Mitigating treatment failure of pulmonary pre-extensively drug-resistant tuberculosis: The role of new and repurposed drugs.

BACKGROUND: Pre-extensively drug-resistant tuberculosis (pre-XDR-TB), defined as multidrug-resistant TB (MDR-TB) with additional resistance to any fluoroquinolone (FQ) is difficult to treat. We assessed whether the use of new or repurposed drugs (bedaquiline, delamanid, linezolid, carbapenem, clofazimine, pretomanid) mitigated treatment failure of pre-XDR-TB. METHODS: MDR-TB patients managed in the Taiwan MDR-TB consortium between July 2009-December 2019 were eligible. Treatment outcomes at 30 months were assessed. Logistic regression models were constructed to investigate factors associated with treatment outcomes. RESULTS: 109 patients with FQ-resistant MDR-TB and 218 patients with FQ-susceptible MDR-TB were included. 60 (55.1%) patients with FQ-resistant MDR-TB and 63 (28.9%) patients with FQ-susceptible MDR-TB have been treated with new or repurposed drugs (p < 0.01). Of the 218 patients with FQ-susceptible MDR-TB, 187 (85.8%) had treatment success, 30 (13.8%) died, no treatment failure, and 1 (0.5%) was loss-to-follow-up; of the 109 patients with FQ-resistant MDR-TB, 78 (71.6%) had treatment success, 21 (19.3%) died, 9 (8.3%) had treatment failure, and 1 (0.9%) was loss-to-follow-up (p < 0.01). The use of new or repurposed drugs was not associated with treatment outcomes among patients with FQ-susceptible MDR-TB. No patients with FQ-resistant MDR-TB treated with ≥2 new or repurposed drugs within 6 months of treatment initiation had treatment failure (p = 0.03). Patients with FQ-resistant MDR-TB treated with 1 new or repurposed drugs was more likely to have treatment failure as compared with patients not treated with new or repurposed drugs (adjOR 7.06, 95% CI 1.72-29.06). CONCLUSIONS: Proper use of new or repurposed anti-TB drugs can mitigate treatment failure in FQ-resistant MDR-TB.

The association between tocilizumab and the secondary bloodstream infection maybe nonsignificant in hospitalized patients with SARS-CoV-2 infection: A cohort study.

BACKGROUND: Immunomodulatory agents, such as tocilizumab (TCZ), exert promising effects against SARS-CoV-2 infection. However, growing evidence indicates that using TCZ may carry higher risks of secondary bloodstream infection (sBSI). This study determined whether TCZ is associated with an increased risk of sBSI. METHODS: We retrospectively collected the demographic and clinical data of hospitalized patients with SARS-CoV-2 infection from two Taiwanese hospitals. The time-to-incident sBSI in the TCZ users and nonusers was compared using the log-rank test. A multivariate Cox proportional hazards model was performed to identify independent risk factors for sBSI. RESULTS: Between May 1 and August 31, 2021, among 453 patients enrolled, 12 (2.65 %) developed sBSI. These patients were in hospital for longer duration (44.2 ± 31.4 vs. 17.6 ± 14.3 days, p = 0.014). Despite sBSI being more prevalent among the TCZ users (7.1 % vs. 1.6 %, p = 0.005), Kaplan-Meier survival analysis and multivariate Cox proportional hazards model both revealed no significant difference in risks of sBSI between the TCZ users and nonusers [adjusted HR (aHR) = 1.32 (95 % confidence interval (CI) = 0.29-6.05), p = 0.724]. Female sex [aHR = 7.00 (95 % CI = 1.45-33.92), p = 0.016], heavy drinking [aHR = 5.39 (95 % CI = 1.01-28.89), p = 0.049], and mechanical ventilation [aHR = 5.65 (95 % CI = 1.67-19.30), p = 0.006] were independently associated with a higher sBSI risk. CONCLUSION: This real-world evidence indicates that in hospitalized patients with SARS-CoV-2 infection, TCZ does not significantly increase the risk of sBSI.

Multiplexed Antibody Glycosylation Profiling Using Dual Enzyme Digestion and Liquid Chromatography-Triple Quadrupole Mass Spectrometry Method.

Antibody glycosylation plays a crucial role in the humoral immune response by regulating effector functions and influencing the binding affinity to immune cell receptors. Previous studies have focused mainly on the immunoglobulin G (IgG) isotype owing to the analytical challenges associated with other isotypes. Thus, the development of a sensitive and accurate analytical platform is necessary to characterize antibody glycosylation across multiple isotypes. In this study, we have developed an analytical workflow using antibody-light-chain affinity beads to purify IgG, IgA, and IgM from 16 µL of human plasma. Dual enzymes, trypsin and Glu-C, were used during on-bead digestion to obtain enzymatic glycopeptides and protein-specific surrogate peptides. Ultra-high-performance liquid chromatography coupled with triple quadrupole mass spectrometry was used in order to determine the sensitivity and specificity. Our platform targets 95 glycopeptides across the IgG, IgA, and IgM isotypes, as well as eight surrogate peptides representing total IgG, four IgG classes, two IgA classes, and IgM. Four stable isotope-labeled internal standards were added after antibody purification to calibrate the preparation and instrumental bias during analysis. Calibration curves constructed using serially diluted plasma samples showed good curve fitting (R2 > 0.959). The intrabatch and interbatch precision for all the targets had relative standard deviation of less than 29.6%. This method was applied to 19 human plasma samples, and the glycosylation percentages were calculated, which were comparable to those reported in the literature. The developed method is sensitive and accurate for Ig glycosylation profiling. It can be used in clinical investigations, particularly for detailed humoral immune profiling.

Corticosteroids for COVID-19-induced olfactory dysfunction: A comprehensive systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Olfactory dysfunction is a common manifestation in COVID-19 patients and can significantly impact their quality of life. Corticosteroids have been proposed as a potential treatment, but their efficacy remains controversial. This systematic review and meta-analysis aims to comprehensively analyze the efficacy of corticosteroid therapy for treating COVID-19-related olfactory dysfunction. METHODS: A literature search was conducted in PubMed, Cochrane Library, and Embase databases up to March 1, 2023. Randomized controlled trials investigating the effects of corticosteroids on olfactory dysfunction in patients with COVID-19 were included. The primary outcome was the olfactory score at the end of follow-up, and the secondary outcomes were the duration and the rate of recovery from olfactory dysfunction. RESULTS: Seven randomized controlled trials with 999 participants were included in the meta-analysis. Compared with the control group, corticosteroid treatment resulted in a statistically significant improvement in olfactory score with a standardized mean difference of 0.55 (95% CI: 0.15 to 0.95). Topical corticosteroids were found to be effective, but systemic corticosteroids were not. In addition, longer durations and higher dosages of corticosteroids treatment may also be associated with significant improvements in olfactory scores. No significant effect was observed on the duration or recovery rate of olfactory dysfunction. CONCLUSIONS: Our findings suggest that topical corticosteroid treatment is a viable option for improving COVID-19-related olfactory dysfunction, but further research is needed to investigate optimal treatment protocols and safety profiles.

Serial electrocardiogram recordings revealed a high prevalence of QT interval prolongation in patients with tuberculosis receiving fluoroquinolones.

BACKGROUND: Fluoroquinolones, crucial components of treatment regimens for drug-resistant tuberculosis (TB), are associated with QT interval prolongation and risks of fatal cardiac arrhythmias. However, few studies have explored dynamic changes in the QT interval in patients receiving QT-prolonging agents. METHODS: This prospective cohort study recruited hospitalized patients with TB who received fluoroquinolones. The study investigated the variability of the QT interval by using serial electrocardiograms (ECGs) recorded four times daily. This study analyzed the accuracy of intermittent and single-lead ECG monitoring in detecting QT interval prolongation. RESULTS: This study included 32 patients. The mean age was 68.6 ± 13.2 years. The results revealed mild-to-moderate and severe QT interval prolongation in 13 (41%) and 5 (16%) patients, respectively. The incremental yields in sensitivity of one to four daily ECG recordings were 61.0%, 26.1%, 5.6%, and 7.3% in detecting mild-to-moderate QT interval prolongation, and 66.7%, 20.0%, 6.7%, and 6.7% in detecting severe QT interval prolongation. The sensitivity levels of lead II and V5 ECGs in detecting mild-to-moderate and severe QT interval prolongation exceeded 80%, and their specificity levels exceeded 95%. CONCLUSION: This study revealed a high prevalence of QT interval prolongation in older patients with TB who receive fluoroquinolones, particularly those with multiple cardiovascular risk factors. Sparsely intermittent ECG monitoring, the prevailing strategy in active drug safety monitoring programs, is inadequate owing to multifactorial and circadian QT interval variability. Additional studies performing serial ECG monitoring are warranted to enhance the understanding of dynamic QT interval changes in patients receiving QT-prolonging anti-TB agents.

Isoniazid level and flu-like symptoms during rifapentine-based tuberculosis preventive therapy: A population pharmacokinetic analysis.

AIM: A population pharmacokinetic (PPK) study of the correlation of adverse drug reactions (ADRs) with the 3HP regimen (weekly high-dose rifapentine plus isoniazid for 12 doses) for latent tuberculosis infection (LTBI) remains lacking. The purpose of this study is to determine the association of rifapentine or isoniazid concentration and ADRs. METHODS: This prospective, multicentre, observational study enrolled LTBI contacts receiving 3HP treatment between January 2017 and August 2020. The concentrations of rifapentine, isoniazid and their metabolites (25-desacetyl-rifapentine and acetyl-isoniazid) in plasma samples collected monthly after 3HP treatment were determined. A PPK model was constructed to predict the maximum concentration (Cmax ) and area under the concentration-time curve from 0 to 24 h (AUC). Their association with ADRs was evaluated by applying three multivariate logistic regression models with adjustment for various covariates. RESULTS: A total of 415 LTBI cases were ultimately enrolled; 355 (85.5%) completed the 3HP treatment. Among them, 47 (11.3%) experienced systemic drug reactions and 291 (70.0%) experienced one or more flu-like symptom. The plasma concentration-time profiles of isoniazid, rifapentine and their metabolites were adequately described by the developed models. A higher Cmax of isoniazid was significantly correlated with a higher risk of any ADR (adjusted odds ratio and 95% confidence interval: 3.04 [1.07-8.65]) and any or at least two flu-like symptoms (all severity grades) (2.76 [1.06-7.17]). CONCLUSIONS: Isoniazid may be responsible for ADRs, especially flu-like symptoms, during 3HP treatment.

Nucleic acid amplification tests reduce delayed diagnosis and misdiagnosis of pulmonary tuberculosis.

The clinical impact of nucleic acid amplification (NAA) tests on reducing delayed diagnosis and misdiagnosis of pulmonary TB (PTB) has rarely been investigated. PTB patients were classified into a frontline NAA group, an add-on NAA group, and a no NAA group. The outcomes of interest were the proportion of PTB case died before anti-TB treatment, the interval between sputum examination and initiation of treatment, and misdiagnosis of PTB. A total of 2192 PTB patients were enrolled, including 282 with frontline NAA, 717 with add-on NAA, and 1193 with no NAA tests. Patients with NAA tests had a lower death rate before treatment initiation compared to those without NAA tests (1.6% vs. 4.4%, p < 0.001) in all cases. Patients with frontline NAA compared to those with add-on NAA and those without NAA, had a shorter interval between sputum examination and treatment initiation in all cases (3 days vs. 6 days (p < 0.001), vs 18 days (p < 0.001)), and less misdiagnosis in smear-positive cases (1.8% vs. 5.6% (p = 0.039), vs 6.5% (p = 0.026)). In conclusion, NAA tests help prevent death before treatment initiation. Frontline NAA tests perform better than add-on NAA and no NAA in avoiding treatment delay in all cases, and misdiagnosis of PTB in smear-positive cases.

Bisphosphonate Use Is Not Associated With Tuberculosis Risk Among Patients With Osteoporosis: A Nationwide Cohort Study.

Bisphosphonates are considered an effective inhibitor of glutamine synthetase and thus can be used for treating tuberculosis (TB). However, its clinical benefit in TB remains unknown. We conducted a population-based cohort study by using the Taiwan National Health Insurance Research Database and TB databases of the Taiwan Centers for Disease Control. Patients with osteoporosis and a history of bone fracture from 2007 to 2014 were identified. Among them, bisphosphonate users and propensity score-matched nonusers were selected. A stratified multivariable Cox proportional hazard regression model was employed to investigate the independent predictors of TB. Among 218 908 patients with osteoporosis and bone fracture, 46 842 bisphosphonate users and 46 842 propensity score-matched nonusers were selected. Within the 2-year follow-up, 723 patients-348 in the user group and 375 in the nonuser group-developed TB. Bisphosphonate use was not an independent predictor of TB in the multivariable Cox proportional hazard model (adjusted hazard ratio, 0.86; 95%CI, 0.71-1.04); however, male sex, older age, being bedridden, and steroid use were independent risk factors. The real-world data revealed that bisphosphonate use did not protect patients with osteoporosis against TB.

Advantages of short-course rifamycin-based regimens for latent tuberculosis infection: an updated network meta-analysis.

OBJECTIVES: We conducted an updated network meta-analysis to elucidate the best regimen for latent tuberculosis infection (LTBI). METHODS: We searched the PubMed, Embase, and Cochrane Library databases on 16 August 2021 to perform an updated network meta-analysis. Only randomised controlled trials on populations with LTBI that reported the efficacy for preventing incident tuberculosis or the completion rates of treatment regimens were included. The Cochrane Collaboration tool was used to assess the risk of bias. We tested for possible global inconsistency with a χ2 test and local inconsistency by calculating inconsistency factors for each comparison in closed loops. The probability of each regimen being at each possible rank was estimated. Comparison-adjusted funnel plots were obtained to assess publication bias, and sensitivity analysis was performed. The major outcomes were the efficacy for preventing incident tuberculosis and the completion rates of treatment regimens. RESULTS: We identified 27 studies that matched our inclusion criteria; the risk of bias was mostly low. Rifampicin for four months (RFMP-4) was the most likely to be effective (probability: 56.3%) and the second most likely treatment to be completed (probability: 22.4%). By applying a multidimensional scaling approach for ranking based on a scatterplot with the surface under the cumulative ranking values for efficacy and completion rates, RFMP-4 was deemed the best choice for treating LTBI. Similar results were demonstrated after sensitivity analysis. CONCLUSION: This updated network meta-analysis revealed RFMP-4 to be the best choice for treating LTBI, per simultaneous consideration of efficacy and completion rates.

Performance of Nucleic Acid Amplification Tests in Patients with Presumptive Pulmonary Tuberculosis in Taiwan.

INTRODUCTION: Several nucleic acid amplification tests (NAATs) for detection of Mycobacterium tuberculosis (TB) complex (MTBC) are available in Taiwan; however, their performances may differ and have not been extensively evaluated. Therefore, we aimed to explore the accuracy of NAATs overall followed by comparison between platforms commonly used in Taiwan. METHODS: This study enrolled presumptive pulmonary TB patients with NAATs throughout Taiwan. The diagnostic performance of smear microscopy and NAATs was assessed using sputum culture as a reference standard. To investigate the performance of NAATs in excluding non-tuberculous mycobacteria (NTM), we quantified the false-positive proportion of NAATs in patients infected with NTM. RESULTS: Of the 4126 enrollees, 860 (20.8%) had positive NAATs. The sensitivity and specificity of NAATs were 83.2% and 96.7%, respectively, compared to 81.5% and 55.3% for smear. There was no significant difference in sensitivity between the NAATs and smear; however, the specificity of smear was significantly lower than that of the NAATs [difference 41.4%, 95% confidence interval (CI) 39.6-43.2%]. There was no significant difference in sensitivity among Roche Cobas Amplicor Mycobacterium tuberculosis assay (Amplicor), Xpert MTB/RIF assay (Xpert) and in-house polymerase chain reaction (in-house PCR) (82.2% versus 83.8% versus 82.4%); however, in-house PCR was significantly less specific than Amplicor (difference 5.3%, 95% CI 2.4-8.2%) and Xpert (difference 5.8%, 95% CI 3.1-8.5%). The sensitivity of NAATs among smear-negative cases was 33.1% (95% CI 26.0-40.3%). In-house PCR had a significantly higher false-positive rate among specimens that were culture positive for NTM than Amplicor (7.7% versus 0.3%; difference 7.4%, 95% CI 3.4-11.5%) and Xpert (7.7% versus 0.7%; difference 7.0%, 95% CI 2.9-11.0%). CONCLUSION: The NAATs overall had a relatively high sensitivity and specificity in detecting MTBC while Amplicor and Xpert performed better than in-house PCR in excluding NTM. Our findings will be useful for the development of national policy.

Whole-Blood 3-Gene Signature as a Decision Aid for Rifapentine-based Tuberculosis Preventive Therapy.

BACKGROUND: Systemic drug reaction (SDR) is a major safety concern with weekly rifapentine plus isoniazid for 12 doses (3HP) for latent tuberculosis infection (LTBI). Identifying SDR predictors and at-risk participants before treatment can improve cost-effectiveness of the LTBI program. METHODS: We prospectively recruited 187 cases receiving 3HP (44 SDRs and 143 non-SDRs). A pilot cohort (8 SDRs and 12 non-SDRs) was selected for generating whole-blood transcriptomic data. By incorporating the hierarchical system biology model and therapy-biomarker pathway approach, candidate genes were selected and evaluated using reverse-transcription quantitative polymerase chain reaction (RT-qPCR). Then, interpretable machine learning models presenting as SHapley Additive exPlanations (SHAP) values were applied for SDR risk prediction. Finally, an independent cohort was used to evaluate the performance of these predictive models. RESULTS: Based on the whole-blood transcriptomic profile of the pilot cohort and the RT-qPCR results of 2 SDR and 3 non-SDR samples in the training cohort, 6 genes were selected. According to SHAP values for model construction and validation, a 3-gene model for SDR risk prediction achieved a sensitivity and specificity of 0.972 and 0.947, respectively, under a universal cutoff value for the joint of the training (28 SDRs and 104 non-SDRs) and testing (8 SDRs and 27 non-SDRs) cohorts. It also worked well across different subgroups. CONCLUSIONS: The prediction model for 3HP-related SDRs serves as a guide for establishing a safe and personalized regimen to foster the implementation of an LTBI program. Additionally, it provides a potential translational value for future studies on drug-related hypersensitivity.

Hemodialysis acutely altered interferon-gamma release assay test result and immune cell profile.

Patients receiving hemodialysis (HD) are at risk of TB development. IGRA-positive patients showed significant decrease in quantitative IGRA result with alterations in CD3+CD4+CD45RO+, NK cell, and monocyte subsets immediately upon HD procedure. Our result suggested that the timing of IGRA testing is crucial in end-stage renal disease population.

Tuberculosis treatment delay and nosocomial exposure remain important risks for patients undergoing regular hemodialysis.

BACKGROUND AND OBJECTIVE: Studies have reported an increased tuberculosis (TB) incidence among patients with end-stage renal disease (ESRD). This nationwide nested Case-control study investigated the risk of active TB due to nosocomial exposure and its correlation with the delay in TB treatment in hemodialysis patients. METHODS: Adult (aged ≥20 years) patients with incident ESRD over 2000-2010 were identified from Taiwan National Health Insurance Research Database; 2331 patients with incident active TB (Case) were matched with 11,655 patients without TB (control) by age, sex, year of ESRD onset, Charlson comorbidity index, chronic obstructive pulmonary disease, and diabetes mellitus, at a 1:5 case-to-control ratio. RESULTS: Compared with the control group, the Case group had greater nosocomial exposure to index patients with pulmonary TB (2.36 vs. 0.11 month of exposure, p < 0.001). Nosocomial exposure increased active TB risk (adjusted odds ratio [OR; 95% confidence interval, CI]: 1.60 [1.55-1.66] per month of exposure), particularly when the exposure time was either within 6 months before the index case was diagnosed or 6-15 months before the ESRD patient became an incident active TB case. For patients with active TB, cough-related medication prescriptions (proxy for cough symptoms) exponentially increased over 6 months before TB treatment. CONCLUSION: Nosocomial exposure attributed to delay in the diagnosis of index pulmonary TB is important in TB transmission among patients undergoing regular hemodialysis. Additional studies investigating how TB can be diagnosed and treated early are warranted. SUMMARY AT A GLANCE: Our study revealed that nosocomial exposure, attributed to delay in pulmonary TB diagnosis, is important in TB transmission among patients undergoing regular hemodialysis. Strategies to diagnose and treat TB early are crucial to infection control, and they warrant further investigations.

Biosafety and Proteome Profiles of Different Heat Inactivation Methods for Mycobacterium tuberculosis.

Studies involving the pathogenic organism Mycobacterium tuberculosis routinely require advanced biosafety laboratory facilities, which might not be readily available in rural areas where tuberculosis burdens are high. Attempts to adapt heat inactivation techniques have led to inconsistent conclusions, and the risk of protein denaturation due to extensive heating is impractical for subsequent mass spectrometry (MS)-based protein analyses. In this study, 240 specimens with one or two loops of M. tuberculosis strain H37Rv biomass and specific inactivated solutions were proportionally assigned to six heat inactivation methods in a thermal block at 80°C and 95°C for 20, 30, and 90 min. Twenty untreated specimens served as a positive control, and bacterial growth was followed up for 12 weeks. Our results showed that 90 min of heat inactivation was necessary for samples with two loops of biomass. Further protein extraction and a matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) MS assay demonstrated adequate scores for bacterial identification (≥1.7), with the highest score achieved in the 80°C/90 min and 95°C/30 min treatment groups. A proteomics study also confidently identified 648 proteins with ∼93% to 96% consistent protein abundances following heating at 95°C for 20, 30, and 90 min. Heat inactivation at 95°C for 90 min yielded the most quantifiable proteins, and a functional analysis revealed proteins located in the ribosomal subunit. In summary, we proposed a heat inactivation method for the M. tuberculosis strain H37Rv and studied the preservation of protein components for subsequent bacterial identification and protein-related assays. IMPORTANCE Inactivation of Mycobacterium tuberculosis is an important step to guarantee biosafety for subsequent M. tuberculosis identification and related research, notably in areas of endemicity with minimal resources. However, certain biomolecules might be denatured or hydrolyzed because of the harsh inactivation process, and a standardized protocol is yet to be determined. We evaluated distinct heating conditions to report the inactivation efficiency and performed downstream mass spectrometry-based M. tuberculosis identification and proteomics study. The results are important and useful for both basic and clinical M. tuberculosis studies.

Effects of various statins on depressive symptoms: A network meta-analysis.

BACKGROUND: Previous studies have indicated that statins can reduce the severity of depressive symptoms. However, the optimal choice of statin remains unclear. Therefore, we conducted a network meta-analysis to determine the optimal statin for treating depression. METHOD: We performed a pairwise and network meta-analysis by searching the PubMed, Embase, and Cochrane Library databases on October 29th, 2020. Eligible studies were randomized controlled trials that reported on changes in depressive symptoms. The Cochrane Collaboration tool was used to assess risk of bias. We tested for possible inconsistency globally by using a χ2-test and locally by calculating inconsistency factors for each comparison in closed loops. The ranking probabilities of being at each possible rank for each intervention were estimated. Comparison-adjusted funnel plots were obtained to assess publication bias. Sensitivity analysis was also performed. RESULTS: We identified 13 studies that matched our inclusion criteria. The risks of bias were mostly low. None of the global or local tests found significance. Compared with placebo, atorvastatin significantly reduced the severity of depressive symptoms (mean difference -3.46, 95% confidence interval -5.26 to -1.67). Atorvastatin had the first and second rank with probabilities of 44.9% and 39.0%, respectively. Comparison-adjusted funnel plots revealed no significant publication bias. LIMITATIONS: Low similarity of included studies and a relative large treatment effect of a single study were observed. CONCLUSIONS: In this first network meta-analysis, atorvastatin, with high intensity and a lipophilic effect, was identified as the optimal choice of statin for treating depression.