Duration Of Anti-tuberculosis Treatment Research Articles

Mesenchymal stem cells-derived extracellular vesicles for therapeutics of renal tuberculosis

Extrapulmonary tuberculosis with a renal involvement can be a manifestation of a disseminated infection that requires therapeutic intervention, particularly with a decrease in efficacy of conventional regimens. In the present study, we investigated the therapeutic potency of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) in the complex anti-tuberculosis treatment (ATT). A rabbit model of renal tuberculosis (rTB) was constructed by injecting of the standard strain Mycobacterium tuberculosis H37Rv into the cortical layer of the kidney parenchyma. Isolated rabbit MSC-EVs were intravenously administered once as an addition to standard ATT (isoniazid, pyrazinamide, and ethambutol). The therapeutic efficacy was assessed by analyzing changes of blood biochemical biomarkers and levels of anti- and pro-inflammatory cytokines as well as by renal computed tomography with subsequent histological and morphometric examination. The therapeutic effect of therapy with MSC-EVs was shown by ELISA method that confirmed a statistically significant increase of the anti-inflammatory and decrease of pro-inflammatory cytokines as compared to conventional treatment. In addition, there is a positive trend in increase of ALP level, animal weigh, and normalization of ADA activity that can indicate an improvement of kidney state. A significant reduction of the area of specific and interstitial inflammation indicated positive affect of MSC-EVs that suggests a shorter duration of ATT. The number of MSC-EVs proteins (as identified by mass-spectometry analysis) with anti-microbial, anti-inflammatory and immunoregulatory functions reduced the level of the inflammatory response and the severity of kidney damage (further proved by morphometric analysis). In conclusion, MSC-EVs can be a promising tool for the complex treatment of various infectious diseases, in particularly rTB.

Pharmacokinetics and Safety of WHO-Recommended Dosage and Higher Dosage of Levofloxacin for Tuberculosis Treatment in Children: a Pilot Study

ObjectivesTo evaluate the pharmacokinetic parameters of the 2020 World Health Organization (WHO)-recommended pediatric dosage of levofloxacin and the higher-than-WHO dosage. MethodsChildren aged 1-15 years with tuberculosis who received levofloxacin-based treatment for at least 7 days were enrolled. First, five children were enrolled to receive the WHO-recommended dosage (15-20 mg/kg/day), then an additional five children received a dosage higher than the WHO-recommended dosage (20-30 mg/kg/day). Blood samples were collected at predose and postdose 1, 2, 4, 6, 8, and 12 hours. A target of the ratio of the free area under the concentration-time curve to minimum inhibitory concentration (fAUC/MIC) was 100. ResultsThe median (interquartile range) age was 9.6 (4.9-10.5) and 12.0 (10.1-12.3) years in the WHO dosage and higher-than-WHO dosage groups, respectively. The median (interquartile range) duration of antituberculosis treatment was 24 (8-24) weeks. The geometric mean (95% confidence interval) of fAUC/MIC was 60.4 (43.5-84.0) and 103.2 (70.1-151.8) in the WHO and higher-than-WHO dosage groups, respectively. There was no adverse event of QT prolongation or any other grade 3 or 4 adverse events. ConclusionLevofloxacin at a higher dose of 20-30 mg/kg/day could achieve the fAUC/MIC target in children.

Targeted transcriptomic signature for monitoring anti-tuberculosis treatment response

Abstract The long duration of anti-tuberculosis treatment is associated with poor adherence and treatment outcomes leading to higher relapse rates. Shortening treatment duration has been suggested to improve treatment outcome by increasing adherence. Sputum conversion, the gold standard for monitoring treatment, has low sensitivity and specificity for predicting relapse. Better markers are therefore needed and blood-based biomarkers have been suggested as potential alternatives. The aim of this study was to identify transcriptional signatures to predict anti-tuberculosis treatment outcomes, relapse, and treatment failure. We extracted RNA from whole blood PAXgene samples from 37 confirmed TB cases at diagnosis (baseline), 14 days and two months of treatment and measured gene expression using targeted sequencing on the NanoString nCounter MAX platform using the 799-gene host response panel. To identify genes that predict treatment response and relapse, we identified differentially expressed genes (DEGs) at Day 14 and two months of treatment and compared expression between fast (sputum converters by 2 months) and slow responders (sputum converters after 2 months). Using a cut-off of 1.5-fold change and a p value of 0.05, we observed 58 DEGs at Day 14 and 175 DEGs at two months relative to baseline. When we compared slow and fast responders, 14 genes were differentially expressed but these were not significant when adjusted for multiple comparisons. We have shown that DEGs can identify different stages of disease or treatment. Further analysis is ongoing to include other treatment timepoints (four months and six months) and importantly to include participants with known relapse.

Diagnostic utility of bronchoalveolar lavage in children with complicated intrathoracic tuberculosis.

Bronchoscopy can be a useful tool in children with pulmonary tuberculosis (PTB) with severe disease potentially requiring intervention or in the face of diagnostic dilemmas. The aim of this study was to determine the value of Xpert MTB/RIF assay (Xpert) on bronchoalveolar lavage (BAL) samples in children with complicated PTB. Retrospective analysis of children with clinically diagnosed PTB, who underwent routine bronchoscopy over a 5-year period at a large referral hospital. BAL and other respiratory samples were tested by microscopy, culture, and Xpert. We explored whether clinical, radiographic and bronchoscopy findings, and duration of antituberculosis treatment were associated with bacteriological confirmation. One hundred and twelve out of one hundred and forty-six (76.7%) children (median age 16 months) were on antituberculosis treatment for a median of 10 days at the time of bronchoscopy. Overall, bacteriological confirmation was achieved in 115 (78.7%), with 101 (69.2%) detected on BAL. Of those bacteriologically confirmed on BAL, 61.4% were positive by both Xpert and culture, 34.7% only by Xpert, and 3.9% only by culture. Sensitivity and specificity of Xpert compared with culture on BAL samples for children not on antituberculosis treatment were 94.1% (95% confidence interval [CI]: 71.3, 99.8) and 68.7% (95% CI: 41.3, 89.0), respectively. In children undergoing bronchoscopy for complicated PTB, Xpert testing of BAL had a high diagnostic yield in children already on antituberculosis treatment. Bronchoscopy should be considered if noninvasive respiratory specimens fail to confirm complicated TB.

Frequency, clinical characteristics, risks, and outcomes of Paradoxical upgrading reactions during anti-tuberculosis treatment in tuberculous lymphadenitis

Objectives:To investigate the clinical characteristics, risks and outcomes of Paradoxical upgrading reactions (PUR) during anti-tuberculosis treatment (ATT) in superficial tuberculous lymphadenitis (TBLA).Methods:In this nested case-control study, all patients diagnosed with TBLA based on combinations of histopathology, acid-fast bacilli (AFB) microscopy, AFB culture, and GeneXpert, between February 2013 and April 2016, were enrolled. Standard ATT was given. Demographics, clinical characteristics, occurrence of PUR and outcome were recorded.Results:TBLA was diagnosed and treated in 189 patients. PUR developed in 33 (17%), of which 77% developed new inflamed glands, 20.6% had increased size and inflammation of pre-existing glands and 5.9% had superficial chest wall abscesses requiring aspiration. All responded to regular NSAIDs except one, where a steroid course was effective. No change in dose or duration of ATT was required. Presence of anorexia (OR; 95%CI: 2.6; 1.003-6.74), bilateral extensive lymphadenopathy (OR; 95%CI: 2.9; 1.1-7.5) and lymph node specimen positive for AFB (OR; 95%CI: 3.2; 1.04-10.1) were significantly associated with PUR.Conclusion:PUR is common in TBLA. It responded to NSAIDS and does not need any modification in ATT.

Proportion of Patients Pulmonary Cancer With History of Slow Diagnosis Due to Diagnosis as Lung Tuberculosis

Background: In tuberculosis (TB) endemic countries, the diagnosis delay in lung cancer is due to initially misdiagnosed as pulmonary tuberculosis. The major concern that rose since early diagnosis of lung cancer could improve survival by tumor resectability chance and chemo-radiotherapy modality options. This study objective was to find out the proportion of lung cancer diagnosis delay due initially to misdiagnosed as pulmonary TB.
 Method: The cross-sectional study was held in Persahabatan Hospital and the subjects were histopatologically proven lung cancer patients between September 2012 to February 2013 involving totally 100 patients. The diagnosis delay were determined as whether the patients had been diagnosed as pulmonary tuberculosis and received anti-tuberculosis treatment (ATT) more than one month since current symptoms onset. All patients were interviewed and all chest X-rays were documented.
 Results: Fourty one of 100 patients were diagnosed as pulmonary TB and 29 of 41 patients received ATT more than one month. It consisted of 21 men and 8 women with the mean age of 51.5 years old. The cytology and histopatological biopsy revealed 28 Non Small Cell Lung Cancer (NSCLC) cases, and One Small Cell Lung Cancer (SCLC) case with all case were in end stage condition (6 cases in stage III and 22 cases in stage IV). Pre-referral sputum Acid Fast Bacilli (AFB) was conducted in only 9 cases with all negative results. Mean duration of ATT taken was 4.5±0.4 months. The ATT were given by 13 general practitioners, 12 pulmonologists and 4 internists.
 Discussion: Similar radiological findings in highly incidence of pulmonary TB could cause a large number of diagnosis delay in lung cancer due to initially diagnosed as pulmonary tuberculosis. Without proper investigation based on International Standard of TB Care, starting ATT with inadequate evaluation leads to diagnosis delay and lung cancer progression. (J Respir Indo 2019; 39(2))

Male gender and duration of anti-tuberculosis treatment are associated with hypocholesterolemia in adult pulmonary tuberculosis patients in Kampala, Uganda.

Patients with Pulmonary tuberculosis (PTB) and hypocholesterolemia have an altered immune function, delayed sputum conversion at two months and increased mortality. However, the assessment for dyslipidemias is not often done in our setting. A cross-sectional study was conducted among adults at an urban TB clinic in Kampala, Uganda. We included different participants at diagnosis (0), 2, 5, 6 and 8 months of anti-TB treatment. Data was collected from a complete physical examination, a pre-tested structured questionnaire, six-hour fasting lipid profiles and random blood glucose levels. Of the 323 included participants, 63.5% (205/323) were males and the median age was 30 years, IQR (23-39). The prevalence of hypocholesterolemia was 43.65% (95% CI 38.3-49.2). The participants at diagnosis had the highest hypocholesterolemia prevalence, 57.3%, 95% CI (46.7-67.2); and lowest amongst those completing treatment at 6/8 months, 32.2%, 95% CI (21.6-45.2). Significant factors associated with hypocholesterolemia were: male gender (PR 1.52, 95% CI: 1.13-2.03), and duration of anti-TB treatment (0.88, 95% CI: 0.80-0.98). Hypocholesterolemia is common among patients with PTB. The risk of hypocholesterolemia increases with being male and reduces with increased duration of treatment. There is a need for further research in lipid abnormalities in TB patients.

PREVALENCE AND FACTORS ASSOCIATED WITH HYPOCHOLESTEROLAEMIA AMONG ADULTS WITH PULMONARY TB AT DIAGNOSIS AND DURING TB TREATMENT IN KAMPALA

BackgroundHypocholesterolaemia is associated with altered immune function, possible delayed conversion at two months, and increased risk of mortality. However, lipid profiles are not done routinely for tuberculosis (TB) patients and...

CD4 Cell Levels during Treatment for Tuberculosis (TB) in Ethiopian Adults and Clinical Markers Associated with CD4 Lymphocytopenia

BackgroundThe clinical correlations and significance of subnormal CD4 levels in HIV-negative patients with TB are unclear. We have determined CD4 cell levels longitudinally during anti-tuberculosis treatment (ATT) in patients, with and without HIV co-infection, and their associations with clinical variables.MethodAdults diagnosed with TB (maximum duration of ATT for 2 weeks, and with no history of antiretroviral therapy (ART) in HIV-positive subjects) were included consecutively in eight out-patient clinics in Ethiopia. Healthy individuals were recruited for comparison at one of the study health centers. Data on patient characteristics and physical findings were collected by trained nurses following a structured questionnaire at inclusion and on follow-up visits at 2 and 6 months. In parallel, peripheral blood CD4 cell levels were determined. The evolution of CD4 cell levels during ATT was assessed, and the association between clinical characteristics and low CD4 cell levels at baseline was investigated using regression analysis.ResultsIn total, 1116 TB patients were included (307 HIV-infected). Among 809 HIV-negative patients, 200 (25%) had subnormal CD4 cell counts (<500 cells/mm3), with <350 cells/mm3 in 82 (10%) individuals. CD4 cell levels increased significantly during the course of ATT in both HIV+ and HIV- TB-patients, but did not reach the levels in healthy subjects (median 896 cells/mm3). Sputum smear status, signs of wasting (low mid upper arm circumference (MUAC)), and bedridden state were significantly associated with low CD4 cell counts.ConclusionA high proportion of Ethiopian TB patients have subnormal CD4 cell counts before starting treatment. Low CD4 cell levels are associated with smear positive disease and signs of wasting. The continuous increase of CD4 cell counts during the course of ATT suggest a reversible impact of active TB on CD4 cell homeostasis, which may be considered in interpretation of CD4 cell counts in HIV/TB co-infected subjects.

A continuously monitored colorimetric method for detection of &lt;I&gt;Mycobacterium tuberculosis&lt;/I&gt; complex in sputum

Mbeya, Tanzania. To develop a new liquid culture method to detect Mycobacterium tuberculosis complex (MTC) in sputum using 2,3-diphenyl-5-thienyl-(2)-tetrazolium (STC), the nitrate reductase assay (NRA) and p-nitrobenzoic acid (PNB). Ninety-three sputum samples collected from 18 tuberculosis patients were decontaminated with N-acetyl-L-cysteine-sodium hydroxide using MGIT™ 960 and in STC-NRA cultures, both in the presence and in the absence of PNB, an inhibitor of MTC growth. The reduction of STC by colour change indicated mycobacterial growth; NRA was then performed to confirm MTC. STC-NRA culture was positive for acid-fast bacilli in 66/93 (71%) samples, of which 60/93 (64.5%) were identified as MTC-positive and 6/93 (6.5%) as indeterminate mycobacteria. MGIT indicated MTC in 59/93 (63.4%) cultures. Contamination was detected in 12/93 (13%) STC-NRA cultures vs. 29/93 (31.2%) MGIT cultures. The mean time to detection (TTD) of MTC using STC-NRA was 14 days and 7 days using MGIT. The STC-NRA method is sensitive for the detection of MTC in sputum. TTD increased with duration of anti-tuberculosis treatment, highlighting the value of this method in monitoring treatment success. The method is simple and inexpensive and, unlike MGIT, does not require technical equipment. The preliminary performance characteristics of the method should be further evaluated in larger studies.

Distribution of the human immunodeficiency virus coreceptors CXCR4 and CCR5 on leukocytes of persons with human immunodeficiency virus type 1 infection and pulmonary tuberculosis: implications for pathogenesis.

Expression of CXCR4 was significantly reduced from normal on all cell subsets of persons with pulmonary tuberculosis (TB group), with HIV-1 infection (HIV group), and those with both infections (HIV/TB group), except for on monocytes in the HIV group. The reductions were most notable in the two TB groups. Interestingly, the duration of antituberculosis treatment was significantly negatively correlated with the expression of CXCR4 on CD4+ and CD8+CD45RO+ cells, monocytes and NK cells, viral load, and proportions of CD38-expressing CD8+ lymphocytes, in HIV/TB patients. By contrast, CCR5 expression on most cell subsets analyzed was increased in all the disease groups, except for on monocytes in the two TB groups. There was no change in CCR5 expression on CD4+ cells when based on the disease groupings. However, higher proportions of CD4+CD45RA+ and CD8+ lymphocytes as well as B cells expressing CCR5 correlated with advancing HIV-1 disease, as did decreased proportions of CXCR4-expressing CD4+CD45RA+ cells.