Evaluating the cost-effectiveness of Cy-Tb for LTBI in India: a comprehensive economic modelling analysis.

BACKGROUND: Latent tuberculosis infection (LTBI) remains a significant challenge, as there is no gold standard diagnostic test. Current methods used for identifying LTBI are the interferon-γ release assay (IGRA), which is based on a blood test, and the tuberculin skin test (TST), which has low sensitivity. Both these tests are inadequate, primarily because they have limitations with the low bacterial burden characteristic of LTBI. This highlights the need for the development and adoption of more specific and accurate diagnostic tests to effectively identify LTBI. Herein we estimate the cost-effectiveness of the Cy-Tb test as compared with the TST for LTBI diagnosis. METHODS: An economic modelling study was conducted from a health system perspective using decision tree analysis, which is most widely used for cost-effectiveness analysis using transition probabilities. Our goal was to estimate the incremental cost and number of TB cases prevented from LTBI using the Cy-Tb diagnostic test along with TB preventive therapy (TPT). Secondary data such as demographic characteristics, treatment outcome, diagnostic test results and cost data for the TST and Cy-Tb tests were collected from the published literature. The incremental cost-effectiveness ratio was calculated for the Cy-Tb test as compared with the TST. The uncertainty in the model was evaluated using one-way sensitivity analysis and probability sensitivity analysis. RESULTS: The study findings indicate that for diagnosing an additional LTBI case with the Cy-Tb test and to prevent a TB case by providing TPT prophylaxis, an additional cost of 18 658 Indian rupees (US${\$}$223.5) is required. The probabilistic sensitivity analysis indicated that using the Cy-Tb test for diagnosing LTBI was cost-effective as compared with TST testing. If the cost of the Cy-Tb test is reduced, it becomes a cost-saving strategy. CONCLUSIONS: The Cy-Tb test for diagnosing LTBI is cost-effective at the current price, and price negotiations could further change it into a cost-saving strategy. This finding emphasizes the need for healthcare providers and policymakers to consider implementing the Cy-Tb test to maximize economic benefits. Bulk procurements can also be considered to further reduce costs and increase savings.

Combined analysis of host IFN-γ, IL-2 and IP-10 as potential LTBI biomarkers in ESAT-6/CFP-10 stimulated blood.

Background: Accurate diagnosis of latent tuberculosis infected (LTBI) individuals is important in identifying individuals at risk of developing active tuberculosis. Current diagnosis of LTBI routinely relies on the detection and measurement of immune responses using the Tuberculin Skin Test (TST) and interferon gamma release assays (IGRAs). However, IGRA, which detects Mycobacterium tuberculosis specific IFN-γ, is associated with frequent indeterminate results, particularly in immunosuppressed patients. There is a need to identify more sensitive LTBI point of care diagnostic biomarkers. The aim of this study was to assess the validity of early secreted antigen target 6 kDa (ESAT-6) and culture filtrate protein 10 (CFP-10) stimulated plasma to identify additional cytokines and chemokines as potential biomarkers of LTBI. Method: The levels of 27 cytokines and chemokines were measured by Bio-Plex Pro cytokine, chemokine and growth factor assay in ESAT-6 and CFP-10 co-stimulated plasma from 20 LTBI participants with positive IGRA (Quantiferon TB Gold plus) and 20 healthy controls with negative IGRA. Traditional ELISA was used to validate the abundance of the best performing markers in 70 LTBI and 72 healthy participants. All participants were HIV negative. Results: We found that Interleukin 1 receptor antagonist (IL1ra) (p = 0.0056), Interleukin 2 (IL-2) (p < 0.0001), Interleukin 13 (IL-13) (p < 0.0001), Interferon gamma-induced protein 10 (IP-10) (p < 0.0001), and Macrophage inflammatory protein-1 beta (MIP1b) (p = 0.0010) were significantly higher in stimulated plasma of LTBI compared to healthy individuals. Stimulated plasma IL-2 (cutoff 100 pg/mL), IP-10 (cutoff 300 pg/mL) and IL-13 (5 pg/mL) showed potential in diagnosing LTBI with PPV = 100%, 0.89.4%, and 80.9% and NPV = 86.9%, 0.85.7%, and 84.2%, respectively. Conclusion: Our data shows that co-stimulating whole blood with ESAT-6 and CFP-10 may help distinguish LTBI from healthy individuals. We also identified IL-2 and IP-10 as potential biomarkers that could be added to the currently used IFN-γ release assays in detection of LTBI.

Higher blood manganese level associated with increased risk of adult latent tuberculosis infection in the US population.

Background: The associations between blood heavy metal levels and latent tuberculosis infection (LTBI) have not been fully elucidated. The aim of this study was to investigate the potential association between blood heavy metal levels and LTBI in adults using National Health and Nutrition Examination Survey data from 2011 to 2012. Methods: We enrolled 1710 participants in this study, and compared the baseline characteristics of participants involved. Multivariate logistic regression analysis, restricted cubic splines (RCS) analysis, along with subgroup analysis and interaction tests were utilized to explore the association between blood manganese (Mn) level and LTBI risk. Results: Participants with LTBI had higher blood Mn level compared to non-LTBI individuals (p < 0.05), while the levels of lead, cadmium, total mercury, selenium, copper, and zinc did not differ significantly between the two groups (p > 0.05). In the fully adjusted model, a slight increase in LTBI risk was observed with each 1-unit increase in blood Mn level (OR = 1.00, 95% CI: 1.00-1.01, p = 0.02). Participants in the highest quartile of blood Mn level had a threefold increase in LTBI risk compared to those in the lowest quartile (OR = 4.01, 95% CI: 1.22-11.33, p = 0.02). RCS analysis did not show a non-linear relationship between blood Mn level and LTBI (non-linear p-value = 0.0826). Subgroup analyses and interaction tests indicated that age, alcohol consumption, and income-to-poverty ratio significantly influenced LTBI risk (interaction p-values<0.05). Conclusion: Individuals with LTBI had higher blood Mn level compared to non-LTBI individuals, and higher blood Mn level associated with increased LTBI risk.

Specific Cytokines Analysis Incorporating Latency-Associated Antigens Differentiates Mycobacterium tuberculosis Infection Status: An Exploratory Study.

Introduction: Current immunologic methods cannot distinguish Mycobacterium tuberculosis (Mtb) infection statuses, especially to discriminate active tuberculosis (ATB) from latent tuberculosis infection (LTBI). This study explored the potential of latency-associated antigens (Rv1733cSLP and Rv2028c) and multifactorial cytokine detection to distinguish tuberculosis infection states. Methods: ATB patients (20), LTBI healthcare workers (25), fever patients (11), and healthy controls (10) were enrolled. Cytokine levels (IFN-γ, TNF-α, IL-2, IL-6, IP-10, IL-1Ra, CXCL-1, and MCP-1) were measured using Luminex with/without MTB-specific virulence factor and latency-associated antigens stimulation. Results: Without antigen stimulation, IL-6, IP-10, MCP-1, and IL-1Ra were higher in the ATB group than in the LTBI group (p<0.05), but no significant differences between the ATB group and the fever group. Stimulated with the four antigens, respectively, the cytokines, including IP-10Esat-6, IP-10CFP-10, IFN-γRv1733cSLP, IFN-γRv2028c, IL-6Esat-6, IL-6Rv1733cSLP, IL-6Rv2028c, IL-2Rv1733cSLP, IL-2 Rv2028c, IL-1RaEsat-6, IL-1RaCFP-10, IL-1RaRv2028c, CXCL-1Esat-6, CXCL-1CFP-10, CXCL-1Rv1733cSLP, CXCL-1Rv2028c, MCP-1Esat-6 and MCP-1CFP-10, demonstrated accurate discrimination between ATB and LTBI (p<0.05). Additive concentrations demonstrated significant secretion differences of IFN-γ, IP-10 and IL-2, primarily by virulence factors in ATB and latency-associated antigens in LTBI. Latency-associated antigens synergized with virulence factors, enhancing TH1-type cytokine diagnostic efficacy for discriminating ATB from LTBI, the AUC for TNF-α increased from 0.696 to 0.820 (p=0.038), IFN-γ increased from 0.806 to 0.962 (p=0.025), and IL-2 increased from 0.565 to 0.868 (p=0.007). Model selected by forward likelihood method indicated combined detection of IFN-γCFP-10, IFN-γRv1733cSLP, IP-10Rv1733cSLP, and CXCL-1Rv1733cSLP achieved ATB diagnosis (AUC=0.996) and ATB-LTBI differentiation (AUC=0.992). Combined detection of IFN-γCFP-10 and IFN-γRv1733cSLP achieved tuberculosis infection diagnosis (AUC=0.943). Conclusion: Latency-associated antigens enhance multiple cytokine discriminatory ability, particularly TH1-type cytokines, for differentiating Mtb infection statuses.

Knowledge and Attitudes About Screening and Preventive Treatment of Latent Tuberculosis Infection Among Patients with Rheumatic Diseases in Beijing, China.

Objective: Tuberculosis preventive treatment (TPT) is an important strategy for tuberculosis (TB) control. Rheumatic diseases (RD) patients are at high risk for active TB development. More researches are needed in terms of patient compliance in clinical practice. This study aims to explore the potential difficulties and obstacles in latent tuberculosis infection (LTBI) screening and TPT in RD patients. Methods: Convenience sampling was used to recruit RD outpatients who had indications for LTBI screening and TPT. All participants were given questionnaires on knowledge and attitudes regarding screening and preventive treatment of LTBI. Results: Of the 200 RD patients, most people were aware that they were at increased risk of ATB due to their rheumatic disease and knew that TB was curable. The main association with willingness to have screening for LTBI was tertiary education (P = 0.013). The main association with willingness to take treatment for LTBI was a sense of personal risk and belief that the treatment would reduce risk of ATB (P < 0.001). More than half of the people surveyed could not accept taking 6 or more pills per day, while more than half of the patients could tolerate a treatment course of 9 months or longer. Most (65.4%) preferred their own rheumatologists to initiate treatment. Conclusion: Educating RD patients about their individual risks of TB and the side effects of treatment, and educating/empowering rheumatologists to discuss these aspects with their patients and to offer LTBI screening and treatment, may help improve patients' compliance with LTBI screening and TPT.

Tuberculosis preventive treatment in newborns.

OBJECTIVE: To describe the reported cases of newborns subjected to tuberculosis preventive treatment (TPT) in the state of Paraná, Brazil, and to evaluate the safety and effectiveness in preventing the progression of TB disease in this population. METHOD: Observational, descriptive case series, with secondary data. The characteristics of the participants were analyzed from the information systems of preventive treatment of TB (of Paraná), between 2009 and 2016. To evaluate which children had developed tuberculosis later or died, we used the data from the information systems of TB (in Brazil), and mortality (in Paraná), covering the years 2009 to 2018. RESULTS: A total of 24 children underwent TPT with the age at treatment onset ranging from 0 to 87 days (median: 23 days). In 95.8 %, the exposure occurred at home, and in 33.3 % of cases, the mother was the source of the infection. A total of 20.8 % of the children tested positive for tuberculosis test at 3 months of age, 83.3 % completed treatment, and 2 experienced adverse events (gastrointestinal issues). No children developed TB or died during the minimum of a 2-year evaluation period through the official databases. CONCLUSIONS: In this case series, the adherence to the plan was high, with few adverse events and 100 % protection against infection.

Incidence of Tuberculosis Among Immigrants in Korea Who Participated in a Latent Tuberculosis Infection Screening Program.

BACKGROUND: With a rapid decrease in tuberculosis (TB) incidence, the significance of latent tuberculosis infection (LTBI) has been underscored in South Korea. Although South Korea does not have a high proportion of immigrants compared to other countries, there is a growing argument that it should actively embrace immigrants as a solution to address issues of low birth rates and population aging. This study aimed to assess TB incidence among immigrants who participated a pilot LTBI screening program in South Korea. METHODS: Records of immigrants participated in a pilot LTBI screening program in South Korea between 2018 and 2019 were linked with Korean National TB Surveillance System to determine TB development. Participants underwent interferon-gamma release assay (IGRA) and chest X-rays. Standardized incidence ratios (SIRs) stratified by age, country of origin's TB burden was calculated with a reference group of general South Korean population. RESULTS: Of a total of 9,517 participants, 14 TB cases were identified. Participants with positive IGRA results who did not initiate LTBI treatment showed TB incidence of 312.5 per 100,000 person-years, whereas those with negative results showed TB incidence of 34.4 per 100,000 person-years, resulting in an incidence rate ratio of 9.08 (95% confidence interval [CI], 2.50-32.99). SIR of TB among total participants including those with negative IGRA results was 2.60 (95% CI, 1.54-4.38; P < 0.001), whereas SIR among those with positive IGRA results was 5.86 (95% CI, 3.15-10.89; P < 0.001). In the calculation of SIR among participants with positive IGRA results, those aged under 35 from high TB-burden countries or intermediate TB-burden countries showed a high SIR (18.08; 95% CI, 2.55-128.37; P = 0.004), and 11.30 (95% CI, 2.82-45.16; P < 0.001), respectively). Contrary to previous reports that suggest the majority of elderly population with a positive IGRA result were due to remote infection and had a lower TB risk compared to younger ages, SIR among those aged 65 or over from intermediate TB-burden countries was 6.15 (95% CI, 0.87-43.69; P = 0.069), which was comparable to that in younger participants aged between 35 and 49 (SIR, 4.87; 95% CI, 1.22-19.49; P = 0.025) or those aged between 50 and 64 (SIR, 4.62; 95% CI, 1.73-12.31; P = 0.002). CONCLUSION: Young immigrants with positive IGRA results from countries with high or intermediate TB burden showed a relatively high TB risk compared to a general South Korea population. In addition, unexpected high TB risk was observed among elderly immigrants with positive IGRA results. In establishing future policies for LTBI in immigrants in South Korea, screenings should primarily focus on younger age group (who aged under 35). Additionally, further research is needed on the high TB risk observed in elderly immigrants.

Comparison of QuantiFERON Gold In-Tube Versus Tuberculin Skin Tests on the Initiation of Tuberculosis Preventive Therapy Among Patients Newly Diagnosed With Human Immunodeficiency Virus in the North West Province of South Africa (the Teko Study): A Cluster Randomized Trial.

BACKGROUND: Tuberculosis (TB) preventive therapy (TPT) reduces the risk of TB disease in people with human immunodeficiency virus (HIV), yet uptake has been suboptimal in many countries. We assessed whether QuantiFERON Gold In-Tube (QGIT) during routine HIV care increased TB infection (TBI) testing and TPT prescriptions. METHODS: This parallel-arm, 1:1 cluster-randomized controlled trial compared the standard-of-care tuberculin skin test to QGIT in South Africa. We enrolled consenting, TPT-eligible adults diagnosed with HIV ≤30 days prior and used intention-to-treat analyses for the outcomes: proportion of patients with documented TBI results, proportion with documented TPT, and time from enrollment to outcomes. FINDINGS: We enrolled 2232 patients across 14 clinics from November 2014 to May 2017 (58% in intervention clinics). At 24 months of follow-up, more participants in intervention clinics had TBI results (69% vs 2%, P < .001) and TPT prescriptions (45% vs 30%, P = .13) than control clinics. Controlling for baseline covariates, intervention clinics had 60% (95% confidence interval, 51-68; P < .001) more participants with TBI results and 12% (95% confidence interval, -6 to 31; P = .18) more with TPT prescriptions. Among participants with results, those in intervention clinics received results and TPT faster (intervention: median of 6 and 29 days after enrollment vs control: 21 and 54 days, respectively). INTERPRETATION: In this setting, QGIT in routine HIV care resulted in more patients with TBI results. Clinicians also initiated more people with HIV on TPT in QGIT intervention clinics, and did so more quickly, than the control arm. CLINICAL TRIALS REGISTRATION: NCT02119130.

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.

Identification of MORN3 and LLGL2 as novel diagnostic biomarkers for latent tuberculosis infection using machine learning strategies and experimental verification.

BACKGROUND: Current diagnostic methods cannot effectively distinguish between latent tuberculosis infection (LTBI) and active tuberculosis (ATB). This study aims to explore novel non-invasive diagnostic biomarkers for LTBI and to elucidate possible molecular mechanisms of LTBI pathogenesis. METHODS: Three GEO datasets (GSE19439, GSE19444, and GSE62525) were utilized to analyze the differentially expressed genes (DEGs). Functional enrichment studies were then performed on these DEGs. To ascertain potential diagnostic biomarkers, we utilized two different machine learning techniques: LASSO and RF. ROC curves were constructed in both the training and validation datasets to assess the diagnostic efficacy. The expression of identified biomarkers was verified by RT-qPCR in our own Chinese cohort. Using CIBERSORT, we estimated the abundances of 22 immune cell types in LTBI group, and subsequently analyzed the relationship between biomarker expression and immune cell infiltration. RESULTS: 166 DEGs were identified between ATB and LTBI groups, which are primarily associated with immune responses, inflammatory signaling pathways, and infection factors. Following that, 22 candidate diagnostic biomarkers for LTBI were selected in the machine learning process. Three up-regulated genes, MORN3, LLGL2, and IFT140, whose expression levels were not previously reported in TB, were validated using the training and validation cohort datasets. In our own Chinese cohort, we also found that MORN3 and LLGL2 showed good diagnostic effect using RT-qPCR method. Finally, we revealed the specific infiltration features of immune cells in LTBI and observed a notable correlation between potential marker expression and immune cells. CONCLUSIONS: MORN3 and LLGL2 emerged as candidate diagnostic biomarkers for LTBI, following the elucidation of the key immune cell types involved. Our findings will contribute to providing a potential target for early noninvasive diagnosis of LTBI patients.

Investigating the Diagnostic and Therapeutic Potential of a T Cell Receptor (TCR)-like single Domain Antibody (sDAb)-Human IgG1 Antibody against Heat Shock Protein (HSP) 16KDa/HLA-A2 for Latent Tuberculosis.

Heat shock protein 16-kDa (HSP 16-kDa) is essential for the survival of Mycobacterium tuberculosis (M. tuberculosis) during the latent period; hence, a peptide-MHC presentation of HSP 16-kDa could be a potential diagnostic and therapeutic target for latent tuberculosis (LTB). This study aimed to generate a TCR-like single-domain antibody (sDAb)-human IgG1 antibody and subsequently investigate its diagnostic and therapeutic potential in LTB, utilizing a model cell presenting the target peptide. A previously generated TCR-like sDAB that can bind to HSP 16-kDa was first fused to a human IgG1 Fc-receptor via a linker. The fusion product, sDAb-IgG1, was expressed with HEK293-F and was subsequently purified. Its diagnostic potential was investigated via cell-based ELISA utilizing MCF-7 cells peptide-pulsed with HSP 16-kDa peptides. Investigation into the antibody-dependent cell-mediated cytotoxicity (ADCC) of MCF-7 cells was also conducted to investigate its therapeutic potential. Finally, TCR-like sDAb-IgG1 was successfully produced transiently with HEK-293F and was purified using protein A chromatography. The generated antibody was tested using cell-based ELISA, which demonstrated the effective binding of the TCR-like sDAb-IgG1 to the 16-kDa peptide-MHC on the cell surface. The ADCC assay also showed that the antibody effectively mediated the ADCC of MCF-7 cells with the help of 16-kDa peptide-MHC. This allows us to hypothesize the possible utility of the said antibody for both diagnostics and therapeutics of latent tuberculosis after more investigations with clinical samples.

Cervical Tuberculosis Mimicking Tumor Persistence: A Case Report.

Tuberculosis can coexist with malignancy in the same organ, but cancer with TB in the cervix is rare. This is a case of cervical tuberculosis diagnosed in a cervical cancer patient after concurrent chemoradiotherapy and brachytherapy. This is the case of a 38-year-old G2P2 (2002) diagnosed with squamous cell carcinoma, large cell non-keratinizing cervix, Stage IIIB. The patient underwent concurrent chemoradiotherapy and brachytherapy. One month after the last brachytherapy dose, the attending physician noted a nodularity on the anterior lip of the cervix. A cervical punch biopsy was done to rule out tumor persistence. The histopathology revealed chronic granulomatous inflammation with Langhan's type multinucleated giant cells consistent with tuberculous infection. She was diagnosed with cervical tuberculosis, postulated to be from latent TB reactivation, and was given Anti-Koch's medication for six months. After receiving Anti-Koch's treatment, the cervical nodularity was no longer appreciated, and the rest of the cervix was smooth on palpation. Her Pap Test was negative for any intraepithelial lesion and was declared with no evidence of carcinoma. A possible latent TB infection should always be screened in cancer patients from high-burden areas or those with close contact treated for tuberculosis because immunosuppression during cancer treatment can cause the reactivation of tuberculous disease. Cervical tuberculosis complicating cervical malignancy is treatable with Anti-Koch's therapy and has not been shown to affect the course of the carcinoma.

Accelerated Bacille Calmette-Guérin reactions: More than meets the eye.

An accelerated local injection site reaction following Bacille Calmette-Guérin (BCG) vaccination has been associated with underlying active tuberculosis (TB) in high TB-prevalence settings. The clinical significance of this accelerated BCG reaction in individuals without TB symptoms, particularly in low TB-prevalence countries, is unclear. Using safety surveillance data and baseline interferon-gamma release assays (IGRA) within an international randomised trial of BCG vaccination in healthcare workers (the BRACE trial), we aimed to determine the incidence, and investigate for clinical implications, of an accelerated BCG reaction in asymptomatic adults in low and high TB-prevalence settings. An accelerated BCG reaction occurred in 755/1984 (38 %) of BCG-vaccinees. Although more frequently painful, tender, erythematous and/or swollen within the first fourteen days of vaccination, compared with non-accelerated reactions, the majority of injection site reactions were mild and did not meet criteria for an adverse event. Prior mycobacterial exposure, through prior BCG vaccination (OR 2.46, 95%CI 1.93-3.13, p < 0.001) or latent TB infection (OR 4.17, 95%CI 1.16-14.93, p = 0.03), and female sex (OR 1.27, 95%CI 1.03-1.57, p = 0.02), were key determinants for the occurrence of an accelerated BCG reaction. The development of an accelerated local reaction to BCG vaccination in an individual without prior history of BCG vaccination, should prompt consideration of further investigations for potential underlying TB infection.

Acute Leukemia and Latent Tuberculosis Infection in Italy: Quantiferon-Tb Test Screening in a Low Tuberculosis Incidence Country.

Background: Identification of latent tuberculosis infection (LTBI) is a critical step of tuberculosis surveillance, especially in low-incidence countries. However, it is limited to situations with a higher probability of developing active disease, e.g., patients with hematological malignancies. According to guidelines, in TB non-endemic countries, no clear screening program is established at diagnosis for patients with acute leukemia (AL). The primary endpoint of this study was to establish the prevalence of LTBI in patients with a diagnosis of AL using QuantiFERON (QFT)-TB. Secondarily, radiological and clinical features driving the increased risk of LTBI were evaluated. Methods: QFT-TB screening was performed before induction or consolidation in all patients with AL (myeloid and lymphoid) treated at our Institution between October 2019 and August 2023. Results: We accrued 62 patients, of whom 7 (11,3%) tested positive, without any symptoms or signs of active TB, and 2 (3,2%) resulted as indeterminate. All positive patients started prophylaxis with isoniazid 300 mg daily, while patients whose test was indeterminate did not receive any prophylaxis. Active TB was excluded by imaging, as well as microscopic, cultural, and molecular examination on bronchoalveolar lavage if signs of any infection were detected. During the 46 months of observation, no patients developed TB reactivation. Conclusions: Despite the low sample size, 1/10 of our patients had prior TB exposure, hinting that LTBI could be more common than expected in Italy. This finding suggests implementing TB screening in the pre-treatment setting, particularly at a time when more active treatments are becoming available also for patients ineligible for intensive chemotherapy.

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

BACKGROUND: 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. METHODS: 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. RESULTS: Our findings revealed that individuals in the progressor group exhibited significantly decreased levels of IFNγ, IL-2, TNFα, IL1α, IL1ß, IL-17A, and IL-1Ra at baseline, months 4 and 12. In contrast, the progressor group displayed significantly elevated levels of IFNα, IFNß, 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. CONCLUSIONS: 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.

Adherence to preventive treatment for latent tuberculosis infection in close contacts of pulmonary tuberculosis patients: A cluster-randomized controlled trial in China.

OBJECTIVES: This study examined adherence rates to tuberculosis preventive treatment (TPT) among close contacts of individuals with pulmonary tuberculosis (PTB) and identified factors associated with TPT adherence in China. METHODS: A multicenter, cluster-randomized, open-label control trial was carried out across three sites involving 34 counties in China. Close contacts of bacteriologically confirmed rifampin and isoniazid-susceptible PTB cases were identified and screened for latent tuberculosis infection (LTBI). Eligible participants were randomly assigned to either the 3H2P2 group, which consisted of a 3-month, twice-weekly regimen of rifapentine and isoniazid, or the 6H group, which entailed a 6-month daily regimen of isoniazid. To assess the factors influencing adherence, a two-level logistic regression model was utilized. RESULTS: Out of the 2434 close contacts who initiated TPT, 2121 (87.1%) completed the regimen. Of the 313 individuals who did not complete TPT, 60.1% refused to continue, and 27.8% discontinued due to adverse effects. The two-level logistic regression model revealed several factors associated with enhanced TPT adherence: enrollment in the 3H2P2 group (odds ratio [OR] = 2.09), management by a TB dispensary responsible for TPT (OR = 2.55), supervision by healthcare workers (OR = 6.40), and clinician incentives (OR = 2.49). Conversely, the occurrence of any adverse effects (OR = 0.08) was identified as a risk factor for nonadherence. CONCLUSION: Administering TPT to individuals with LTBI is feasible among close contacts. Adherence to TPT can be enhanced through shorter, safer treatment regimens and supportive interventions, such as directly supervised therapy for TPT recipients and incentives for healthcare providers managing TPT.

Evaluation of concordance of new QuantiFERON-TB Gold Plus platforms for Mycobacterium tuberculosis infection diagnosis in a prospective cohort of household contacts.

Interferon-gamma (IFN-γ) release assays play a pivotal role in tuberculosis infection (TBI) diagnosis, with QuantiFERON-TB Gold Plus-an enzyme-linked immunosorbent assay (ELISA)-among the most widely utilized. Newer QuantiFERON-TB platforms with shorter turnaround times were recently released. We aimed to evaluate these platforms' agreement in the diagnosis of TBI. Blood samples from a prospective cohort of tuberculosis household contacts were collected at baseline and after 12 weeks of follow-up, and tested with LIAISON, an automated chemiluminescence immunoassay (CLIA) system, QIAreach, a lateral flow (QFT-LF) semi-automated immunoassay, and the ELISA QuantiFERON-TB Gold Plus platform. Test concordances were analyzed. ELISA vs CLIA overall agreement was 83.3% for all tested samples (120/144) [Cohen's kappa coefficient (κ): 0.66 (95% CI: 0.54-0.77)]. Samples positive with CLIA provided consistently higher IFN-γ levels than with ELISA (P < 0.001). Twenty-four (16.7%) discordant pairs were obtained, all CLIA-positive/ELISA-negative: 15 (62.5%) had CLIA IFN-γ levels within borderline values (0.35-0.99 IU/mL) and 9 (37.5%) >0.99 IU/mL. QFT-LF showed only 76.4% (68/89) overall agreement with ELISA [κ: 0.53 (95% CI: 0.37-0.68)] with 21 (23.6%) discordant results obtained, all QFT-LF-positive/ELISA-negative. Overall concordance between ELISA and CLIA platforms was substantial, and only moderate between ELISA and QFT-LF. The CLIA platform yielded higher IFN-γ levels than ELISA, leading to an almost 17% higher positivity rate. The techniques do not seem interchangeable, and validation against other gold standards, such as microbiologically-confirmed tuberculosis disease, is required to determine whether these cases represent true new infections or whether CLIA necessitates a higher cutoff. IMPORTANCE: Tuberculosis is an airborne infectious disease caused by Mycobacterium tuberculosis that affects over 10 million people annually, with over 2 billion people carrying an asymptomatic tuberculosis infection (TBI) worldwide. Currently, TBI diagnosis includes tuberculin skin test and the blood-based interferon-gamma (IFN-γ) release assays, with Qiagen QuantiFERON-TB Gold Plus (QFT) being among those most widely utilized. We evaluated Qiagen's newer QFT platforms commercially available in a prospective cohort of tuberculosis contacts. A substantial agreement was obtained between the current QFT-enzyme-linked immunosorbent assay (ELISA) and the new QFT-chemiluminescence immunoassay (CLIA) platform, although QFT-CLIA provided higher concentrations of IFN-γ, leading to a 16.6% higher positivity rate. We highlight that both platforms may not be directly interchangeable and that further validation is required.

One-month daily and three-month weekly rifapentine plus isoniazid are comparable in completion rate and safety for latent tuberculosis infection in non-HIV Population: a randomized controlled trial.

OBJECTIVES: The weekly rifapentine plus isoniazid for 3 months (3HP) improves completion rate of latent tuberculosis infection treatment, but flu-like symptoms are common. The novel 1HP regimen, involving daily rifapentine plus isoniazid for 28 days, has demonstrated low toxicity in HIV-infected populations. We aimed to investigate whether 1HP has a lower incidence rate of systemic drug reaction (SDR) compared with 3HP during treatment in non-HIV populations. METHODS: This randomized, multicentre trial compared the completion rate and risks of SDRs of 1HP and 3HP in aged ≥13 years non-HIV subjects with latent tuberculosis infection between September 2019 and September 2023 (ClinicalTrials.gov: NCT04094012). We also investigated associations between SDRs and plasma levels of drugs and their metabolites. RESULTS: A total of 251 and 239 individuals were randomly assigned to 1HP and 3HP groups, respectively, with completion rates of 82.9% (208/251) and 84.5% (202/239), respectively. Among them, 12.7% (32/251) and 10.9% (26/239) of 1HP and 3HP groups experienced SDRs, respectively (p 0.522), predominantly urticaria in 1HP group (59.4% [19/32]) and flu-like syndrome in 3HP group (80.8% [21/26]). Among participants experiencing SDRs, 43.8% (14/32) and 34.6% (9/26) in 1HP and 3HP groups, respectively, completed treatment (p 0.470). Cutaneous reactions were more common in 1HP than 3HP group (32.7% [82/251] vs. 13.0% [31/239], p < 0.001). In 1HP group, urticaria was associated with a higher plasma desacetyl-rifapentine level (ug/mL) at both 2 (median [interquartile range]: 36.06 [17.46-50.79] vs. 22.94 [14.67-31.65], p 0.018) and 6 hours (26.13 [15.80-53.06] vs. 29.83 [18.13-34.01], p 0.047) after dosing. DISCUSSION: In non-HIV population, the incidence rate of SDR under 1HP is not lower than 3HP. Notably, urticaria, rather than flu-like syndrome, was the predominant SDR associated 1HP. The findings of this study underscore the feasibility of 1HP regimen in non-HIV populations with a high-completion rate exceeding 80%.

Infecção latente pelo Mycobacterium tuberculosis em trabalhadores da saúde na Bahia / Latent Infection by Mycobacterium tuberculosis in health Workers in Bahia, Brazil

Objetivo: Estimar a prevalência de positividade do Teste Tuberculínico (TT) no rastreamento da infecção latente pelo Mycobacterium tuberculosis (ILTB) e identificar fatores associados entre trabalhadores da Atenção Primária à Saúde (APS) e média complexidade no segundo maior município do Estado da Bahia. Métodos: Inquérito epidemiológico, com 370 participantes, que avaliou dados sociodemográficos, ocupacionais, consumo de tabaco, álcool e variáveis relacionadas à tuberculose (TB), no período de abril/2021 a março/2022. Aplicou-se o TT por via intradérmica, com leitura após 72h. Resultados: A prevalência de positividade do TT foi de 41,3% e 17,6% para TT ≥ 5mm e TT ≥ 10mm, respectivamente. Para TT ≥ 5mm, as variáveis associadas foram: possuir cicatriz da vacina Bacilo Calmette-Guérin (BCG) e contato prévio com pessoas com TB. Conclusão: A prevalência de positividade do TT foi elevada entre os participantes do estudo. Fazem-se necessárias medidas de proteção ambiental, coletiva e individual para redução do risco de ILTB.

Objective: To estimate the prevalence of tuberculin test (TT) positivity in screening for Latent Mycobacterium tuberculosis Infection (LTBI) and to identify associated factors in Primary Health Care (PHC) and medium complexity workers in the second largest municipality in the State of Bahia, Brazil. Methods: Epidemiological survey with 370 workers on sociodemographic and occupational data, tobacco and alcohol use and variables related to Tuberculosis (TB), during April 2021 and March 2022. TT was applied intradermally, with reading after 72 hours. Results: The prevalence of positive TT was 41.3% and 17.6% for TT ≥ 5mm and TT ≥ 10mm, respectively. For TT ≥ 5mm, the associated variables were: presence of Bacillus Calmette-Guérin (BCG) vaccine scar and previous contact with TB patients. Conclusion: The prevalence of TST positivity was high among study participants. Environmental, collective and individual protection measures are necessary to reduce the risk of LTBI.

Mixed methods study on latent tuberculosis among agate stone workers and advocacy for testing silica dust exposed individuals in India.

The 2021 tuberculosis (TB) preventive treatment guidelines in India included silicosis as a screening group, yet latent TB infection (LTBI) testing for silica-dust-exposed individuals is underemphasized. Focusing on an estimated 52 million silica-dust-exposed workers, particularly agate-stone workers in Khambhat, Gujarat, our study aims to estimate LTBI prevalence, identify predictors, and gather insights from TB and silicosis experts. Employing a sequential explanatory mixed-methods approach, a cross-sectional study involved 463 agate-stone workers aged ≥ 20 years in Khambhat, using IGRA kits for LTBI testing. In-depth interviews with experts complemented quantitative findings. Among agate-stone workers, 58% tested positive for LTBI, with predictors including longer exposure, type of work, and BCG vaccination. Our findings reveal a nearly double burden of LTBI compared to the general population, particularly in occupations with higher silica dust exposure. Experts advocate for including silica-dust-exposed individuals in high-risk groups for LTBI testing, exploring cost-effective alternatives like improved skin sensitivity tests, and shorter TB preventive treatment regimens to enhance compliance. Future research should explore upfront TB preventive treatment for silica-dust-exposed individuals with high LTBI prevalence and optimal exposure duration. This study underscores the urgent need for policy changes and innovative approaches to TB prevention among silica-dust-exposed populations, impacting global occupational health strategies.