Latent Tuberculosis Infection Patients Research Articles

Serum exosome tRFs as a promising biomarker for active tuberculosis and latent tuberculosis infection

ObjectiveTo analyse the expression profiles of serum exosome tRFs/tiRNAs and to explore their diagnostic value in tuberculosis (TB) activity. MethodsThe serum exosome tRF/tiRNA profile was analysed using high-throughput sequencing technology in 5 active tuberculosis (ATB) patients, 5 latent tuberculosis infection (LTBI) patients and 5 healthy controls (HCs). Then, serum exosome tRFs/tiRNAs were validated by quantitative real-time polymerase chain reaction (qRT–PCR), and their diagnostic value was evaluated by receiver operating characteristic curve (ROC) and area under the curve (AUC). Finally, bioinformatics analysis was performed to explore and identify the potential biological pathways induced by tRFs/tiRNAs. ResultsThe sequencing results revealed that serum exosome tRF/tiRNA expression profiles were different among ATB patients, LTBI patients and HCs. Three tRFs (tRF-56:75-Trp-CCA-4, tRF-1:22-chrM.Ser-GCT and tRF-56:76-Val-TAC-1-M2) were selected for qRT–PCR validation. The results demonstrated that the expression level of tRF-1-22-chrM.Ser-GCT was upregulated in ATB patients, while tRF-56-75-Trp-CCA-4 was downregulated, which was consistent with the sequencing data. The AUCs of tRF-56:75-Trp-CCA-4 and tRF-1:22-chrM. Ser-GCT were 0.824 and 1.000, respectively, which have significant values in the diagnosis of ATB patients. Moreover, the expression levels of tRF-56:75-Trp-CCA-4 and tRF-1:22-chrM.Ser-GCT and tRF-56:76-Val-TAC-1-M2 in ATB patients and LTBI were different, which indicated that these three tRFs could effectively distinguish ATB patients and LTBI patients. ConclusionOur findings indicate that serum exosome tRFs can be used as potential markers for the diagnosis of ATB and LTBI.

Tetrad metal ion mediated molecular switch aptamer sensor for fluorescence assay of plasma IP-10 in clinical tuberculosis

Interferon-γ-inducible protein 10 (IP-10) has demonstrated enormous potential as a novel biomarker for tuberculosis (TB), particularly in the monitoring of patient progression for active or latent tuberculosis infection (LTBI). Herein, we established a tetrad metal ion-mediated molecular switch aptamer sensor for the convenient detection of IP-10 in plasma and the diagnosis of TB. The simple sensor relied on the partially complementary IP-10 aptamer and four DNA hairpin strands rich in cytosine (C), which can form a relatively stable tetrad C-Ag+-C structure when combined with Ag+ without additional modification. Based on the specific recognition of IP-10 and aptamer, a large amount of Ag+ could be released in a short time. Combining with cadmium telluride quantum dots (CdTe QDs) as the signal reporter, we achieved superior analytical performance, with the limits of detection (LOD) reaching 3 fg/mL for IP-10 analysis in 1 h. Clinical practicality was confirmed by evaluating 38 clinical samples (19 TB-positive patients, 14 non-TB patients, and 5 latent TB infection patients). The results showed that the detected IP-10 levels were significantly different between the non-TB and TB/LTBI groups, and the results aligned with clinical computed tomography (CT) results, indicating that the method could represent a reliable diagnostic technique for TB.

Incidence and Risk Factors of Active Tuberculosis Among Hospitalized Patients with Latent Tuberculosis Infection in China: A Cohort Study.

The population with latent tuberculosis infection (LTBI) represents a potential pool of patients with active tuberculosis (ATB). T-SPOT.TB is an important test tool for screening LTBI. Owing to the large population of LTBI patients in China, it is necessary to identify a high-risk group for LTBI and enlarge tuberculosis preventive treatment (TPT) to reduce the incidence of ATB. Hospitalized patients with positive T-SPOT.TB results were recruited from January 2013 to December 2016. Patients with ATB were excluded. Basic information was collected and the development of ATBs was examined during follow-up. The life-table method was used to calculate cumulative incidence rates. Potential risk factors were analyzed through Cox regression analysis. A total of 1680 patients with LTBI were recruited in the follow-up cohort, and 377 (22.44%) patients dropped out. With a median follow-up time of 81 months [interquartile range (IQR):61-93], 19 of 1303 patients with LTBI developed ATB. The 1-year incidence of ATB was 614 per 100,000 individuals [95%confidence interval (95% CI):584-644]. Over 5-year period, the cumulative incidence of ATB was 1496 per 100,000 [95% CI:1430-1570], and the incidence density was 240 per 100,000 person-years[95% CI:144-375]. In the Cox regression model, exposure of pulmonary tuberculosis (PTB) [adjusted hazard ratio (aHR)=10.557, 95% CI:2.273-49.031], maximum daily dosage of glucocorticoids (GCs)≥ 50 mg/d (aHR=2.948, 95% CI:1.122-7.748), leflunomide (LEF) treatment (aHR=8.572, 95% CI:2.222 -33.070), anemia (aHR=2.565, 95% CI:1.015-6.479) and T-SPOT.TB level≥300SFCs/106 PBMCs (aHR=4.195, 95% CI:1.365-12.892) were independent risk factors for ATB development in LTBI patients. The incidence of ATB is significantly higher in hospitalized patients with LTBI than in the general population. The exposure history of PTB, maximum daily dosage of GCs≥ 50 mg/day, LEF treatment, anemia, and T-SPOT.TB level≥300SFCs/106PBMCs, were the risk factors of tuberculosis reactivation. Hospitalized LTBI patients with the above factors may need TPT.

Safety and outcome of treatment of latent tuberculosis infection in liver transplant recipients.

Liver transplant (LT) recipients have an increased risk of tuberculosis (TB), which is associated with higher mortality rates. This retrospective cohort study assessed the outcome and tolerability of screening and treatment of latent tuberculosis infection (LTBI) in LT recipients. Between March 2020 and February 2022, all adult LT candidates at our institution were screened for LTBI. The candidates who tested positive for interferon-γ-releasing assay or met epidemiological or clinical-radiological criteria for LTBI were treated and monitored. Among the 857 LT recipients, 199 (23.2%) were diagnosed with LTBI, of which 171 (85.9%) initiated LTBI treatment. The median duration of follow-up was 677days. Adequate LTBI treatment occurred in 141/171 (82.5%) patients and was discontinued prematurely in 30/171 (17.5%) patients. The most common reason for discontinuation was liver enzyme elevation (11/30, 36.7%), although only five discontinued treatment due to suspicion of isoniazid-associated hepatotoxicity. None of the LTBI-treated patients developed active TB during the follow-up period, while 3.6% (1/28) of untreated LTBI patients and 0.6% (4/658) of patients without LTBI developed TB. These findings demonstrate that LTBI screening and treatment is a safe and effective strategy to prevent TB in LT recipients. However, monitoring for adverse events and liver enzyme elevation is recommended.

Isoniazid-induced hepatotoxicity in patients with latent tuberculosis – Experience from a tuberculosis center

BackgroundAlthough the prevalence of isoniazid-induced hepatotoxicity (IIH) has been documented in patients with tuberculosis, its prevalence in latent tuberculosis infection (LTBI) patients is less studied. The aim of this study was to investigate the prevalence of IIH in a group of LTBI patients who received isoniazid monotherapy. MethodsRetrospective cohort study including patients who underwent isoniazid monotherapy for LTBI in an outpatient clinic between January 1st, 2020, and June 30th, 2021. ResultsA total of 274 cases were analyzed. About half (50.4 %) were male; median age was 53 years-old (minimum: six; maximum 89). The most common comorbidities were dyslipidemia (25.5 %), body mass index between 25 and 30 kg/m2 (20.4 %), obesity (14.7 %) and chronic hepatic disease (CHD; 12.8 %). 47.4 % had systemic inflammatory diseases. Significant elevation of liver enzymes was documented in 27 % of patients. IIH was documented in 20.4 % of patients; there was a statistically significant relation with dyslipidemia (p < 0.001), CHD (p = 0.023), psoriasis (p = 0.025), spondyloarthropathies (p = 0.017) and male sex (p = 0.042). Dyslipidemia showed a strong correlation to IIH (adjusted odds ratio: 8.045). ConclusionPatients with dyslipidemia had an adjusted odds ratio of 8.045 to develop IIH. Future multicentric studies should be started to better explore this relation, as well as treatment options.

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

Objective: This paper aims to explore the effect of individualized nursing intervention on patients with activetuberculosis (ATB) and latent tuberculosis infection (LTBI). Methods: The nursing study started in January 2020 and ended in January 2023. A total of 60 patients with ATB and LTBI were included, and they were divided into two groups according to the intervention schemes selected for control testing, each with 30 cases. The intervention program selected for group A was routine care, and for group B was individualized nursing. The proportion of adverse reactions, changes in the level of lung items, self-management outcomes and satisfaction were evaluated and compared. Results: After evaluating the proportion of adverse reactions, the total proportion of ATB and LTBI in group B was lower than that in group A (P &lt; 0.05). Based on the evaluation and testing of the expiratory flow (EF), expiratory volume (EV), and vital capacity (VC) after the intervention, these levels in group B showed higher outcomes than those in group A (P &lt; 0.05). The scores in terms of living habits, sleep, diet, and compliance in group B were higher than those in group A (P &lt; 0.05). The total proportionof the satisfaction of ATB and LTBI patients in group B was higher than that in group A (P &lt; 0.05). Conclusion: After the intervention of individualized nursing measures in patients with ATB and LTBI, it was found that it can not only play a positive role in the prevention and control of adverse reactions, but also improve their lung function, and promote their self-management, with good satisfaction level, thus it has high research and clinical application values.

Untargeted Metabolomics of Feces Reveals Diagnostic and Prognostic Biomarkers for Active Tuberculosis and Latent Tuberculosis Infection: Potential Application for Precise and Non-Invasive Identification.

Distinguishing latent tuberculosis infection (LTBI) from active tuberculosis (ATB) is important to control the prevalence of tuberculosis; however, there is currently no effective method. The aim of this study was to discover specific metabolites through fecal untargeted metabolomics to discriminate ATB, individuals with LTBI, and healthy controls (HC) and to probe the metabolic perturbation associated with the progression of tuberculosis. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed to comprehensively detect compounds in fecal samples from HC, LTBI, and ATB patients. Differential metabolites between the two groups were screened, and their underlying biological functions were explored. Candidate metabolites were selected and enrolled in LASSO regression analysis to construct diagnostic signatures for discriminating between HC, LTBI, and ATB. A receiver operating characteristic (ROC) curve was applied to evaluate diagnostic value. A nomogram was constructed to predict the risk of progression of LTBI. A total of 35 metabolites were found to exist differentially in HC, LTBI, and ATB, and eight biomarkers were selected. Three diagnostic signatures based on the eight biomarkers were constructed to distinguish between HC, LTBI, and ATB, demonstrating excellent discrimination performance in ROC analysis. A nomogram was successfully constructed to evaluate the risk of progression of LTBI to ATB. Moreover, 3,4-dimethylbenzoic acid has been shown to distinguish ATB patients with different responses to etiological tests. This study constructed diagnostic signatures based on fecal metabolic biomarkers that effectively discriminated HC, LTBI, and ATB, and established a predictive model to evaluate the risk of progression of LTBI to ATB. The results provide scientificevidence for establishing an accurate, sensitive, and noninvasive differential diagnosis scheme for tuberculosis.

Assessment of ferroptosis-associated gene signatures as potential biomarkers for differentiating latent from active tuberculosis in children.

Ferroptotic cell death is a regulated process that is governed by iron-dependent membrane lipid peroxide accumulation that plays a pathogenic role in several disease-related settings. The use of ferroptosis-related genes (FRGs) to distinguish active tuberculosis (ATB) from latent tuberculosis infection (LTBI) among children, however, remains to be analysed. Tuberculosis-related gene expression data and FRG lists were obtained, respectively, from Gene Expression Omnibus (GEO) and FerrDb. Differentially expressed FRGs (DE-FRGs) detected when comparing samples from paediatric ATB and LTBI patients were explored using appropriate bioinformatics techniques, after which enrichment analyses were performed for these genes and hub genes were identified, with these genes then being used to explore potential drug interactions and construct competing endogenous RNA (ceRNA) networks. The GSE39939 dataset yielded 124 DE-FRGs that were primarily related to responses to oxidative, chemical and extracellular stimulus-associated stress. In total, the LASSO and SVM-RFE algorithms enabled the identification of nine hub genes (MAPK14, EGLN2, IDO1, USP11, SCD, CBS, PARP8, PARP16, CDC25A) that exhibited good diagnostic utility. Functional enrichment analyses of these genes suggested that they may govern ATB transition from LTBI through the control of many pathways, including the immune response, DNA repair, transcription, RNA degradation, and glycan and energy metabolism pathways. The CIBERSORT algorithm suggested that these genes were positively correlated with inflammatory and myeloid cell activity while being negatively correlated with the activity of lymphocytes. A total of 50 candidate drugs targeting 6 hub DE-FRGs were also identified, and a ceRNA network was used to explore the complex interplay among these hub genes. The nine hub FRGs defined in this study may serve as valuable biomarkers differentiating between ATB and LTBI in young patients.

Anti-interferon-γ autoantibodies in patients with indeterminate QuantiFERON®-TB Gold Plus Assay results

BackgroundThe QuantiFERON®-TB Gold Plus Assay (QFT-G), a commercial interferon-γ (IFNγ) release assay, is used to screen patients for latent tuberculosis infection. Although anti-IFN-γ autoantibodies (Abs) have been recognized to cause indeterminate results, the prevalence and neutralizing capacity of these autoantibodies in general population indeterminate samples are unknown. ObjectivesWe sought to determine whether anti-IFN-γ autoantibodies accounted for indeterminate results in the QFT-G Assay.Design/Methods: Patient plasmas from the nil tube of the QFT-G were screened in a blinded fashion for IFN-γ antibodies using a particle-based approach. Samples were from TB positive, TB negative, and indeterminate samples. Binding activity of IgG to IFNγ was determined as a function of fluorescence intensity. Neutralizing capacity as a measure of antibody function was assessed by intranuclear staining of normal peripheral blood mononuclear cells (PBMCs) for IFNγ-induced pSTAT-1 in the presence of patient plasma. ResultsWe screened 537 patient plasmas (151 positive, 352 negative, 34 indeterminate) for anti-IFN-γ Abs from the nil tubes of QFT-G. Of those screened, 14 samples had binding activity to IFNγ. Three samples with high-titer anti-IFN-γ Abs (> mean plus three standard deviations of healthy control samples) neutralized IFNγ in vitro. Two of these samples were indeterminate, and 1 QFT-G negative. Therefore, of 14 samples with anti- IFNγ binding activity, 3 were neutralizing and 2 of those were indeterminate in QFT-G. ConclusionsAnti-IFN-γ autoantibodies were found in approximately 3% of plasmas submitted to a commercial laboratory. Of the 14 samples with binding activity for IFNγ, only 3 were fully neutralizing, and 2 of those occurred in the indeterminate group, accounting for 5% of all indeterminate samples. Anti-IFN-γ Abs are not rare in the population undergoing QFT-G testing and some of these autoantibodies are neutralizing and can affect the result of the assay.

Combined Detection of IFN-γ and Lymphocyte Subsets with Activation Indicators in the Clinical Application of Mycobacterium Tuberculosis Infection at Different Times

The immune status of mycobacterium tuberculosis (MTB) infection is essential for the diagnosis and treatment of this disease. In this work, we aim to evaluate the clinical significance of the combination of serum IFN-γ, IGRAs (Interferon-Gamma Release Assay), lymphocyte subset with activation indicators detection in active and latent tuberculosis infection patients. For this study, anticoagulant whole blood were collected from 45 active tuberculosis (AT group), 44 latent tuberculosis (LT group) and 32 healthy controls (HCs group). The serum IFN-γ and IGRAs detected by chemiluminescence, and the percentage of lymphocyte subsets and activated lymphocytes detected by flow cytometry. The results showed combined IGRAs, serum IFN-γ and NKT cells not only has good diagnostic efficiency for the AT, but also provides a laboratory diagnostic method to distinguish AT from LT. Activation indicator of CD3+HLA-DR+T and CD4+HLA-DR+T can effectively distinguish LT from HCs. While combined CD3+T, CD4+T, CD8+CD28+T, Treg and CD16+CD56+CD69+ cells can distinguish AT from HCs. This study showed combined direct detection of serum IFN-γ and IGRAs as well as lymphocyte subsets with activation indicators which may provide laboratory basis for the diagnosis and differential diagnosis of active and latent MTB infection.

Designing, Development, and Evaluation of an Informatics Platform for Enhancing Treatment Adherence in Latent Tuberculosis Infection Patients: A Study Protocol

Introduction: Digital health interventions are gradually being incorporated into the management of tuberculosis to ensure treatment adherence, but only a small number of trials focusing on latent tuberculosis infection (LTBI) care have tested and evaluated them. It is anticipated that 170 million persons with LTBI may eventually develop active TB; thus, treatment of LTBI patients is an important aspect, along with ensuring treatment adherence. Digital platforms can be beneficial to ensure treatment adherence in LTBI patients, as various studies have shown the positive impact of digital interventions in improving patients’ treatment adherence and treatment outcome. This study aims to explore the various available digital interventions worldwide for treatment adherence in LTBI patients and develop an informatics platform for enhancing treatment adherence in LTBI patients. Methods: This will be a quasi-experimental study divided into three phases. In the first phase, a scoping review method will be used to conduct a systematic literature review using the PRISMA tool to report on various digital interventions focused on treatment adherence in LTBI patients. In the second phase, a text message-based digital platform will be developed, and in the third phase of the study, an evaluation of the digital platform will be done using qualitative and quantitative questionnaires. The study will be conducted using a mixed-methods approach between January 2023 and December 2023. The sample size will be 162 participants, of whom 81 will be assigned to an intervention group and 81 will receive the usual care from the respective chest clinic as a control group. Results: A descriptive analysis of demographic variables and other variables will be done. Continuous variables will be described as mean ± standard deviation (M ± SD), medians (inter-quartile ranges) (M (IQR)), and medians (5th percentile to 95th percentile) (P5-P95). A two-sample independent T-test, the chi-square test, and the Mann-Whitney test will be used for comparisons between groups. Treatment success between control and intervention will be compared through a chi-square test. Conclusions: The key finding of the study will be an understanding of the efficiency of digital platforms for improving treatment adherence in latent TB patients in India.

Latent Tuberculosis in India: An Overview.

Treatment of latent tuberculosis infection (LTBI) is essential for tuberculosis (TB) eradication. LTBI patients serve as a reservoir for active TBcases. The WHO's End TB Strategy now prioritises the detection and treatment of LTBI. A comprehensive approach focused on integrated LTBI control is required to accomplish this goal. This review aims to summarise what we know about LTBI in the existing literature, its prominence, diagnostic strategies, and new interventions to alert people of its occurrence and symptoms. We used Medical Subject Heading (MeSH) phrases to search for published publications on the English language in PubMed, Scopus, and Google Scholar. To provide clarity and impact, we examined several government websites to identify the most effective and current treatment regimens. LTBI is a spectrum of infections, such as intermittent, transitory, or progressive, with early, subclinical, and ultimately active TB cases. The global burden of LTBI cannot be firmly established because no "gold-standard" test exists. Screening is advised for high-risk individuals, such as immigrants, occupants and staff members of congregate living facilities, and those who are HIV-positive. The most reliable form of LTBI screening is still the targeted tuberculin skin test (TST). Although LTBI therapy is challenging, for India to become TB-free, it must first focus on testing and treating LTBI. The government should focus on generalising the new diagnostic criteria and adopting a more specific treatment known to all to eliminate TB once and for all.

The Adjusted Cut-Off Value of Interferon-Γ Release Assays (IGRA) to Diagnose LTBI in Indonesia

Latent Tuberculosis Infection (LTBI) is as a condition when Mycobacterium tuberculosis (MTB) persists in the body without causing symptoms while maintaining viability with the possibility to become active tuberculosis in the future. The detection of LTBI is an important strategy from WHO to end the chain of tuberculosis. LTBI can be diagnosed by using the IGRA test. IGRA uses specific antigens of MTB, early antigenic target-6 (ESAT-6), to induce interferon-gamma production by antigen-specific T cells. In the IGRA test, the cut-off value is explicitly needed to distinguish healthy people from LTBI patients. This study aimed to find IGRA's adjusted cut-off value in Indonesia. The subjects were 150 people, which were 50 healthy people, 50 subjects with active TB, and 50 with suspected LTBI. Isolated Lymphocytes derived from PBMC sand were cultured in a complete RPMI medium and induced by Esat-6 for six days. IFN-g levels were assayed from supernatants by the sandwich Elisa technique. Statistical analysis was used to determine cut-off values for IFN-g derived from healthy and diseased patients. The highest aptitude index (κ value) that could discriminate between healthy and LTBI groups was 0.925 at a concentration of 0.792 ng/ml of IFN-g, hence the cut-off value to diagnose LTBI was 0.792 ng/ml of IFN-g. Based on this value, out of 40 suspected cases of LTBI, up to 17 (42.5%) and 23 without LTBI (57.5%) were found. So, the conclusion was that the adjusted cut-off value for IFN-g to diagnose LTBI in Indonesia was 0.792 ng/ml.

STAT3 regulation of Mtb-specific T cell function in active pulmonary tuberculosis patients

BackgroundTuberculosis (TB) remains one of the most serious infectious diseases in the world. Our aim was to investigate the regulatory role of STAT3 and pSTAT3 in the regulation of T cell immunophenotype and cell function. MethodsTwenty-five active pulmonary tuberculosis (APTB) patients, 18 latent tuberculosis infection (LTBI) patients, and 20 healthy controls (HCs) enrolled in this study. T cell phenotype and expression of STAT3 and pSTAT3 were detected by flow cytometry. ResultsCompared with HCs, the expression of pSTAT3 in CD4+ T and CD8+ T cells in peripheral blood of APTB patients was increased, and the expression was higher in pleural effusion. Multifunctional T cells that simultaneously secrete IFN-γ, TNF-α and IL-17A have higher pSTAT3 expression levels. Mtb-specific T cells from APTB patients had a higher cell frequency of the STAT3+ pSTAT3+ phenotype and a reduced cell frequency of the STAT3+ pSTAT3- phenotype compared with LTBI patients. Mtb-specific T cells with STAT3+ pSTAT3+ phenotype had higher expression of PD-1 and PD-L1, while cells with STAT3+ pSTAT3- phenotype had higher expression of Bcl-2. ConclusionsSTAT3 and pSTAT3 in T cells of APTB patients feature in the process of anti-apoptosis and cytokine secretion. At the same time, the higher pSTAT3 may be related to the degree of cell functional exhaustion. The pSTAT3 level of T cells is related to the infection status and may indicate the clinical activity of the disease, which provides a new idea for the clinical identification and treatment of active pulmonary tuberculosis.

Factors associated with refusal of preventive therapy after initial willingness to accept treatment among college students with latent tuberculosis infection in Shandong, China

BackgroundPreventive therapy of latent tuberculosis infection (LTBI) is an important component of tuberculosis (TB) control. Research on acceptance of TB preventive therapy (TPT) is an important topic. Current studies focus on acceptability and compliance. However, it is unclear whether LTBI patients will start TPT after accepting treatment. The study assessed the factors associated with TPT refusal after initial willingness to accept treatment.MethodsData were derived from a baseline survey of prospective study of LTBI treatment among college students in Shandong Province, China. A total of 723 students initially willing to accept TPT were included in the analysis. Stepwise logistic regression was used to explore the individual- and family-level characteristic variables that factors associated with TPT refusal after initial willingness to accept treatment.ResultsOf the 723 LTBI college students who initially had acceptance willingness, 436 (60.3%) finally refused TPT. At the individual level, non-medical students were more likely to refuse TPT [odds ratio (OR) = 4.87, 95% confidence interval (CI): 3.10–7.67)], as were students with moderate physical activity (OR = 1.45, 95% CI: 1.04–2.04). Students with boarding experience (OR = 0.49, 95% CI: 0.31–0.78) and a high level of knowledge about TB (OR = 0.97, 95% CI: 0.95–0.99) were less likely to refuse TPT. At the family level, those with high father’s educational level (OR = 1.50, 95% CI: 1.07–2.10) or high household income (OR = 1.80, 95% CI: 1.20–2.71) were more likely to refuse TPT after initially accepting treatment.ConclusionsFactors associated with TPT refusal after initial willingness to accept treatment, such as personal (type of students, physical activity, boarding experiences, knowledge of TB) and family characteristics (father’s education level, household income) among college student with LTBI, might help identify persons for whom tailored interventions could improve the start of LTBI treatment.

A diagnostic model for distinguishing between active tuberculosis and latent tuberculosis infection based on the blood expression profiles of autophagy-related genes.

Autophagy is closely involved in the control of mycobacterial infection. Here, a diagnostic model was developed using the levels of autophagy-related genes (ARGs) in the blood to differentiate active tuberculosis (ATB) and latent tuberculosis infection (LTBI). Secondary data analysis of three prospective cohorts. The expression of ARGs in patients with ATB and LTBI were analyzed using the GSE37250, GSE19491, and GSE28623 datasets from the GEO database. Twenty-two differentially expressed ARGs were identified in the training dataset GSE37250. Using least absolute shrinkage and selection operator and multivariate logistic regression, three ARGs (FOXO1, CCL2, and ITGA3) were found that were positively associated with adaptive immune-related lymphocytes and negatively associated with myeloid and inflammatory cells. A nomogram was constructed using the three ARGs. The accuracy, consistency, and clinical relevance of the nomogram were evaluated using receiver operating characteristic curves, the C-index, calibration curves, and validation in the datasets GSE19491 and GSE28623. The nomogram showed good predictive performance. The nomogram was able to accurately differentiate between ATB and LTBI patients. These findings provide evidence for future study on the pathology of autophagy in tuberculosis infection.

Influence of genetic variability in toll-like receptors (TLR 2, TLR 4, and TLR 9) on human immunodeficiency virus-1 disease progression.

It has been demonstrated that toll-like receptors (TLR2), TLR4, and TLR9 which were initially known for recognizing bacterial products are involved in the detection of viral components. It was planned to undertake a prospective longitudinal study among ethnically homogeneous antiretroviral treatment and antitubercular treatment naïve human immunodeficiency virus (HIV)-positive patients representing the north Indian population. The aim of the study was to investigate the influence of TLR2, TLR4, and TLR9 polymorphism in HIV disease progression. The present study was designed to investigate genetic polymorphism in TLRs (TLR2, TLR4, and TLR9) among HIV-infected patients with and without TB coinfection. The study population consisted of two groups: (i) HIV-positive patients without TB infection and disease (n = 223, HIV-positive patients); (ii) HIV-positive patients with latent tuberculosis infection (LTBI) (n = 150, HIV-positive LTBI patients). These participants were of either gender between 18 and 60 years of age and treatment naïve for both TB and HIV. HIV-positive and HIV-positive LTBI patients were longitudinally followed up for t2 years to study HIV disease progression. On comparing TLR2 and TLR4 allelic and genotypic frequencies between 306 HIV-positive patients (no TB/AIDS) and 47 HIV-positive patients progressed to active TB/AIDS, no significant difference was observed between the two groups. The frequency of "A" allele in TLR9 was found to be significantly increased in 47 HIV-positive patients who progressed to active TB/AIDS (61.7%) as compared to 42.16% in 306 HIV-positive patients (no TB/AIDS), (P < 0.001). Furthermore, a significantly increased frequency of "AA" genotype in TLR9 was observed in 47 HIV-positive patients progressed to active TB/AIDS (55.32%) as compared to 20.26% in HIV-positive patients (no TB/AIDS). Findings of the present study revealed that genetic variability in TLR9 may influence HIV disease progression. The AA genotype in TLR9 may be associated with progression to TB/AIDS for 2 years in HIV-positive patients.

Advances in TB testing.

Globally, tuberculosis (TB) was the leading cause of death from a single infectious agent until the coronavirus (COVID-19) pandemic. In 2020, an estimated 10 million people fell ill with TB and a total of 1.5 million people died from the disease. About one-quarter of the global population, almost two billion people, is estimated to be latently infected with Mycobacterium tuberculosis (MTB). Although latent TB infection (LTBI) is asymptomatic and noncontagious, about 5-10% of LTBI patients have a lifetime risk of progression to active TB. The diagnosis and treatment of active cases are extremely vital for TB control programs. However, achieving the End TB goal of 2035 without the ability to identify and treat the pool of latently infected individuals will be a big challenge. To do so, improved technology to provide more accurate diagnostic tools and accessibility are crucial. Therefore, this chapter covers the current WHO-endorsed tests and advances in diagnostic and screening tests for active and latent TB.

1403. Facilitators and barriers to latent tuberculosis infection diagnosis and care in Massachusetts: a convergent mixed methods study of clinicians

Abstract Background Understanding barriers and facilitators to latent tuberculosis infection (LTBI) diagnosis and care is needed to successfully treat children/adolescents with LTBI in the US. We explored physicians’ perspectives on pediatric LTBI diagnosis and care, and strategies to improve care. Methods We conducted a convergent mixed methods study with physicians in Massachusetts. Participants were purposefully sampled from primary care clinics (n=10), clinics seeing immunocompromised patients (n=2), and TB clinics (n=2). Physicians participated in individual qualitative semi-structured interviews exploring experience and comfort with LTBI care, and perceived barriers and facilitators to care. We used applied thematic analysis to analyze transcripts. Participants completed surveys to assess comfort with LTBI care and volume of LTBI patients in their care. Results Of the 25 physicians invited, 14 participated. Most participants reported “medium” or “high” comfort with current LTBI guidelines; volume of LTBI care varied by physician type (Table 1). Analysis revealed perceived barriers (Figure 1) at four steps of care: 1) identification of risk and testing for LTBI (e.g., family/patient risk perception, physician knowledge gaps), 2) completion of referral after a positive test (e.g., communication barriers), 3) treatment acceptance and initiation (e.g., lack of social support), and 4) treatment adherence and completion (e.g., adolescents’ emerging autonomy). Facilitators such as protocolized screening, counseling strategies, free medication, and telehealth (Figure 2) overcame some barriers. Important emergent themes included: 1) COVID-19 has induced rapid positive and negative changes in LTBI care in primary care clinics; 2) immigrant adolescents are uniquely at risk for disengagement due to lack of social support; and 3) physicians and clinics are ill-equipped to provide TB care for patients’ close contacts, despite knowledge of need for care. Table 1.Volume of patients by clinician type (N=13 respondents)Figure 1.Barriers to LTBI diagnosis and care.Figure 2.Facilitators of LTBI care. Conclusion Lack of perceived risk, family and clinic resource constraints, and accessibility challenges hindered LTBI care; protocolized screening, telehealth, and free medications were among the facilitators that overcame some but not all barriers. These results will inform improvement of LTBI care within and between clinics. Disclosures Jessica Haberer, MD, MS, Merck: Advisor/Consultant|Natera: Stocks/Bonds.

1438. Latent tuberculosis infection (LTBI) in hematopoietic stem cell transplantation (HSCT) recipients: a retrospective Italian cohort study in Tor Vergata University Hospital, Rome.

Abstract Background Patients undergoing haematopoietic stem cell transplantation (HSCT) have severe and prolonged immunodeficiency and the incidence of tuberculosis (TB) disease in those patients is 10 to 40 times higher than the general population Methods This retrospective study performed at Tor Vergata University Hospital in Rome (Italy) included all adult patients who underwent a HSCT in the Hematologic Transplant Unit from January 2015 to December 2019. Data on TB screening, performed through interferon-γ release assay (IGRA), were collected; patients were observed for TB reactivation in a follow up period of at least 3 years Results 323 HSCT recipients were enrolled in this study. Patients’ characteristics are summarized in table 1. 63 patients (19.5%) were not screened for TB, of which 6.3% were born overseas. 260 HSCT recipients (80.5%) were screened: 228 patients (87.7%) had a negative IGRA result, 21 (8.1%) tested positive, and 11 (4.2%) had an indeterminate result. 98.5% were screened before the HSCT. Of the 21 patients with a positive pre-HSCT IGRA test, 14 (66.7%) were males and significantly (p&amp;lt; 0.001) older (median age 60 [IQR] 58-65 years) than those with negative or indeterminate results. Almost all patients (95.2%) were Italian. Patients with a positive IGRA showed a higher monocyte count compared to the other groups (p=0.044), while those with indeterminate IGRA showed a tendence to lower lymphocyte absolute counts, compared to the other groups (p=0.060) (Table 2). All the 21 patients with a pre-HSCT positive IGRA test were radiologically and clinically screened for active TB and, once it was ruled out, treated for latent TB (LTBI) with isoniazid (INH) for 6 months. No events of toxicity or treatment interruption were reported. None of the patients was treated with rifampin. None of the 21 patients with pre-HSCT positive IGRA test developed active TB during the follow up period. Table 1.Characteristics of the study population, overall and divided according to IGRA testingTable 2.Characteristics of the IGRA tested patients, overall and divided by IGRA test results Conclusion To our knowledge, this is the first Italian study on the prevalence of LTBI in patients undergoing HSCT. 8.1% of the 260 patients screened with an IGRA tested positive. The great majority (95.2%) of LTBI patients were Italian and significantly older than IGRA-negative patients. All LTBI HSCT patients received INH treatment and no drug toxicity, nor TB reactivation was observed during the follow-up period Disclosures All Authors: No reported disclosures.