Autophagy-related molecular clusters identified as indicators for distinguishing active and latent TB infection in pediatric patients.

BACKGROUND: Autophagy is crucial for controlling the manifestation of tuberculosis. This study intends to discover autophagy-related molecular clusters as biomarkers for discriminating between latent tuberculosis (LTBI) and active tuberculosis (ATB) in children through gene expression profile analysis. METHODS: The expression of autophagy modulators was examined in pediatric patients with LTBI and ATB utilizing public datasets from the Gene Expression Omnibus (GEO) collection (GSE39939 and GSE39940). RESULTS: In a training dataset (GSE39939), patients with LTBI and ATB exhibited the expression of autophagy-related genes connected with their active immune responses. Two molecular clusters associated with autophagy were identified. Compared to Cluster 1, Cluster 2 was distinguished through decreased adaptive cellular immune response and enhanced inflammatory activation, according to single-sample gene set enrichment analysis (ssGSEA). Per the study of gene set variation, Cluster 2's differentially expressed genes (DEGs) played a role in synthesizing transfer RNA, DNA repair and recombination, and primary immunodeficiency. The peak variation efficiency, root mean square error, and area under the curve (AUC) (AUC = 0.950) were all lowered in random forest models. Finally, a seven-gene-dependent random forest profile was created utilizing the CD247, MAN1C1, FAM84B, HSZFP36, SLC16A10, DTX3, and SIRT4 genes, which performed well against the validation dataset GSE139940 (AUC = 0.888). The nomogram calibration and decision curves performed well in identifying ATB from LTBI. CONCLUSIONS: In summary, according to the present investigation, autophagy and the immunopathology of TB might be correlated. Furthermore, this investigation established a compelling prediction expression profile for measuring autophagy subtype development risks, which might be employed as possible biomarkers in children to differentiate ATB from LTBI.

Routine tuberculosis contact investigation yield and preventive treatment cascade in central Ethiopia.

Introduction: There is a global gap between tuberculosis incident cases and the notified cases. Active household contact investigation is one of the strategies to narrow this gap. It has the advantage of giving early diagnosis and preventive treatment to vulnerable and eligible groups. This study assessed the practice of contact investigation and tuberculosis preventive treatment adherence in central Ethiopia. Method: A cross-sectional study covering all registered bacteriologically confirmed pulmonary tuberculosis patients and their close contacts was conducted in central Ethiopia from January 1, 2022, to December 30, 2022. Result: A total of 1372 household contacts were declared by the index cases. From these 79.44 % (1090) contacts received a one-time tuberculosis screening giving a total of four (0.36 %) active TB cases. Among 484 household contacts of drug-resistant tuberculosis index cases, 5.53 % (14) had presumptive tuberculosis and 0.79 % (2) had active tuberculosis. While among 837 household contacts of drug-susceptible tuberculosis index cases presumptive TB cases were 1.91 % (16) and active TB cases were 0.23 % (2). Of the 142 eligible under 15 children 81.69 % (116) had started tuberculosis preventive treatment and 84.48 % (98) completed the treatment. On multivariable logistic regression, the associated factor for tuberculosis preventive treatment non-adherence was age 2-5 years (aOR, 0.02, 95 % CI (0.002-0.20) and age 5-15 years (aOR, 0.04,95 % CI (0.002-0 0.95)) P=<0.05). Conclusion: There was low contact screening practice in the DR-TB index cases as compared to national and global targets. The yield of routine contact investigation was low and it indicates the quality of screening. Tuberculosis preventive treatment initiation and completion rates were also low as compared to those of many other countries and global achievements which need further improvement, especially for completion. Alternative mechanisms should be planned to increase the yield of tuberculosis screening and tuberculosis preventive treatment adherence.

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

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

Functional outcome of total hip arthroplasty in tubercular hip arthritis: A prospective study.

Background: Total hip arthroplasty (THA) is a well-established procedure to cure tubercular hip arthritis in patients with healed tuberculosis while its role in active tuberculosis is still debatable. The aim of the study is to investigate the functional outcomes of THA in active tuberculosis with advanced hip arthritis. The reactivation of tuberculosis and complications postoperatively has also been assessed. Materials and methods: The current open-ended prospective cohort study was carried out at a tertiary center from 2018 to 2020. Twenty patients of active tubercular hip arthritis (8 females and 12 males) were taken with a follow-up period ranging from 1 year to 3 years, with a mean of 14 months.Biochemical investigations were done both preoperatively and postoperatively. Preoperative anti-tubercular therapy (ATT) regimen was administered, as per standard norms, to patients for a minimum period of 6 weeks, and postoperatively for 6 months-12 months. Postero-lateral and Hardinge approaches were employed in all cases. Clinical and radiological parameters were assessed and functional outcomes were evaluated using the Harris Hip score (HHS). Results: The mean age of patients was 37.6 ± 11.38 years. Biochemical parameters were also found to improve postoperatively (p < 0.0001). The mean flexion, extension, abduction, external and internal rotation were found to increase postoperatively (p < 0.001). The mean flexion deformity in the preoperative period was 12.35 ± 4.716, whereas none of the patients had flexion deformities post operatively. The mean shortening was 2.12 ± 0.60 and 1 ± 0 at preoperative and postoperative respectively. The Total hip arthroplasty implant was found stable in all patients. The mean Harris score increased subsequently throughout the follow-up interval and differences were statistically significant (p < 0.0001). None of the patients had reactivation of tuberculosis infection postoperatively. Conclusion: Total hip arthroplasty is a reliable option to treat active advanced tubercular hip arthritis and gives good functional outcome with proper preoperative and postoperative ATT regimen.

Tuberculosis and lung cancer: metabolic pathways play a key role.

Despite the fact that some cases of tuberculosis (TB) are undiagnosed and untreated, it remains a serious global public health issue. In the diagnosis, treatment, and control of latent and active TB, there may be a lack of effectiveness. An understanding of metabolic pathways can be fundamental to treat latent TB infection and active TB disease. Rather than targeting Mycobacterium tuberculosis, the control strategies aim to strengthen host responses to infection and reduce chronic inflammation by effectively enhancing host resistance to infection. The pathogenesis and progression of TB are linked to several metabolites and metabolic pathways, and they are potential targets for host-directed therapies. Additionally, metabolic pathways can contribute to the progression of lung cancer in patients with latent or active TB. A comprehensive metabolic pathway analysis is conducted to highlight lung cancer development in latent and active TB. The current study aimed to emphasize the association between metabolic pathways of tumor development in patients with latent and active TB. Health control programs around the world are compromised by TB and lung cancer due to their special epidemiological and clinical characteristics. Therefore, presenting the importance of lung cancer progression through metabolic pathways occurring upon TB infection can open new doors to improving control of TB infection and active TB disease while stressing that further evaluations are required to uncover this correlation.

Diagnostic value of microRNAs in active tuberculosis based on quantitative and enrichment analyses.

BACKGROUND: Tuberculosis (TB) infection remains a crucial global health challenge, with active tuberculosis (ATB) representing main infection source. MicroRNA (miRNA) has emerged as a potential diagnostic tool in this context. This study aims to identify candidate miRNAs for ATB diagnosis and explore their possible mechanisms. METHODS: Differentially expressed miRNAs in ATB were summarized in qualitative analysis. The diagnostic values of miRNAs for ATB subtypes were assessed by overall sensitivity, specificity, and area under the curve. Additionally, we conducted enrichment analysis on miRNAs and target genes. RESULTS: Over 100 differentially expressed miRNAs were identified, with miR-29 family being the most extensively studied. The miR-29 family demonstrated sensitivity, specificity, and area under the curve of 80 %, 80 % and 0.86 respectively for active pulmonary TB (PTB). The differentially expressed miR-29-target genes in PTB were enriched in immune-related pathways. CONCLUSIONS: The miR-29 family exhibits good diagnostic value for active PTB and shows association with immune process.

Identification of apoptosis-related gene signatures as potential biomarkers for differentiating active from latent tuberculosis via bioinformatics analysis.

Background: Apoptosis is associated with the pathogenesis of Mycobacterium tuberculosis infection. This study aims to identify apoptosis-related genes as biomarkers for differentiating active tuberculosis (ATB) from latent tuberculosis infection (LTBI). Methods: The tuberculosis (TB) datasets (GSE19491, GSE62525, and GSE28623) were downloaded from the Gene Expression Omnibus (GEO) database. The diagnostic biomarkers differentiating ATB from LTBI were identified by combining the data of protein-protein interaction network, differentially expressed gene, Weighted Gene Co-Expression Network Analysis (WGCNA), and receiver operating characteristic (ROC) analyses. Machine learning algorithms were employed to validate the diagnostic ability of the biomarkers. Enrichment analysis for biomarkers was established, and potential drugs were predicted. The association between biomarkers and N6-methyladenosine (m6A) or 5-methylated cytosine (m5C) regulators was evaluated. Results: Six biomarkers including CASP1, TNFSF10, CASP4, CASP5, IFI16, and ATF3 were obtained for differentiating ATB from LTBI. They showed strong diagnostic performances, with area under ROC (AUC) values > 0.7. Enrichment analysis demonstrated that the biomarkers were involved in immune and inflammation responses. Furthermore, 24 drugs, including progesterone and emricasan, were predicted. The correlation analysis revealed that biomarkers were positively correlated with most m6A or m5C regulators. Conclusion: The six ARGs can serve as effective biomarkers differentiating ATB from LTBI and provide insight into the pathogenesis of Mycobacterium tuberculosis infection.

Pulmonary Tuberculosis Incidence among Interferon-Gamma Release Assay-Positive Individuals with Latent Tuberculosis Infection and Fibrotic Lesions in a Vulnerable Urban Population in Osaka City, Japan, 2015-2021.

Latent tuberculosis infection (LTBI) with fibrotic lesions (FL) can progress to active tuberculosis (TB). Most previous studies have used tuberculin skin tests, which have lower specificity than interferon-gamma release assays (IGRAs), for LTBI diagnosis. This study evaluated the incidence of active TB among individuals with LTBI (diagnosed using IGRAs) and FL in Nishinari District, Osaka City. In total, 54 men (mean age: 68.7 years) were enrolled, of whom 10 (18.5%) were homeless, and 36 (66.7%) were welfare recipients. The median observation period was 1,084 days (range: 64-2,907 days). The incidence rate of active TB among individuals with LTBI and FL was 1.18 (95% confidence interval: 0.32-4.29) cases per 100 person-years. Among the 19 participants who had not been treated with anti-TB therapy, one (5.3%) progressed to active TB, and among the 30 participants who had completed anti-TB treatment, one (3.3%) progressed to active TB. The other 5 participants did not have TB. This study revealed the incidence of active TB among individuals with LTBI, diagnosed using IGRAs, and FL in a vulnerable urban population. The higher incidence than that reported in previous studies reinforces the importance of improved LTBI management strategies, including chest radiography screening, and LTBI treatment.

Alterations in the intestinal microbiota associated with active tuberculosis and latent tuberculosis infection.

Objectives: To study the characteristics of intestinal microbiota at different stages of Mycobacterium tuberculosis infection. Methods: Fecal samples of 19 active tuberculosis (ATB) patients, 21 latent tuberculosis infection (LTBI) individuals, and 20 healthy controls (HC) were collected. Gut microbiota of all the participants were analyzed by 16S rDNA sequencing. Clinical information of ATB patients was also collected and analyzed. Results: Both ATB and LTBI groups showed significant decreases in microbial diversity and decline of Clostridia. For ATB patients, bacteria within phylum Proteobacteria increased. While for LTBI individuals, genera Prevotella and Rosburia enriched. The abundance of Faecalibacterium, Clostridia and Gammaproteobacteria has the potential to diagnose ATB, with the area under the curve (AUC) of 0.808, 0.784 and 0.717. And Prevotella and Rosburia has the potential to diagnose LTBI, with the AUC of 0.689 and 0.689. Notably, in ATB patients, the relative abundance of Blautia was negatively correlated with the proportions of peripheral T cells and CD8+T cells. And serum direct bilirubin was positively correlated with Bacteroidales, while negatively correlated with Clostridiales in ATB patients. Conclusions: The specifically changed bacteria are promising markers for ATB and LTBI diagnosis. Some gut bacteria contribute to anti-MTB immunity through interactions with T cells and bilirubin.

Host factors associated with false negative results in an interferon-γ release assay in adults with active tuberculosis.

Objective: To identify host factors associated with false-negative results of interferon-γ release tests in adults with active tuberculosis. Methods: The clinical data of 943 patients with active tuberculosis diagnosed by acid-fast smear staining, Mycobacterium tuberculosis culture, Mycobacterium tuberculosis PCR and pathological examination at West China Hospital of Sichuan University were retrospectively analysed. According to the results of the interferon γ release test (IGRA), the patients were divided into the IGRA- group and IGRA+ group. Logistic regression was used to analyze the sociodemographic data and clinical characteristics of participants in the IGRA- group and IGRA+ group. Results: Among 943 patients with active tuberculosis, 174 (18.5 %) were IGRA negative (false negative), and 769 (81.5 %) were IGRA positive. Multivariate logistic regression analysis identified the following characteristics independently associated with IGRA negativity: age (OR: 1.02; 95 % CI: 1.01 1.03; p = 0.006), anti-tuberculosis treatment >1 month (OR: 1.68; 95 % CI: 1.12 2.52; p = 0.013), HIV infection (OR: 9.48; 95 % CI: 3.23 27.85; p = 0.000), combined with connective tissue diseases (OR: 2.78; 95 % CI: 1.30 5.94; p = 0.008) and low hemoglobin (OR: 0.99; 95 % CI: 0.98 1.00; p = 0.044) was associated with an increased false-negative probability of IGRA. Conclusion: Age, anti-tuberculosis therapy >1 month, coinfection with HIV, coassociated connective tissue disease and decreased hemoglobin were identified as risk factors for false-negative results of IGRA. Our results suggest a careful interpretation of IGRA in adults with these characteristics.

Diagnostic value of chemiluminescence for urinary lipoarabinomannan antigen assay in active tuberculosis: insights from a retrospective study.

Purpose: This study aimed to assess the efficacy of chemiluminescence-based urinary lipoarabinomannan (LAM) antigen assay as a diagnostic tool for identifying active tuberculosis. Methods: A retrospective study was conducted on 166 Tuberculosis (TB), 22 Non-Tuberculous Mycobacteria (NTM), 69 Non-TB cases, and 73 healthy controls from Zhangjiagang First Peoples Hospital between July 2022 and November 2022. Clinical and laboratory data were collected, including urine samples for LAM antigen detection, sputum samples and pleural effusion for GeneXpert, TB-DNA, and culture. Results: TB group exhibited a higher LAM positivity rate (P < 0.001). CD4 count and diabetes as independent factors influencing the diagnostic accuracy of LAM. The LAM assay showed a sensitivity of 50.6% and a specificity of 95.65%. Notably, LAM's sensitivity was superior to TB-DNA (50.60% vs. 38.16%, P < 0.05). LAM's PTB detection rate was 51.7%, superior to TB-DNA (P = 0.047). Moreover, in EPTB cases, the LAM detection rate was 42.11%, surpassing Gene Xpert (P = 0.042), as well as exceeding the detection rates of TB-DNA and sputum culture. Conclusion: LAM antigen detection using chemiluminescence has demonstrated outstanding clinical diagnostic value for active TB, especially in the diagnosis of extrapulmonary TB. The convenience of sample collection in this diagnostic approach allows for widespread application in the clinical diagnosis of active tuberculosis, particularly in cases of EPTB and sputum-negative patients.

The performance of VCS(volume, conductivity, light scatter) parameters in distinguishing latent tuberculosis and active tuberculosis by using machine learning algorithm.

BACKGROUND: Tuberculosis is a chronic infectious disease caused by mycobacterium tuberculosis (MTB) and is the ninth leading cause of death worldwide. It is still difficult to distinguish active TB from latent TB,but it is very important for individualized management and treatment to distinguish whether patients are active or latent tuberculosis infection. METHODS: A total of 220 subjects, including active TB patients (ATB, n = 97) and latent TB patients (LTB, n = 113), were recruited in this study .46 features about blood routine indicators and the VCS parameters (volume, conductivity, light scatter) of neutrophils(NE), monocytes(MO), and lymphocytes(LY) were collected and was constructed classification model by four machine learning algorithms(logistic regression(LR), random forest(RF), support vector machine(SVM) and k-nearest neighbor(KNN)). And the area under the precision-recall curve (AUPRC) and the area under the receiver operating characteristic curve (AUROC) to estimate of the model's predictive performance for dentifying active and latent tuberculosis infection. RESULTS: After verification,among the four classifications, LR and RF had the best performance (AUROC = 1, AUPRC = 1), followed by SVM (AUROC = 0.967, AUPRC = 0.971), KNN (AUROC = 0.943, AUPRC = 0.959) in the training set. And LR had the best performance (AUROC = 0.977, AUPRC = 0.957), followed by SVM (AUROC = 0.962, AUPRC = 0.949), RF (AUROC = 0.903, AUPRC = 0.922),KNN(AUROC = 0.883, AUPRC = 0.901) in the testing set. CONCLUSIONS: The machine learning algorithm classifier based on leukocyte VCS parameters is of great value in identifying active and latent tuberculosis infection.

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

BACKGROUND: Autophagy is closely involved in the control of mycobacterial infection. OBJECTIVES: 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). DESIGN: Secondary data analysis of three prospective cohorts. METHODS: The expression of ARGs in patients with ATB and LTBI were analyzed using the GSE37250, GSE19491, and GSE28623 datasets from the GEO database. RESULTS: 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. CONCLUSION: 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.

Characteristics of subclinical tuberculosis compared to active symptomatic tuberculosis using nationwide registry cohort in Korea: prospective cohort study.

Objective: The clinical manifestations of tuberculosis (TB) range from asymptomatic to disseminated depending on the microbiological and immunological status, making the diagnosis challenging. To improve our understanding of the disease progression mechanism, we aimed to identify the characteristics of subclinical TB and important predictors of symptom development. Methods: From July 2018 to June 2019, we systemically collected data from the National Surveillance System of South Korea on patients with pulmonary TB, and compared the characteristics of subclinical and active symptomatic TB patients. Results: A total of 4,636 patients with pulmonary TB were included, and the prevalence of subclinical TB was 37.1% (1,720/4,636). In subclinical TB patients, the positivity rates of acid-fast bacilli (AFB) smear and culture were 16.2 and 50.2%, respectively. Subclinical TB patients were younger (55.6 ± 19.2 vs. 60.7 ± 19.5, P < 0.001), had a higher body mass index (21.7 ± 3.1 vs. 21.0 ± 3.5, P < 0.001), less under Medicaid support, and had lower rates of chronic lung disease, AFB smear and culture positivity, and bilateral disease. Regarding the characteristic differences of individual TB-related symptoms, age was positively associated with dyspnoea and general weakness but negatively associated with chest pain, haemoptysis, and weight loss. Male patients were more prone to weight loss. Chronic lung disease was related to symptoms including cough/phlegm, dyspnoea, and haemoptysis, while autoimmune diseases were associated with fever and weight loss. Conclusions: The development of TB-related symptoms was associated with microbiological burden and clinical characteristics including underlying comorbidities, which should be evaluated carefully.

Ultrasonography - a novel auxiliary interpretive approach for tuberculin-purified pure protein derivative skin test: a comparative study.

BACKGROUND: The tuberculin-purified protein derivative (PPD) test is commonly used as a screening tool for tuberculosis (TB). However, the traditional judgment standard of the PPD test is influenced by subjective factors, which can lead to less accurate and intuitive test results. OBJECTIVES: To evaluate the accuracy of ultrasonography as a novel auxiliary judgment method for the tuberculin-PPD test and its clinical application. DESIGN: This study was designed as a comparative study following the STROBE guidance. METHODS: From February to May 2022, 208 patients with active tuberculosis infection were enrolled. Manual judgment and ultrasonography were employed in a double-blind-utilized manner, and the PPD examination results were recorded. Kappa statistic was performed to measure the concordance between the two diagnostic methods. Fisher's exact test was used for the analyses of the PPD test results of all 208 active tuberculosis infection patients' PPD results. RESULTS: There was a significant difference between the two methods in the PPD result judgment (p < 0.001), particularly in the positive ratio of the PPD test results, (p < 0.05). Overall, 50 patients were determined as PPD positive based on manual judgment. However, only 24 patients' PPD test results were determined as positive via ultrasonography. The remaining 26 patients should have been classified as strong positive but were misclassified as positive. The misdiagnosis ratio was 52% (26/50). CONCLUSION: Ultrasonography has superior accuracy to traditional manual judgment. Moreover, it does not rely on sophisticated clinical experience or training and can reveal subtle changes of the skin corresponding to each PPD test result providing intuitive results. In conclusion, ultrasonography can be used as an auxiliary interpretive approach for PPD test and has a promising future for clinical application.

Sequence of COVID-19 Vaccination and COVID-19 Infection and Their Association With the Development of Active Tuberculosis: A Case-Control Study.

Introduction Information regarding the cross-risk of coronavirus disease 2019 (COVID-19) and tuberculosis (TB) is still sparse. This study aimed to identify the patterns of sequence of COVID-19 vaccination and COVID-19 infection and to explore the association between COVID-19 vaccination, COVID-19 infection, and the development of active TB. Methods It was a case-control study conducted in RSUD Dr. Iskak Hospital, Tulungagung, between October 2022 and April 2023. Active cases of TB patients were compared with non-TB controls in the same hospital, with the same age and sex. Their pattern of sequence of COVID-19 vaccination and infection was investigated. Logistic regression was used to assess the association between these key variables. Results Of 296 case-control sets, 64.2% were female. The mean ± standard deviation of age was 46 ± 15.6 years. 5.7% of the cases and 6.4% of the controls had a history of COVID-19 infection, whereas 58.8% and 68.4% had been vaccinated (mostly after infection). The adjusted odds ratio (95% confidence interval) of COVID-19 infection on risk to the development of active TB was 1.45 (0.58, 3.65). Those of COVID-19 vaccination of one to four doses were 0.42 (0.17, 1), 0.98 (0.58, 1.66), 0.48 (0.25, 0.93), and 0.09 (0.01, 0.81), respectively. Conclusion It was found that there were five patterns of sequence of COVID-19 infection and COVID-19 vaccination, with the most frequent being having COVID-19 infection before COVID-19 vaccination. Our data did not support the association between COVID-19 infection and the subsequent development of active TB. On the other hand, COVID-19 vaccination has been demonstrated to increase some protection against the development of active TB.

Excluding Participants With Mycobacteria Infections From Clinical Trials: A Critical Consideration in Evaluating the Efficacy of BCG Against COVID-19.

In the context of the coronavirus disease 2019 (COVID-19) pandemic, Bacillus Calmette-Guérin (BCG), a tuberculosis (TB) vaccine, has been investigated for its potential to prevent COVID-19 with conflicting outcomes. Currently, over 50 clinical trials have been conducted to assess the effectiveness of BCG in preventing COVID-19, but the results have shown considerable variations. After scrutinizing the data, it was discovered that some trials had enrolled individuals with active TB, latent TB infection, or a history of TB. This finding raises concerns about the reliability and validity of the trial outcomes. In this study, we explore the potential consequences of including these participants in clinical trials, including impaired host immunity, immune exhaustion, and the potential masking of the BCG vaccine's protective efficacy against COVID-19 by persistent mycobacterial infections. We also put forth several suggestions for future clinical trials. Our study underscores the criticality of excluding individuals with active or latent TB from clinical trials evaluating the efficacy of BCG in preventing COVID-19.

Observer Performance Evaluation of a Deep Learning Model for Multilabel Classification of Active Tuberculosis Lung Zone-Wise Manifestations.

Background Chest X-rays (CXRs) are widely used for cost-effective screening of active pulmonary tuberculosis despite their limitations in sensitivity and specificity when interpreted by clinicians or radiologists. To address this issue, computer-aided detection (CAD) algorithms, particularly deep learning architectures based on convolution, have been developed to automate the analysis of radiography imaging. Deep learning algorithms have shown promise in accurately classifying lung abnormalities using chest X-ray images. In this study, we utilized the EfficientNet B4 model, which was pre-trained on ImageNet with 380x380 input dimensions, using its weights for transfer learning, and was modified with a series of components including global average pooling, batch normalization, dropout, and a classifier with 12 image-wise and 44 segment-wise lung zone evaluation classes using sigmoid activation. Objectives Assess the clinical usefulness of our previously created EfficientNet B4 model in identifying lung zone-specific abnormalities related to active tuberculosis through an observer performance test involving a skilled clinician operating in tuberculosis-specific environments. Methods The ground truth was established by a radiologist who examined all sample CXRs to identify lung zone-wise abnormalities. An expert clinician working in tuberculosis-specific settings independently reviewed the same CXR with blinded access to the ground truth. Simultaneously, the CXRs were classified using the EfficientNet B4 model. The clinician's assessments were then compared with the model's predictions, and the agreement between the two was measured using the kappa coefficient, evaluating the model's performance in classifying active tuberculosis manifestations across lung zones. Results The results show a strong agreement (Kappa ≥0.81) seen for lung zone-wise abnormalities of pneumothorax, mediastinal shift, emphysema, fibrosis, calcifications, pleural effusion, and cavity. Substantial agreement (Kappa = 0.61-0.80) for cavity, mediastinal shift, volume loss, and collapsed lungs. The Kappa score for lung zone-wise abnormalities is moderate (0.41-0.60) for 39% of cases. In image-wise agreement, the EfficientNet B4 model's performance ranges from moderate to almost perfect across categories, while in lung zone-wise agreement, it varies from fair to almost perfect. The results show strong agreement between the EfficientNet B4 model and the human reader in detecting lung zone-wise and image-wise manifestations. Conclusion The clinical utility of the EfficientNet B4 models to detect the abnormalities can aid clinicians in primary care settings for screening and triaging tuberculosis where resources are constrained or overburdened.

Assessment of the Cepheid 3-gene Host Response Fingerstick Blood Test (MTB-HR) on rapid diagnosis of tuberculosis.

ABSTRACTThe World Health Organization has identified high-priority target product profiles for new TB diagnostics which include rapid biomarker-based, non-sputum-based diagnostic testing, using an easily accessible sample. The Cepheid 3-gene Host Response Fingerstick Blood Prototype Test (MTB-HR) quantifies relative mRNA levels of a 3-gene signature (GBP5, DUSP3, and KLF2) from a whole-blood sample on the GeneXpert platform. The objective of the present study was to evaluate the performance of the MTB-HR to distinguish between active tuberculosis (ATB), latent Mycobacterium tuberculosis infection (LTBI), other pulmonary diseases, and healthy volunteers at a tertiary care centre. Among 653 participants enrolled in this study, 192 were diagnosed as having ATB, and the remaining 461 were classified as non-ATB, including 137 cases of LTBI, 224 cases of other pulmonary diseases, and 100 healthy volunteers. The corresponding AUCs of the MTB-HR in distinguishing untreated ATB from non-ATB, LTBI, other pulmonary diseases, and healthy volunteers were 0.814 (95% CI, 0.760-0.868, sensitivity 76.1%, specificity 71.6%), 0.739 (95% CI, 0.667-0.812, sensitivity 59.7%, specificity 78.1%), 0.825 (95% CI, 0.770-0.880, sensitivity 82.1%, specificity 65.6%), 0.892 (95% CI, 0.839-0.945, sensitivity 76.1%, specificity 88.0%), respectively. When only samples with TAT of less than 1 h were included, the AUC of the MTB-HR in distinguishing untreated ATB from non-ATB was largest, 0.920 (95% CI, 0.822-1.000, sensitivity 81.3%, specificity 87.7%). In conclusion, the MTB-HR assay shows potential as a rapid, blood-based screening and triage test for ATB, especially for untreated ATB, with the advantage of increased diagnostic yield since blood is more readily available.

Association of Cytokine Gene Polymorphisms and Their Impact on Active and Latent Tuberculosis in Brazil's Amazon Region.

Some genetic variations in cytokine genes can alter their expression and influence the evolution of Mycobacterium tuberculosis (Mtb) infection. This study aimed to investigate the association of polymorphisms in cytokine genes and variability in plasma levels of cytokines with the development of tuberculosis (TB) and latent tuberculosis infection (LTBI). Blood samples from 245 patients with TB, 80 with LTBI, and healthy controls (n = 100) were included. Genotyping of the IFNG +874A/T, IL6 -174G/C, IL4 -590C/T, and IL10 -1082A/G polymorphisms was performed by real-time PCR, and cytokine levels were determined by flow cytometry. Higher frequencies of genotypes AA (IFNG +874A/T), GG (IL6 -174G/C), TT (IL4 -590C/T), and GG (IL10 -1082A/G) were associated with an increased risk of TB compared to that of LTBI (p = 0.0027; p = 0.0557; p = 0.0286; p = 0.0361, respectively) and the control (p = <0.0001, p = 0.0021; p = 0.01655; p = 0.0132, respectively). In combination, the A allele for IFNG +874A/T and the T allele for IL4 -590C/T were associated with a higher chance of TB (p = 0.0080; OR = 2.753 and p < 0.0001; OR = 3.273, respectively). The TB group had lower levels of IFN-γ and higher concentrations of IL-6, IL-4, and IL-10. Cytokine levels were different between the genotypes based on the polymorphisms investigated (p < 0.05). The genotype and wild-type allele for IFNG +874A/T and the genotype and polymorphic allele for IL4 -590C/T appear to be more relevant in the context of Mtb infection, which has been associated with the development of TB among individuals infected by the bacillus and with susceptibility to active infection but not with susceptibility to latent infection.