Active Tuberculosis Disease Research Articles

Levofloxacin for the Prevention of Multidrug-Resistant Tuberculosis in Vietnam

BackgroundPrevention of drug-resistant tuberculosis is a global health priority. However, trials evaluating the effectiveness of treating Mycobacterium tuberculosis infection among contacts of persons with drug-resistant tuberculosis are lacking.MethodsWe conducted a double-blind, randomized, controlled trial comparing 6 months of daily levofloxacin (weight-based doses) with placebo to treat M. tuberculosis infection. The trial population comprised household contacts of persons with bacteriologically confirmed rifampicin-resistant or multidrug-resistant (MDR) tuberculosis in Vietnam. Contacts of any age with a positive tuberculin skin test or immunologic impairment were eligible. The primary end point was bacteriologically confirmed tuberculosis within 30 months. Secondary end points included grade 3 or 4 adverse events, death from any cause, and acquired drug resistance.ResultsOf 3948 persons screened for eligibility, 61 (1.5%) had coprevalent tuberculosis (defined as active tuberculosis disease diagnosed before randomization) and 2041 underwent randomization. Of these 2041 participants, 1995 (97.7%) completed 30 months of follow-up, had a primary end-point event, or died. Confirmed tuberculosis occurred in 6 participants (0.6%) in the levofloxacin group and 11 (1.1%) in the placebo group (incidence rate ratio, 0.55; 95% confidence interval [CI], 0.19 to 1.62); this difference was not significant. There was little difference in grade 3 or 4 adverse events between the two groups (risk difference, 1.0 percentage point; 95% CI, −0.3 to 2.4). Adverse events of any grade were reported in 306 participants (31.9%) taking levofloxacin and 125 (13.0%) taking placebo (risk difference, 18.9 percentage points; 95% CI, 14.2 to 23.6). No acquired fluoroquinolone resistance was observed.ConclusionsAlthough the incidence of tuberculosis was lower in the levofloxacin group than in the placebo group at 30 months, the difference was not significant. (Funded by the National Health and Medical Research Council of Australia; VQUIN MDR Australia New Zealand Clinical Trials Registry number, ACTRN12616000215426.)

Dendritic Cell Vaccine Harboring Inactivated Mycobacteria Induces Immune Protection Against Tuberculosis in Murine Models and is Well Tolerated in Humans

The limited success of tuberculosis (TB) control measures reflects the inadequacy of Bacille Calmette‐Guérin (BCG), the only licensed TB vaccine. There is a recent resurgence of interest in intravenous administration of BCG. However, direct injection of live BCG bacteria into the bloodstream of human beings is not likely to be practical due to safety concerns. In this study, it is showed that debris of BCG‐infected macrophages induces activation and maturation of dendritic cells (DCs) in vitro, and an intravenous DCs vaccine phagocytosing noninfective cell debris induces robust antigen‐specific T‐cell immune responses and immune protection against Mycobacterium tuberculosis infection in murine models. Further, an investigator‐initiated clinical trial shows the safety of a DCs vaccine harboring the noninfective Mycobacterium vaccae vaccine. Infusions of naive DCs and DCs harboring Mycobacterium vaccae are well tolerated and safe in six active TB patients. Tests of the peripheral blood mononuclear cells of a patient who receives two doses of DCs vaccine infusion show enhanced secretion of IFN‐γ, IL‐2, IL‐17, and TNF‐α in both CD4 and CD8 T cells. The study provides evidence that DC‐based vaccines harboring inactivated mycobacteria can expand T‐cell immune responses in TB‐infected mice and are well tolerated in patients with active TB disease.

Predictive metabolite signatures for risk of progression to active TB from QuantiFERON supernatants of Household Contacts of TB patients

The identification of individuals with the greatest risk of progression to active tuberculosis (TB) disease from the huge reservoir of Mycobacterium tuberculosis (Mtb) infected individuals continues to remain an arduous ascent in the global effort to control TB. In a two-year prospective study, we analysed metabolic profiles in the unstimulated and TB antigen stimulated QuantiFERON supernatants of 14 household contacts (HHCs) who progressed to TB (Progressors) and 14 HHCs who remained healthy (Non-Progressors). We identified 21 significantly dysregulated metabolites in the TB antigen-stimulated QuantiFERON supernatants of Progressors, of which the combination of Malic acid and N-Arachidonoylglycine had maximum AUC of 0.99. Eighteen significantly dysregulated metabolites were identified in the unstimulated QuantiFERON supernatants of Progressors, among which the combination of Orotic acid and the phosphatidylcholines PC (O-34:1), PC (O-18:1(9Z)/16:0), PC (O-18:1(11Z)/16:0) had the maximum AUC of 0.98. Most of the dysregulated metabolites belonged to the pathways of fatty acid metabolism, lipid metabolism and nitric oxide metabolism. Validation of these metabolic signatures in large, diverse cohorts would pave way for targetted intervention of TB disease.

Active tuberculosis disease among people living with HIV on ART who completed tuberculosis preventive therapy at three public hospitals in Uganda.

Tuberculosis (TB) preventive therapy (TPT) reduces the incidence of TB among people living with the human immunodeficiency virus (PLHIV). However, despite an increase in TPT uptake, TB/HIV coinfection remains stagnant in Uganda especially in areas of increasing HIV incidence such as the Bunyoro sub-region. This study was a retrospective review records (antiretroviral therapy [ART] files) of PLHIV who were active on ART and completed TPT in 2019/2020 at three major hospitals in the Bunyoro sub-region, Uganda: Masindi General Hospital, Hoima Regional Referral Hospital, and Kiryandongo General Hospital. The sample size (987) for each facility was determined using a proportionate sampling method to ensure the study's power and precision. Factors independently associated with acquiring TB disease post TPT were determined using modified Poisson regression analysis. An adjusted prevalence risk ratio (aPRR) with corresponding 95% confidence intervals were reported. The participants' mean age was 38.23 (±11.70) and the majority were female (64.94%). Overall, 9.63% developed active TB disease post TPT completion. In the adjusted analysis, factors associated with active TB disease were a history of an unsuppressed viral load after TPT (aPRR 4.64 (2.85-7.56), p<0.001), opportunistic infections after TPT completion (aPRR 4.31 (aPRR 2.58-7.2), p<0.001), a history of TB active TB disease (aPRR 1.60 (1.06-2.41), p = 0.026), and chronic illness during or after TPT (aPRR 1.68 (1.03-2.73), p = 0.038). To reduce the development of TB disease post TPT thereby improving the effectiveness of TPT, ART adherence should be emphasized to resolve viral suppression and active management of chronic and opportunistic infections. Further clinical management consideration and research is needed for PLHIV who receive TPT but have a previous history of TB disease.

Association of TLR-2 gene polymorphisms with susceptibility to Pulmonary Tuberculosis at Northwest Ethiopian population, a case control study.

Background: Tuberculosis is one of the leading causes of mortality and morbidity worldwide. Polymorphisms in the TLR-2 gene have a diverse influence on the innate immune response and may result in the susceptibility of active pulmonary tuberculosis diseases among particular families, ethnicities, and races. However, the genetic variation in TLR2 in the susceptibility to PTB in our population has not been previously investigated. Thus, this study assesses the association of TLR-2 gene polymorphisms with susceptibility to PTB in Northwest Ethiopian population.

Discovery of a blood-based miRNA signature that can predict onset of active tuberculosis among household contacts of TB patients

BackgroundNon-sputum based predictive biomarkers capable of identifying individuals with high risk of progression to active tuberculosis (TB) are critical for global TB control. MicroRNAs (miRNAs) are significant regulators involved in TB pathogenesis and hence we aimed to identify a miRNA signature capable of predicting progression to TB disease.MethodsWe compared the differential miRNA expression profile of QuantiFERON supernatants of TB Progressors, defined as healthy household contacts (HHCs) of TB patients, who developed active TB disease during a 2-year follow-up period, and Non-progressors defined as HHCs from the same longitudinal cohort who did not develop TB disease during the entire follow-up period, using the nanostring nCounter platform. Receiver Operator Characteristic (ROC) analysis was performed to evaluate the diagnostic accuracy of the identified miRNA biomarkers, followed by random forest analysis to determine the best predictive model.ResultsWe identified 30 differentially regulated miRNAs between the two groups. Of these, hsa-miR-585-3p and hsa-miR-92a-3p were up-regulated with a maximum fold change of 1.74 and 1.71 respectively, while hsa-miR-223-3p and hsa-miR-451a were down-regulated by −2.05 and −2.04 fold respectively. Random forest analysis revealed that hsa-miR-181a-5p, hsa-miR-204-5p, hsa-miR-197-3p, hsa-miR-92a-3p, hsa-miR-451a, hsa-miR-24-3p, and hsa-miR-487a-3p exhibited 100% accuracy in identifying Progressors. This panel of 7 miRNAs demonstrated excellent diagnostic performance characteristics with 100% sensitivity and specificity.ConclusionWe propose that the identified miRNA signature has the potential to serve as a very useful tool for early identification of individuals who bear the highest risk of progression to TB, so that they can be targeted for timely intervention.

Indole Propionic Acid (IPA), A Gut Microbiota-Derived Metabolite, in Active Pulmonary Tuberculosis (TB) Infection: A Case Control Study

Introduction: A metabolomics study revealed that the tryptophan (Trp) pathway is upregulated in tuberculosis (TB) infection. Indole propionic acid (IPA) is a gut microbiota-derived tryptophan metabolite with antimycobacterial properties through TrpE inhibition and as ligand for AhR in in vitro and in vivo studies. TB infection is associated with gut dysbiosis. However, plasma IPA levels and related factors in active TB patients have not yet been explored. This study aimed to determine the differences and correlations between plasma IPA levels and patient characteristics (age, gender, BMI and GeneXpert result), IPA-producing gut microbiota (Clostridium sporogenes, Lactobacillus sp., and Peptostreptococcus anaerobius), and IFN-γ concentrations in active TB patients and healthy subjects. Materials and methods: A case-control study was performed in 29 active TB patients and 30 healthy controls (HCs) in Aceh, Indonesia. The plasma IPA and IFN-γ levels were measured by ELISA, and the relative abundance of gut microbiota was determined by quantitative PCR (qPCR). The results and discussion: Increased plasma IPA levels (median (IQR) of 22.2 pmol/L (21.3 - 23.9) vs. 18.9 pmol/L (17 - 22.8), p 0.000) were associated with active TB according to the adjusted model (AOR 1.36 (95 % CI 0.37 - 5.1)). Increase of plasma IPA level in higher mycobacterial load patients was found. Higher plasma IPA was positively associated with female, normo- and overweight status, and higher relative abundance of C. sporogenes. The metabolite could be used to discriminate active TB disease at a cutoff of 21.40 pmol/L (72 % sensitivity, 70 % specificity and AUC 0.77). Dysbiosis in IPA-producing bacteria was showed in active TB patients. Conclusion: Plasma IPA could be considered as TB biomarker, and it may also influence disease progression. Future works are needed to validate plasma IPA as biomarker in LTBI and other respiratory infection, as well as its role as biomarker of treatment monitoring response. HIGHLIGHTS The upregulation of the tryptophan (Trp) pathway in tuberculosis infection. Indole propionic acid (IPA) is a Trp metabolite with antimycobacterial properties Higher plasma IPA levels were found in TB patients than in healthy subjects. Dysbiosis of several IPA-producing gut microbiota was revealed in this study. GRAPHICAL ABSTRACT

New admissions and asymptomatic TB cases seem to fuel TB epidemic in prisons, a cross sectional survey in Tanzania.

There is an increased risk for tuberculosis (TB) infection and disease progression in prison settings. TB prevalence in prisons in low- and middle-income countries have been measured to be up to 50 -times higher than in the general population. The aim of the study was to perform active TB screening and estimate the burden of TB in central prisons in Tanzania mainland. We performed TB active case finding in five central prisons, Keko, Segerea, Ukonga, Butimba and Ruanda prison in Tanzania, using the Xpert on early morning or spot sputum sample from inmates and new entries between April 2014 and July 2015. A questionnaire that asked about the symptoms and risk factors for TB was administered before a sputum sample was collected. Out of 13,868 incarcerated individuals tested, 13,763 had valid results. TB prevalence among tested was 1550 per 100,000 population (214/13,763); new admissions contributed to the majority (61.68%) of TB cases, but prevalence was higher among inmates (1.75%) compared to new admissions (1.45%). Ukonga, an urban prison which incarcerates long-term convicted inmates had the highest prevalence of 4.02%. Male gender (OR = 2.51, p<0.001), repeated incarcerations (OR = 2.85, p<0.001), history of TB treatment (OR = 1.78, p = 0.002), TB symptoms (OR = 2.78, p = 0.006) and HIV infection (OR = 2.86, p = 0.002) were associated with positive TB results. New admissions could be the driving force of the TB epidemic in the penitentiary system. However, prison environments remain a major risk factor for developing active TB disease.

Advances in tuberculosis biomarkers: unravelling risk factors, active disease and treatment success.

Tuberculosis (TB) is a major global health threat and demands improved diagnostic and treatment monitoring methods. Conventional diagnostics, such as sputum smear microscopy and culture, are limited by slow results and low sensitivity, particularly in certain patient groups. Recent advances in biomarker research offer promising solutions in three key areas: risk of disease, diagnosis of active disease and monitoring of treatment response. For risk assessment, novel genetic signatures and metabolites show potential in predicting the progression from TB infection to active TB. A 16-gene signature, for example, predicts this progression with significant accuracy. In diagnosing active TB, RNA-based transcriptomic signatures provide higher diagnostic accuracy than traditional methods. These signatures, such as a three-gene RNA sequence, effectively differentiate active TB from other diseases and infections, addressing issues of specificity and sensitivity. Monitoring treatment response is crucial, given the varying response rates in treating TB. Emerging biomarkers focus on bacterial burden and host response. They offer more precise and timely assessments of treatment efficacy, enhance personalised treatment approaches and potentially improve patient outcomes. These advancements in biomarkers for TB risk, diagnosis and treatment response represent significant steps towards more effective TB management and control, aligning with global efforts to decrease the burden of TB. Here we aim to highlight several promising biomarkers used to predict risk of disease progression, active TB disease and treatment success.

Pulmonary and Hepatic Tuberculosis in a Single Individual

Tuberculosis (TB) is a contagious bacterial infection caused by the Mycobacterium tuberculosis bacterium. It primarily affects the lungs but can also target other parts of the body, known as extra pulmonary tuberculosis (EPTB). TB spreads through the air when an infected person coughs, sneezes, or talks.[1] Asia bears a significant burden of TB cases worldwide, accounting for approximately 60% of the global TB incidence. The region's large population, varying health systems, and socioeconomic factors contribute to this high prevalence. Countries like India, China, Indonesia, and Bangladesh have particularly high TB rates.[1,2] India has the highest number of TB cases globally, making it a major concern for public health. Factors such as poverty, overcrowding, inadequate healthcare infrastructure, and limited access to diagnostics and treatment contribute to the high prevalence. The Indian government has implemented various initiatives to combat TB and improve prevention, diagnosis, and treatment services.[3] Despite the rapid decline in tuberculosis (TB) prevalence globally following the introduction of anti-TB medications in the 1940s, recent years have witnessed a resurgence in TB incidence rates. This resurgence can be attributed to various factors including governmental complacency, inadequate public health interventions, HIV coinfection, intravenous drug abuse, multidrug resistance, and an increasing number of immunocompromised individuals.[1] As a consequence, hepatic tuberculosis, which is part of disseminated tuberculosis, has been observed in 50-80% of cases, reflecting the growing prevalence of TB. Hepatic TB often presents challenges in clinical diagnosis due to its atypical symptoms and imaging findings, leading to potential misdiagnosis and delayed treatment initiation.[2-3] Through our literature review, it became apparent that the majority of existing studies are comprised of case reports, highlighting a lack of comprehensive understanding in diagnosing and treating hepatic tuberculosis.[4] An immunocompromised host refers to an individual with a weakened immune system, making them more susceptible to infections and diseases. This can result from conditions such as HIV/AIDS, chemotherapy, organ transplantation, or certain medications that suppress the immune response.[5] Immunocompromised individuals face a higher risk of contracting TB due to their weakened immune defenses. The risk of developing active TB disease is significantly increased in this population. Timely diagnosis and appropriate management are crucial to prevent serious complications and mortality.[5] In immunocompromised hosts, TB can manifest in various extra pulmonary sites outside the lungs. Common sites of EPTB involvement include the lymph nodes, bones and joints, central nervous system, genitourinary system, gastrointestinal tract, and skin. Prompt recognition and appropriate treatment are essential to prevent complications and morbidity associated with EPTB.[6] By understanding the prevalence of TB in Asia and India, the impact on immunocompromised individuals, the definition of disseminated TB, and the sites of EPTB in immunocompromised hosts, we can better address and manage this public health issue. Increased awareness, early diagnosis, and effective treatment strategies are crucial in reducing the burden of TB and improving patient outcomes.[7]

Test and treat approach for tuberculosis infection amongst household contacts of drug-susceptible pulmonary tuberculosis, Mumbai, India.

Mumbai is one of the most densely populated areas in the world and is a major contributor to the tuberculosis (TB) epidemic in India. A test and treat approach for TB infection (TBI) amongst household contacts (HHC) is part of the national policy for TB preventive treatment (TPT). However, in practice, the use of interferon-gamma release assay (IGRA) tests for infection are limited, and prevalence of TBI in Mumbai is not known. We conducted a cross-sectional study among HHCs exposed to persons with microbiologically-confirmed, drug-susceptible pulmonary TB that were notified for antituberculosis treatment in Mumbai, India during September-December, 2021. Community-based field workers made home visits and offered IGRA (QuantiFERON-TB® Gold In-Tube Plus) tests to HHC aged 5 years and older. After ruling out active TB disease, HHC with IGRA-positive test results were referred for TPT. All HHC were monitored for at least 24 months for progression to active TB disease. Among 502 HHCs tested, 273 (54%) had IGRA-positive results. A total of 254 (93%) were classified as TBI and were eligible for TPT, of which 215 (85%) initiated TPT, and 194 (90%) completed TPT successfully. There was substantial variation in rates of TBI per household. In 32% of households, all HHC (100%) were IGRA positive and in 64% of households >50% of HHC were infected. In all, 22 HHCs (4%; 22/558) were diagnosed with TB disease; of these, five HHC were diagnosed during follow up, of which three were IGRA positive and had no evidence of disease at initial screening but chose not to initiate TPT. A test and treat strategy for HHC resulted in the detection of a substantial proportion of TBI and secondary TB cases. Home-based IGRA testing led to high participation rates, clinical evaluations, TPT initiation, and early diagnoses of additional secondary cases. A community-focused, test and treat approach was feasible in this population and could be considered for broader implementation.

Relevance of antigen-induced IL-6 and mitogen-induced or spontaneous IFN-γ secretions in whole blood cultures for detection of Mycobacterium tuberculosis infection and disease.

For an effective control of tuberculosis (TB), there is a persistent need for biomarkers that can report true estimates of TB infection (TBI) and predict its progression towards active TB disease. We investigated whether the cell-mediated immune responses to Mycobacterium tuberculosis (Mtb) antigens could provide such biomarkers. The study subjects (n = 174) comprised a cohort of smear-positive, drug-sensitive, HIV-negative pulmonary TB patients (n = 54) and their household contacts (HC, n = 120). Whole blood cultures, in the presence or absence of Mtb antigens- membrane (MtM), purified protein derivative (PPD) and alpha-crystallin (Acr), or the mitogen PHA were subjected to determinations, by flow cytometry, for T cell proliferative and, by ELISA, for IFN-γ, TNF-α, and IL-6 cytokine responses. Additionally, serum levels of the three cytokines were also estimated. The strongest cell-proliferative and cytokine responses were induced by MtM and IL-6 was the most abundantly produced cytokine. While none of the responses induced by Mtb antigens or the serum cytokines levels could discriminate between TB and HC, the exvivo cytokine responses induced by PHA or 'spontaneously' could apparently do so. The concentrations of IFN-γ induced by PHA in TB blood cultures were significantly lower than in HC cultures (AUC = 0.72). Conversely, the spontaneous IFN-γ or TNF-α secretions in TB cultures were significantly higher than in HC cultures (AUC = 0.66). Our results suggest that IL-6 responses to MtM could be a sensitive indicator of TBI, and low levels of PHA-induced or high levels of spontaneous IFN-γ secretions in HC blood cultures may indicate a progressive infection.

HBHA induces IL-10 from CD4+ T cells in patients with active tuberculosis but IFN-γ and IL-17 from individuals with Mycobacterium tuberculosis infection.

To effectively control tuberculosis (TB), it is crucial to distinguish between active TB disease and latent TB infection (LTBI) to provide appropriate treatment. However, no such tests are currently available. Immune responses associated with active TB and LTBI are dynamic and exhibit distinct patterns. Comparing these differences is crucial for developing new diagnostic methods and understanding the etiology of TB. This study aimed to investigate the relationship between pro- and anti-inflammatory CD4+ cytokine production following stimulation with two types of latency-associated Mycobacterium tuberculosis (M.tb) antigens to allow differentiation between active TB and LTBI. Cryopreserved PBMCs from patients with active TB disease or LTBI were stimulated overnight with replication-related antigen [ESAT-6/CFP-10 (E/C)] or two latency-associated antigens [heparin-binding hemagglutinin (HBHA) and alpha-crystallin-like protein (Acr)]. Responses were analyzed using multiparameter flow cytometry: active TB disease (n=15), LTBI (n=15) and ELISA: active TB disease (n=26) or LTBI (n=27). CD4+ central memory T cells (Tcm) specific to E/C and CD4+ effector memory T cells specific to Acr and HBHA were higher in LTBI than in TB patients. IFN-γ+Tcm and IL-17+ Tem cells was higher in the LTBI group (p= 0.012 and p=0.029 respectively), but IL-10+ Tcm was higher in the active TB group (p= 0.029) following HBHA stimulation. Additionally, following stimulation with HBHA, IL-10 production from CD4+ T cells was significantly elevated in patients with active TB compared to those with LTBI (p= 0.0038), while CD4+ T cell production of IL-17 and IFN-γ was significantly elevated in LTBI compared to active TB (p= 0.0076, p< 0.0001, respectively). HBHA also induced more CCR6+IL-17+CD4Tcells and IL-17+FoxP3+CD25+CD4Tcells in LTBI than in TB patients (P=0.026 and P=0.04, respectively). HBHA also induced higher levels of IFN-γ+IL-10+CD4+ T cells in patients with active TB (Pp=0.03) and higher levels of IFN-γ+IL-17+ CD4+ T cells in those with LTBI (p=0.04). HBHA-specific cytokine production measured using ELISA showed higher levels of IFN-γ in participants with LTBI (P=0.004) and higher levels of IL-10 in those with active TB (P=0.04). Stimulation with HBHA and measurement of CD4+ T cell production of IFN-γ, IL-10, and IL-17 could potentially differentiate active TB from LTBI. The characteristics of cytokine-expressing cells induced by HBHA also differed between participants with active TB and LTBI.

Effects of the Beijing genotype on latent tuberculosis infection, TB disease risk, and clustering of TB cases

BackgroundThe Beijing genotype of Mycobacterium tuberculosis (Mtb) has sparked debate regarding its virulence and transmissibility. This study contributes to this discussion by assessing its effect on the risk of latent tuberculosis infection (LTBI), active tuberculosis (TB) disease among contacts, and clustering of known TB cases. MethodsWe conducted a retrospective cohort study using the records of 4457 culture-confirmed TB patients and their contacts (20,448) reported to the Florida Department of Health between 2009 and 2023. Univariate and multivariate analyses were used to evaluate the effect of the Beijing strain on LTBI, active TB risk among contacts, and case clustering. ResultsOur study revealed no significant difference in transmissibility between the Beijing and non-Beijing genotypes among contacts. LTBI prevalence was 19.9%, slightly higher in non-Beijing than Beijing genotypes (20.2% vs. 15.5%, p < 0.001). The prevalence of active TB was 1.8%, with no significant difference between the Beijing and non-Beijing genotypes (1.4% vs. 1.8%, p = 0.296). Increased LTBI risk was associated with older age, male sex, Hispanic ethnicity, multidrug-resistant TB exposure, household exposure, and a longer exposure duration. Active TB risk was higher for males, HIV-positive individuals, and contacts with more prolonged exposure to index cases. The Beijing genotype was associated with increased TB case clustering (aOR = 1.98, 95%CI: 1.53, 2.55, p < 0.001) as compared to the non-Beijing genotypes. US birthplace (aOR = 2.75, 95%CI: 2.37, 3.19, p < 0.001), pulmonary disease (aOR = 1.27, 95%CI: 1.04, 1.56, p < 0.020), cavitary TB (aOR = 1.25, 95% CI: 1.08, 1.44, p < 0.003), previous year alcohol use (aOR = 1.68, 95%CI: 1.38, 2.04, p < 0.001), and recreational drug use (aOR = 1.32, 95%CI: 1.04, 1.67, p < 0.024) were also associated with an increased risk of TB case clustering. ConclusionWhile the Beijing genotype did not increase the risk of LTBI or active TB among contacts, it showed a higher tendency for case clustering. Hence, interventions should prioritize populations where this genotype is prevalent.

Plasma Immune Biomarkers Predictive of Progression to Active Tuberculosis in Household Contacts of TB Patients.

The progression from Mycobacterium tuberculosis infection to active tuberculosis (TB) disease varies among individuals, and identifying biomarkers to predict progression is crucial for guiding interventions. In this study, we aimed to determine plasma immune biomarker profiles in healthy household contacts of index pulmonary TB (PTB) patients who either progressed to TB or remained as non-progressors. A cohort of household contacts of adults with PTB was enrolled, consisting of 15 contacts who progressed to TB disease and 15 non-progressors. Plasma samples were collected at baseline, 4 months, and 12 months to identify predictive TB progression markers. Our findings revealed that individuals in the progressor group exhibited significantly decreased levels of IFNγ, IL-2, TNFα, IL1α, IL1β, IL-17A, and IL-1Ra at baseline, months 4 and 12. In contrast, the progressor group displayed significantly elevated levels of IFNα, IFNβ, IL-6, IL-12, GM-CSF, IL-10, IL-33, CCL2, CCL11, CXCL8, CXCL10, CX3CL1, VEGF, Granzyme-B and PDL-1 compared to the non-progressor group at baseline, months 4 and 12. ROC analysis identified IFNγ, GM-CSF, IL-1Ra, CCL2 and CXCL10 as the most promising predictive markers, with an AUC of ≥90. Furthermore, combinatorial analysis demonstrated that GM-CSF, CXCL10 and IL-1Ra, when used in combination, exhibited high accuracy in predicting progression to active TB disease. Our study suggests that a specific set of plasma biomarkers GM-CSF, CXCL10 and IL-1Ra, can effectively identify household contacts at significant risk of developing TB disease. These findings have important implications for early intervention and preventive strategies in TB-endemic regions.

Single and Combined Serum Proteins Expressed in TB Infection are Candidates for Point-of-care Diagnostic Testing of Active TB Patients in Lambaréné, Gabon.

Point-of-care testing using nonsputum samples like serum or plasma proteins can improve tuberculosis (TB) patients access to a definitive diagnosis, especially in resource-constrained and remote areas. Recently, approximately 400 proteins were identified as playing a role in the pathogenesis of TB, offering a translational clinical research repository for TB. In a previous manuscript, we proved the potential use of these proteins for point-of-care testing for active TB diagnosis. The present work aims to confirm the performance of single and combination proteins to select the best candidate biomarkers for further development as a diagnostic testing tool for active TB. Seventy-four participants were assessed on the diagnostic performance of 17 single proteins and combinations of 2 to 4 proteins to diagnose active TB. The selection criteria included differential expression of the proteins between active TB and community-acquired pneumonia (CAP) and a performance rate ≥70% for active TB. SULT4A1, WASPF3, SPTLC1, FAM107B, SORCS2, and CYTOb561 were differentially expressed in TB compared to CAP patients. Two single proteins, SULT4A1 and WASPF3, performed ≥70% to discriminate active TB from CAP patients. The diagnostic performance of 3 protein-based combinations of active TB was 81% after leave-one-out cross-validation. Single proteins and 3 protein-based combinations are candidate biomarkers for diagnosing active TB disease. A large and prospective study will confirm their performance as complementary diagnostic tools to rapid diagnostic methods for detecting active TB.

Exosomal Small RNA Sequencing Profiles in Plasma from Subjects with Latent Mycobacterium tuberculosis Infection.

Despite huge efforts, tuberculosis (TB) is still a major public health threat worldwide, with approximately 23% of the human population harboring a latent TB infection (LTBI). LTBI can reactivate and progress to active and transmissible TB disease, contributing to its spread within the population. The challenges in diagnosing and treating LTBI patients have been major factors contributing to this phenomenon. Exosomes offer a novel avenue for investigating the process of TB infection. In this study, we conducted small RNA sequencing to investigate the small RNA profiles of plasma exosomes derived from individuals with LTBI and healthy controls. Our findings revealed distinct miRNA profiles in the exosomes between the two groups. We identified 12 differentially expressed miRNAs through this analysis, which were further validated via qRT-PCR using the same exosomes. Notably, six miRNAs (hsa-miR-7850-5p, hsa-miR-1306-5p, hsa-miR-363-5p, hsa-miR-374a-5p, hsa-miR-4654, has-miR-6529-5p, and hsa-miR-140-5p) exhibited specifically elevated expression in individuals with LTBI. Gene ontology and KEGG pathway analyses revealed that the targets of these miRNAs were enriched in functions associated with ferroptosis and fatty acid metabolism, underscoring the critical role of these miRNAs in regulating the intracellular survival of Mycobacterium tuberculosis (Mtb). Furthermore, our results indicated that the overexpression of miR-7850-5p downregulated the expression of the SLC11A1 protein in both Mtb-infected and Mtb-uninfected THP1 cells. Additionally, we observed that miR-7850-5p promoted the intracellular survival of Mtb by suppressing the expression of the SLC11A1 protein. Overall, our findings provide valuable insights into the role of miRNAs and repetitive region-derived small RNAs in exosomes during the infectious process of Mtb and contribute to the identification of potential molecular targets for the detection and diagnosis of latent tuberculosis.

Thyroid tuberculosis mimicking multinodular goiter: a case report

BackgroundMycobacterium tuberculosis is the second most common infectious cause of death in adults worldwide. The ability of this organism to efficiently establish latent infection has enabled it to spread to nearly one-third of individuals worldwide. Approximately 8 million new cases of active tuberculosis disease occur each year, leading to about 1.7 million deaths. The disease incidence is magnified by the concurrent epidemic of human immunodeficiency virus infection. A total of 1.3 million people died from tuberculosis in 2022. In 2022, an estimated 10.6 million people fell ill with tuberculosis worldwide, including 5.8 million men, 3.5 million women, and 1.3 million children. We report a case of thyroid tuberculosis presenting as multinodular goiter. Neck ultrasound was done and revealed abscess collection on the background of multinodular colloid goiter. The diagnosis of thyroid tuberculosis was confirmed by a positive GeneXpert of the pus sample and the presence of extensive caseous necrosis on cytopathology examination. Furthermore, anterior neck swelling may provide a diagnostic challenge by clinically mimicking multinodular goiter or thyroid neoplasms. Owing to its rarity and its tendency to pose a clinical diagnostic challenge, we decided to report it.Case presentationA 60-year-old retired female Ethiopian high-school teacher presented to University of Gondar Hospital, Gondar, Ethiopia with firm, nontender multinodular anterior neck swelling measuring at largest 2 × 3 cm that moves with swallowing. GeneXpert of the pus sample and cytopathology examination confirmed the diagnosis of thyroid tuberculosis, and the patient was started on 2 rifampicin−ethambutol−isoniazid−pyrazinamide/4 rifampicin−isoniazid 3 tablets by mouth/day, which is defined as the preferred first-line anti-tuberculosis regimen in Ethiopia, and pyridoxine 50 mg by mouth per day for 6 months. Since then, she has been followed with regular liver function tests. The patient has shown a smooth course with no significant adverse effects encountered. Currently, the patient has completed her anti-tuberculosis treatment and is doing well.ConclusionIn the clinical evaluation of a patient with anterior neck swelling, tuberculosis must be considered as a differential diagnosis in subjects from endemic areas for early diagnostic workup and management.

Scoping review of post-TB pulmonary vascular disease: Proceedings from the 2nd International Post-Tuberculosis Symposium.

Tuberculosis (TB) may cause significant long-term cardiorespiratory complications, of which pulmonary vascular disease is most under-recognized. TB is rarely listed as a cause of pulmonary hypertension (PH) in most PH guidelines, yet PH may develop at various stages in the time course of TB, from active infection through to the post-TB period. Predisposing risk factors for the development of PH are likely multifactorial, involving active TB disease and post-TB lung disease (PTLD), host-related and environment-related factors. Moreover, post-TB PH should likely be classified in Group 3 PH, with the pathogenesis similarly complex and multifactorial as other Group 3 PH causes. Identifying risk factors that predispose to post-TB PH may aid in developing risk stratification criteria for early identification and referral for confirmatory diagnostic tests. Given that universal screening for PH in TB survivors may be impractical and unfeasible, a targeted screening approach for high-risk individuals would be sensible. In this scoping review of post-TB PH, resulting from the proceedings of the 2nd International Post-Tuberculosis Symposium, we aim to describe the epidemiology, risk factors, and pathophysiology of post-TB PH. We emphasize diagnosing PH with an alternative set of diagnostic guidelines in resource-constrained settings where right heart catheterization may not be feasible. Research to describe the burden and distribution of post-TB PH should be prioritized as there is a current gap in knowledge regarding the prevalence and incidence of post-TB PH among persons with TB.

Comparison of gene set scoring methods for reproducible evaluation of tuberculosis gene signatures

BackgroundBlood-based transcriptional gene signatures for tuberculosis (TB) have been developed with potential use to diagnose disease. However, an unresolved issue is whether gene set enrichment analysis of the signature transcripts alone is sufficient for prediction and differentiation or whether it is necessary to use the original model created when the signature was derived. Intra-method comparison is complicated by the unavailability of original training data and missing details about the original trained model. To facilitate the utilization of these signatures in TB research, comparisons between gene set scoring methods cross-data validation of original model implementations are needed.MethodsWe compared the performance of 19 TB gene signatures across 24 transcriptomic datasets using both rrebuilt original models and gene set scoring methods. Existing gene set scoring methods, including ssGSEA, GSVA, PLAGE, Singscore, and Zscore, were used as alternative approaches to obtain the profile scores. The area under the ROC curve (AUC) value was computed to measure performance. Correlation analysis and Wilcoxon paired tests were used to compare the performance of enrichment methods with the original models.ResultsFor many signatures, the predictions from gene set scoring methods were highly correlated and statistically equivalent to the results given by the original models. In some cases, PLAGE outperformed the original models when considering signatures’ weighted mean AUC values and the AUC results within individual studies.ConclusionGene set enrichment scoring of existing gene sets can distinguish patients with active TB disease from other clinical conditions with equivalent or improved accuracy compared to the original methods and models. These data justify using gene set scoring methods of published TB gene signatures for predicting TB risk and treatment outcomes, especially when original models are difficult to apply or implement.