Tuberculosis (TB) remains the leading cause of death worldwide from a single infectious disease. An estimated quarter of the world's population, about 2 billion people, has an immune response to Mycobacterium tuberculosis (Mtb) without clinical, microbiological, or radiological signs of TB disease. This condition is known as TB infection (TBI) and carries a lifelong risk of reactivation with 5%-10% of individuals eventually developing TB disease during their lifetime. Interferon-γ release assay and skin-tests are World Health Organization (WHO)-approved tests for TBI diagnosis and allow to identify those needing TB preventive therapy. The WHO End TB Strategy proposes several approaches to mitigate the global burden of TB. Achieving the goal of TB elimination requires improved early diagnosis of TBI individuals at risk of developing TB disease, provision of preventive therapy, and development of new diagnostic tests to address the current limitations. This review provides an update on the tests currently used for TBI diagnosis and offers an overview of experimental tests based on either host response analysis or pathogen detection. Additionally, we briefly report experimental tests, such as those based on host RNA signatures, which can help identifying TBI individuals at high risk of progressing toward TB disease. Although these experimental tests show promise, further investigation and randomized clinical trials are required to establish reliable proof-of-concept.

Tuberculosis infection (TBI) is diagnosed based on a positive immune response to M. tuberculosis antigens. This study aimed to evaluate both the qualitative and quantitative performance of two novel IGRA-based tests, the STANDARD E TB-Feron ELISA (TB-Feron-ELISA) and the STANDARD F TB-Feron FIA (IFN-γ) (TB-Feron-FIA), and compare their results to those of QuantiFERON-TB Gold Plus (QuantiFERON).

At Chiril Draganiuc Phthisiopneumology Institute in the Republic of Moldova, we prospectively enrolled three cohorts of adults: healthy individuals with no known close contact with TB, patients with active tuberculosis (TB), and individuals with a history of TB. The active TB and past TB cohorts were used to assess the tests' sensitivity, while the healthy group was used to evaluate specificity. Both qualitative and quantitative results from the TB-Feron ELISA and TB-Feron FIA were compared with those of QuantiFERON.

The TB-Feron-FIA demonstrated a sensitivity of 80.58 % (95 %CI: 71.90-87.06) in the active TB cohort and 82.93 % (95 %CI: 68.74-91.47) in the past TB cohort, with a specificity of 85.19 % (95 % CI: 73.40-92.30). The TB-Feron-ELISA showed a sensitivity of 80.58 % (95 %CI: 71.90-87.06) in the active TB cohort and 78.57 % (95 %CI: 64.06-88.29) in the past TB cohort, with a specificity of 85.19 % (95 %CI: 73.40-92.30). The agreement coefficient (κ) with QuantiFERON was 0.766 (95 %CI: 0.689-0.843) for TB-Feron-FIA and 0.809 (95 %CI: 0.739-0.880) for TB-Feron-ELISA.

Both the TB-Feron-ELISA and TB-Feron-FIA demonstrated good diagnostic accuracy for identifying individuals with TBI, comparable to the performance of QuantiFERON.

California data demonstrate failures in latent tuberculosis screening to prevent progression to tuberculosis disease. Therefore, we developed a clinical risk prediction model for tuberculosis disease using electronic health records. This study included Kaiser Permanente Southern California and Northern California members ≥18 years during 2008-2019. Models used Cox proportional hazards regression, Harrell's C-statistic, and a simulated TB disease outcome accounting for cases prevented by current screening which includes both observed and simulated cases. We compared sensitivity and number-needed-to-screen for model-identified high-risk individuals with current screening. Of 4,032,619 and 4,051,873 Southern and Northern California members, tuberculosis disease incidences were 4.1 and 3.3 cases per 100,000 person-years, respectively. The final model C-statistic was 0.816 (95% simulation interval 0.805-0.824). Model sensitivity screening high-risk individuals was 0.70 (0.68-0.71) and number-needed-to-screen was 662 (646-679) persons-per tuberculosis disease case, compared to a sensitivity of 0.36 (0.34-0.38) and number-needed-to-screen of 1632 (1485-1774) with current screening. Here, we show our predictive model improves tuberculosis screening efficiency in California.

Patients with rheumatic disease (RD) are particularly vulnerable to progressing to tuberculosis disease (TBD). The effectiveness of tuberculosis preventive treatment (TPT) in this high risk group needs systematic assessment.

We conducted a systematic review and meta-analysis by searching PubMed, Embase, the Cochrane Library, Web of Science, Scopus, and China National Knowledge Internet (CNKI) for relevant cohort studies from inception through January 2025. Eligible studies evaluated the incidence of TBD and/or the effectiveness of TPT in patients with RD. Two authors independently reviewed and extracted summary data from published reports. Pooled incidence rate (IR), risk ratio (RR) and their 95% confidence interval (CI) were calculated as the primary effect measure. Prospero registration number is CRD42023473966.

64 studies with 116,015 patients with RD were included to evaluate effectiveness of TPT. TPT decreased the overall risk of TBD in patients with RD (RR: 0.76, 95% CI 0.63-0.91). TPT showed better effectiveness in high tuberculosis (TB) burden countries/regions (RR: 0.46, 95% CI 0.27-0.77). Using isoniazid (INH) monotherapy for 9-12 months was effective (RR: 0.54, 95% CI 0.35-0.85). Taking tuberculin skin test (TST) combined with interferon gamma release assays (IGRA) as tuberculosis infection (TBI) screening methods might maximize the benefits of TPT (RR: 0.58, 95% CI 0.39-0.88). TPT showed optimal protective effects in patients with RD in TBI positive status (RR: 0.11, 95% CI 0.04-0.32). Compared with patients with RD receiving biologics, TPT showed better effects in patients with RD only receiving traditional treatment (RR: 0.44, 95% CI 0.27-0.73). And TPT performed more effectively in systematic lupus erythematosus (SLE) than arthritis.

TPT decreased the risk of TBD in patients with RD, especially in TB high burden countries/regions. When using isoniazid monotherapy, extending the treatment course might have better protection. TST combined with IGRA might be optimal when screening the TBI. More types of RDs, short-course regimens containing rifamycins and high-quality randomized controlled trials (RCT) should be the focus of future research.

This study was supported by the National Natural Science Foundation of China (82373648), Capital's Funds for Health Improvement and Research (2024-2-4016), and the National High Level Hospital Clinical Research Funding (2022-PUMCH-C-013, 2022-PUMCH-A-119).

In recent paleopathological literature, granular impressions on the endocranial surface are considered pathognomonic of tuberculous meningitis. This study aims to verify the presence of granular impressions and assess their relationship with tuberculosis in an archeological human skeletal assemblage.

The study analyzed the endocranial surfaces of 212 skulls (38 non-adults and 174 adults) from the medieval site of Pieve di Pava, Italy.

Macroscopic and stereomicroscopic examination of the endocranial surface was conducted to evaluate the presence, location, and manifestation of granular impressions.

Granular impressions affected more than half of the individuals, with no statistical difference between males and females.

The high frequency of granular impressions challenges their interpretation as pathognomonic of tuberculous meningitis, a rare complication of tuberculosis affecting the central nervous system. Instead, these lesions should be considered indicative of bacteremia, when bacilli reach the central nervous system and form tubercles on the meninges. It cannot be established whether these tubercles were quiescent or had ruptured, leading to tuberculous meningitis.

Based on the pathogenic life cycle of M. tuberculosis, as defined in clinical settings, it seems prudent to consider granular impressions as a marker of tuberculosis infection, rather than of active tuberculosis disease or tuberculous meningitis in paleopathology.

Research limitations include the smaller number of non-adults compared to adults.

Screening of granular impressions in other large osteoarcheological assemblages could provide new and more reliable data on the spread of tuberculosis infection across different social contexts, geographical settings, and historical periods.

Background/Objectives:Pneumocystis jirovecii pneumonia (PJP) is the most frequently diagnosed AIDS-defining illness in Europe, with especially high mortality in HIV-negative patients caused by delayed diagnosis and low awareness. This study aims to evaluate cytokine release assays (CRA) to facilitate a less invasive and resource-efficient PJP specific diagnostic test. We focus on the P. jirovecii antigens Kexin 1 (KEX1), MSG1, and MSG2, which were identified in prior studies as immunologically relevant. Methods: Whole blood samples from 50 participants-22 healthy individuals and 28 immunocompromised individuals, including 8 with proven PJP-were stimulated in vitro with full-length and partial KEX1, MSG1, MSG2, and a combination of all three antigens (PJ-MIX). Following 24 h incubation at 37 °C, cytokine levels of IL-2, IFN-γ, IL-17A, and IL-17F were measured. Results: Stimulation with full-length KEX1, MSG1, MSG2, and PJ-MIX antigens induced higher IL-2 concentrations in the healthy control group compared to the groups IL-2 baseline levels and to the group of proven PJP cases. Similarly, stimulation with full-length KEX1, MSG1, and PJ-MIX elevated IFN-γ levels in the healthy control group compared to baseline IFN-γ levels. Conclusions: Our findings highlight the potential of IL-2 and IFN-γ release following stimulation with PJ antigens, with PJ-MIX eliciting the strongest and most significant responses, suggesting a cumulative antigen effect. This pilot study establishes a foundation for a PJP-specific CRA, deepening our knowledge of T-cell immunity against PJP. Clinically, such a test could, among other applications, evaluate at-risk patients who should receive prophylaxis and may consequently reduce PJP-related morbidity and mortality.

This study aims to screen common immunological markers of lung tissues and blood for diagnosis of tuberculosis (TB).

Differentially expressed miRNAs (DEmRs) and mRNAs (DEGs) were obtained by whole-transcriptome sequencing profiles on 18F-FDG PET/CT high and low metabolic active regions in lung tissues of nine TB patients. Common miRNAs were screened by intersecting with DEmRs, four miRNA GEO datasets, and their target mRNAs were predicted through the miRTarbase and Tarbase databases. Then these mRNAs were intersected with DEGs, mRNAs from blood samples and immune-related genes, to construct a miRNA-mRNA interaction network, and the hub genes were identified by Cytoscape. The relationship between immune infiltration and hub genes were evaluated using Cibersort. Finally, a diagnostic model based on Lasso regression analysis was established and validated by qRT-PCR.

Five common miRNAs were obtained in both blood and tissues. Six immune-related mRNAs (NEDD4, PLTP, RNASEL, SEMA7A, TAPBP, and THBS1) were screened out. A diagnostic model was established and validated in the blood samples of 30 pairs (TB/health volunteers). The AUC for the 6-mRNA combination was 0.79.

We screened six mRNAs as a combination for diagnosing tuberculosis.

Tuberculosis (TB) remains a prominent cause of illness and mortality worldwide. Prisons are hotspots for TB transmission worldwide. We reviewed the literature on TB in prisons worldwide, including TB risk factors, delays in diagnosis including drug resistance, the treatment accorded, and operational and logistical issues of TB care in prison. The quantity and quality of data on TB in prisons varies worldwide. The TB incidence rate in prisons varies by World Health Organization region, with African countries having the highest rates of TB and TB/HIV co-infection. Its incidence rate among inmates is about 10 times higher than that of the general population. The growing prevalence of multidrug-resistant TB is particularly concerning, as it may affect high-risk settings and disproportionately affects vulnerable populations, such as prisoners and incarcerated individuals who go undiagnosed for extended periods of time. Factors that drive the high TB rates in prisons include limited access to health services such as TB care, overcrowding, poor ventilation, malnutrition, HIV, alcohol use disorders, illegal drug use, smoking, and other comorbidities, compounded by limited access to healthcare. Addressing TB in prisons requires a multifaceted approach, that includes improving living conditions, enhancing healthcare services, and developing innovative detection methods. The ongoing conflicts in Europe, the Middle East, Asia, and Africa further complicated TB prevention and control efforts in prisons, emphasizing the need for targeted interventions to address TB in these high-risk settings. Structured interventions tailored to the specific risk factors present in each environment should be investigated to effectively focus measures aimed at diminishing the overall burden of TB in prisons. Electronic record-keeping worldwide will allow for accurate data to be collected and shared.

Caulerpin, a bis-indole alkaloid isolated from Caulerpa racemosa, has several documented pharmacological activities, including antineoplastic and antiviral properties. This study aimed to evaluate the anti-inflammatory and anti-tubercular potentials of caulerpin and its analogues in RAW 264.7 macrophages infected with Mycobacterium spp. Additionally, we evaluated cytokine production and NLRP3 expression in this infection model. Toxicity tests were performed using Vero E6 and HepG2 cell lines and Artemia salina. Pre-incubation of RAW 264.7 cells with caulerpin and its analogues decreased internalized M. smegmatis and M. tuberculosis H37Ra. Furthermore, treatment of M. smegmatis-infected macrophages with caulerpin and its analogues reduced bacterial loads. Caulerpin reduced the CFU count of internalized bacilli in the M. tuberculosis H37Ra infection model. In addition, caulerpin and its diethyl derivative were notably found to modulate IL-1β and TNF-α production in the M. smegmatis infection model after quantifying pro-inflammatory cytokines and NLRP3. Caulerpin and its derivates did not affect the viability of Vero E6 and HepG2 cell lines or nauplii survival in toxicity studies. These findings demonstrate that caulerpin and its analogues exhibit anti-inflammatory activity against Mycobacterium spp. infection in RAW 264.7 macrophages and show promising potential for further efficacy and safety evaluation.

Tuberculosis (TB) is a major global health issue. Early diagnosis of TB is still a challenge. Studies are seeking non-sputum biomarker-based TB test. Emerging evidence indicates potential significance of blood microbiome signatures for diseases. However, blood microbiome RNA profiles are unknown in TB. We aimed to characterize the blood microbiome of TB patients and identify Mycobacterium tuberculosis (Mtb) genome-derived small RNA molecules to serve as diagnostic biomarkers for TB.

RNA sequencing data of the blood from TB patients and healthy controls were retrieved from the NCBI-SRA database for analyzing the blood microbiome and identifying rRNA-derived small RNA (rsRNA) of Mtb. Small RNA-seq was performed on plasma exosomes from TB patients and healthy controls. The levels of the candidate Mtb rsRNAs were determined by real-time quantitative reverse transcription PCR (RT-qPCR) on plasma from a separate cohort of 73 TB patients and 62 healthy controls.

The blood microbiome of TB patients consisted of RNA signals from bacteria, fungi, archaea, and viruses, with bacteria accounting for more than 97% of the total. Reduced blood microbial diversity and abundance of 6 Mycobacterium-associated bacterial genera, including Mycobacterium, Priestia, Nocardioides, Agrobacterium, Bradyrhizobium, and Escherichia, were significantly altered in the blood of TB patients. A diagnostic model for TB based on the 6 genera achieved an area under the curve (AUC) of 0.8945. rsRNAs mapped to the Mtb genome were identified from blood and plasma exosomes of TB patients. RT-qPCR results showed that 2 Mtb-derived rsRNAs, 16 S-L1 and 16 S-L2, could be used as diagnostic biomarkers to differentiate TB patients from healthy controls, with a high co-diagnostic efficacy (AUC = 0.7197).

A panel of blood microbiome signatures and Mtb-derived rsRNAs can serve as blood biomarkers for TB diagnosis.

Tuberculosis (TB) is the leading cause of death in the world from an infectious disease. Its etiologic agent, the Mycobacterium tuberculosis (Mtb), is a slow-growing bacterium that has coexisted in humans for thousands of years. According to the World Health Organization, 10.6 million new cases of TB and over 1 million deaths were reported in 2022. It is widely recognized that patients affected by chronic autoimmune arthritis such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) have an increased incidence rate of TB disease compared to the general population. As conceivable, the risk is associated with age ≥65 years and is higher in endemic regions, but immunosuppressive therapy plays a pivotal role. Several systematic reviews have analysed the impact of anti-TNF-α agents on the risk of TB in patients with chronic autoimmune arthritis, as well as for other biologic disease-modifying immunosuppressive anti-rheumatic drugs (bDMARDs) such as rituximab, abatacept, tocilizumab, ustekinumab, and secukinumab. However, the data are less robust compared to those available with TNF-α inhibitors. Conversely, data on anti-IL23 agents and JAK inhibitors (JAK-i), which have been more recently introduced for the treatment of RA and PsA/AS, are limited. TB screening and preventive therapy are recommended in Mtb-infected patients undergoing bDMARDs and targeted synthetic (ts)DMARDs. In this review, we evaluate the current evidence from randomized clinical trials, long-term extension studies, and real-life studies regarding the risk of TB in patients with RA, PsA, and AS treated with bDMARDs and tsDMARDs. According to the current evidence, TNF-α inhibitors carry the greatest risk of TB progression among bDMARDs and tsDMARDs, such as JAK inhibitors and anti-IL-6R agents. The management of TB screening and the updated preventive therapy are reported.

The diagnosis and management of abdominal tuberculosis, i.e Gastrointestinal Tuberculosis (GITB) and tuberculous peritonitis (TBP) is challenging. Abdominal tuberculosis, presenting usually with abdominal pain, intestinal obstruction, and constitutional symptoms, is typically a paucibacillary condition. The diagnosis hinges on a correct interpretation of clinical, radiological, histological, biochemical, and microbiological findings as also appropriately assessing response to therapy.

The authors review potential missteps that could occur in managing GITB and TBP sourced from published literature and clinical experience. These include avoiding excess use of tests with limited accuracy, understanding limitations of ascitic adenosine deaminase (ADA) and granulomas, avoiding empirical antitubercular therapy (ATT) where possible but also understanding that microbiological tests may not always be positive, and finally not to bank solely on subjective clinical responses but to use objective markers in assessing response to therapy. In addition, diagnosis of predisposing immunosuppressed states, attention to nutrition, appropriate management of sequelae with endoscopic dilatation/surgery, and early surgery when indicated are some of the additional issues discussed.

In future, a more secure diagnosis banking on the use of better microbiological tools, multiparameter-based models, artificial intelligence-based approaches, and use of advances in -omics-based approaches can improve diagnosis and avoid some missteps.

To describe and compare clinical features, treatment approaches, and treatment outcomes of ocular tuberculosis (OTB) patients in the Netherlands, a low tuberculosis (TB)-endemic country, and Indonesia, a high TB-endemic country. We also aimed to identify predictors of treatment outcomes.

A medical chart review of 339 OTB patients (n = 93 from the Netherlands and n = 246 from Indonesia) was performed. The primary outcome was response to treatment, whether with or without anti-tubercular treatment, after six months of treatment initiation (good versus poor responders).

Indonesian OTB patients displayed a higher prevalence of chest radiograph findings indicative of TB infection (p < 0.001) and concurrent active systemic TB (p = 0.011). Indonesian cohort exhibited a more acute and severe disease profile, including uveitis duration ≤ 3 months (p < 0.001), blindness (p < 0.001), anterior chamber (AC) cells ≥ 2+ (p < 0.001), and posterior synechiae (p < 0.001). Overall proportions of good responders to treatment were 67.6% in the Netherlands and 71.5% in Indonesia. Presence of AC cell ≥ 2+ (adjusted odds ratio (aOR): 2.12, 95% CI: 1.09-4.14), choroidal lesions other than serpiginous-like choroiditis (SLC) or tuberculoma (aOR: 4.47, 95% CI: 1.18-16.90), and retinal vasculitis (aOR: 2.32, 95% CI: 1.10-4.90) at baseline were predictors for poor response to treatment.

Despite a more severe initial clinical presentation in the Indonesian cohort, the overall treatment outcomes of OTB was comparable in both cohorts. Three baseline clinical features were identified as predictors of treatment outcomes.

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a significant global health problem. In immunocompetent individuals, the microorganism can remain in a latent, non-contagious form, however, it may become active under conditions of immunosuppression. Tumour necrosis factor (TNF) inhibitors, which are frequently used for the management of immune-mediated disorders like psoriasis, have been associated with a significantly increased risk of reactivating latent TB. Consequently, international guidelines recommend TB screening and preventive treatment before starting anti-TNF therapy. These recommendations have extended to IL-12/23, IL-17, IL-23 and TYK2 inhibitors under a caution principle, despite their different mechanisms of action. However, current evidence suggests that some of these agents are arguably not associated with an increased risk of TB reactivation or development of TB disease after infection, which calls for a critical reassessment of these guidelines. We have conducted a literature search evaluating the risk of TB reactivation associated with these innovative therapies, integrating findings from both randomized clinical trials and real-world evidence. The identified evidence is limited but the low number of identified cases of reactivation with IL-17 and IL-23 inhibitors prompts reconsidering the need for preventive treatment for latent TB in all cases, regardless of biologic class or individual patient's risk of TB reactivation or drug toxicity. This review, along with the clinical insight of a panel of experts on behalf of the SPIN-FRT, led to the development of these consensus recommendations for managing psoriasis treatment in patients with latent TB infection or at risk of TB infection, who are receiving or are intended to receive biologic and non-biologic targeted therapies. These recommendations highlight the need for updates to the existing guidelines, aiming to provide a more differentiated approach that reflects the evolving landscape of psoriasis treatment and its implications for TB management.

To assess the clinical relevance of pathophysiology-based biomarkers, specifically serum C1q and whole blood interferon gene signature score (IGSS), in ocular tuberculosis (OTB) diagnosis by conducting an integrative analysis of clinical presentations and treatment response.

This retrospective cohort study analysed data from 70 patients with suspected OTB at a tertiary care uveitis practice in Indonesia. Serum C1q levels and whole blood IGSS were quantified. Patients were categorized into four quadrants based on their biomarker profiles: quadrant 1 (high C1q & low IGSS), quadrant 2 (high C1q & high IGSS), quadrant 3 (low C1q & high IGSS), and quadrant 4 (low C1q & low IGSS). Characteristics of clinical presentations, work-up results, and treatment outcomes were explored according to the predefined quadrants.

We identified that the majority of OTB patients diagnosed with concurrent active pulmonary TB were in quadrant 1, 2, or 3 (20/23, 87.0%). Twenty-seven patients (27/47, 57.4%) with clinically undifferentiated uveitis were in quadrant 4 (p < 0.001). Among patients in quadrants 1, 2, and 3, completion of a full course of antitubercular treatment (ATT) was associated with a lower number of patients showing persistence or recurrence of ocular inflammation compared to those who were not fully treated with ATT (14.3% vs 85.7%, p = 0.001).

Based on the analysis of clinical features and treatment outcomes, patients with elevated levels of either or both serum C1q and whole blood IGSS may reflect active TB disease in the eye, necessitating full ATT management.

Ubiquitous magnesium transporter, CorA of Mycobacterium smegmatis is well known for its role in maintaining magnesium homeostasis. However, little is known about its involvement in exerting antimicrobial resistance. Here, by using molecular genetics, in vivo and in silico studies, we tried to envisage the role of CorA of M. smegmatis in antimicrobial resistance of M. smegmatis and Escherichia coli.

Expression of corA in M. smegmatis and E. coli decreased the susceptibility of the host cells towards various antibiotics and anti-tubercular drugs, which was elucidated by determining minimum inhibitory concentrations using the micro-broth dilution method. The intracellular antibiotic accumulation assay indicated that the host cells expressing corA accumulated less EtBr, norfloxacin, and ofloxacin than the control cells. Moreover, the presence of a sub-inhibitory concentration of Mg2+ further decreased the susceptibility towards the drugs tested. Furthermore, CorA enhanced the biofilm-forming ability of cells expressing it.

CorA (MSMEG_5056), a magnesium transporter of M. smegmatis influences the extrusion of multiple structurally unrelated classes of drugs and enhances the biofilm formation of E. coli and M. smegmatis.

The existing clinical diagnostic methods of pulmonary tuberculosis (TB) usually have some of the following limitations, such as time-consuming, invasive, radioactive, insufficiently sensitive and accurate. This study demonstrates the possibility of using blood plasma autofluorescence spectroscopy and Artificial Neural Network (ANN) algorithm for the rapid and accurate diagnosis of latent and active pulmonary TB from healthy subjects. The fluorescence spectra of blood plasma from 18 healthy volunteers, 12 individuals with latent TB infections and 80 active TB patients are measured and analyzed. By optimizing the ANN structure and activation functions, the ANN three-classification model achieves average classification accuracy of 96.3 %, and the accuracy of healthy persons, latent TB infections and active TB patients are 100 %, 83.3 % and 97.5 %, respectively, which is much better than the results of traditional Principal component analysis (PCA) and Linear discriminant analysis (LDA) method. To the best of our knowledge, this is the first research work of differentiating latent, active pulmonary TB cases from healthy samples with autofluorescence spectroscopy. As a rapid, accurate, safe, label-free, non-invasive and cost-effective technique, it can be developed as a promising diagnostic tool for the screening of pulmonary TB disease in the early stage.

Identifying stage-specific antigens is essential for developing tuberculosis (TB) diagnostics and vaccines. In a low TB endemic country, we characterized, the Mycobacterium tuberculosis (Mtb)-specific immune response to a pool of Mtb-derived epitopes (ATB116), demonstrated as associated with TB disease.

In this prospective observational cross-sectional study, we enrolled healthy donors (HD), subjects with TB disease, and TB infection (TBI) at baseline and therapy completion. T-cell response after whole blood stimulation with the peptide pools was characterized by ELISA, flow cytometry, and multiplex assay.

ATB116-specific IFN-γ response (by ELISA) significantly associates with Mtb regardless of infection/disease (p < 0.0001) and decreases during TB therapy (p = 0.0002). Flow cytometry confirms that ATB116-specific CD4+ T-cell response associated with Mtb regardless of infection/disease (p < 0.0001) and shows a significantly higher frequency of IFN-γ/IL-2 and central memory T-cells in TBI compared to TB (p = 0.016; p = 0.0242, respectively). CD4+ T cell-specific response decreases after TB therapy completion. The antigen-specific CD8+ T-cell response mirrors the CD4+ response. Finally, the multiplex assay analysis showed that ATB116 induces several immune factors in both TB and TBI.

We characterized the immune response to Mtb peptide pools that is modulated by TB therapy. These results are important for our understanding of TB immunopathogenesis and vaccine design.

Tuberculosis (TB) risk associated with tumor necrosis factor-alpha (TNF-α) antagonist therapy in patients with autoimmune diseases is a significant concern. This study aims to evaluate the risk of TB disease associated with TNF-α antagonist therapy.

An extensive search of PubMed/MEDLINE, EMBASE, and the Cochrane CENTRAL databases was conducted to identify randomized controlled trials (RCTs) assessing TB disease risk in patients receiving TNF-α antagonist therapy available until November 1, 2024. The pooled statistic used was the weighted odds ratio (OR) and a corresponding 95 % confidence interval (CI). Statistical analysis was performed using Comprehensive Meta-Analysis software, version 3.0 (Biostat Inc., Englewood, NJ, USA).

Fifty-six RCTs, totaling 22,212 adult patients, met the specified eligibility criteria. Pooled analysis revealed an increased risk of TB disease associated with TNF-α antagonist therapy (OR 1.52, 95 % CI 1.03-2.26, p = 0.03). Subgroup analyses indicated a higher risk in patients with rheumatoid arthritis (RA) (OR 2.25, 95 % CI 1.13-4.45, p = 0.02), while no significant associations were found in patients with ankylosing spondylitis (AS) or psoriasis (Ps). Analyses by specific TNF-α antagonist drugs did not yield significant associations with risk of TB disease.

Our study highlights an increased risk of TB disease associated with TNF-α antagonist therapy, particularly in patients with RA. However, the absence of significant associations in AS or Ps patients suggests disease-specific variations in risk of TB disease. Further research is needed to elucidate the long-term safety profile of TNF-α antagonist drugs and their associations with risk of TB disease in different patient populations.

Rapid diagnosis of pulmonary tuberculosis (PTB) is urgently needed. We aimed to improve diagnosis rates by combining tuberculosis-interferon (IFN)-γ release assays (TB-IGRA) with metagenomic next-generation sequencing (mNGS) for PTB diagnosis.

A retrospective study of 29 PTB and 32 non-TB patients from our hospital was conducted between October 2022 and June 2023. Samples were processed for TB-IGRA and mNGS tests according to the manufacturer's protocol.

The levels of IFN-γ release in PTB patients were significantly higher than those in non-TB patients (604.15 ± 112.18 pg/mL, and 1.04 ± 0.38 pg/mL, respectively; p < 0.0001). Regarding presenting symptoms or signs, cough and thoracalgia were less common in PTB patients than in non-TB patients (p = 0.001 and p = 0.024, respectively). Total protein and albumin levels in the sera of PTB patients were significantly elevated compared to non-TB patients (p = 0.039 and p = 0.004, respectively). The area under the ROC curve (AUC) for TB-IGRA in PTB diagnosis was 0.939. With an optimal IFN-γ cut-off value of 14.3 pg/mL (Youden's index 0.831), sensitivity was 86.2% and specificity was 96.9%. ROC curve analysis for mNGS and TB-IGRA combined with mNGS showed AUCs of 0.879 and 1, respectively. The AUC of TB-IGRA combined with mNGS was higher than that of TB-IGRA and mNGS alone.

TB-IGRA combined with mNGS may be an effective method for diagnosing tuberculosis, and can be used in the clinical diagnosis of PTB.

Tuberculosis (TB) infection screening of high-risk groups is an important strategy for achieving End TB targets. A TB infection screening program was implemented for quarry workers from a Portuguese high-incidence area in 2018-2022. We aimed to calculate the cost-benefit of the screening program from the societal perspective.

We calculated medical and non-medical direct and indirect screening costs and compared them with the cost savings from averted cases of TB disease. We estimated the number of potentially averted TB disease cases based on the risk of progression of TB infection to TB disease found in the literature.

During the screening program, 997 workers were screened. TB infection was diagnosed in 215 workers, 150 of those initiated preventive treatment. Screening program total costs were €136,295. Twenty-nine TB cases were potentially prevented, what would have costed €152,386. Savings of €16,091 were obtained (€4516, €40898, and -€29322 from the workers, employers, and NHS, respectively).

The monetary benefit of a TB infection screening program directed to quarry workers in a high-incidence area was greater than its cost. Companies and workers saved substantially more money. TB infection tests that are better predictors of progression to TB disease could reduce NHS costs.

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 ex vivo 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.

Identifying active tuberculosis (ATB) from latent tuberculosis infection (LTBI) persists as a challenge, and interferon-γ inducible protein-10 (IP-10) has been employed as the solution. To further improve its diagnostic performance, the sample can be stimulated with TB specific antigen (TBAg).

To perform meta-analysis on diagnostic accuracy of unstimulated and TBAg-stimulated IP-10 in differentiating ATB from LTBI.

Systematic search was performed on five major scientific databases as of 29 November 2023. Observational studies reporting diagnostic values of unstimulated or TBAg-stimulated IP-10 in identifying ATB from LTBI were included. Meta-analysis was carried out using two-level mixed-effect logistic regression model.

Twenty-five studies recruiting 2301 patients (1137 ATB versus 1164 LTBI) were included in the quantitative analysis. The pooled sensitivity and specifity of IP-10 were 72% (95%CI: 0.59-0.82) and 78% (95%CI: 0.63-0.88), respectively. As for TBAg-stimulated IP-10, the sensitivity and specifity were 82% (95%CI: 0.76-0.87) and 85% (95%CI: 0.73-0.92), respectively. The senstivity was reduced signiticantly (p < 0.01) when the patients with human immunodeficiency virus infection were included, except after the TBAg stimulation.

Stimulating IP-10 with TBAg could improve the diagnostic accuracy in differentiating ATB from LTBI.

Cysteamine, a drug approved to treat cystinosis, has been proposed as a host-directed therapy for M. tuberculosis (Mtb) and SARS-CoV-2. The impact of cysteamine on the immune responses has not been fully investigated. We aimed to in vitro evaluate the immunomodulatory effects of cysteamine on peripheral blood mononuclear cells (PBMCs) using the purified protein derivative (PPD) as a recall antigen, and an unspecific stimulus as staphylococcal enterotoxin B (SEB).

PBMCs isolated from subjects with tuberculosis infection (TBI), those with tuberculosis disease (TB), and healthy controls (HC) were in vitro stimulated with PPD or SEB and treated or not with cysteamine at different concentrations (50 µM-400 µM) for 6 hours (h) and 24 h. We evaluated the T helper1 (Th1) and T cytotoxic1 (Tc1) cell cytokine production by flow cytometry and immune-enzymatic assays. In HC, we also evaluated apoptosis and/or necrosis by flow cytometry.

We observed an immunomodulatory effect of cysteamine at 400 µM in PBMCs from TB and TBI subjects. It significantly reduced PPD-specific Th1 responses at 24 h and at 6 h (p=0.0004 and p=0.0009, respectively), and a similar non-significant trend was observed with cysteamine at 200 µM (p=0.06 at 24 h and p=0.14 at 6 h). Moreover, cysteamine at both 400 µM (p<0.0001 and p=0.0187 at 24 h, respectively, and p<0.0001 at 6 h for both) and 200 µM (p=0.0119 and p=0.0028 at 24 h and p=0.0028 and p=0.0003 at 6 h, respectively) significantly reduced SEB-induced Th1 and Tc1 responses. Furthermore, we found that cysteamine induced morphological lymphocyte changes and significantly reduced the lymphocyte percentage in a dose- and time-dependent manner. Cysteamine at 400 µM induced 8% late apoptosis and 1.6% necrosis (p<0.05) at 24 h. In contrast, despite significant differences from untreated conditions (p<0.05), cysteamine at 400 µM for 6 h induced approximately 1% late apoptosis and 0.1% necrosis in the cells.

High doses of cysteamine in vitro reduce the percentages of PPD- and SEB-induced Th1 and Tc1 cells and induce late apoptosis and necrosis. Differently, cysteamine at lower doses retains the immunomodulatory effect without affecting cell viability. These findings suggest cysteamine as a potential adjunct to antimicrobial regimens as in the TB or COVID-19 field, for its ability to reduce the inflammatory status.

The immunization of mice with the sterile culture medium supernatants of Mycobacterium tuberculosis (Mtb) H37Rv permitted the production of several monoclonal antibodies (mAbs) specific for secreted and/or released antigens. Two mAbs bound and immunoprecipitated an 80-kDa protein that was identified by mass spectrometry as Rv1133c, the methionine synthase MetE. The protein MetE is ubiquitous among prokaryota and shows a significant sequence homology in many bacteria. We produced both the full-length recombinant MetE and its N-terminal fragment, whose sequence is more conserved among mycobacteria, to select mAbs recognizing an Mtb-specific region of MetE. Finally, we produced and selected eight mAbs that specifically detect the MetE protein in the supernatant and cell lysate of Mtb and BCG, but not other bacteria such as non-tuberculous mycobacteria (NTM), Streptococcus pneumoniae, Staphylococcus aureus, Acinetobacter baumanii, or Escherichia coli. Taking advantage of our mAbs, we studied (i) the vitamin B12 dependence for the synthesis of MetE in Mtb and NTM and (ii) the kinetics of MetE production and secretion in supernatants during the in vitro reproduced replicative, dormant, and resuscitation cycle of Mtb. Our data demonstrate that dormant Mtb, which are assumed to be prevalent in latent infections, as well as NTM do not produce and secrete MetE. Results indicate an unexpected specificity for Mtb of our anti-MetE mAbs and encourage the use of rMetE and our mAbs as tools for the immunodiagnosis of TB and its stages.

In this editorial, we comment on an article published in a recent issue of the World Journal of Clinical Cases. There is a pressing need for reliable tools for diagnosing tuberculosis (TB) of the gastrointestinal tract. Despite advancements in the diagnosis and treatment, TB remains a global health challenge. Ali et al demonstrated that TB may mimic gastrointestinal conditions, such as gastric outlet obstruction, causing a delay in the diagnosis. Furthermore, the latter complication is frequently observed during infections, including Helicobacter pylori, and rarely is related to TB, as in the presented case. In line with this, we think that laboratory tests based on interferon-gamma release assays can be a helpful tool for diagnosing latent TB paced in the gastrointestinal tract. Innovative strategies and approaches for diagnosing latent/active extra pulmonary TB are crucial for establishing the diagnosis early and enhancing treatment strategies to mitigate the global burden of TB.

Interferon-gamma release assays (IGRAs) have gained attention for the diagnosis of latent tuberculosis infection (LTBI) due to their higher specificity compared to the tuberculin skin test (TST). However, the IGRA's performance varies across different populations. This study evaluated the diagnostic performance of three IGRAs (TBF-FIA, TBF-ELISA, and QFT-Plus) in Ghana, comparing them among individuals exposed and unexposed to MTB infection. Conducted in TB clinics across three regions, this prospective and cross-sectional study included healthy individuals with no known TB exposure (unexposed group) and patients with confirmed active TB (exposed group). Blood samples were tested using all three assays as per the manufacturers' guidelines. The TBF-ELISA showed 3.4% higher sensitivity but 4.6% lower specificity compared to QFT-Plus. The TBF-FIA had sensitivity of 78.5-87.3% and specificity of 82.9-90.0%. These findings indicate that while the three IGRAs offer similar diagnostic accuracy, the variations in specificity and limited data on assays like TBF-FIA require further investigation.

This study aimed to investigate the differential expression levels of the cGAS-STING pathway in peripheral blood mononuclear cells (PBMCs) of spinal tuberculosis (TB) patients with different progression and its feasibility as a diagnostic marker.

Peripheral blood and medical records of 25 patients with spinal TB and 10 healthy individuals, were prospectively collected and analyzed. PBMCs and serum were extracted from peripheral blood and the expression levels of the cGAS-STING pathway in PBMCs were measured by real-time PCR (RT-PCR) and serum interferon β (IFN-β) expression levels were measured by enzyme-linked immunosorbent assay (ELISA). The expression of Interferon regulatory Factor 3 (IRF3) in PBMCs was measured using western blot. Statistical analysis was performed using the SPSS 26.0 statistical package.

The results showed that the expression level of the TANK-binding kinase 1 (TBK1) and IRF3 was significantly higher in PBMCs (P < 0.05), in patients with active lesions than in patients with stable lesions. The serum concentration of IFN-β was significantly higher in patients with active lesions (P = 0.028). Compared with healthy individuals, the expression level of the cGAS-STING pathway was elevated in PBMCs of TB patients (P < 0.05), and the difference in the expression level of IFN-β was not statistically significant (P > 0.05), and the serum IFN-β concentration was elevated (P < 0.05). The calculated AUC values for TBK1 and IRF3 in PBMCs, IFN-β in serum and erythrocyte sedimentation rate (ESR) to distinguish between patients with active and stable lesions were 0.732, 0.714, 0.839, and 0.714 respectively.

The expression level of TBK1 and IRF3 in PBMCs, and IFN-β in the serum of patients with spinal TB is positively correlated with disease activity. TBK1 has higher specificity and IFN-β in serum has higher sensitivity when used to differentiate between patients with active and stable lesions.

The double burden of tuberculosis (TB) and diabetes mellitus (DM) represents a major public health challenge that demands urgent and integrated approaches. The interplay between these two chronic conditions presents unique clinical and public health management challenges, as well as social and economic implications. We explored the bidirectional relationship between TB and DM, emphasizing how DM increases susceptibility to TB and complicates its management, while TB may exacerbate glycemic control in diabetic patients. This review underscores the challenges associated with the management of both diseases, obstacles in screening TB patients for DM and TB preventive therapy for DM since inadequate glycemic control can impact treatment outcomes. Several studies have investigated the disease interplay; however, the results have been equivocal, and this may be exerting negative impacts on the disease prevention and treatment. TB-diabetes comorbidity has been linked to poor treatment outcomes whereas TB prevention in people with DM at present is a dilemma. In addition to highlighting how urgent it is to address this comorbidity, this review offers a road map for better prevention, treatment, and control of several factors underlying the TB-diabetes syndemic interaction.

The diagnosis of extensive pulmonary tuberculosis, especially in young people, should take into account the possibility of an associated systemic autoimmune disease. Infections remain an important cause of morbidity and mortalityin systemic lupus erythematosus. This case illustrates the importance of recognizing the association of systemic autoimmune diseases and infections and the need for a multidisciplinary approach.

The purpose of this study was to determine the contribution of genetic factors, i.e., the level of expression and polymorphisms of Toll-like receptors (TLR), to the susceptibility of latent tuberculosis infection in a Russian cohort of individuals infected with HIV. The patients (n = 317) with confirmed HIV infection were divided into two groups according to the results of the STANDARD E TB-Feron test: 63 cases with a latent TB infection and 274 controls without LTBI. Total DNA and RNA were isolated from whole-blood samples. SNP genotyping and expression levels of five TLR genes (TLR1, TLR2, TLR4, TLR6, and TLR8) were determined by means of real-time PCR. There were no significant differences in the expression levels of the TLRs between the case and control groups. In addition, we did not observe any significant association between the analyzed SNPs and the susceptibility of Latent tuberculosis infection (LTBI) in patients with HIV. However, patients from an entire cohort with the rs4986790-GG (TLR4) and rs5743708-GG (TLR2) genotypes were characterized by lower CD4 T-cell counts compared to carriers of alternative alleles. Moreover, we found a significant risk of a hazardous drop in the CD4 T-cell count below 350 cells/mm3 associated with the rs4986790-G (TLR4) allele. Latent tuberculosis infection in individuals infected with HIV does not significantly modify the level of TLR gene expression.

The spatial delays of pulmonary tuberculosis (PTB) have been less explored. In this study, a total of 151,799 notified PTB cases were included, with median patient and diagnostic delays of 15 [interquartile range (IOR), 4-35] and 2 (IOR, 0-8) days, respectively. The spatial autocorrelation analysis and spatial-temporal scan statistics were used to determine the clusters, indicating that the regions in the southwestern and northeastern parts of Zhejiang Province exhibited high rates of long-term patient delay (LPD, delay ≥ 15 days) and long-term diagnostic delay (LDD, delay ≥ 2 days). Besides, the Mantel test indicated a moderately positive correlation between public awareness of suspicious symptoms and the LPD rate in 2018 (Mantel's r = 0.4, P < 0.05). These findings suggest that PTB delays can reveal deficiencies in public health education and the healthcare system. Also, it is essential to explore methods to shift PTB knowledge towards real changes in attitude and behavior to minimize patient delay. Addressing these issues will be crucial for improving public health outcomes related to PTB in Zhejiang Province.

This review explores the evolving landscape of blood biomarkers in the diagnosis of tuberculosis (TB), focusing on biomarkers derived both from the pathogen and the host. These biomarkers provide critical insights that can improve diagnostic accuracy and timeliness, essential for effective TB management. The document highlights recent advancements in molecular techniques that have enhanced the detection and characterization of specific biomarkers. It also discusses the integration of these biomarkers into clinical practice, emphasizing their potential to revolutionize TB diagnostics by enabling more precise detection and monitoring of the disease progression. Challenges such as variability in biomarker expression and the need for standardized validation processes are addressed to ensure reliability across different populations and settings. The review calls for further research to refine these biomarkers and fully harness their potential in the fight against TB, suggesting a multidisciplinary approach to overcome existing barriers and optimize diagnostic strategies. This comprehensive analysis underscores the significance of blood biomarkers as invaluable tools in the global effort to control and eliminate TB.

The Tigray region of Ethiopia, which has been affected by civil war from 2020 to 2022, is facing an increase in tuberculosis in the damaged health system. Our study employed mathematical modeling to predict the incidence of tuberculosis and its trends during the war and in the post-conflict setting of Tigray, Northern Ethiopia.

We predicted the incidence of tuberculosis from 2020 to 2025 in Tigray using the SEIRD model in the context of the recent war and compared it with its counterfactual trend in the absence of war. The counterfactual trend was forecasted using an autoregressive integrated moving average (ARIMA) model for stationary time-series data. We performed rolling origin cross-validation for ARIMA and sensitivity analysis for the SEIRD model. The initial tuberculosis data and model parameters were obtained from the Institute for Health Metrics and Evaluation and the literature, respectively.

Between 2000 and 2017, the incidence of tuberculosis in Tigray decreased at an annual rate of 3.0%. Shortly before the war, the incidence of tuberculosis in the region was 178 per 100,000 people. In a counterfactual scenario where there was no war, the incidence was projected to decrease to 144.3 in 2022 and 126.3 in 2025. However, owing to the war and siege, the SEIRD-projected incidence of tuberculosis would have increased to 965.5 (95% CI: 958.5-972.7) in 2022 and 372.4 (95% CI: 367.7-376.6) in 2025. Over 800 cases of tuberculosis per 100,000 people were attributed to the war in 2022. In the postwar period, the incidence is projected to decrease by 30% by 2023.

The Tigray War reversed a two-decade decline in tuberculosis cases, causing a five-fold increase compared to the no-war scenario. Urgent interventions are needed to support tuberculosis prevention, testing, and treatment, particularly in key and vulnerable populations.

This study presented a nanoparticle-enhanced aptamer-recognizing homogeneous detection system combined with a portable instrument (NASPI) to quantify lipoarabinomannan (LAM). This system leveraged the high binding affinity of aptamers, the high sensitivity of nanoparticle cascade amplification, and the stabilization effect of dual stabilizers (fructose and histone), and used probe-Cu2+ to achieve LAM detection at concentrations ranging from 10 ag mL-1 to 100 fg mL-1, with a limit of detection of 3 ag mL-1 using a fluorometer. It can also be detected using an independently developed handheld fluorometer or the red-green-blue (RGB) camera of a smartphone, with a minimum detection concentration of 10 ag mL-1. We validated the clinical utility of the biosensor by testing the LAM in the urine of patients. Forty urine samples were tested, with positive LAM results in the urine of 18/20 tuberculosis (TB) cases and negative results in the urine of 6/10 latent tuberculosis infection cases and 10/10 non-TB cases. The assay results revealed a 100% specificity and a 90% sensitivity, with an area under the curve of 0.9. We believe that the NASPI biosensor can be a promising clinical tool with great potential to convert LAM into clinical indicators for TB patients.