From immunology to artificial intelligence: revolutionizing latent tuberculosis infection diagnosis with machine learning

Latent tuberculosis infection(LTBI)has become a major source of active tuberculosis(ATB).Although the tuberculin skin test and interferon-gamma release assay can be used to diagnose LTBI,these methods can only differentiate infected individuals from healthy ones but cannot discriminate between LTBI and ATB.Thus,the diagnosis of LTBI faces many challenges,such as the lack of effective biomarkers from Mycobacterium tuberculosis(MTB)for distinguishing LTBI,the low diagnostic efficacy of biomarkers derived from the human host,and the absence of a gold standard to differentiate between LTBI and ATB.Sputum culture,as the gold standard for diagnosing tuberculosis,is time-consuming and cannot distinguish between ATB and LTBI.In this article,we review the pathogenesis of MTB and the immune mechanisms of the host in LTBI,including the innate and adaptive immune responses,multiple immune evasion mechanisms of MTB,and epigenetic regulation.Based on this knowledge,we summarize the current status and challenges in diagnosing LTBI and present the application of machine learning(ML)in LTBI diagnosis,as well as the advantages and limitations of ML in this context.Finally,we discuss the future development directions of ML applied to LTBI diagnosis.

Does “Latent Tuberculosis Infection” (LTBI)” Really Exist? Genealogy of a Medical Nosology

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 the 20th century, the epidemic of AIDS impeded tuberculosis decrease, making LTBI search more efficient. In 2000, the American Thoracic Society and the Centers for Disease Controls and Prevention proposed the systematic used of LTBI, relayed through public health policies. A significant higher scientific production about LTBI was noted, supported by IGRA tests commercialization. Conclusion: In the recent years, health public policies, combined with epidemiologic and economic factors, strengthened the use of LTBI terminology.

Fluoroquinolones for the treatment of latent Mycobacterium tuberculosis infection in liver transplantation

Solid organ transplantation(SOT)is the best treatment option for end-stage organ disease.Newer immunosuppressive agents have reduced the incidence of graft rejection but have increased the risk of infection,particularly due to the reactivation of latent infections due to opportunistic agents such as Mycobacterium tuberculosis.Active tuberculosis(TB)after SOT is a significant cause of morbidity and mortality.Most cases of posttransplant TB are secondary to reactivation of latent tuberculosis infection(LTBI)due to the effects of long-term immunosuppressive therapy.Risk minimization strategies have been developed to diagnose LTBI and initiate treatment prior to transplantation.Isoniazid with vitamin B6 supplementation is the treatment of choice.However,liver transplantation(LT)candidates and recipients have an increased risk of isoniazid-induced liver toxicity,leading to lower treatment completion rates than in other SOT populations.Fluoroquinolones(FQs)exhibit good in vitro antimycobacterial activity and a lower risk of drug-induced liver injury than isoniazid.In the present review,we highlight the disease burden posed by posttransplant TB and summarize the emerging clinical evidence supporting the use of FQs for the treatment of LTBI in LT recipients and candidates.

Acceptance of Chemo-prophylaxis for Latent Tuberculosis Infection among High School/College Student Contacts of Tuberculosis Patients in Shanghai, China

Student contacts of tuberculosis（TB）cases are susceptible to latent tuberculosis infection（LTBI）,and chemo-prophylaxis can reduce the risk of active TB among them.This study aimed to assess the acceptance of chemo-prophylaxis for LTBI among students, and their concerns regarding TB and its preventive treatment.

Evaluation of IFIT3 and ORM1 as Biomarkers for Discriminating Active Tuberculosis from Latent Infection

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,P<0.0001)in discriminating patients with active TB from individuals with latent 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,P<0.0001),with a sensitivity of 81.94%and a specificity of 70.00%.Conclusion IFIT3 and ORM1 might be potential biomarkers for discriminating active TB from latent TB infection.

The Impact of Directly Observed Therapy on Preventive Treatment for Latent Tuberculosis Infection among Students in Dalian, China

Preventive treatment has an essential effect on latent tuberculosis infection(LTBI)[purified protein derivative(PPD)induration≥15 mm].Between2010 and 2013,there were 6 tuberculosis(TB)outbreaks in the universities in Dalian,China.So far,in Dalian,the directly observed therapy(DOT)and

Latent tuberculosis infection among medical students in Malaysia

Objective: This study aimed to determine prevalence of latent tuberculosis infection among medical students and tuberculosis exposure at the health facilities. Methods: A cross-section of study year 1(n=68) and year 5(n=75) medical students in a local university were recruited for latent tuberculosis infection testing using QuantiFERON-TB Gold Plus and a questionnaire analyzed for multivariate risk. Results: The majority of the study were vaccinated with BCG. None of year 1 medical students were positive for latent tuberculosis infection, however, six(8.0%) year 5 students were tested positive for latent tuberculosis infection. A higher incidence of year 5 medical students claimed to be exposed to tuberculosis at health facility(65.3% vs. 4.4%) and a higher percentage reported contact with tuberculosis case over the preceding year compared to year 1 students(30.7% vs. 8.8%). Conclusion: We observed a higher incidence of latent tuberculosis infection and higher exposure to tuberculosis in health facilities among year 5 medical students. Baseline screening and monitoring for progression to tuberculosis infection may benefit tuberculosis management programs.

Interferon γ in patients with HIV/AIDS and suspicion or latent tuberculosis infection

Objective:To assess the usefulness of IGRA test(QuantiFERON? -Cell mediated immune) compared with the tuberculin skin test.Methods:A cross-sectional study was carried out in Mexico,25 infected patients with HIV-AIDS and the suspicion or with latent tuberculous infection （LTBI） who were】18 years of age and without treatment for tuberculosis（TB）,were enrolled in the study.Results:Median cluster of differentiation（CD4） count was 364 cells/μL and median HIV viral load was 50 copies/mL.Overall,20 patients（80%） had at least one positive diagnostic test for LTBI:four（16%） had a positive tuberculin skin test and 19（76%）,a positive QuantiFERON ? -tuberculosis.Conclusions:No agreement is found between the two diagnostic tests:k = -0.004,95%confidence interval（-0.2219,0.2210）.Additional longitudinal studies among HIV-infected populations with high prevalence of TB are needed to further assess the usefulness of IGRAs in this patient population.

Latent Tuberculosis Infection among Household Contacts of Pulmonary Tuberculosis Cases in Central State, Sudan: Prevalence and Associated Factors

Introduction: Tuberculosis is a major health problem in developing countries including Sudan. Screening for TB cases through Household contacts (HHCs) investigation is an appropriate strategy to interrupt transmission of TB. Objectives: To determine the prevalence tuberculosis infection and risk factors for tuberculosis infection among household contacts in Wadimadani locality, Central State, Sudan, between November 2015 and April 2016. Methods: An analytical cross-sectional study conducted. During study period, to confirm TB diagnosis, all suspect contacts were tested through sputum samples, tuberculin skin test or chest X-ray. Structured questionnaire was used to collect socio-demographic and environmental factors. Results: One hundred forty six patients of smear-positive pulmonary tuberculosis were included in the study, 657 household contacts were identified and screened. Forty three new TB cases were detected from household contacts, yielding a prevalence of 6.5% (95% confidence interval = 0.05, 0.09) of latent tuberculosis infection (LTBI). Two factors were significantly associated with LTBI among HHCs: duration of contact with a TB patient ≤ 4 months (P = 0.03) and the educational status (P = 0.02). Conclusion: Screening of HHCs of index case of TB will contribute in early detection and treatment of new cases, and considered as a forward step towards eliminating TB.

Interferon-gamma ELISPOT for the screening and diagnosis of latent tuberculosis infection in healthy population of China

The aim of this study was to analyze the combination of three kinds of in-house IFN-γ ELISPOT using peptide A53 and peptide mixtures (E6 + E7 and E6 + E7 + C14) with tuberculin skin test (TST) to detect latent TB infection (LTBI) in China. A total of 788 healthy people were recruited and analyzed by three kinds of IFN-g ELISPOT, 581 of them had TST results, of which 147 samples were also compared with the T- SPOT.TB test. The positive detection rates for T- SPOT.TB and three kinds of IFN-γ ELISPOT with A53, E6 + E7 and E6 + E7 + C14 were 14.28% (21/147), 29.43% (171/581), 23.24% (135/581) and 28.40% (165/581), respectively. These results were significantly lower than the positive TST results, which were positive in 82.99% (122/147) and 75.73% (440/ 581), respectively. The positive detection rates of three kinds of IFN-γ ELISPOT (31.60%, 26.65% and 32.11% in 788 cases, respectively) could better reflect over 40.00% of Mycobacterium tuberculosis (MTB) infection rate in China. Detection rates between contacts and non-contacts by three kinds of IFN-γ ELIS-POT were not significantly different (p > 0.05). It can be seen that the three kinds of in-house IFN-γ ELIS- POT might be used as a complementary tool of T- SPOT.TB for detecting LTBI in the healthy population of China.

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

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.

Recent Progress in Diagnosis Methods for Latent Tuberculosis Infection and Its Clinical Applications

Most people with latent Mycobacterium tuberculosis infection can partly develop active tuberculosis (TB). Therefore, diagnosis of this condition bears significance in early TB prevention. To date, the main methods for diagnosis of latent TB infection (LTBI) include tuberculin skin test and interferon γ release test. These two methods feature their own advantages and disadvantages. Although new diagnostic markers continually emerge, no uniform diagnostic criteria are available for TB detection. This study summarizes several methods for diagnosis of LTBI and new related markers and their application value in clinical practice.

Effect of Individualized Nursing Intervention on Patients with Tuberculosis Latent Infection and Active Tuberculosis

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.

Latent tuberculosis:Risk factors,screening and treatment in liver transplantation recipients from an endemic area

BACKGROUND Patients undergoing solid organ transplantation,particularly those who live or have lived in tuberculosis(TB)endemic areas,are at a high risk of developing TB.The majority of post-transplantation TB cases are associated with reactivation of latent TB infection(LTBI).Brazil is in a single position with overlapping areas of high TB endemicity and high transplant activity.In liver transplant(LT),one should be aware of the potential hepatotoxicity associated with the treatment regimens for LTBI.AIM To evaluate the frequency of LTBI in LT patients and treatment-related issues.METHODS This was a retrospective analysis of a cohort of cirrhotic patients aged≥18 years,who underwent LT at a high-complexity teaching hospital from January 2005 to December 2012.RESULTS Overall,429 patients underwent LT during the study period.Of these,213(49.7%)underwent the tuberculin skin test(TST)during the pre-transplant period,and 35(16.4%)of them had a positive result.The treatment for LTBI was initiated after LT in 12(34.3%)of the TST-positive patients;in 3(25.0%),treatment was maintained for at least 6 mo.CONCLUSION The prevalence of LTBI was lower than expected.Initiation and completion of LTBI treatment was limited by difficulties in the management of these special patients.

Barriers to the Acceptance of Tuberculosis Preventive Treatment:A Multicenter Cross-sectional Study in China

Objective We aimed to understand the willingness and barriers to the acceptance of tuberculosis(TB)preventive treatment(TPT)among people with latent TB infection(LTBI)in China.Methods A multicenter cross-sectional study was conducted from May 18,2023 to December 31,2023 across 10 counties in China.According to a national technical guide,we included healthcare workers,students,teachers,and others occupations aged 15-65 years as our research participants.Results Overall,17.0%(183/1,077)of participants accepted TPT.There were statistically significant differences in the acceptance rate of TPT among different sexes,ages,educational levels,and occupations(P<0.05).The main barriers to TPT acceptance were misconceptions that it had uncertain effects on prevention(57.8%,517/894),and concerns about side effects(32.7%,292/894).Conclusion An enhanced and comprehensive understanding of LTBI and TPT among people with LTBI is vital to further expand TPT in China.Moreover,targeted policies need to be developed to address barriers faced by different groups of people.

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

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.

Prevalence and Clinical Relevance of Schistosoma mansoni Co-Infection with Mycobacterium tuberculosis: A Systematic Literature Review

Tuberculosis disease stands for the second leading cause of death worldwide after COVID-19, most active tuberculosis cases result from the reactivation of latent TB infection through impairment of immune response. Several factors are known to sustain that process.Schistosoma mansoni, a parasite of the helminth genus that possesses switching power from an immune profile type Th1 to Th2 that favors reactivation of latent TB bacteria. The aim of the study was to assess the prevalence of the co-infection between the two endemic infections. Systematic literature was contacted at the University Clinical Research Center at the University of Sciences, Techniques, and Technologies of Bamako in Mali. Original articles were included, and full texts were reviewed to assess the prevalence and better understand the immunological changes that occur during the co-infection. In total, 3530 original articles were retrieved through database search, 53 were included in the qualitative analysis, and data from 10 were included in the meta-analysis. Prevalence of the co-infection ranged from 4% to 34% in the literature. Most of the articles reported that immunity against infection with helminth parasite and more specifically Schistosoma mansoni infection enhances latent TB reactivation through Th1/Th2. In sum, the impact of Schistosoma mansoni co-infection with Mycobacterium tuberculosis is under-investigated. Understanding the role of this endemic tropical parasite as a contributing factor to TB epidemiology and burden could help integrate its elimination as one of the strategies to achieve the END-TB objectives by the year 2035.

Development and Evaluation of a Promising Biomarker for Diagnosis of Latent and Active Tuberculosis Infection

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]).Conclusions:Our study revealed that CP19128P is a potential MEBDBfor the diagnosis of LTBI andATB.Our findings suggest a promising strategy for developing novel,accurate,and sensitive diagnostic biomarkers and identifying new targets for TB diagnosis and management.

T-SPOT.TB检测白塞病(BD)患者潜伏结核感染(LTBI)的临床意义及随访观察

目的探讨连续的结核分枝杆菌特异性T细胞检测(T-SPOT.TB)技术对白塞病(Behcet’s disease,BD)患者中潜伏结核感染(latent tuberculosis infection,LTBI)的辅助诊断价值。方法对225例BD患者进行T-SPOT.TB检测,结果阳性但无结核临床表现的BD患者为LTBI。根据检测结果分为LTBI组(66例)和非LTBI组,比较两组患者临床资料。对LTBI组患者给予预防性抗结核药物治疗并每3个月随访1次。诊断标准参照1990年BD国际诊断标准。结果 BD患者中LTBI感染率为29.3%(66/225)。LTBI组患者口腔溃疡发生的频率、次数及口腔溃疡的范围均明显高于非LTBI组(P值分别为0.008、<0.001和0.001);LTBI组患者外阴溃疡及眼炎的发生率明显高于非LTBI组(P值分别为<0.001和0.001)。两组之间其他临床资料及实验室检查的差异无统计学意义。LTBI组患者随访的中位时间为27.9(3～58)个月,未发现活动性结核病发生。结论 T-SPOT.TB可应用于BD患者LTBI的筛查,其LTBI感染率高于健康人群(<20%)的整体水平,对合并LTBI的BD患者进行预防性抗结核治疗后未见活动性结核病的发生。

潜伏性结核感染预防性治疗中的医学困境及解决策略

潜伏性结核感染有发展为活动性结核病可能,长周期的预防性抗结核治疗存在诊疗方案不统一、医疗费用高、各种不同程度的药物不良反应等问题。以西安市某结核病专科医院2021—2023年潜伏性结核感染门诊患者为研究对象,分析讨论潜伏性结核感染在预防性治疗中面临的医学困境。针对目前潜伏性结核感染患者人次逐年成倍增加、患病人群年轻化、以女性为主、≥90%患者为自费支付这些现状,需制定潜伏性结核感染诊疗标准、减少不良反应发生;保证患者对长周期规范性治疗的充分知情;完善医保支付范畴,减少个人经济负担,尤其对育龄期妇女进行专项资助等,为潜伏性结核感染的临床诊疗和有效防控提供实践参考。