Adjunctive surgery improves treatment outcomes among patients with multidrug-resistant and extensively drug-resistant tuberculosis

SummaryObjectivesTo determine risk factors for poor outcomes among patients with pulmonary multidrug- or extensively drug-resistant (M/XDR) tuberculosis (TB) in Georgia.MethodsThis was a prospective, population-based observational cohort study.ResultsAmong 380M/XDR-TB patients (mean age 38 years), 179 (47%) had a poor outcome: 59 (16%) died, 37 (10%) failed, and 83 (22%) defaulted. Newly diagnosed M/XDR-TB cases were significantly more likely to have a favorable outcome than retreatment cases (odds ratio (OR) 4.26, 95% confidence interval (CI) 1.99–9.10, p<0.001). In the multivariable analysis, independent risk factors for a poor treatment outcome included previous treatment history (OR 2.92, 95% CI 1.29–6.58), bilateral disease (OR 1.90, 95% CI 1.20–3.01), body mass index (BMI, kg/m2) ≤18.5 (OR 1.91, 95% CI 1.11–3.29), and XDR-TB (OR 2.28, 95% CI 1.11–4.71). Patients who underwent surgical resection (OR 0.27, 95% CI 0.11–0.64) and had sputum culture conversion by 4 months (OR 0.33, 95% CI 0.21–0.52) were significantly less likely to have poor treatment outcomes.ConclusionsAdjunctive surgery appeared to be beneficial in treating patients with M/XDR-TB. Retreatment cases, XDR-TB, bilateral disease, and low BMI were associated with a poor outcome. Additional studies are needed to further define the apparent beneficial role of surgery in the treatment of M/XDR-TB

Developing customized stepwise MIRU-VNTR typing for tuberculosis surveillance in Georgia

INTRODUCTION: Mycobacterial Interspersed Repetitive Units-Variable Tandem Repeats (MIRU-VNTR) typing has been widely used for molecular epidemiological studies of tuberculosis (TB). However, genotyping tools for Mycobacterium tuberculosis (Mtb) may be limiting in some settings due to high cost and workload. In this study developed a customized stepwise MIRU-VNTR typing that prioritizes high discriminatory loci and validated this method using penitentiary system cohort in the country of Georgia. METHODS: We used a previously generated MIRU-VNTR dataset from recurrent TB cases (32 cases) in Georgia and a new dataset of TB cases from the penitentiary system (102 cases) recruited from 2014 to 2015. A Hunter-Gaston Discriminatory Index (HGDI) was calculated utilizing a 24 standard loci panel, to select high discriminatory power loci, subsequently defined as the customized Georgia-specific set of loci for initial typing. The remaining loci were scored and hierarchically grouped for second and third step typing of the cohort. We then compared the processing time and costs of the customized stepwise method to the standard 24-loci method. RESULTS: For the customized Georgia-specific set that was used for initial typing, 10 loci were selected with a minimum value of 0.32 to the highest HGDI score locus. Customized 10 loci (step 1) typing of 102 Mtb patient isolates revealed 35.7% clustered cases. This proportion was reduced to 19.5% after hierarchical application of 2nd and 3rd step typing with the corresponding groups of loci. Our customized stepwise MIRU-VNTR genotyping approach reduced the quantity of samples to be typed and therefore overall processing time and costs by 42.6% each. CONCLUSION: Our study shows that our customized stepwise MIRU-VNTR typing approach is a valid alternative of standard MIRI-VNTR typing panels for molecular epidemiological investigation in Georgia that saves time, workload and costs. Similar approaches could be developed for other settings

Contacts of Retreatment Tuberculosis Cases with a Prior Poor Treatment Outcome are at Increased Risk of Latent Tuberculosis Infection

Objectives: To estimate the prevalence of and risk factors for latent tuberculosis infection (LTBI) among contacts of index patients with tuberculosis (TB) with a prior history of active TB disease and TB treatment (retreatment cases). Methods: A cross-sectional population-based study was conducted using data from the national TB contact surveillance program in the country of Georgia. Contacts of retreatment cases were investigated and tuberculin skin testing was offered. Bivariate and multivariable analyses were performed to calculate odds ratios (OR) and 95% confidence intervals for risk of LTBI among contacts. Results: The prevalence of LTBI was significantly higher among contacts whose index TB patient had had a prior unfavorable treatment outcome compared to those who had had a favorable outcome (OR 3.14). Contacts whose index TB case had previously failed therapy (OR 6.43), was lost to follow-up (OR 5.63), or had completed treatment (OR 3.33) had a significantly higher prevalence of LTBI compared to contacts of previously cured TB cases. Conclusions: Among contacts of active TB retreatment cases, the risk of LTBI was related to the outcome of the index case’s previous TB treatment. Efforts aimed at reducing treatment loss to follow-up should be emphasized to enhance TB control efforts and may also decrease LTBI and active TB among contacts

High utility of active tuberculosis case finding in an Ethiopian prison

SETTING: Hawassa Prison, Southern Region of Ethiopia. OBJECTIVE: To determine the burden of pulmonary tuberculosis (TB) using active case finding among prisoners. DESIGN: In this cross-sectional study, prisoners were screened for TB using a symptom screen. Those with cough of 2 weeks had spot and morning sputum samples collected for acid-fast bacilli (AFB) smear microscopy and molecular diagnostic testing (Xpert® MTB/RIF). RESULTS: Among 2068 prisoners, 372 (18%) had a positive cough screen. The median age of these 372 persons was 23 years, 97% were male and 63% were from urban areas. Among those with a positive symptom screen, 8 (2%) were AFB sputum smear-positive and 31 (8%) were Xpert-positive. The point prevalence of pulmonary TB at the prison was 1748 per 100 000 persons. In multivariate analysis, persons with cough >4 weeks were more likely to have TB (OR 3.34, 95%CI 1.54–7.23). CONCLUSION: A high prevalence of TB was detected among inmates at a large Ethiopian prison. Active case finding using a cough symptom screen in combination with Xpert had high utility, and has the potential to interrupt transmission of Mycobacterium tuberculosis in correctional facilities in low- and middle-income, high-burden countries

Antimicrobial resistance through the lens of one health in Ethiopia: a review of the literature among humans, animals, and the environment

OBJECTIVES: We aimed to review and describe antimicrobial resistance (AMR) prevalence in humans, animals, and the environment in Ethiopia. METHODS: We conducted a structured review of the literature on AMR in humans, animals, and the environment in Ethiopia from 2016 to 2020. We reported the pooled prevalence of AMR of bacterial pathogens in all three sectors. RESULTS: We included 43 articles in our review. Only five studies evaluated AMR across multiple sectors. The most common bacteria in humans were Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus. High prevalence of resistance to third-generation cephalosporins, fluoroquinolones, and sulfamethoxazole-trimethoprim were seen in gram-negative organisms, often with >50% prevalence of resistance. Highest resistance rates were seen in humans, followed by environmental isolates. Salmonella spp. exhibited higher rates of resistance than previously reported in the literature. We found methicillin-resistant S. aureus (MRSA) in approximately half of S. aureus from the environment and a third from human isolates. Few studies evaluated AMR across all three sectors. CONCLUSION: Our review demonstrated high prevalence of AMR among bacteria in humans, animals, and the environment in Ethiopia. Integrating a One Health approach into AMR surveillance as part of Ethiopia's national surveillance program will inform future implementation of One Health interventions

Tobacco Smoking and Tuberculosis Treatment Outcomes: A Prospective Cohort Study in Georgia

Objective To assess the effect of tobacco smoking on the outcome of tuberculosis treatment in Tbilisi, Georgia. Methods We conducted a prospective cohort study of adults with laboratory-confirmed tuberculosis from May 2011 to November 2013. History of tobacco smoking was collected using a standardized questionnaire adapted from the global adult tobacco survey. We considered tuberculosis therapy to have a poor outcome if participants defaulted, failed treatment or died. We used multivariable regressions to estimate the risk of a poor treatment outcome. Findings Of the 591 tuberculosis patients enrolled, 188 (31.8%) were past smokers and 271 (45.9%) were current smokers. Ninety (33.2%) of the current smokers and 24 (18.2%) of the participants who had never smoked had previously been treated for tuberculosis (P \u3c 0.01). Treatment outcome data were available for 524 of the participants, of whom 128 (24.4%) – including 80 (32.9%) of the 243 current smokers and 21 (17.2%) of the 122 individuals who had never smoked – had a poor treatment outcome. Compared with those who had never smoked, current smokers had an increased risk of poor treatment outcome (adjusted relative risk, aRR: 1.70; 95% confidence interval, CI: 1.00–2.90). Those who had ceased smoking more than two months before enrolment did not have such an increased risk (aRR: 1.01; 95% CI: 0.51–1.99). Conclusion There is a high prevalence of smoking among patients with tuberculosis in Georgia and smoking increases the risk of a poor treatment outcome

Genomic analyses of Mycobacterium tuberculosis from human lung resections reveal a high frequency of polyclonal infections

Polyclonal infections occur when at least two unrelated strains of the same pathogen are detected in an individual. This has been linked to worse clinical outcomes in tuberculosis, as undetected strains with different antibiotic resistance profiles can lead to treatment failure. Here, we examine the amount of polyclonal infections in sputum and surgical resections from patients with tuberculosis in the country of Georgia. For this purpose, we sequence and analyse the genomes of Mycobacterium tuberculosis isolated from the samples, acquired through an observational clinical study (NCT02715271). Access to the lung enhanced the detection of multiple strains (40% of surgery cases) as opposed to just using a sputum sample (0-5% in the general population). We show that polyclonal infections often involve genetically distant strains and can be associated with reversion of the patient's drug susceptibility profile over time. In addition, we find different patterns of genetic diversity within lesions and across patients, including mutational signatures known to be associated with oxidative damage; this suggests that reactive oxygen species may be acting as a selective pressure in the granuloma environment. Our results support the idea that the magnitude of polyclonal infections in high-burden tuberculosis settings is underestimated when only testing sputum samples

Plasma Metabolomics in Human Pulmonary Tuberculosis Disease: A Pilot Study

We aimed to characterize metabolites during tuberculosis (TB) disease and identify new pathophysiologic pathways involved in infection as well as biomarkers of TB onset, progression and resolution. Such data may inform development of new anti-tuberculosis drugs. Plasma samples from adults with newly diagnosed pulmonary TB disease and their matched, asymptomatic, sputum culture-negative household contacts were analyzed using liquid chromatography high-resolution mass spectrometry (LC-MS) to identify metabolites. Statistical and bioinformatics methods were used to select accurate mass/charge (m/z) ions that were significantly different between the two groups at a false discovery rate (FDR) of q<0.05. Two-way hierarchical cluster analysis (HCA) was used to identify clusters of ions contributing to separation of cases and controls, and metabolomics databases were used to match these ions to known metabolites. Identity of specific D-series resolvins, glutamate and Mycobacterium tuberculosis (Mtb)-derived trehalose-6-mycolate was confirmed using LC-MS/MS analysis. Over 23,000 metabolites were detected in untargeted metabolomic analysis and 61 metabolites were significantly different between the two groups. HCA revealed 8 metabolite clusters containing metabolites largely upregulated in patients with TB disease, including anti-TB drugs, glutamate, choline derivatives, Mycobacterium tuberculosis-derived cell wall glycolipids (trehalose-6-mycolate and phosphatidylinositol) and pro-resolving lipid mediators of inflammation, known to stimulate resolution, efferocytosis and microbial killing. The resolvins were confirmed to be RvD1, aspirin-triggered RvD1, and RvD2. This study shows that high-resolution metabolomic analysis can differentiate patients with active TB disease from their asymptomatic household contacts. Specific metabolites upregulated in the plasma of patients with active TB disease, including Mtb-derived glycolipids and resolvins, have potential as biomarkers and may reveal pathways involved in TB disease pathogenesis and resolution

High Prevalence of Cryptococcal Antigenemia among HIV-infected Patients Receiving Antiretroviral Therapy in Ethiopia

Abstract Background: Cryptococcal disease is estimated to be responsible for significant mortality in Sub-Saharan Africa; however, only scarce epidemiology data exists. We sought to evaluate the prevalence of and risk factors for cryptococcal antigenemia in Ethiopia

Use of a Molecular Diagnostic Test in AFB Smear Positive Tuberculosis Suspects Greatly Reduces Time to Detection of Multidrug Resistant Tuberculosis

Background: The WHO has recommended the implementation of rapid diagnostic tests to detect and help combat M/XDR tuberculosis (TB). There are limited data on the performance and impact of these tests in field settings. Methods: The performance of the commercially available Genotype MTBDRplus molecular assay was compared to conventional methods including AFB smear, culture and drug susceptibility testing (DST) using both an absolute concentration method on Löwenstein-Jensen media and broth-based method using the MGIT 960 system. Sputum specimens were obtained from TB suspects in the country of Georgia who received care through the National TB Program. Results: Among 500 AFB smear-positive sputum specimens, 458 (91.6%) had both a positive sputum culture for Mycobacterium tuberculosis and a valid MTBDRplus assay result. The MTBDRplus assay detected isoniazid (INH) resistanc