with latent TB infection by transcriptome sequencing.Methods The differentially expressed genes in unstimulated PBMCs and in Mycobacterium tuberculosis(Mtb)antigen-stimulated PBMCs from patients with active TB and individuals with latent TB infection were identified by transcriptome sequencing.Selected candidate genes were evaluated in cohorts consisting of 110 patients with TB,30 individuals with latent TB infections,and 50 healthy controls by quantitative real-time RT-PCR.Receiver operating characteristic(ROC)curve analysis was performed to calculate the diagnostic value of the biomarker candidates.Results Among the differentially expressed genes in PBMCs without Mtb antigen stimulation,interferon-induced protein with tetratricopeptide repeats 3(IFIT3)had the highest area under curve(AUC)value(0.918,95%CI:0.852-0.984,Platent TB infection,with a sensitivity of 91.86%and a specificity of 84.00%.In Mtb antigen-stimulated PBMCs,orosomucoid 1(ORM1)had a high AUC value(0.833,95%CI:0.752-0.915,Platent TB infection.

关键词： tuberculosis biomarker latent tuberculosis infection interferon-induced protein with tetratricopeptide repeats 3 orosomucoid 1

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A prospective longitudinal study for latent tuberculosis infection in hospital in Beijing evaluating a T-cell-based assay health-care workers in a general

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Chinese Medical Journal 2013年第11期126卷 2039-2044页

作者： ZHANG Li-fan LIU Xiao-qing ZHANG Yao DENG Guo-hua Manish Pareek Ajit Lalvani Department of Infectious Diseases Peking Union Medical College Hospital Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100730 China Clinical Epidemiology Unit Peking Union Medical College Hospital Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100730 China

Background The health-care workers （HCWs） are at high risk of acquiring infection with Mycobacterium tuberculosis. The objectives of this study were to compare the performance of the T-SPOT.TB and tuberculin skin test （TST） for latent tuberculosis infection （LTBI）, evaluate diagnostic concordance and risk factors for LTBI, and observe the progression to active tuberculosis （TB） disease among HCWs in a general hospital in Beijing. Methods The prospective cohort study enrolled HCWs in a tertiary general hospital in Beijing, China, to evaluate LTBI with T-SPOT.TB and TST. The subjects were evaluated every 12 months during the 60-month follow-up. Results Of 101 participating HCWs, 96 and 101 had valid TST and T-SPOT.TB results, respectively. Twenty-nine （28.7%, 95% confidence interval （C/）, 19.9%-37.5%） were defined as positive by T-SPOT.TB and 53 （55.2%, 95% CI, 45.2%-64.9%） were defined as positive by TST （using a ≥10 mm cutoff）. An agreement between the two tests was poor （57.3%, K=0.18, 95% CI, 0.01%-0.52%）. In multJvariate analysis, direct exposure to sputum smear-positive TB patients was a significant risk factor for a positive T-SPOT.TB （OR 5.76; 95% CI 1.38-24.00）. Pooled frequency of antigen- specific IFN-y secreting T-cells for subjects who reported direct contact with sputum smear-positive TB patients was significantly higher than that for participants without direct contact （P=0.045）. One of 20 participants with positive result of T-SPOT.TB and TST developed active TB at 24-month follow-up.Conclusion T-SPOT.TB is a more accurate, targeted method of diagnosing LTBI than TST.

关键词： T-SPOT.TB latent tuberculosis infection tuberculin skin test exposure follow-up study

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Effect of Individualized Nursing Intervention on Patients with tuberculosis latent infection and Active tuberculosis

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Journal of Clinical and Nursing Research 2023年第5期7卷 155-160页

作者： Junling Wang Wuhai Infectious Disease Hospital Wuhai 016000Inner Mongolia Autonomous RegionChina

Objective:This paper aims to explore the effect of individualized nursing intervention on patients with active tuberculosis(ATB)and latent tuberculosis infection(LTBI).Methods:The nursing study started in January 2020 and ended in January 2023.A total of 60 patients with ATB and LTBI were included,and they were divided into two groups according to the intervention schemes selected for control testing,each with 30 cases.The intervention program selected for group A was routine care,and for group B was individualized nursing.The proportion of adverse reactions,changes in the level of lung items,self-management outcomes and satisfaction were evaluated and compared.Results:After evaluating the proportion of adverse reactions,the total proportion of ATB and LTBI in group B was lower than that in group A(P<0.05).Based on the evaluation and testing of the expiratory flow(EF),expiratory volume(EV),and vital capacity(VC)after the intervention,these levels in group B showed higher outcomes than those in group A(P<0.05).The scores in terms of living habits,sleep,diet,and compliance in group B were higher than those in group A(P<0.05).The total proportion of the satisfaction of ATB and LTBI patients in group B was higher than that in group A(P<0.05).Conclusion:After the intervention of individualized nursing measures in patients with ATB and LTBI,it was found that it can not only play a positive role in the prevention and control of adverse reactions,but also improve their lung function,and promote their self-management,with good satisfaction level,thus it has high research and clinical application values.

关键词： Active tuberculosis latent tuberculosis infection Individualized nursing intervention

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Does “latent tuberculosis infection” (LTBI)” Really Exist? Genealogy of a Medical Nosology

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Journal of tuberculosis Research 2021年第3期9卷 197-204页

作者： Patricia Etienne University Hospital of Guadeloupe Pointe-à-Pitre France

Introduction: The diagnosis of latent tuberculosis infection (LTBI) is based on secular ways: chest radiography and tuberculin skin test (TST). In front of a recent enthusiasm for LTBI, this paper reports a historical perspective of this concept. Method: Bibliometric analysis and literature review from medical databases, using the terms “latent tuberculosis infection (“LTBI”), “primary tuberculosis”, “tuberculin skin test”, “tuberculosis”, and from reference books on tuberculosis. Results: In the PubMED/MEDLINE search for LTBI, a total of 7787 articles were found between 1901 and 2020, 95% from 2000 to 2020. In the first part of the 20th century, LTBI term was used for sub-clinical tuberculosis disease, the latency being also called “primary tuberculosis” or “abortive tuberculosis infection”. From 1960, randomized prospective therapeutic studies mentioned “tuberculosis chemoprophylaxis”. By the end of t

关键词： Tuberculin Skin Test latent tuberculosis infection IGRA Tests Medical History

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Prevalence and Risk Factors for latent tuberculosis infection among Close Contacts of Smear Positive Pulmonary tuberculosis in China

Prevalence and Risk Factors for Latent Tuberculosis Infectio...

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中华医学会结核病学分会2019年全国结核病学术大会

作者： Fengjiao Du Beijing Chest Hospital Capital Medical UniversityBeijing Tuberculosis and Thoracic Tumor Research Institute

Background:Close Contacts of Smear Positive Pulmonary tuberculosis are at risk of tuberculosis infection.In China,tuberculosis (TB) is a major public health problem,but the prevalence of LTBI in close contacts has not been assessed enough.The aim of this study was to determine the prevalence and putative risk factors of LTBI among close contacts of smear positive pulmonary tuberculosis in China.Methods:In this study,76 newly diagnosed pulmonary TB cases were used as index cases,totally 243subjects with close contacts of index cases were enrolled.LTBI was assessed by T-SPOT.TB,and information on HCWs was collected using a standardised questionnaire.Risk factors for LTBI were analyzed by univariate and multivariate regression.Results Of the 248 individuals with close contacts of smear positive pulmonary tuberculosis,5 (2.02%) were active tuberculosis and were ruled out,The T-SPOT.TB positive rate were 46.9%(114/243)in close contacts.By univariate and multivariate analysis in the logistic regression model,the proportion of LTBI was significantly higher (Ptuberculosis patients within 2 months before diagnosis than within 1 month after treatment,The spousal relationship was higher (Ptuberculosis patients.The duration of exposure had a impact on the prevalence of LTBI,but no statistical difference.old age,long time contact and the amount of bacteria discharged from index cases significantly increased the likelihood of LTBI.Conclusions:Prevalence of LTBI estimated by T-SPOT.TB is high among close contact with smear positive pulmonary tuberculosis(TB) and conjugal relations,long time contact and the amount of bacteria discharged from index cases were associated with increased risk.These data highlight adequate infection control measures should be undertaken.

关键词： Mycobacterium tuberculosis latent tuberculosis infection Interferon-γ release assay

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Controlling strategy of dormant Mycobacterium tuberculosis

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Chinese Medical Journal 2014年第18期127卷 3316-3321页

作者： Gan Yiling Guo Shuliang Department of Respiratory Medicine First Affiliated Hospital ofChongqing Medical University Chongqing 400016 China

Objective This study aimed to review the available literatures on control of latent tuberculosis （TB） infection and propose a new control strategy to shorten the course of TB chemotherapy. Data sources The data used in this review were mainly obtained from articles listed in PubMed. The search terms were ＂therapy （treatment） of tuberculosis; ＂therapy （treatment） of latent TB infection; and ＂vaccine of TB.＂ Study selection Articles regarding treatment and vaccine of TB were selected and reviewed. Results The most crucial reason causing the prolonged course of TB chemotherapy is the dormant state of Mycobacterium tuberculosis （M. tuberculosis）. Nevertheless, there are, to date, no effective drugs that can directly kill the dormant cells of M. tuberculosis in clinical therapy. In accordance with the growth cycle of dormant M. tuberculosis in the body, the methods for controlling dormant M. tuberculosis include direct killing with drugs, prevention of dormant M. tuberculosis resuscitation with vaccines, and resuscitating dormant M. tuberculosis with preparations or drugs and then thoroughly killing these resuscitated M. tuberculosis by using anti-TB therapy. Conclusions The comprehensive analysis of the above three methods suggests that the drugs directly killing dormant cells are in clinical trials, TMC207 is the most beneficial for controlling TB. Because the side effect of vaccines is less and their action period is long, prevention of dormant cells resuscitation with vaccines is promising. The last control method makes it probable that when a huge number of active cells of M. tuberculosis have been killed and eradicated after 1-month short chemotherapy, only a strong short-term subsequent chemotherapy can completely kill and eradicate the remaining M. tuberculosis. This control strategy is expected to significantly shorten the course of TB chemotherapy and bring a new change and breakthrough in TB treatment.

关键词： latent tuberculosis infection dormant cells of M. tuberculosis control therapy

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Comparison between Quanti-FERON-TB Gold In-Tube test and tuberculin skin test for diagnosis of latent tuberculosis in children: A cross-section study

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Journal of Acute Disease 2020年第2期9卷 73-77页

作者： Keyghobad Ghadiri Alisha Akya Maryam Janatolmakan Mansour Rezaei Seyed AmirabbasSharif Shahla Masoomshahi Raha Khosravi Roya chegenelorestani Infectious Diseases Research Center Kermanshah University of Medical SciencesKermanshahIran Clinical Research Development Center Imam Reza HospitalKermanshah University of Medical SciencesKermanshahIran Social Development and Health Promotion Research Center Kermanshah University of Medical SciencesKermanshahIran Infectious Diseases Research Centre Kashan University of Medical SciencesKashanIran Pediatric Pathology Research Center Research Institute for Children HealthMofid Children HospitalShahid Behehsti University of Medical SciencesTehranIran

Objective: To compare Quanti-FERON-TB Gold In-Tube (QFT-GIT) test and tuberculin skin test (TST) for the diagnosis of latent tuberculosis infection in children. Methods: In this cross-sectional study, 64 participants who were between 3 months and 14 years old and had close contact with smear-positive pulmonary tuberculosis were included. Both QFT-GIT test and TST were done and the results were analyzed by SPSS software and Kappa test. Results: The distribution of gender and age according to QFT-GIT and TST results were matched (P>0.05). Overall agreement between QFT-GIT and TST for diagnosis of latent tuberculosis infection in children was 75%. In addition, the contingency coefficient was 0.257, and the Kappa measure of agreement was 0.246 (P=0.034). Conclusions: Compared to TST, QFT-GIT shows no apparent advantage for diagnosis of latent tuberculosis infection in children.

关键词： tuberculosis latent tuberculosis infection Tuberculin skin test Quanti FERON

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