A high-dose vitamin D3 regimen safely corrected vitamin D deficiency but did not improve the rate of sputum Mtb clearance over 16 wk in this pulmonary tuberculosis cohort. This trial was registered at clinicaltrials.gov at NCT00918086.
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.
The current clinical management of TB is complicated by the lack of suitable diagnostic tests that can be employed in infrastructure and resource poor regions. The mannose-capped form of lipoarabinomannan (ManLAM) is unique to the surface envelope of slow-growing, pathogenic mycobacteria such as M.tuberculosis (M.tb) and facilitates passive invasion of mononuclear phagocytes. The detection of this virulence factor in urine, sputum and serum has engendered interest in its employment as a biomarker for M.tb infection. In this study, we utilize a subtractive screening methodology to engineer the first high affinity recombinant antibody (My2F12) with exquisite specificity for the α1-2 mannose linkages enriched in ManLAM from M.tb. My2F12 binds to pathogenic mycobacterial species but not fast growing non-pathogenic species. Testing on matched urine and serum samples from TB patients indicates that My2F12 works in patient cohorts missed by other diagnostic methodologies.
ObjectivesOur aim was to retrospectively compare clinical data and characteristics of removed lesions of the cohort of patients undergoing therapeutical surgery for their tuberculosis.Design and methodsDemographic and epidemiological details, clinical data, data on the surgery performed, macroscopic characteristics of the TB lesions removed, and outcome were recorded retrospectively from the 137 patients who underwent therapeutical surgery for their TB in Tbilisi, Georgia during 2014 and 2015.ResultsMen represented 70% of the included patients, presented more comorbidities and underwent operation earlier in terms of days between diagnostic and surgery. Women underwent operation at younger ages, and in MDR/XDR-TB cases, showed higher percentages of sputum conversion at >2 months and of fresh necrosis in the surgical specimens, suggesting a worse evolution. Half of cases were MDR/XDR-TB cases. In spite of being considered microbiologically cured according to WHO, a non despricable percentage of cases showed viable bacilli in the surgical specimen. Even if no causality could be statistically demonstrated, differences could be encountered according to gender and drug susceptibility of the responsible strains.ConclusionsAccording to our results, host factors such as gender, type of necrosis found in the lesions, size of lesions and presence of viable bacilli in the surgical specimen, should be included in future studies on therapeutical surgery of TB. As most of studies are done in MDR/XDR-TB, more data on DS-TB operated cases are needed. Our results also highlight that, in spite of achieving the microbiologically cured status, sterilization might not occur, and thus new biomarkers and new methods to evaluate the healing process of TB patients are urgently needed and radiological assays should be taken into account.
Background Hepatitis C virus (HCV) infection causes dysregulation and suppression of immune pathways involved in the control of tuberculosis (TB) infection. However, data on the role of chronic hepatitis C as a risk factor for active TB are lacking. We sought to evaluate the association between HCV infection and the development of active TB. Methods We conducted a cohort study in Georgia among adults tested for HCV antibodies (January 2015 – September 2o2o) and followed longitudinally for the development of newly diagnosed active TB. Data were obtained from the Georgian National programs of hepatitis C and TB. The exposures of interest were untreated and treated HCV infection. Cox proportional hazards model was used to calculate adjusted hazards ratios. Results A total of 1,828,808 adults were included (median follow-up time: 26 months, IQR: 13-39 months). Active TB was diagnosed in 3,163 (0.17%) individuals after a median of 6 months follow-up (IQR: 1-18 months). The incidence rate per 100,000 person-years was 296 among persons with untreated HCV infection, 109 among those with treated HCV infection, and 65 among HCV-negative persons. In multivariable analysis, both untreated (aHR = 2.9, 95%CI: 2.4-3.4) and treated (aHR = 1.6, 95%CI: 1.4-2.0) HCV infection were associated with a higher hazard of active TB, compared to HCV-negative persons. Conclusions Adults with HCV infection, particularly untreated individuals, were at higher risk of developing active TB disease. Screening for latent TB infection and active TB disease should be part of clinical evaluation of people with HCV infection, especially in high TB burden areas.
This study aimed to determine the health-related quality of life (HRQoL) of patients with pulmonary tuberculosis (TB) and to assess its change after a therapeutic surgical procedure. In this scenario, the purpose was to elucidate and quantify the effect of various demographic, epidemiological, clinical, surgical and psychosocial details on this variable.A prospective cohort of 40 patients undergoing therapeutic surgery for pulmonary TB (Study of Human Tuberculosis Lesions (SH-TBL) cohort) was recruited in Tbilisi, Georgia, between 2016 and 2018. HRQoL was assessed by administering the St George's Respiratory Questionnaire (SGRQ) and a novel psychosocial questionnaire, the BCN-Q, both at baseline and at 6 months post-surgery.A statistically and clinically significant improvement in the SGRQ total score was observed at follow-up, although it did not reach the values found for the healthy population. The differences between time points were statistically significant for the following groups: women, age <40 years, body mass index ≥20 kg·m−2, nonsmokers, drug-susceptible and drug-resistant participants, both new and relapsed patients, early culture negativisation, cases with a single lesion, either lesions <35 mm or ≥35 mm, and lesion, lobe and lung resections.The analysis of BCN-Q together with the SGRQ showed that several of its items, such as marital status, living conditions, nutrition, employment, external support, certain attitudes towards the healthcare system, emotional burden and sleep troubles, can impact HRQoL.These results highlight the benefit of adjuvant therapeutic surgery for pulmonary TB in selected patients in terms of HRQoL and suggest that a comprehensive approach including demographic, epidemiological, clinical and psychosocial variables may more accurately predict TB evolution and prognosis.
Background: Characterization of metabolites altered by tuberculosis (TB) disease may identify pathophysiologic pathways. Resolvins are lipid mediators derived from endogenous EPA and DHA critical for resolution of inflammation. Methods: Plasma samples from 17 patients (35±12 yrs old) with new pulmonary TB and 17 matched household contacts without TB (controls) were analyzed using high‐resolution LC‐MS. False discovery rate (FDR; q=0.05) and hierarchal cluster analysis was used to distinguish accurate mass ions (metabolites) significantly different between groups. The METLIN Metabolite Database was used to match ions to known metabolites. Identification of specific D‐series resolvins (RvD1 and RvD2) was confirmed by LC‐UV‐MS/MS. Results: Over 23,000 metabolites were detected in untargeted metabolomic analysis, of which 61 were significantly different between the two groups by FDR. Eight metabolite clusters were evident containing several metabolites quantitatively upregulated in patients with TB (e.g. glutamate, choline derivatives, anti‐TB drug metabolites and several lipids, including likely M. tb cell wall lipids and resolvins RvD1 and RvD2. Conclusions: This pilot study revealed metabolites that are upregulated during newly diagnosed TB potentially involved in pathogenesis. Upregulation of specific resolvins may mediate recovery from inflammation in TB disease. Grant Funding Source: Supported by grants from the National Institutes of Health Fogarty grants D43 TW007124
Background: Malnutrition and lean tissue wasting are common in patients with tuberculosis (TB) disease, yet little information is available on habitual dietary intake or links with body composition. Methods: Dietary intake was obtained in a randomized clinical trial of high‐dose vitamin D (Vit D) in patients with pulmonary TB in Tbilisi, Georgia. Food intake was obtained (0, 8 and 16 weeks) using a validated, culture‐specific tool. Serial body composition was by BMI and bioelectrical impedance analysis (BIA; % fat mass and % fat‐free mass). Descriptive statistics and repeated measures ANOVA were used. Results: 192 subjects (mean age 35 y; 100 Vit D, 99 placebo) were studied. Mean daily intake of kcal, fat and protein were adequate at diagnosis and increased (with BMI) over time (time effect p<0.0001, treatment effect NS). There were no differences in % of fat mass or % fat‐free mass between groups over time. Multi‐drug resistant TB patients (n=23) had lower body weight, BMI (p=0.05) and fat‐free mass vs. drug‐susceptible patients, despite increased intake of kcal, protein, fat and CHO at 8 and 16 weeks. Conclusions: Macronutrient intake was adequate in this TB patient cohort. Increased macronutrient intake occurred concomitant with increased BMI and maintained proportions of body fat and fat‐free mass. MDR‐TB patients demonstrated less efficient anabolism than drug‐susceptible TB patients. 1 Grant Funding Source: Supported by grants from the National Institutes of Health Fogarty grant D43 TW007124 and K24 RR0233
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