Background The AID line probe assay has shown promising evaluation data on the detection of Mycobacterium tuberculosis as well as 1.sup.st - and 2.sup.nd -line drug resistance, using isolates and ...selected clinical samples in previous studies. Methods The diagnostic performance of three AID-modules (AID INH/RIF, AID FQ/EMB and AID AG) was analyzed in sputum samples from patients with presumed tuberculosis against culture methods and phenotypic drug resistance as reference standards. Results 59 patients had culture-confirmed tuberculosis. All AID modules showed moderate sensitivity (46/59, 78.0%, 65.3-87.7) and very good specificity (100%, 95.5%, 93.7%). There was a high proportion of invalid tests, resulting in 32.6%, 78.3% and 19.6% of 46 AID-positive tuberculosis cases, who could not be assessed for drug resistance by the AID INH/RIF-, AID FQ/EM- and AID AG-module, respectively. A small number of patients showed drug resistance by reference standards: Three MDR-TB cases plus three, one and one patients with resistance to streptomycin, fluoroquinolones and aminoglycosides, respectively. The AID-assay detected all MDR-TB cases, two of three streptomycin-resistant TB cases, one of one of fluoroquinolone-resistant and missed one aminoglycoside-resistant TB case. Discussion The high proportion of invalid results precludes the use of the AID-assay from direct sputum-based tuberculosis and drug-resistance testing.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Air pollution is a serious problem in Romania, with the country ranking 13th among the most polluted countries in Europe in the 2021 World Air Quality Report. Despite the recognized impact of ...pollutants on health, there has been a lack of large-scale studies conducted in Romania. This study investigated the impact of air pollutants on patients with chronic respiratory, cardiovascular, cerebrovascular, or metabolic diseases in Bucharest and its metropolitan area from 20 August 2018 to 1 June 2022. The daily limit values for particulate matter PM10 and PM2.5 were exceeded every month, especially during the cold season, with a decrease during the COVID-19 pandemic restrictions. A significant statistical correlation was found between the monthly average values of PM2.5 and PM10 and hospitalizations for respiratory and cardiovascular diseases. A 10 µg/m3 increase in monthly average values resulted in a 40–60% increase in admissions for each type of pathology, translating to more than 2000 admissions for each pathology for the study period. This study highlights the urgent need for national and local measures to ensure a cleaner environment and enhance public health in Romania according to international regulations.
Background: Neuropathic adverse events occur frequently in linezolid-containing regimens, some of which remain irreversible after drug discontinuation. Objective: We aimed to identify and validate a ...host RNA-based biomarker that can predict linezolid-associated neuropathy before multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment initiation and to identify genes and pathways that are associated with linezolid-associated neuropathy. Methods: Adult patients initiating MDR/RR-TB treatment including linezolid were prospectively enrolled in 3 independent cohorts in Germany. Clinical data and whole blood RNA for transcriptomic analysis were collected. The primary outcome was linezolid-associated optic and/or peripheral neuropathy. A random forest algorithm was used for biomarker identification. The biomarker was validated in an additional fourth cohort of patients with MDR/RR-TB from Romania. Results: A total of 52 patients from the 3 identification cohorts received linezolid treatment. Of those, 24 (46.2%) developed peripheral and/or optic neuropathies during linezolid treatment. The majority (59.3%) of the episodes were of moderate (grade 2) severity. In total, the expression of 1,479 genes differed significantly at baseline of treatment. Suprabasin (SBSN) was identified as a potential biomarker to predict linezolid-associated neuropathy. In the validation cohort, 10 of 42 (23.8%) patients developed grade ≥3 neuropathies. The area under the curve for the biomarker algorithm prediction of grade ≥3 neuropathies was 0.63 (poor; 95% confidence interval: 0.42 – 0.84). Conclusions: We identified and preliminarily validated a potential clinical biomarker to predict linezolid-associated neuropathies before the initiation of MDR/RR-TB therapy. Larger studies of the SBSN biomarker in more diverse populations are warranted.
Globally, there is substantial concern regarding the challenges of treating complex drug resistance patterns in multidrug resistant tuberculosis cases. Utilising data from three different settings ...(Estonia, Latvia, Romania) we sought to contrast drug susceptibility profiles for multidrug resistant tuberculosis cases, highlight the difficulties in designing universal regimen, and inform future regimen selection. Demographic and microbiological surveillance data for multidrug resistant tuberculosis cases from 2004-13 were analysed. High levels of additional resistance to currently recommended second line drugs were seen in all settings, with extensive variability between countries. Accurate drug susceptibility testing and drug susceptibility testing data are vital to inform the development of comprehensive, flexible, multidrug resistant tuberculosis guidance.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) substantially challenges TB control, especially in the European Region of the World Health ...Organization, where the highest prevalence of MDR/XDR cases is reported. The current management of patients with MDR/XDR-TB is extremely complex for medical, social and public health systems. The treatment with currently available anti-TB therapies to achieve relapse-free cure is long and undermined by a high frequency of adverse drug events, suboptimal treatment adherence, high costs and low treatment success rates. Availability of optimal management for patients with MDR/XDR-TB is limited even in the European Region. In the absence of a preventive vaccine, more effective diagnostic tools and novel therapeutic interventions the control of MDR/XDR-TB will be extremely difficult. Despite recent scientific advances in MDR/XDR-TB care, decisions for the management of patients with MDR/XDR-TB and their contacts often rely on expert opinions, rather than on clinical evidence. This document summarises the current knowledge on the prevention, diagnosis and treatment of adults and children with MDR/XDR-TB and their contacts, and provides expert consensus recommendations on questions where scientific evidence is still lacking.
The World Health Organization recommends standardised treatment durations for patients with tuberculosis. We identified and validated a host-RNA signature as a biomarker for individualised therapy ...durations for patients with drug-susceptible (DS)- and multidrug-resistant (MDR)-tuberculosis.
Adult patients with pulmonary tuberculosis were prospectively enrolled into 5 independent cohorts in Germany and Romania. Clinical and microbiological data, and whole-blood for RNA transcriptomic analysis were collected at pre-defined timepoints throughout therapy. Treatment outcomes were ascertained Treatment outcomes were ascertained by TBNET criteria (6-month culture status/one-year follow-up). A whole-blood RNA therapy end model was developed in a multi-step process involving a machine-learning algorithm to identify hypothetical individual end-of-treatment timepoints.
Fifty patients with drug-susceptible (DS)-tuberculosis and 30 patients with MDR-tuberculosis were recruited in the German identification cohorts (DS- and MDR-GIC), 28 patients with DS-tuberculosis and 32 patients with MDR-tuberculosis in the German validation cohorts (DS- and MDR-GVC), and 52 patients with MDR-tuberculosis in the Romanian validation cohort (MDR-RVC). A 22-gene RNA model that defined cure-associated end-of-therapy timepoints was derived from the DS- and MDR-GIC data. The model was superior to other published signatures to accurately predict clinical outcomes for patients in the DS-GVC (AUC=0.94 95%CI:0.9-0.98) and suggests that cure may be achieved with shorter treatment durations for tuberculosis patients in the MDR-GIC (mean reduction 218.0 days, 34.2%, p<0.001), the MDR-GVC (mean reduction 211.0 days, 32.9%, p<0.001), and the MDR-RVC (mean reduction of 161.0 days, 23.4%, p=0.001).
Biomarker-guided management may substantially shorten the duration of therapy for many patients with MDR-tuberculosis.
BackgroundTuberculosis (TB) is the #1 bacterial killer worldwide. Despite of successful antibiotic treatment, exacerbated patients did not regain sufficient lung capacity and develop postTB lung ...disease (PTLD). We hypothesized, that neutrophils play an important role in disease exacerbation and associated marker can be used for early detection of PTLD.Methods25 confirmed MDR-TB Patients were recruited, sputum samples were taken over 6 months and analyzed for neutrophil associated proteins by ELISA. TB severity was assessed at baseline and month 6 using spirometry (lung function) and x-ray (lung pathology). Patients were categorized in mild and severe diseased by using Ralph score (threshold 40 pts) or spirometry (threshold FVC<0.85*LLN.FVC or gli.FEV1.zscore<-2).Results16 patients (64%) had a stable severe impairment in lung function and no improvement after 6 month was observed. In contrast, x-ray pathology was improving in 10 patients (40%) and remained stable severe in 10 patients (40%). Ralph scores were significantly higher in patients with impaired lung function. Neutrophil associated marker significantly declined under antibiotic treatment. Patients with stable severe impairment have significantly increased MMP8 sputum concentrations at baseline (p = 0.017) and increased concentrations of Calprotectin (p = 0.008), MPO (p = 0.034), ELA2 (p =0.031) and NGAL (p = 0.01) at week 2. In addition, Calprotectin (p = 0.005), MMP8 (p = 0.011) and NGAL (p = 0.03) concentrations were increased in males at month 4, while no sex differences in x-ray pathology was observed.ConclusionEarly postTB lung impairment was associated with neutrophil proteins in acute TB and elucidate the impact of neutrophils on disease progression and immune pathology. These proteins will be further analyzed as targets for Host Directed Therapies to reduce oxidative stress, tissue degradation, as well as immune modulators to prevent PTLD.Funding: Funded by German Center for Infection Research
, animal model, and clinical evidence suggests that tuberculosis is not a monomorphic disease, and that host response to tuberculosis is protean with multiple distinct molecular pathways and ...pathologies (endotypes). We applied unbiased clustering to identify separate tuberculosis endotypes with classifiable gene expression patterns and clinical outcomes.
A cohort comprised of microarray gene expression data from microbiologically confirmed tuberculosis patients were used to identify putative endotypes. One microarray cohort with longitudinal clinical outcomes was reserved for validation, as was two RNA-seq cohorts. Finally, a separate cohort of tuberculosis patients with functional immune responses was evaluated to clarify stimulated from unstimulated immune responses.
A discovery cohort, including 435 tuberculosis patients and 533 asymptomatic controls, identified two tuberculosis endotypes. Endotype A is characterised by increased expression of genes related to inflammation and immunity and decreased metabolism and proliferation; in contrast, endotype B has increased activity of metabolism and proliferation pathways. An independent RNA-seq validation cohort, including 118 tuberculosis patients and 179 controls, validated the discovery results. Gene expression signatures for treatment failure were elevated in endotype A in the discovery cohort, and a separate validation cohort confirmed that endotype A patients had slower time to culture conversion, and a reduced cure rate. These observations suggest that endotypes reflect functional immunity, supported by the observation that tuberculosis patients with a hyperinflammatory endotype have less responsive cytokine production upon stimulation.
These findings provide evidence that metabolic and immune profiling could inform optimisation of endotype-specific host-directed therapies for tuberculosis.
To evaluate the access to comprehensive diagnostics and novel antituberculosis medicines in European countries.
We investigated the access to genotypic and phenotypic Mycobacterium tuberculosis drug ...susceptibility testing and the availability of antituberculosis drugs and calculated the cost of drugs and treatment regimens at major tuberculosis treatment centres in countries of the WHO European region where rates of drug-resistant tuberculosis are the highest among all WHO regions. Results were stratified by middle-income and high-income countries.
Overall, 43 treatment centres from 43 countries participated in the study. For WHO group A drugs, the frequency of countries with the availability of phenotypic drug susceptibility testing was as follows: (a) 75% (30/40) for levofloxacin, (b) 82% (33/40) for moxifloxacin, (c) 48% (19/40) for bedaquiline, and (d) 72% (29/40) for linezolid. Overall, of the 43 countries, 36 (84%) and 24 (56%) countries had access to bedaquiline and delamanid, respectively, whereas only 6 (14%) countries had access to rifapentine. The treatment of patients with extensively drug-resistant tuberculosis with a regimen including a carbapenem was available only in 17 (40%) of the 43 countries. The median cost of regimens for drug-susceptible tuberculosis, multidrug-resistant/rifampicin-resistant tuberculosis (shorter regimen, including bedaquiline for 6 months), and extensively drug-resistant tuberculosis (including bedaquiline, delamanid, and a carbapenem) were €44 (minimum–maximum, €15–152), €764 (minimum–maximum, €542–15152), and €8709 (minimum–maximum, €7965–11759) in middle-income countries (n = 12) and €280 (minimum–maximum, €78–1084), €29765 (minimum–maximum, €11116–40584), and €217591 (minimum–maximum, €82827–320146) in high-income countries (n = 29), respectively.
In countries of the WHO European region, there is a widespread lack of drug susceptibility testing capacity to new and repurposed antituberculosis drugs, lack of access to essential medications in several countries, and a high cost for the treatment of drug-resistant tuberculosis.
Lung cancer and pulmonary tuberculosis are two significant public health problems that continue to take millions of lives each year. They may have similar symptoms and, in some cases, are diagnosed ...simultaneously or may have a causal relationship. In tuberculosis disease, the chronic inflammation, different produced molecules, genomic changes, and fibrosis are believed to be important factors that may promote carcinogenesis. As a reverse reaction, the development of carcinogenesis and the treatment may induce the reactivation of latent tuberculosis infection. Moreover, the recently used checkpoint inhibitors are a debatable subject since they help treat lung cancer but may lead to the reactivation of pulmonary tuberculosis and checkpoint-induced pneumonitis. Pulmonary rehabilitation is an effective intervention in post-tuberculosis patients and lung cancer patients and should be recommended to improve outcomes in these pathologies.
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