Active Pulmonary Tuberculosis Research Articles

Predictors of positive tuberculin skin test in neonates exposed to pulmonary tuberculosis.

Neonates are at risk of nosocomial tuberculosis (TB) infection from health care workers (HCWs) in neonatal care facilities, which can progress to severe TB diseases. Tuberculin skin test (TST) is commonly used for TB diagnosis, but its accuracy in neonates is influenced by various factors, including bacilli Calmette-Guérin (BCG) vaccination. This study aimed to identify predictors of positive TSTs in neonates exposed to HCWs with pulmonary TB. A retrospective observational study was conducted to compare the frequency of predictors between TST-positive and TST-negative neonates. Demographic, epidemiological, and clinical data of neonates exposed to TB, along with that of HCW and household contacts, were collected retrospectively through contact investigations with the Korean National TB Surveillance System (KNTSS) database. TSTs using 2 tuberculin units of purified protein derivative RT23 were performed on exposed neonates at the end of preventive TB treatment. Firth logistic regression was performed to identify predictors of TST positivity. Contact investigations revealed that 152 neonates and 54 HCWs were exposed to infectious TB index cases in 3 neonatal care facilities. Of 152 exposed neonates, 8 (5.3%) had positive TST results. Age of 6 days or more at the initial exposure is a statistically significant predictor of positive TST (Firth coefficient 2.1, 95% confidence interval 0.3-3.9, P = 0.024); BCG vaccination showed no statistical significance in both univariable and multivariable analysis. Sex, prematurity, exposure duration, duration from initial exposure to contact investigation, and isoniazid preventive treatment duration were not significant predictors. Age at the initial exposure is a significant predictor of positive TST in neonates exposed to active pulmonary TB. Given the complexities of TST interpretation, including false positives due to BCG vaccination, careful risk assessment is necessary for appropriate decision-making and resource allocation in the management of neonatal TB exposure.

The potential association between metabolic disorders and pulmonary tuberculosis: a Mendelian randomization study

BackgroundMetabolic disorders (MetDs) have been demonstrated to be closely linked to numerous diseases. However, the precise association between MetDs and pulmonary tuberculosis (PTB) remains poorly understood.MethodSummary statistics for exposure and outcomes from genome-wide association studies (GWASs) for exposures and outcomes were obtained from the BioBank Japan Project (BBJ) Gene–exposure dataset. The 14 clinical factors were categorized into three groups: metabolic laboratory markers, blood pressure, and the MetS diagnostic factors. The causal relationship between metabolic factors and PTB were analyzed using two-sample Mendelian Randomization (MR). Additionally, the direct effects on the risk of PTB were investigated through multivariable MR. The primary method employed was the inverse variance-weighted (IVW) model. The sensitivity of this MR analysis was evaluated using MR-Egger regression and the MR-PRESSO global test.ResultsAccording to the two-sample MR, HDL-C, HbA1c, TP, and DM were positively correlated with the incidence of active TB. According to the multivariable MR, HDL-C (IVW: OR 2.798, 95% CI 1.484–5.274, P = 0.001), LDL (IVW: OR 4.027, 95% CI 1.140–14.219, P = 0.03) and TG (IVW: OR 2.548, 95% CI 1.269–5.115, P = 0.009) were positively correlated with the occurrence of PTB. TC (OR 0.131, 95% CI 0.028–0.607, P = 0.009) was negatively correlated with the occurrence of PTB. We selected BMI, DM, HDL-C, SBP, and TG as the diagnostic factors for metabolic syndrome. DM (IVW, OR 1.219, 95% CI 1.040–1.429 P = 0.014) and HDL-C (IVW, OR 1.380, 95% CI 1.035–1.841, P = 0.028) were directly correlated with the occurrence of PTB.ConclusionsThis MR study demonstrated that metabolic disorders, mainly hyperglycemia, and dyslipidemia, are associated with the incidence of active pulmonary tuberculosis.

Construction of ceRNA regulatory networks for active pulmonary tuberculosis

Delayed diagnosis in patients with pulmonary tuberculosis (PTB) often leads to serious public health problems. High throughput sequencing was used to determine the expression levels of lncRNAs, mRNAs, and miRNAs in the lesions and adjacent health lung tissues of patients with PTB. Their differential expression profiles between the two groups were compared, and 146 DElncRs, 447 DEmRs, and 29 DEmiRs were obtained between lesions and adjacent health tissues in patients with PTB. Enrichment analysis for mRNAs showed that they were mainly involved in Th1, Th2, and Th17 cell differentiation. The lncRNAs, mRNAs with target relationship with miRNAs were predicted respectively, and correlation analysis was performed. The ceRNA regulatory network was obtained by comparing with the differentially expressed transcripts (DElncRs, DEmRs, DEmiRs), then 2 lncRNAs mediated ceRNA networks were established. The expression of genes within the network was verified by quantitative real-time PCR (qRT-PCR). Flow cytometric analysis revealed that the proportion of Th1 cells and Th17 cells was lower in PTB than in controls, while the proportion of Th2 cells increased. Our results provide rich transcriptome data for a deeper investigation of PTB. The ceRNA regulatory network we obtained may be instructive for the diagnosis and treatment of PTB.

Risk factors associated with pulmonary hypertension in patients with active tuberculosis and tuberculous destroyed lung: a retrospective study

Pulmonary tuberculosis (TB) can result in irreversible damage and lead to tuberculous destructive lung (TDL), a severe chronic lung disease that is associated with a high mortality rate. Additionally, pulmonary hypertension (PH) is a hemodynamic disorder that can be caused by lung diseases. The objective of this study is to investigate the risk factors associated with PH in active TB patients diagnosed with TDL. We conducted a retrospective review of the medical records of 237 patients who were diagnosed with TDL, active pulmonary tuberculosis, and underwent echocardiography at the Third People’ Hospital of Shenzhen from January 1, 2016, to June 30, 2023. Univariate and multivariate logistic regression analyses were performed to identify factors that correlated with the development of pulmonary hypertension. Univariate and multivariate logistic regression analyses revealed that several factors were associated with an increased risk of pulmonary hypertension (PH) in individuals with tuberculosis destroyed lung (TDL). These factors included age (OR = 1.055), dyspnea (OR = 10.728), D-dimer (OR = 1.27), PaCO2 (OR = 1.040), number of destroyed lung lobes (OR = 5.584), bronchiectasis (OR = 3.205), and chronic pleuritis (OR = 2.841). When age, D-dimer, PaCO2, and number of destroyed lung lobes were combined, the predictive value for PH in patients with TDL was found to be 80.6% (95% CI 0.739–0.873),with a sensitivity of 76.6% and specificity of 73.2%. Advanced age, elevated D-dimer levels, hypercapnia, and severe lung damage were strongly correlated with the onset of PH in individuals with active pulmonary tuberculosis (PTB) and TDL. Furthermore, a model incorporating age, D-dimer, PaCO2, and the number of destroyed lung lobes might be valuable in predicting the occurrence of PH in patients with active PTB and TDL.

Integrating systemic immune-inflammation index, fibrinogen, and T-SPOT.TB for precision distinction of active pulmonary tuberculosis in the era of mycobacterial disease research.

The clinical challenge of differentiating suspected tuberculosis with positive T-SPOT.TB results persist. This study aims to investigate the utility of the Systemic Immune-Inflammation Index (SII), Fibrinogen, and T-SPOT.TB in distinguishing between active pulmonary tuberculosis (PTB) and non-tuberculous lung diseases. A retrospective analysis included 1,327 cases of active PTB with positive T-SPOT.TB results and 703 cases of non-tuberculous lung diseases from May 2016 to December 2020 at Meizhou People's Hospital. These were designated as the case group and the control group, respectively. The detection indicators of T-SPOT.TB: Early Secreted Antigenic Target 6 (ESAT-6), Culture Filtrate Protein 10 (CFP-10), as well as SII and Fibrinogen levels-were compared and analyzed for association and joint diagnostic value between the two groups. The case group showed higher values of ESAT-6, CFP-10, SII, and Fibrinogen compared to the control group (all p < 0.001). In the case group, SII and Fibrinogen did not correlate with ESAT-6 and CFP-10 (∣rs∣ all < 0.3) but were positively correlated with C-reactive protein (CRP; rs all > 0.3). SII and Fibrinogen values in smear-positive pulmonary tuberculosis were higher than in smear-negative cases (all p < 0.05). The optimal diagnostic thresholds for ESAT-6, CFP-10, SII, and Fibrinogen in differentiating between active PTB and non-tuberculous lung diseases were 21.50 SFCs/106 PBMC, 22.50 SFCs/106 PBMC, 2128.32, and 5.02 g/L, respectively. Regression logistic analysis showed that ESAT-6 < 21.5 (OR: 1.637, 95% CI: 1.311-2.043, p < 0.001), CFP-10 < 22.5 (OR: 3.918, 95% CI: 3.138-4.892, p = 0.025), SII < 2128.32 (OR: 0.763, 95% CI: 0.603-0.967, p < 0.001), and FIB < 5.02 (OR: 2.287, 95% CI: 1.865-2.806, p < 0.001) were independent risk factors for active PTB. The specificity for ESAT-6 + CFP-10, ESAT-6 + CFP-10 + SII, ESAT-6 + CFP-10 + FIB, and ESAT-6 + CFP-10 + SII + FIB was 82.5%, 83.2%, 95.8%, and 80.1%, respectively, while sensitivity was 52.6%, 53.0%, 55.8%, and 44.7%, and positive predictive values were 85.0%, 85.6%, 84.1%, and 89.6%, respectively. SII and Fibrinogen are positively correlated with the degree of tuberculosis inflammation and the bacterial load of Mycobacterium tuberculosis. The combined detection of SII, Fibrinogen, and T-SPOT.TB is significant in distinguishing between active PTB with positive T-SPOT.TB results and non-tuberculous lung diseases.

Immune profiles of MCP-1 with M tb antigens and recombinant cytokines stimulation in tuberculosis

Tuberculosis is caused by Mycobacterium tuberculosis (M tb), which is recognized by macrophages and produces inflammatory cytokines, and chemokines at the site of infection. The present study was proposed to understand the interaction of M tb antigens, cytokines, and chemokines. We have evaluated the chemokine MCP-1 levels and its expression in PBMCs stimulated with M tb antigens Ag85A, ESAT6 and recombinant cytokines rhTNF-α, rhIFN-γ, rhTGF-β, and rhIL-10 in active pulmonary TB (APTB) patients, household contacts (HHC) at 0 months, 6 months and healthy controls (HC). We have observed low levels of MCP-1 with Ag85A, ESAT6, and rhTNF-α stimulations in APTB 0M compared to HHC and HC (p < 0.0067, p < 0.0001, p < 0.01, p < 0.005, p < 0.0065, p < 0.0001) and significantly increased after treatment with rhTNF-α. The MCP-1 levels with rhIFN-γ were high in APTB, HHC at 0 M and significant between APTB 0 M vs. 6 M, HHC vs. HC, and HHC 0M vs. 6M (p < 0.0352, p < 0.0252, p < 0.00062). The rhTGF-β, rhIL-10 induced high MCP-1 levels in APTB, HHC compared to HC (p < 0.0414, p < 0.0312, p < 0.004, p < 0.0001) and significantly decreased after treatment with rhIL-10 (p < 0.0001). The MCP-1 expression was low with all the stimulations in APTB 0M when compared to HC and after treatment. Whereas, HHC shown low MCP-1 expression with rhTNF-α, rhIFN-γ and Ag85A and high with rhTGF-β, rhIL-10 and ESAT6. In conclusion, the study determined the differential expression and production of MCP-1 with M tb antigens and recombinant cytokines. Further, cohort studies are required to study these interaction to identify the high risk individuals, which might help for TB control.

A systematic review and meta-analysis of circulating serum and plasma microRNAs in TB diagnosis

BackgroundTuberculosis (TB) ranks as the second leading cause of death globally among all infectious diseases. This problem is likely due to the lack of biomarkers to differentiate the heterogeneous spectrum of infection. Therefore, the first step in solving this problem is to identify biomarkers to distinguish the different disease states of an individual and treat them accordingly. Circulating microRNA (miRNA) biomarkers are promising candidates for various diseases. In fact, we are yet to conceptualize how miRNA expression influences and predicts TB disease outcomes. Thus, this systematic review and meta-analysis aimed to assess the diagnostic efficacy of circulating miRNAs in Latent TB (LTB) and Active Pulmonary TB (PTB).MethodsLiterature published between 2012 and 2021 was retrieved from PubMed, Web of Science, Cochrane, Scopus, Embase, and Google Scholar. Articles were screened based on inclusion and exclusion criteria, and their quality was assessed using the QUADAS-2 tool. Funnel plots and forest plots were generated to assess the likelihood of study bias and heterogeneity, respectively.ResultsAfter the screening process, seven articles were selected for qualitative analysis. The study groups, which consisted of Healthy Control (HC) vs. TB and LTB vs. TB, exhibited an overall sensitivity of 81.9% (95% CI: 74.2, 87.7) and specificity of 68.3% (95% CI: 57.8, 77.2), respectively. However, our meta-analysis results highlighted two potentially valuable miRNA candidates, miR-197 and miR-144, for discriminating TB from HC. The miRNA signature model (miR197-3p, miR-let-7e-5p, and miR-223-3p) has also been shown to diagnose DR-TB with a sensitivity of 100%, but with a compromised specificity of only 75%.ConclusionmiRNA biomarkers show a promising future for TB diagnostics. Further multicentre studies without biases are required to identify clinically valid biomarkers for different states of the TB disease spectrum.Systematic review registrationPROSPERO (CRD42022302729).

Evaluation of cytokine profiles related to Mycobacterium tuberculosis latent antigens using a whole-blood assay in the Philippines.

There is no useful method to discriminate between latent tuberculosis infection (LTBI) and active pulmonary tuberculosis (PTB). This study aimed to investigate the potential of cytokine profiles to discriminate between LTBI and active PTB using whole-blood stimulation with Mycobacterium tuberculosis (MTB) antigens, including latency-associated antigens. Patients with active PTB, household contacts of active PTB patients and community exposure subjects were recruited in Manila, the Philippines. Peripheral blood was collected from the participants and used for whole-blood stimulation (WBS) with either the early secretory antigenic target and the 10-kDa culture filtrate protein (ESAT-6/CFP-10), Rv3879c or latency-associated MTB antigens, including mycobacterial DNA-binding protein 1 (MDP-1), α-crystallin (Acr) and heparin-binding hemagglutinin (HBHA). Multiple cytokine concentrations were analyzed using the Bio-Plex™ multiplex cytokine assay. A total of 78 participants consisting of 15 active PTB patients, 48 household contacts and 15 community exposure subjects were eligible. The MDP-1-specific IFN-γ level in the active PTB group was significantly lower than that in the household contact group (p < 0.001) and the community exposure group (p < 0.001). The Acr-specific TNF-α and IL-10 levels in the active PTB group were significantly higher than those in the household contact (TNF-α; p = 0.001, IL-10; p = 0.001) and community exposure (TNF-α; p < 0.001, IL-10; p = 0.01) groups. However, there was no significant difference in the ESAT-6/CFP-10-specific IFN-γ levels among the groups. The patterns of cytokine profiles induced by latency-associated MTB antigens using WBS have the potential to discriminate between LTBI and active PTB. In particular, combinations of IFN-γ and MDP-1, TNF-α and Acr, and IL-10 and Acr are promising. This study provides the first demonstration of the utility of MDP-1-specific cytokine responses in WBS.

Timely Pulmonary Tuberculosis Diagnosis Based on the Epidemiological Disease Spectrum: Population-Based Prospective Cohort Study in the Republic of Korea.

Timely pulmonary tuberculosis (PTB) diagnosis is a global health priority for interrupting transmission and optimizing treatment outcomes. The traditional dichotomous time-divided approach for addressing time delays in diagnosis has limited clinical application because the time delay significantly varies depending on each community in question. We aimed to reevaluate the diagnosis time delay based on the PTB disease spectrum using a novel scoring system that was applied at the national level in the Republic of Korea. The Pulmonary Tuberculosis Spectrum Score (PTBSS) was developed based on previously published proposals related to the disease spectrum, and its validity was assessed by examining both all-cause and PTB-related mortality. In our analysis, we integrated the PTBSS into the Korea Tuberculosis Cohort Registry. We evaluated various time delays, including patient, health care, and overall delays, and their system-associated variables in line with each PTBSS. Furthermore, we reclassified the scores into distinct categories of mild (PTBSS=0-1), moderate (PBTBSS=2-3), and severe (PBTBSS=4-6) using a multivariate regression approach. Among the 14,031 Korean patients with active PTB whose data were analyzed from 2018 to 2020, 37% (n=5191), 38% (n=5328), and 25% (n=3512) were classified as having a mild, moderate, and severe disease status, respectively, according to the PTBSS. This classification can therefore reflect the disease spectrum of PTB by considering the correlation of the score with mortality. The time delay patterns differed according to the PTBSS. In health care delays according to the PTBSS, greater PTB disease progression was associated with a shorter diagnosis period, since the condition is microbiologically easy to diagnose. However, with respect to patient delays, the change in elapsed time showed a U-shaped pattern as PTB progressed. This means that a remarkable patient delay in the real-world setting might occur at both apical ends of the spectrum (ie, in both mild and severe cases of PTB). Independent risk factors for a severe PTB pattern were age (adjusted odds ratio 1.014) and male sex (adjusted odds ratio 1.422), whereas no significant risk factor was found for mild PTB. Timely PTB diagnosis should be accomplished. This can be improved with use of the PTBSS, a simple and intuitive scoring system, which can be more helpful in clinical and public health applications compared to the traditional dichotomous time-only approach.

Integrated plasma proteomics identifies tuberculosis-specific diagnostic biomarkers.

BACKGROUNDNovel biomarkers to identify infectious patients transmitting Mycobacterium tuberculosis are urgently needed to control the global tuberculosis (TB) pandemic. We hypothesized that proteins released into the plasma in active pulmonary TB are clinically useful biomarkers to distinguish TB cases from healthy individuals and patients with other respiratory infections.METHODSWe applied a highly sensitive non-depletion tandem mass spectrometry discovery approach to investigate plasma protein expression in pulmonary TB cases compared to healthy controls in South African and Peruvian cohorts. Bioinformatic analysis using linear modeling and network correlation analyses identified 118 differentially expressed proteins, significant through 3 complementary analytical pipelines. Candidate biomarkers were subsequently analyzed in 2 validation cohorts of differing ethnicity using antibody-based proximity extension assays.RESULTSTB-specific host biomarkers were confirmed. A 6-protein diagnostic panel, comprising FETUB, FCGR3B, LRG1, SELL, CD14, and ADA2, differentiated patients with pulmonary TB from healthy controls and patients with other respiratory infections with high sensitivity and specificity in both cohorts.CONCLUSIONThis biomarker panel exceeds the World Health Organization Target Product Profile specificity criteria for a triage test for TB. The new biomarkers have potential for further development as near-patient TB screening assays, thereby helping to close the case-detection gap that fuels the global pandemic.FUNDINGMedical Research Council (MRC) (MR/R001065/1, MR/S024220/1, MR/P023754/1, and MR/W025728/1); the MRC and the UK Foreign Commonwealth and Development Office; the UK National Institute for Health Research (NIHR); the Wellcome Trust (094000, 203135, and CC2112); Starter Grant for Clinical Lecturers (Academy of Medical Sciences UK); the British Infection Association; the Program for Advanced Research Capacities for AIDS in Peru at Universidad Peruana Cayetano Heredia (D43TW00976301) from the Fogarty International Center at the US NIH; the UK Technology Strategy Board/Innovate UK (101556); the Francis Crick Institute, which receives funding from UKRI-MRC (CC2112); Cancer Research UK (CC2112); and the NIHR Biomedical Research Centre of Imperial College NHS.

Active Tuberculosis Is Associated with Depletion of HIV-Specific CD4 and CD8 T Cells in People with HIV.

Infection with Mycobacterium tuberculosis (Mtb) in people with HIV (PWH) is associated with depletion of Mtb-specific CD4 T cell responses, increased risk of progression to active tuberculosis (TB) disease, and increased immune activation. Although higher HIV viral loads have been reported in Mtb/HIV co-infection, the extent to which Mtb infection and TB disease impact the frequency and phenotype of HIV-specific T cell responses has not been well described. We enrolled a cohort of PWH in Kenya across a spectrum of Mtb infection states, including those with no evidence of Mtb infection, latent Mtb infection (LTBI), and active pulmonary TB disease, and evaluated the frequency, immune activation, and cytotoxicity phenotype of HIV-specific CD4 and CD8 T cell responses in peripheral blood by flow cytometry. We found evidence of depletion of HIV-specific CD4 and CD8 T cells in people with TB, but not with LTBI. Expression of the immune activation markers human leukocyte antigen-DR isotype (HLA-DR) and Ki67 and of the cytotoxic molecules granzyme B and perforin were increased in total CD4 and CD8 T cell populations in individuals with TB, although expression of these markers by HIV-specific CD4 and CD8 T cells did not differ by Mtb infection status. These data suggest that TB is associated with overall increased T cell activation and cytotoxicity and with depletion of HIV-specific CD4 and CD8 T cells, which may contribute to further impairment of T cell-mediated immune control of HIV replication in the setting of TB.

Neutrophil lncRNA ZNF100-6:2 is a potential diagnostic marker for active pulmonary tuberculosis

Active pulmonary tuberculosis (PTB) poses challenges in rapid diagnosis within complex clinical conditions. Given the close association between neutrophils and tuberculosis, we explored differentially expressed long non-coding RNAs (lncRNAs) in neutrophils as potential molecular markers for diagnosing active PTB. We employed a gene microarray to screen for lncRNA alterations in neutrophil samples from three patients with active PTB and three healthy controls. The results revealed differential expression of 1457 lncRNAs between the two groups, with 916 lncRNAs upregulated and 541 lncRNAs down-regulated in tuberculosis patients. Subsequent validation tests demonstrated down-regulation of lncRNA ZNF100-6:2 in patients with active PTB, which was restored following anti-tuberculosis treatment. Our findings further indicated a high diagnostic potential for lncRNA ZNF100-6:2, as evidenced by an area under the receiver operating characteristic (ROC) curve of 0.9796 (95% confidence interval: 0.9479 to 1.000; P < 0.0001). This study proposes lncRNA ZNF100-6:2 as a promising and novel diagnostic biomarker for active PTB.

Evaluation of Systemic Inflammation Before and After Standard Anti-tuberculosis Treatment in Patients With Active Pulmonary Tuberculosis and Diabetes Mellitus.

Background Diabetes mellitus (DM) is a common comorbidity of active pulmonary tuberculosis (APTB) that increases the risk of treatment failure during anti-tuberculosis chemotherapy. Evaluating systemic inflammatory response could help determine differences in response to treatment between APTB patients and those with APTB and DM. Methodology To explore changes in systemic inflammation, measured by a set of inflammatory mediators in subjects with APTB and TBDM before and after six months of anti-tuberculosis chemotherapy, 30 APTB and nine TBDM subjects underwent cytokine testing, including interleukin (IL)-6, IL-8, IL-10, interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta 1 (TGF-β1) by enzyme-linked immunosorbent assay, C-reactive protein by nephelometry, and sialic acid by colorimetric assay at baseline and following six months of standard anti-tuberculosis treatment. Sputum smear microscopy or molecular biology (Xpert MTB/RIF) was used for diagnosis, and sputum smear microscopy was performed monthly during the treatment of the patient with pulmonary tuberculosis to evaluate his evolution. Principal component analysis examined changes in the inflammatory status. Results Both groups showed negative sputum smear microscopy in the sixth month after starting anti-tuberculosis chemotherapy. TGF-β1 was found to be significantly higher in subjects with TBDM before treatment compared to APTB patients (p<0.001), and systemic inflammation continued only in TBDM subjects after treatment (accumulation and persistence of inflammatory mediators like IL-6, IL-8, IL-10, IFN-γ, TNF-α, TGF-β1, C-reactive protein, and sialic acid in blood). On the other hand, the mediators IFN-γ, C-reactive protein, and total sialic acid were found to be most influential in distinguishing pre- and post-treatment inflammatory response in subjects with APTB without DM. Conclusions Inflammatory mediators analyzed in combination, including IFN-γ, CRP, and total sialic acid, may be useful in evaluating the systemic inflammatory response in subjects with APTB and TBDM before and after anti-tuberculosis treatment. Determining these mediators revealed persistent systemic inflammation in TBDM subjects after six months of standard tuberculosis treatment, despite negative sputum smear microscopy results and good glycemic control. This suggests a need for inflammation-modulating therapies during tuberculosis control. Finally, monitoring sputum smear microscopy results alongside the determination of proposed inflammatory mediators (IFN-γ, CRP, and total sialic acid) are effective in evaluating the response to anti-tuberculosis treatment in APTB subjects without DM, warranting further investigation.

Discovering novel biomarkers for diagnosis and treatment monitoring of active pulmonary tuberculosis by ion metabolism analysis

Tuberculosis (TB) is a highly lethal infectious disease that poses a global threat. Timely and accurate biomarker for TB diagnosis and treatment monitoring remains a pressing need. Ions, the crucial trace element for humans, may be potential targets for TB diagnosis and the forecasting of TB development. To explore the potential of ions as biomarkers, we measured and compared the levels of various ions in whole blood and plasma samples from healthy control (HC), pulmonary TB patients (TB), cured pulmonary TB patients (RxTB), and other non-TB pneumonia patients (PN) by using ultra-high performance liquid chromatography-tandem mass spectrometry. Our study demonstrated that Cu (AUC = 0.670), Pb (AUC = 0.660), and Zn (AUC = 0.701) in whole blood exhibited promising diagnostic performance for TB. Then we used a neural network (NNET) for TB prediction, the AUC values used to differentiate definite TB from HC or PN in plasma were 0.867 and 0.864, respectively. The AUC values used to differentiate definite TB from HC or PN in whole blood were 0.818 and 0.660, respectively. Our correlation analysis showed that Zn (r= 0.356, p=0.001) and Cu (r= 0.361, p=0.0004) in plasma are most closely related to disease severity. Additionally, six ions (Cu, Sb, V, Mn, Fe, Sr) in plasma and whole blood were altered following anti-TB therapy. These results showed that ions could be diagnostic biomarkers for TB. Furthermore, the level of particular ions can forecast the degree of lung damage and the success of the TB treatment. In conclusion, this study highlights the possibility of using ions from blood samples to enable rapid tuberculosis diagnosis.

Prevalence and Risk Factors of Diabetes in Patients with Active Pulmonary Tuberculosis: A Cross-Sectional Study in Two Financially Affluent China Cities.

Tuberculosis (TB) and diabetes mellitus (DM) present a dual burden to public health. The screening of DM in TB patients may aid in the early detection and management of diabetes, ultimately improving treatment outcomes for those with the comorbidity of TB-DM. We aim to examine the prevalence and identify risk factors of diabetes in individuals with active pulmonary tuberculosis (PTB) in financially affluent China cities. A cross-sectional survey was conducted in adult patients with highly suspected TB in two cities of China, spanning from May 9, 2023, to June 30, 2023. We compare the clinical characteristics, nutrition status, fasting blood glucose (FBG) level, living style, and knowledge of TB and DM at admission between patients with and without DM. Univariate and multivariate logistic regression analyses were employed to identify risk factors associated with TB-DM comorbidities. Of the 322 patients diagnosed with pulmonary tuberculosis (PTB), 54 individuals (16.8%) had comorbid diabetes mellitus (DM). This included 43 males (13.4%) and 11 females (3.4%). The average age was 55.44 ± 12.36 in DM patients and 46.09 ± 16.87 in non-DM patients. A multivariate logistic regression analysis revealed that male (adjusted odds ratio [aOR]=3.29, 95% confidence interval [CI]: 1.05-10.30), age older than 47 years (aOR = 1.04, 95% CI: 1.01-1.07), having a family history of diabetes (aOR = 5.09, 95% CI: 1.28-20.32), and an elevated random blood glucose level (aOR = 1.6, 95% CI: 1.38-1.86) were risk factors for DM in patients with PTB. Furthermore, it was found that diabetes awareness (aOR = 0.07, 95% CI: 0.03-0.21) and zero, light to moderate alcohol consumption were associated with a lower risk of diabetes. Diabetes is prevalent in patients with active PTB. Screening and raising awareness of DM are recommended, particularly in men after middle age with a family history of diabetes and elevated random blood glucose. Early diagnosis of diabetes and effective diabetes prevention may reduce the dual burden of TB-DM comorbidity.

Carbon 13 urea breath test as a novel technique in the diagnosis of pulmonary tuberculosis

BackgroundThe Urea Breath Test (UBT) is the golden standard of investigation for Helicobacter pylori. Tuberculosis is common and endemic in Iraq, with limited investigations. This study was conducted to determine the safety and importance of UBT as a method for the diagnosis of active pulmonary tuberculosis. Material and methodA prospective, case-control study trial was conducted to determine the safety of 75 mg of inhaled C13-urea in 50 healthy participants. Then, in national TB, Over the course of a one-year study at a medical city in Baghdad, 50 participants with confirmed active pulmonary tuberculosis were enrolled. The safety of inhaled C13-urea was assessed by physical examination and spirometry. The C13-urea was administered by using a jet nebulizer, followed by the collection of exhaled breath at 15 and 30 min’ post-inhalation. A double-beam infrared spectrophotometer examined the isotopic ratio of (C13) CO2 to (C12) CO2. ResultsThe lung function test, which included forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1), did not show any changes that were clinically significant when healthy people and people with pulmonary tuberculosis (PTB) were compared to their baseline values. Additionally, there was no recorded incidence of adverse events among both healthy individuals and those with pulmonary tuberculosis (PTB). After 15 min of the nebulization process, the delta over baseline (DOB) means of the control group and PTB patients were −1.2381 ± 1.8392 and 4.8215 ± 5.1889, respectively. After 15 min of the nebulization process, the DOB means of the control group and PTB patients were −1.9628 ± 3.0717 and 3.5686 ± 3.8484, respectively. ConclusionInhaling 13 C-urea seemed safe. DOB values in PTB patients were greater than in controls. Preliminary data suggest that DOB values at 15 min were higher than 30 min. This has potential for diagnosing Mycobacterium tuberculosis.

Changes of Mycobacterium tuberculosis specific antigen-stimulated CD27−CD38+IFN-γ+CD4+ T cells before and after anti-tuberculosis treatment

BackgroundThe aim of the study was to investigate whether the expression of CD27−CD38+ in interferon (IFN)-γ+CD4+ T cells stimulated by the specific antigen early secreted antigenic target-6 (ESAT-6)/culture filter protein-10 (CFP-10) could be a potential new therapeutic evaluation indicator for anti-tuberculosis (TB) treatment.MethodsNewly diagnosed active pulmonary TB patients, latent TB infection (LTBI) and healthy controls were enrolled from January 2021 to December 2021. PTB patients were treated by standard anti-TB regimen 2HREZ/4HR (2 months of isoniazid (H), rifampin (R), ethambutol (E), and pyrazinamide (Z) followed by 4 months of isoniazid (H) and rifampin (R)). The difference of CD27−CD38+ expression in IFN-γ+CD4+ T cells before treatment, 2 months after treatment, and 6 months after treatment were compared.ResultsTotal 45 PTB patients, 38 LTBI cases and 43 healthy controls were enrolled. The expression of CD27−CD38+ decreased significantly after anti-TB treatment and was comparable with that in LTBI and healthy controls when the 6-month anti-TB treatment course was completed. The decline rate of CD27−CD38+ between 6 months after treatment and baseline was positively correlated with erythrocyte sedimentation rate (r = 0.766, P < 0.0001), C-reactive protein (r = 0.560, P = 0.003) and chest computerized tomography severity score (r = 0.632, P = 0.0005). The area under receiver operator characteristic curve of CD27−CD38+ in distinguish pulmonary TB patients before and after treatment was 0.779.ConclusionThe expression of CD27−CD38+ in ESAT-6/CFP-10 stimulated IFN-γ+CD4+T cells can well reflect the changes of the disease before and after anti-TB treatment, which is expected to be a potential new therapeutic evaluation index.Clinical Registry number chiCTR1800019966.

Candidate Blood MicroRNAs as Potential Biomarkers in Patients with Active and Latent Pulmonary Tuberculosis Infection

Infection with tuberculosis (TB) has been a leading cause of death worldwide. The accurate detection of Mycobacterium tuberculosis (M. tuberculosis) is integral for the prevention and control programs for TB disease. Host-encoded microRNAs (miRNAs) are known to be triggered upon TB infection, raising possibilities of their utility as biomarkers. Here, we investigated the value of miRNAs in pointing active TB (ATB) and predicting the progression from latent TB (LTB) to ATB infection. We then constructed signaling pathways predicted to be involved in TB disease pathobiology. Our analyses identified miR-21-5p, miR-29a-3p and miR-361-5p as being down regulated in ATB and upregulated in LTB compared to healthy subjects with an area under the curve (AUC) of &gt; 0.9, indicating potentially promising biomarker. Pathways related to estrogen signaling, TNF and apoptosis signaling were enriched targets for those miRNAs. This study provides evidence for the significance of miRNA as diagnostic and prognostic markers for ATB and LTB infections in humans. These results could be extrapolated and validated using future large-scale studies.

Comparison of the Single Cell Immune Landscape between Subjects with High Mycobacterium tuberculosis Bacillary Loads during Active Pulmonary Tuberculosis and Household Members with Latent Tuberculosis Infection.

It is unclear how the immune system controls the transition from latent tuberculosis (TB) infection (LTBI) to active pulmonary infection (PTB). Here, we applied mass spectrometry cytometry time-of-flight (CyTOF) analysis of peripheral blood mononuclear cells to compare the immunological landscapes in patients with high tuberculous bacillary load PTB infections and LTBI. A total of 32 subjects (PTB [n = 12], LTBI [n = 17], healthy volunteers [n = 3]) were included. Participants with active PTBs were phlebotomized before administering antituberculosis treatment, whereas participants with LTBI progressed to PTB at the time of household screening. In the present study, CyTOF analysis identified significantly higher percentages of mucosal-associated invariant natural killer T (MAIT NKT) cells in subjects with LTBI than in those with active PTB and healthy controls. Moreover, 6 of 17 (35%) subjects with LTBI progressed to active PTB (LTBI progression) and had higher proportions of MAIT NKT cells and early NKT cells than those without progression (LTBI non-progression). Subjects with LTBI progression also showed a tendency toward low B cell levels relative to other subject groups. In conclusion, MAIT NKT cells were substantially more prevalent in subjects with LTBI, particularly those with progression to active PTB.

Spontaneous tension pneumothorax: a devastating consequence of pulmonary tuberculosis

Tuberculosis (TB) was the world’s second leading cause of death from a single infectious agent, with mortality reaching 50% in untreated cases. It has been acknowledged as a potential cause of secondary spontaneous pneumothorax. A 57-year-old male presented to emergency department due to shortness of breath since 12 hours before admission. He had a history of chronic cough along with significant weight loss. He was cachexic and fully alert, with normal blood pressure, tachypnea, and slight tachycardia. Decreased breath sounds on the right hemithorax was noted. Chest x-ray revealed right tension pneumothorax and active pulmonary TB. Emergency needle decompression was performed with 14-gauge intravenous catheter. Unfortunately, he died eight hours later following a cardiac arrest. Occurrence of spontaneous tension pneumothorax in TB involves several mechanisms such as pleural porosity, chronic inflammation, and alveolar rupture. Compensatory mechanisms including gradual tachycardia, respiratory rate elevation, along with increasingly negative contralateral intrathoracic pressures could preserve venous return, serving as protective factors against hypotension until the late stages. Late presentation of 12 hours after the first onset might contribute to enormous air leak that could not be effectively managed by needle decompression. Undiagnosed and untreated TB could lead to morbid consequence such as tension pneumothorax, highlighting the importance of TB detection within the community. Clinicians should be aware of variations in the clinical presentation of tension pneumothorax as compensatory mechanisms may hinder the diagnosis at initial presentation. Strategic approaches are imperative to reinforce our commitment to eliminate TB by 2030.