BackgroundVitamin D enhances host protective immune responses to Mycobacterium tuberculosis by suppressing Interferon-gamma (IFN-g) and reducing disease associated inflammation in the host. The objectives of this study were to determine whether vitamin D supplementation to patients with tuberculosis (TB) could influence recovery.MethodsTwo hundred and fifty nine patients with pulmonary TB were randomized to receive either 600,000 IU of Intramuscular vitamin D3 or placebo for 2 doses. Assessments were performed at 4, 8 and 12 weeks. Early secreted and T cell activated 6 kDa (ESAT6) and Mycobacterium tuberculosis sonicate (MTBs) antigen induced whole blood stimulated IFN-g responses were measured at 0 and 12 weeks. Statistical comparisons between outcome variables at 0 and 12 weeks were performed using Student’s t-test and Chi2 tests.ResultsAfter 12 weeks, the vitamin D supplemented arm demonstrated significantly greater mean weight gain (kg) + 3.75, (3.16 – 4.34) versus + 2.61 (95% CI 1.99 – 3.23) p 0.009 and lesser residual disease by chest radiograph; number of zones involved 1.35 v/s 1.82 p 0.004 (95% CI 0.15, 0.79) and 50% or greater reduction in cavity size 106 (89.8%) v/s 111 (94.8%), p 0.035. Vitamin D supplementation led to significant increase in MTBs-induced IFN-g secretion in patients with baseline ‘Deficient’ 25-hydroxyvitamin D serum levels (p 0.021).ConclusionsSupplementation with high doses of vitamin D accelerated clinical, radiographic improvement in all TB patients and increased host immune activation in patients with baseline ‘Deficient’ serum vitamin D levels. These results suggest a therapeutic role for vitamin D in the treatment of TB.Trial registrationClinicalTrials.gov; No. NCT01130311; URL: clinicaltrials.gov
BackgroundAppropriate immune activation of T cells and macrophages is central for the control of Mycobacterium tuberculosis infections. IFN-γ stimulated responses are lowered in tuberculosis (TB), while expression of Suppressor of Cytokine Signaling (SOCS) molecules – 1 and 3 and CD4+CD25+FoxP3+T regulatory cells is increased. Here we investigated the association of these molecules in regard to clinical severity of TB.MethodsPeripheral blood mononuclear cells (PBMCs) were isolated from patients with pulmonary TB (PTB, n = 33), extra-pulmonary TB (ETB, n = 33) and healthy endemic controls (EC, n = 15). Cases were classified as moderately advanced or far advanced PTB, and less severe or severe disseminated ETB. M. tuberculosis -stimulated IFN-γ, SOCS1, SOCS3 and FoxP3 gene expression and secretion of Th1 and Th2 cytokines was measured. Statistical analysis was performed using Mann–Whitney U, Wilcoxon Rank and Kruskal Wallis non-parametric tests.ResultsIn un-stimulated PBMCs, IL-6 (p = 0.018) and IL-10 (p = 0.013) secretion levels were increased in PTB while IL-10 was also increased in ETB (p = 0.003), all in comparison with EC. M. tuberculosis-stimulated IL-6 (p = 0.003) was lowered in ETB as compared with EC. SOCS1 mRNA expression in M. tuberculosis stimulated PBMCs levels in moderately advanced PTB (p = 0.022), far advanced (p = 0.014) PTB, and severe ETB (p = 0.009) were raised as compared with EC. On the other hand, SOCS1 mRNA titers were reduced in less severe ETB, in comparison with severe ETB (p = 0.027) and far advanced PTB (p = 0.016). SOCS3 mRNA accumulation was reduced in far advanced PTB (p = 0.007) and FoxP3 mRNA expression was increased in less severe ETB as compared with EC (p = 0.017).ConclusionsThe lowered SOCS1 mRNA levels in patients with less severe extra-pulmonary TB as compared to those with more severe ETB and PTB may lead to elevated IFN-γ pathway gene expression in the latter group. As localized ETB has shown to be associated with more effective Th1 immunity and adaptive responses, this suggests a role for SOCS1 in determining disease outcome in extra-pulmonary TB.
Suppressors of cytokine signalling (SOCS) molecules inhibit cytokine signalling and may regulate protective immunity in tuberculosis (TB). We investigated the association of SOCS with disease progression in patients with pulmonary TB. For this purpose, we studied peripheral blood mononuclear cells (PBMCs) and T cells from patients with pulmonary TB (TB, n = 33) and healthy endemic controls (EC, n = 15). Cases were stratified into those with moderately advanced (Mod-PTB) or far advanced disease (Adv-PTB). Interferon-gamma (IFN-c), SOCS1 and SOCS3 gene expression was determined by RT-PCR. Statistical analysis was performed using the Mann-Whitney test. Levels of IL6 (P = 0.018) and IL10 (P = 0.013) were found to be elevated in PBMC supernatants from patients with TB as compared with EC. SOCS1 mRNA gene expression in T cells from patients with TB was increased as compared with that of EC (P = 0.02). In addition, levels of SOCS1 mRNA transcripts were found to be elevated in PBMCs of Adv-PTB as compared with Mod-PTB (P = 0.008) cases. Our data show that raised SOCS1 levels are associated with increased disease severity in TB. As SOCS1 regulates IFN-c-driven immunity and SOCS1 can be further upregulated by IL6 levels, the increase in SOCS1 in severe disease indicates a mechanism by which mycobacteria impede disease control in TB.
BackgroundLeukotriene receptor antagonists (LTRAs) are well established in the management of outpatient asthma. However, there is very little information as to their role in acute asthma exacerbations. We hypothesized that LTRAs may accelerate lung function recovery when given in an acute exacerbation.MethodsA randomized, double blind, placebo-controlled trial was conducted at the Aga Khan University Hospital to assess the efficacy of oral montelukast on patients of 16 years of age and above who were hospitalized with acute asthma exacerbation. The patients were given either montelukast or placebo along with standard therapy throughout the hospital stay for acute asthma. Improvements in lung function and duration of hospital stay were monitored.Results100 patients were randomized; their mean age was 52 years (SD +/− 18.50). The majority were females (79%) and non-smokers (89%). The mean hospital stay was 3.70 ± 1.93 days with 80% of patients discharged in 3 days. There was no significant difference in clinical symptoms, PEF over the course of hospital stay (p = 0.20 at day 2 and p = 0.47 at day 3) and discharge (p = 0.15), FEV1 at discharge (p = 0.29) or length of hospital stay (p = 0.90) between the two groups. No serious adverse effects were noted during the course of the study.ConclusionOur study suggests that there is no benefit of addition of oral montelukast over conventional treatment in the management of acute asthma attack.Trial registrationTrial registration number: 375-Med/ERC-04
IntroductionTuberculosis is a major health problem in Pakistan. The prevalence of pulmonary as well as extrapulmonary tuberculosis is quite high. Tuberculin skin test, radiological imaging, and sputum smear microscopy have limitations in the diagnosis of tuberculosis. Xpert MTB/RIF was recently approved for the diagnosis of pulmonary tuberculosis and has shown promising results. The aim of this study was to determine the diagnostic accuracy of Xpert MTB/RIF in sputum smear-negative pulmonary tuberculosis using acid-fast bacilli (AFB) culture as the gold standard.Materials and methodsThis cross-sectional study was conducted at Iqbal Yad Chest Clinic and Nazimabad Chest Clinic of Ojha Institute of Chest Diseases, Dow University of Health Sciences. Patients of either gender aged 18-65 years suspected to have pulmonary tuberculosis with at least two sputum samples negative for AFB underwent Xpert MTB/RIF testing. Early morning sputum samples were obtained and sent for AFB smear microscopy, Xpert testing and also for culture analysis.ResultsMean age of the patients was 37.48 ±17.49 years. There were 84 (37.3%) females and 141 (62.7%) males. Positive findings on Xpert MTB/RIF were found in 147 (65.3%) patients whereas AFB culture showed positive findings in 174 (77.3%) patients. Sensitivity, specificity, positive predicted value, negative predicted value and overall diagnostic accuracy of Xpert MTB/RIF was found to be 84.48%, 100%, 100%, 65.38%, and 88%, respectively.ConclusionXpert MTB/RIF has high sensitivity, specificity, and diagnostic accuracy in diagnosis of sputum smear-negative cases of pulmonary tuberculosis.
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