Tuberculosis Progression Research Articles

The Trend of Tuberculosis Case Notification Rates from 1995 to 2022 by Country Income and World Health Organization Region

Over the past 27 years, three major global TB control strategies have been implemented, and it is important at this stage to evaluate their impact on tuberculosis (TB) case notification rates (CNRs). This study, therefore, analyzed TB CNR trends from 1995 to 2022 across 208 countries and islands, using data from the WHO Global TB Programme database. Countries were classified by income level and population size based on World Bank criteria. The analysis revealed significant disparities in TB CNRs across income groups: Low-income, lower-middle-income, and upper-middle-income countries consistently reported higher CNRs compared to high-income countries. Regional analysis further demonstrated notable variations influenced by both economic and geographical factors. These findings reaffirm the strong link between TB and poverty, underscoring the need for a holistic approach to combat the disease. Efforts must extend beyond enhancing health care access and delivery to addressing the social determinants that drive TB transmission and progression.

Benzothiazinone analogs as Anti-Mycobacterium tuberculosis DprE1 irreversible inhibitors: Covalent docking, validation, and molecular dynamics simulations.

Mycobacterium tuberculosis is a lethal human pathogen, with the key flavoenzyme for catalyzing bacterial cell-wall biosynthesis, decaprenylphosphoryl-D-ribose oxidase (DprE1), considered an Achilles heal for tuberculosis (TB) progression. Inhibition of DprE1 blocks cell wall biosynthesis and is a highly promising antitubercular target. Macozinone (PBTZ169, a benzothiazinone (BTZ) derivative) is an irreversible DprE1 inhibitor that has attracted considerable attention because it exhibits an additive activity when combined with other anti-TB drugs. Herein, 754 BTZ analogs were assembled in a virtual library and evaluated against the DprE1 target using a covalent docking approach. After validation of the employed covalent docking approach, BTZ analogs were screened. Analogs with a docking score less than -9.0 kcal/mol were advanced for molecular dynamics (MD) simulations, followed by binding energy evaluations utilizing the MM-GBSA approach. Three BTZ analogs-namely, PubChem-155-924-621, PubChem-127-032-794, and PubChem-155-923-972- exhibited higher binding affinities against DprE1 compared to PBTZ169 with ΔGbinding values of -77.2, -74.3, and -65.4 kcal/mol, versus -49.8 kcal/mol, respectively. Structural and energetical analyses were performed for the identified analogs against DprE1 throughout the 100 ns MD simulations, and the results demonstrated the great stability of the identified BTZ analogs. Physicochemical and ADMET characteristics indicated the oral bioavailability of the identified BTZ analogs. The obtained in-silico results provide promising anti-TB inhibitors that are worth being subjected to in-vitro and in-vivo investigations.

Decoding differentially expressed genes to identify potential immunity associated biomarkers in Tuberculosis: An integrative bioinformatics approach

Tuberculosis (TB) poses a significant threat to the Indian population, with India accounting for 20 % of the global TB cases. The current study aims to identify molecular biomarkers for better diagnostics by comparing the transcriptome signatures of healthy individuals against TB-affected individuals. Next-generation sequencing (NGS) tools were used to identify critical differentially expressed genes (DEGs). 302 DEGs were identified based on a logFC threshold of |3| and adjusted p-value < 0.05. STRING database was used to plot the interactions amongst the 302 DEGs. The DEGs were functionally annotated, highlighting numerous physiological functions affected due to the dysregulation of the identified hub genes. TLR4, FCGR1A, ITGAM, LTF, and CXCR2 were the hub genes identified and observed to dysregulate crucial physiological functions. TLR4 has been implicated in the progression of TB in various populations, and the findings of this study will enable researchers to improve the current landscape of diagnostics for TB.

Modulating sonic hedgehog (SHH) pathway to create a rapid CNS-TB model: Facilitating drug discovery

Tuberculous meningitis, a severe complication of Mycobacterium tuberculosis (M. tb) infection, involves the dissemination of bacilli in the brain. This study explored the role of the sonic hedgehog (SHH) signaling pathway in regulating blood-brain barrier (BBB) integrity, M. tb invasion into the central nervous system (CNS), and disease progression of Central Nervous System Tuberculosis (CNS-TB) in a Balb/c mouse model. The modulation of the SHH pathway using agonist Purmorphamine (PUR) and antagonist Cyclopamine (CYC) revealed that CYC treatment led to a rapid and extensive invasion of M. tb in the brain, with bacterial loads increasing by 99 % compared to the untreated-infected group. In contrast, PUR reduced M. tb loads by 50 % and delayed disease progression. Histopathological analysis showed that CYC exacerbated inflammation and immune cell infiltration, while PUR mitigated these responses. Immunohistochemistry demonstrated that CYC caused severe BBB breakdown and reactive gliosis, while PUR partially attenuated this response. Further analysis revealed that CYC upregulated Matrix Metalloproteinase-9 (MMP-9) secretion, a key contributor to BBB disruption. These findings highlight the critical role of the SHH pathway in maintaining BBB integrity and regulating the immunopathological response during CNS-TB, opening up future scope for drug discovery. This Cyclopamine-induced model of rapid M. tb invasion and chronic inflammation provides a new tool for studying CNS-TB pathogenesis and evaluating potential therapeutic interventions targeting the SHH signaling axis. Significance statementUnderstanding how tuberculosis (TB) infection can spread to the brain is crucial, as this “central nervous system TB” (CNS-TB) is a serious and potentially life-threatening health complication. However, studying CNS-TB in humans is very difficult. Animal models are needed to better understand how TB gets into the brain and the resulting damage. This study in mice showed that blocking a signaling pathway called Sonic Hedgehog (SHH) allowed TB to rapidly spread to the brain, damaging the blood-brain barrier and causing severe inflammation. In contrast, activating the SHH pathway helped protect the brain from TB. These findings provide important insights that could lead to new ways to prevent or treat this dangerous form of TB.

Cost-effectiveness of screening with transcriptional signatures for incipient TB among U.S. migrants.

Host-response-based transcriptional signatures (HrTS) have been developed to identify "incipient tuberculosis (TB)". No study has reported the cost-effectiveness of HrTS for post-arrival migrant screening programs in low-incidence countries. To assess the potential health impact and cost-effectiveness of HrTS for post-arrival TB infection screening among new migrants in the United States. We used a discrete-event simulation model to compare four strategies: (1) no screening for TB infection or incipient TB; (2) 'IGRA-only', screen all with interferon gamma release assay (IGRA), provide TB preventive treatment for IGRA-positives; (3) 'IGRA-HrTS', screen all with IGRA followed by HrTS for IGRA-positives, provide incipient TB treatment for individuals testing positive with both tests; and (4) 'HrTS-only', screen all with HrTS, provide incipient TB treatment for HrTS-positives. We assessed outcomes over the lifetime of migrants entering the U.S. in 2019, assuming HrTS met the WHO Target Product Profile (TPP) optimal criteria. We conducted sensitivity analyses to evaluate the robustness of results. The IGRA-only strategy dominated the HrTS-based strategies under both healthcare sector and societal perspectives, with an incremental cost-effectiveness ratio of $78,943 and $89,431 per quality-adjusted life-years (QALY) gained, respectively. This conclusion was robust to varying costs ($15-300) and characteristics of HrTS, and the willingness-to-pay threshold ($30,000-150,000/ QALY gained), but sensitive to the rate of decline in TB progression risk after U.S. entry. Our findings suggest that HrTS meeting the WHO TPP is unlikely to be a cost-effective component of post-arrival screening for migrants entering the U.S.

Vitamin D Receptor Gene Polymorphisms Differentiated Between Tuberculosis Disease and Infection: Causal Association Study.

Latent tuberculosis infection (LTBI) is a critical stage in tuberculosis (TB)control, and few studies have addressed the role of vitamin D receptor(VDR) gene polymorphisms in differentiating between TB and late-onset TB from an immunogenetic perspective. Recruitment of tuberculosis patients and latently infected population in Urumqi, Xinjiang, and use of propensity score matching(PSM) to match the two groups and control confounding to further construct a Bayesian network to analyze causal associations between VDR polymorphisms and tuberculosis disease status. 137 LTBI and 237 TB were obtained through PSM. Logistic regression showed that the VDR gene BsmI locus, TaqI locus, and ApaI locus were associated with a higher risk of TB in a codominant model (P<0.05). Further Bayesian network construction showed that occupation and being a VDR gene BsmI locus were direct influences on TB disease status, and the VDR gene TaqI locus played an indirect role through the BsmI locus, and the probability of TB risk was highest in individuals with manual labour and BsmI locus of the C/T type, which was 84.15%. Bayesian network modelling intuitively revealed that individuals with a C/T type of BsmI locus and physical labour are at high risk of TB compared with TB infection, and they are key factors between with TB disease, providing reference evidence for controlling TB progression.

Assessment of lower respiratory tract microbiota associated with pulmonary tuberculosis in children.

The respiratory microbiota plays a crucial role in the development of tuberculosis (TB). While existing research has underscored imbalances in the respiratory microbiota of adult patients with TB, information regarding the lower respiratory tract (LRT) microbiota in pediatric patients with TB remains scarce. We employed 16S rRNA gene sequencing technology to investigate the LRT microbial communities of 85 children of different ages with active TB of different severities, 33 children with infectious diseases other than TB, and 48 sex- and age-matched healthy children. A marked imbalance in the respiratory microbiota was observed in children with TB, highlighted by reduced alpha diversity and a distinct microbial community structure. Comparative analysis indicated that patients with severe TB exhibited lower Neisseria levels than those with non-severe TB (1.01% vs. 3.93%, respectively; p = .02). Streptococcus and Gemella levels were lower in bacteriologically confirmed TB cases compared with clinically diagnosed cases, and higher in healthy children younger than 10 years old than in the older group. Spearman correlation analysis demonstrated significant associations between the microbiota of the LRT and cytokine concentrations in the sputum of children with TB (e.g., an inverse correlation between Veillonella and interleukin-17A). TB induced significant dysbiosis in the LRT microbiota of children that was associated with disease severity and the immunological response in the respiratory tract. Our findings may offer a deeper understanding of the role of the respiratory microbiome in TB pathogenesis and progression.

Cheminformatics-enhanced discovery of therapeutic agents targeting isocitrate lyase in Mycobacterium tuberculosis infections

Tuberculosis (TB) is a global health challenge; therefore, there is an urgent requirement to develop a novel and more effective anti-TB therapeutic. This study targeted the isocitrate lyase (ICL) protein due to its pivotal role in the pathogenicity of Mycobacterium tuberculosis (Mtb). Virtual screening of 8752 bioactive compounds used an ML-based QSAR model and molecular docking. ADMET testing was performed on the top three hits to identify the compound most closely mimicking a drug molecule. The top hits, 648 and 2785758, showed high binding affinity towards ICL with −7.3 and −7 kcal/mol, comparable to the control. These molecules also showed strong binding with the residue Asp108, which plays a vital role in ICL activity. Molecular dynamics simulations showed stability for 648 and 2785758, comparable to the control compound used in this study. It was found that 648 bound to the protein maintained the RMSD constant and consistent at 0.3 nm for a complete 100 ns simulation. 2785758 showed a comparable RMSD trend to the control. Both 648 and 2785758 showed high RMSF for critical residue Asp108. Further, PCA and FEL confirmed the formation of a stable complex. MM/GBSA estimations of binding free energy indicated that compounds 648 had an elevated level of stability (ΔG TOTAL = −28.11 kcal/mol) and 2785758 (ΔG TOTAL = −21.05 kcal/mol). This study suggests that compounds 648 and 2785758 can potentially affect the activity of ICL, leading to its inactivation and ultimately preventing the progression of tuberculosis. Communicated by Ramaswamy H. Sarma

Dynamic changes of respiratory microbiota associated with treatment outcome in drug-sensitive and drug-resistant pulmonary tuberculosis

BackgroundRespiratory microbiota is closely related to tuberculosis (TB) initiation and progression. However, the dynamic changes of respiratory microbiota during treatment and its association with TB progression remains unclear.MethodsA total of 16 healthy individuals and 16 TB patients (10 drug-sensitive TB (DS-TB) and 6 drug-resistant TB (DR-TB)) were recruited. Sputum samples were collected at baseline for all anticipants and after anti-TB treatment at Month-6 for TB patients. High throughput 16 S RNA sequencing was used to characterize the respiratory microbiota composition.ResultsCompared to the healthy individuals, TB patients exhibited lower respiratory microbiota diversity (p < 0.05). This disruption was alleviated after anti-TB treatment, especially for DS-TB patients. Parvimonas spp. numbers significantly increased after six months of anti-TB treatment in both DS-TB and DR-TB patients (p < 0.05). Rothia spp. increase during treatment was associated with longer sputum-culture conversion time and worse pulmonary lesion absorption (p < 0.05). Besides, Moraxella spp. prevalence was associated with longer sputum-culture conversion time, while Gemella spp. increase was associated with worsening resolving of pulmonary lesions (p < 0.05).ConclusionDynamic changes of respiratory microbiota during anti-TB treatment is closely related to TB progression. The involvement of critical microorganisms, such as Parvimonas spp., Rothia spp., Moraxella, and Gemella spp., appears to be associated with pulmonary inflammatory conditions, particularly among DR-TB. These microorganisms could potentially serve as biomarkers or even as targets for therapeutic intervention to enhance the prognosis of tuberculosis patients.

SARS-CoV-2 coinfection in children with severe airway obstruction due to pulmonary tuberculosis.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic had a significant impact on tuberculosis (TB) control globally, with the number of new TB diagnoses decreasing. Coinfection with some viruses, especially measles, could aggravate TB in children. This is presumably a result of depressed cellular immunity. Reports on children with TB and SARS-CoV-2 coinfection are limited. A retrospective analysis of children up to 13 years old admitted to Tygerberg Hospital, Cape Town, South Africa, from March 2020 to December 2022 with suspected TB-induced airway compression requiring bronchoscopy. Children were included if they presented with severe intrathoracic airway obstruction and/or radiographic evidence of complicated TB. The patients were divided into two groups based on SARS-CoV-2 respiratory polymerase chain reaction results. Demographics, TB exposure, microbiology, SARS-CoV-2 laboratory data, imaging, inflammatory cytokine levels, and bronchoscopy data were collected. Statistical analyses compared SARS-CoV-2 positive and negative groups. Of the 50 children undergoing bronchoscopy for TB airway obstruction, 7 (14%) were SARS-CoV-2 positive. Cough was more prevalent in the SARS-CoV-2 positive group (p = 0.04). There was no difference in TB culture yield between groups. However, SARS-CoV-2 positive children showed slower radiological improvement at 1 month (p = 0.01), pleural effusions (p < 0.001), and a higher need for endoscopic enucleation (p < 0.001). FDG PET/CT scans indicated an ongoing inflammation in the SARS-CoV-2 positive group. Coinfection with SARS-CoV-2 in children with TB airway obstruction appears to complicate the disease course, necessitating more medical interventions and demonstrating a longer duration of the TB inflammatory process. Further research is needed to understand the impact of viral infections on TB progression and outcomes in pediatric patients.

Intestinal Parasitic Infections May Be Overlooked Drivers of the Tuberculosis Pandemic.

The burden of tuberculosis (TB) is disproportionate in tropical and subtropical regions, where parasitic coinfections are common. Given the significant geographical overlap between TB and intestinal parasitic infections, it is important to consider the implications of intestinal parasitic infections for the TB pandemic. Intestinal parasitic infections have been theorized to increase vulnerability to TB by altering the inflammatory milieu, inducing undernutrition that blunts the immune response, and affecting drug pharmacokinetics. In this perspective piece, we provide a background of the epidemiological and immunological evidence that links parasitic infections to increased risk of TB progression and worse treatment outcomes. We also identify gaps in our knowledge and call for increased research on TB-parasitic coinfections to ensure action on a potentially widespread TB comorbidity.

Single-cell RNA sequencing in tuberculosis: Application and future perspectives.

Tuberculosis (TB) has one of the highest mortality rates among infectious diseases worldwide. The immune response in the host after infection is proposed to contribute significantly to the progression of TB, but the specific mechanisms involved remain to be elucidated. Single-cell RNA sequencing (scRNA-seq) provides unbiased transcriptome sequencing of large quantities of individual cells, thereby defining biological comprehension of cellular heterogeneity and dynamic transcriptome state of cell populations in the field of immunology and is therefore increasingly applied to lung disease research. Here, we first briefly introduce the concept of scRNA-seq, followed by a summarization on the application of scRNA-seq to TB. Furthermore, we underscore the potential of scRNA-seq for clinical biomarker exploration, host-directed therapy, and precision therapy research in TB and discuss the bottlenecks that need to be overcome for the broad application of scRNA-seq to TB-related research.

Permissive lung neutrophils facilitate tuberculosis immunopathogenesis in male phagocyte NADPH oxidase-deficient mice.

NADPH oxidase 2 (NOX2) is an enzyme responsible for generating reactive oxygen species, primarily found in phagocytes. Chronic Granulomatous Disease (CGD), along with bacterial infections such as Mycobacterium tuberculosis (Mtb), is a representative NOX2-deficient X-linked disease characterized by uncontrolled inflammation. However, the precise roles of host-derived factors that induce infection-mediated hyperinflammation in NOX2-deficient condition remain incompletely understood. To address this, we compared Mtb-induced pathogenesis in Nox2-/- and wild type (WT) mice in a sex-dependent manner. Among age- and sex-matched mice subjected to Mtb infection, male Nox2-/- mice exhibited a notable increase in bacterial burden and lung inflammation. This was characterized by significantly elevated pro-inflammatory cytokines such as G-CSF, TNF-α, IL-1α, IL-1β, and IL-6, excessive neutrophil infiltration, and reduced pulmonary lymphocyte levels as tuberculosis (TB) progressed. Notably, lungs of male Nox2-/- mice were predominantly populated with CD11bintLy6GintCXCR2loCD62Llo immature neutrophils which featured mycobacterial permissiveness. By diminishing total lung neutrophils or reducing immature neutrophils, TB immunopathogenesis was notably abrogated in male Nox2-/- mice. Ultimately, we identified G-CSF as the pivotal trigger that exacerbates the generation of immature permissive neutrophils, leading to TB immunopathogenesis in male Nox2-/- mice. In contrast, neutralizing IL-1α and IL-1β, which are previously known factors responsible for TB pathogenesis in Nox2-/- mice, aggravated TB immunopathogenesis. Our study revealed that G-CSF-driven immature and permissive pulmonary neutrophils are the primary cause of TB immunopathogenesis and lung hyperinflammation in male Nox2-/- mice. This highlights the importance of quantitative and qualitative control of pulmonary neutrophils to alleviate TB progression in a phagocyte oxidase-deficient condition.

Breaking the Cycle: Matrix Metalloproteinase Inhibitors as an Alternative Approach in Managing Tuberculosis Pathogenesis and Progression.

Mycobacterium tuberculosis (Mtb) has long posed a significant challenge to global public health, resulting in approximately 1.6 million deaths annually. Pulmonary tuberculosis (TB) instigated by Mtb is characterized by extensive lung tissue damage, leading to lesions and dissemination within the tissue matrix. Matrix metalloproteinases (MMPs) exhibit endopeptidase activity, contributing to inflammatory tissue damage and, consequently, morbidity and mortality in TB patients. MMP activities in TB are intricately regulated by various components, including cytokines, chemokines, cell receptors, and growth factors, through intracellular signaling pathways. Primarily, Mtb-infected macrophages induce MMP expression, disrupting the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs), thereby impairing extracellular matrix (ECM) deposition in the lungs. Recent research underscores the significance of immunomodulatory factors in MMP secretion and granuloma formation during Mtb pathogenesis. Several studies have investigated both the activation and inhibition of MMPs using endogenous MMP inhibitors (i.e., TIMPs) and synthetic inhibitors. However, despite their promising pharmacological potential, few MMP inhibitors have been explored for TB treatment as host-directed therapy. Scientists are exploring novel strategies to enhance TB therapeutic regimens by suppressing MMP activity to mitigate Mtb-associated matrix destruction and reduce TB induced lung inflammation. These strategies include the use of MMP inhibitor molecules alone or in combination with anti-TB drugs. Additionally, there is growing interest in developing novel formulations containing MMP inhibitors or MMP-responsive drug delivery systems to suppress MMPs and release drugs at specific target sites. This review summarizes MMPs' expression and regulation in TB, their role in immune response, and the potential of MMP inhibitors as effective therapeutic targets to alleviate TB immunopathology.

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.

CD38+ Alveolar macrophages mediate early control of M. tuberculosis proliferation in the lung.

Tuberculosis, caused by M.tuberculosis (Mtb), remains an enduring global health challenge, especially given the limited efficacy of current therapeutic interventions. Much of existing research has focused on immune failure as a driver of tuberculosis. However, the crucial role of host macrophage biology in controlling the disease remains underappreciated. While we have gained deeper insights into how alveolar macrophages (AMs) interact with Mtb, the precise AM subsets that mediate protection and potentially prevent tuberculosis progression have yet to be identified. In this study, we employed multi-modal scRNA-seq analyses to evaluate the functional roles of diverse macrophage subpopulations across different infection timepoints, allowing us to delineate the dynamic landscape of controller and permissive AM populations during the course of infection. Our analyses at specific time-intervals post-Mtb challenge revealed macrophage populations transitioning between distinct anti- and pro-inflammatory states. Notably, early in Mtb infection, CD38- AMs showed a muted response. As infection progressed, we observed a phenotypic shift in AMs, with CD38+ monocyte-derived AMs (moAMs) and a subset of tissue-resident AMs (TR-AMs) emerging as significant controllers of bacterial growth. Furthermore, scATAC-seq analysis of naïve lungs demonstrated that CD38+ TR-AMs possessed a distinct chromatin signature prior to infection, indicative of epigenetic priming and predisposition to a pro-inflammatory response. BCG intranasal immunization increased the numbers of CD38+ macrophages, substantially enhancing their capability to restrict Mtb growth. Collectively, our findings emphasize the pivotal, dynamic roles of different macrophage subsets in TB infection and reveal rational pathways for the development of improved vaccines and immunotherapeutic strategies.

Overview of Small Molecules as Fluorescent Probes of Mycobacterium tuberculosis.

Tuberculosis (TB) remains one of the leading infectious causes of death worldwide. Detecting and precisely quantifying viable Mycobacterium tuberculosis (M. tuberculosis) is crucial for comprehending mycobacterial pathogenicity; the progression and outcomes of tuberculosis; and the action, efficacy, and resistance of drugs. Fluorescent probes have emerged as indispensable tools for studying the intricate structure and dynamic interactions of M. tuberculosis with its host environment. This minireview underscores the significance of small molecules as fluorescent probes in advancing our understanding of mycobacterial biology and highlights their potential for guiding the development of novel therapeutic interventions against tuberculosis.

Postponed Results of Lung Resections for Disseminated Fibrous Cavernous Tuberculosis

The objective: to evaluate postponed results of lung resection for disseminated fibrous cavernous tuberculosis.Subjects and Methods. Postponed treatment results were evaluated 3–5 years after surgery, it was the time when patients were taken off the register at TB dispensary (TBD). Inpatient medical records (Form no. 003/u) and outpatient records (Form no. 025/u-04) were used as the source of information.Results. Out of 702 patients for whom postpones results were available, 571/702 (81.3%) were taken off the register 5 years after the surgery due to cure. Relapse with a chronic course of tuberculosis developed in 49/702 (7.0%) patients, and lethal outcome occurred in 82/702 (11.7%) patients (relapse and progression of tuberculosis were the cause in 51 patients, while surgical complications in 31 patients). Over all period of follow-up, 132 tuberculosis relapses were detected, but a significant limitation of this part of the study was the loss of patients for follow-up every year. By the period of “10 years or more”, there were only 139 people available for follow-up and among them 15 (10.8% ) relapses were registered.It was also found that the chances of an unfavorable outcome of tuberculosis treatment were more than 32 times higher in patients with an unfavorable immediate result of the surgery (including not resolved postoperative complications) versus the patients who achieved a favorable result after the surgery (OR = 32.14, 95 % CI 17.57 – 58.78, p&lt;0.001, χ2 =218.8)

Overlooked, dismissed, and downplayed: reversion of Mycobacterium tuberculosis immunoreactivity.

Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb). Following infection, immune responses to Mtb antigens can be measured using the tuberculin skin test or an interferon-γ release assay. The gain of Mtb immunoreactivity, a change from a negative to a positive tuberculin skin test or interferon-γ release assay result, is called conversion and has long been used as a measure of Mtb exposure. However, the loss of immunoreactivity (reversion; a positive followed by a negative result) has often been overlooked. Instead, in clinical and epidemiological circles, Mtb immunoreactivity is commonly considered to persist lifelong and confer a lifetime of disease risk. We present a critical review, describing the evidence for reversion from cohort studies, ecological studies and studies of TB progression risk. We outline the inconsistent reasons why reversion has been dismissed from common understanding and present evidence demonstrating that, just as conversion predominantly indicates prior exposure to Mtb antigens, so its opposite, reversion, suggests the reduction or absence of exposure (endogenous or exogenous). Mtb immunoreactivity is dynamic in both individuals and populations and this is why it is useful for stratifying short-term TB progression risk. The neglect of reversion has shaped TB research and policy at all levels, influencing clinical management and skewing Mtb infection risk estimation and transmission modelling, leading to an underestimation of the contribution of re-exposure to the burden of TB, a serious oversight for an infectious disease. More than a century after it was first demonstrated, it is time to incorporate reversion into our understanding of the natural history of TB.

History of tuberculosis disease is associated with genetic regulatory variation in Peruvians.

A quarter of humanity is estimated to have been exposed to Mycobacterium tuberculosis (Mtb) with a 5-10% risk of developing tuberculosis (TB) disease. Variability in responses to Mtb infection could be due to host or pathogen heterogeneity. Here, we focused on host genetic variation in a Peruvian population and its associations with gene regulation in monocyte-derived macrophages and dendritic cells (DCs). We recruited former household contacts of TB patients who previously progressed to TB (cases, n = 63) or did not progress to TB (controls, n = 63). Transcriptomic profiling of monocyte-derived DCs and macrophages measured the impact of genetic variants on gene expression by identifying expression quantitative trait loci (eQTL). We identified 330 and 257 eQTL genes in DCs and macrophages (False Discovery Rate (FDR) < 0.05), respectively. Four genes in DCs showed interaction between eQTL variants and TB progression status. The top eQTL interaction for a protein-coding gene was with FAH, the gene encoding fumarylacetoacetate hydrolase, which mediates the last step in mammalian tyrosine catabolism. FAH expression was associated with genetic regulatory variation in cases but not controls. Using public transcriptomic and epigenomic data of Mtb-infected monocyte-derived dendritic cells, we found that Mtb infection results in FAH downregulation and DNA methylation changes in the locus. Overall, this study demonstrates effects of genetic variation on gene expression levels that are dependent on history of infectious disease and highlights a candidate pathogenic mechanism through pathogen-response genes. Furthermore, our results point to tyrosine metabolism and related candidate TB progression pathways for further investigation.