Nutritional markers and proteome in patients undergoing treatment for pulmonary tuberculosis differ by geographic region.

INTRODUCTION: Contemporary phase 2 TB disease treatment clinical trials have found that microbiologic treatment responses differ between African versus non-African regions, the reasons for which remain unclear. Understanding host and disease phenotypes that may vary by region is important for optimizing curative treatments. METHODS: We characterized clinical features and the serum proteome of phase 2 TB clinical trial participants undergoing treatment for smear positive, culture-confirmed TB, comparing host serum protein expression in clinical trial participants enrolled in African and Non-African regions. Serum samples were collected from 289 participants enrolled in the Centers for Disease Control and Prevention TBTC Study 29 (NCT00694629) at time of enrollment and at the end of the intensive phase (after 40 doses of TB treatment). RESULTS: After a peptide level proteome analysis utilizing a unique liquid chromatography IM-MS platform (LC-IM-MS) and subsequent statistical analysis, a total of 183 core proteins demonstrated significant differences at both baseline and at week 8 timepoints between participants enrolled from African and non-African regions. The majority of the differentially expressed proteins were upregulated in participants from the African region, and included acute phase proteins, mediators of inflammation, as well as coagulation and complement pathways. Downregulated proteins in the African population were primarily linked to nutritional status and lipid metabolism pathways. CONCLUSIONS: We have identified differentially expressed nutrition and lipid pathway proteins by geographic region in TB patients undergoing treatment for pulmonary tuberculosis, which appear to be associated with differential treatment responses. Future TB clinical trials should collect expanded measures of nutritional status and further evaluate the relationship between nutrition and microbiologic treatment response.

The Manipulation of the Lipid Mediator Metabolism as Adjunct Host-Directed Therapy in Tuberculosis.

Host-directed therapies (HDTs) enhance the host response to tuberculosis (TB) infection to reduce disease severity. For instance, the manipulation of lipid mediator production diminishes the hyperactive immune response which is a known pathological feature of TB that generates lung tissue damage. Non-steroidal anti-inflammatory drugs (NSAIDs) and omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) are examples of such HDTs. In this mini-review, we recapitulate the literature available on the effects of NSAIDs and n-3 LCPUFA in TB as well as the immunological pathways underpinning these effects. Many NSAIDs have a great deal of data describing their effects and safety and in many jurisdictions are inexpensive, and sold over the counter in neighborhood convenience stores and supermarkets. The potential benefits of NSAIDs in TB are well-documented in pre-clinical studies. The reduction of pro-inflammatory lipid mediator production by inhibiting cyclooxygenase (COX) pathways with NSAIDs has been found to improve lung histopathology, bacterial control, and survival. Additionally, n-3 LCPUFA and its novel bioactive metabolites produced by COX and lipoxygenase (LOX) have been identified as safe and effective pro-resolving and antibacterial pharmaconutrients. Nevertheless, heterogeneous results have been reported in pre-clinical TB studies. Recently, the importance of the correct timing of NSAIDs and n-3 LCPUFA administration in TB has also been highlighted. This mini-review will provide a better understanding of the potential contribution of these therapies toward reducing inflammatory lung damage and improving bactericidal activity, especially during later stages of TB infection. It further highlights that clinical trials are required to confirm benefit and safety in TB patients.

Infections and diabetes: Risks and mitigation with reference to India.

BACKGROUND AND AIMS: The link between diabetes and increased risk of infectious disease has long been recognized, but has re-entered sharp focus following the COVID-19 pandemic. METHODS: A literature search was conducted in PubMed for articles in English on diabetes and infection. RESULTS: Diabetes predisposes to infections through alterations in innate and acquired immune defenses. Outcomes of infection are worse in people with uncontrolled diabetes, and infection can worsen hyperglycemia in hitherto well controlled diabetes (bidirectional relationship). Diabetes does not increase the risk of infection with COVID-19 per se, but predisposes to severe disease and poor outcomes. COVID-19 has also been linked to deterioration of glycemic control as well as new-onset diabetes. CONCLUSIONS: Clinicians caring for people with diabetes should be aware of the increased risk of infections in this population, as well as the possibility of worsening hyperglycemia. A holistic approach with frequent monitoring of blood glucose levels and appropriate titration of medications, along with close attention to nutritional status, is essential to ensure the best possible outcomes.

Old age-associated enrichment of peripheral T regulatory cells and altered redox status in pulmonary tuberculosis patients.

Aging influences the susceptibility and prognosis to various infectious diseases including tuberculosis (TB). Despite the impairment of T-cell function and immunity in older individuals, the mechanism for the higher incidence of TB in the elderly remains largely unknown. Here, we evaluated the age-associated immune alterations, particularly in effector and Treg responses in pulmonary TB patients. We also evaluated the impact of redox status and its modulation with N-acetyl-cysteine (NAC) in elderly TB. Higher frequency of Treg cells and reduced IFN-γ positive T cells were observed among older TB patients. The elevated number of Treg cells correlated tightly with bacillary load (i.e. disease severity); which declined significantly in response to successful anti-tubercular treatment. We could rescue Myobacterium tuberculosis-specific effector T cell (Th1) responses through various in vitro approaches, for example, Treg cell depletion and co-culture experiments, blocking experiments using antibodies against IL-10, TGF-ß, and programmed death-1 (PD-1) as well as NAC supplementation. We report old age-associated enrichment of Treg cells and suppression of M. tuberculosis-specific effector T (Th1) cell immune responses. Monitoring these immune imbalances in older patients may assist in immune potentiation through selectively targeting Treg cells and/or optimizing redox status by NAC supplementation.

Mucosal-Associated Invariant T Cell Levels Are Reduced in the Peripheral Blood and Lungs of Children With Active Pulmonary Tuberculosis.

Mucosal associated invariant T (MAIT) cells are unconventional, semi-invariant T lymphocytes that recognize microbial-derived vitamin B2 (riboflavin) biosynthesis precursor derivatives presented by the monomorphic MHC class 1-related (MR1) molecule. Upon microbial infection, MAIT cells rapidly produce cytokines and cytotoxic effectors, and are thus important players in anti-microbial defense. MAIT cells are protective in experimental models of infection and are decreased in the blood of adult patients with bacterial infections, including Mycobacterium tuberculosis (Mtb). In children, the risk of rapid progression to active tuberculosis (TB) following Mtb infection is higher than in adults. Whether MAIT cells influence the outcome of Mtb infection in children is therefore, an important issue. We analyzed MAIT cell numbers and phenotype in 115 children investigated for pulmonary TB and determined their potential correlation with disease progression. MAIT cells were reduced in numbers and activated in the peripheral blood of children with active TB as compared to those with latent TB infection (LTBI) and healthy children. Moreover, MAIT cells did not accumulate and did not proliferate in the lung of children with active TB. These results suggest that MAIT cells may be important in preventing progression of Mtb infection to active TB in children.

Effect of rifampicin and efavirenz on moxifloxacin concentrations when co-administered in patients with drug-susceptible TB.

Objectives: We compared the pharmacokinetics of moxifloxacin during rifampicin co-treatment or when dosed alone in African patients with drug-susceptible recurrent TB. Methods: Patients in the intervention arm of the Improving Retreatment Success (IMPRESS) randomized controlled TB trial received 400 mg of moxifloxacin, with rifampicin, isoniazid and pyrazinamide in the treatment regimen. Moxifloxacin concentrations were measured in plasma during rifampicin-based TB treatment and again 4 weeks after treatment completion, when given alone as a single dose. Moxifloxacin concentration-time data were analysed using non-linear mixed-effects models. Results: We included 58 patients; 42 (72.4%) were HIV co-infected and 40 (95%) of these were on efavirenz-based ART. Moxifloxacin pharmacokinetics was best described using a two-compartment disposition model with first-order lagged absorption and elimination using a semi-mechanistic model describing hepatic extraction. Oral clearance (CL/F) of moxifloxacin during rifampicin-based TB treatment was 24.3 L/h for a typical patient (fat-free mass of 47 kg), resulting in an AUC of 16.5 mg·h/L. This exposure was 7.8% lower than the AUC following the single dose of moxifloxacin given alone after TB treatment completion. In HIV-co-infected patients taking efavirenz-based ART, CL/F of moxifloxacin was increased by 42.4%, resulting in a further 30% reduction in moxifloxacin AUC. Conclusions: Moxifloxacin clearance was high and plasma concentrations low in our patients overall. Moxifloxacin AUC was further decreased by co-administration of efavirenz-based ART and, to a lesser extent, rifampicin. The clinical relevance of the low moxifloxacin concentrations for TB treatment outcomes and the need for moxifloxacin dose adjustment in the presence of rifampicin and efavirenz co-treatment need further investigation.

Microarray expression profile analysis of mRNAs and long non-coding RNAs in pulmonary tuberculosis with different traditional Chinese medicine syndromes.

BACKGROUND: Combination chemotherapy with Western anti-tuberculosis (TB) drugs is the mainstay of TB treatment. Chinese herbal medicines with either heat clearing and detoxifying effects or nourishing Yin and reducing fire effects have been used to treat TB based on the Traditional Chinese Medicine (TCM) syndromes of TB patients. This study analyzed the expression profiles of long non-coding RNAs (lncRNAs) and mRNAs in TB patients with different TCM syndromes. METHODS: TB patients were classified as pulmonary Yin deficiency (PYD) syndrome, hyperactivity of fire due to Yin deficiency (HFYD) syndrome, and deficiency of Qi and Yin (DQY) syndrome. Total RNA from 44 TB patients and healthy controls was extracted and hybridized with a human lncRNA microarray containing 30586 lncRNAs and 26109 mRNAs probes. Bioinformatics analyses, including gene ontology (GO) and pathways, were performed. Related clinical data were also analyzed. RESULTS: Differentially expressed mRNAs and lncRNAs were identified (fold change >2, and P < 0.05) in PYD (634 mRNAs and 566 lncRNAs), HFYD (47 mRNAs and 55 lncRNAs), and DQY (63 mRNAs and 60 lncRNAs) patients. The most enriched pathways were the hippo signaling pathway (P = 0.000164) and the protein digestion and absorption pathway (P = 5.89017E-05). Clinical analyses revealed that the lipid indexes of TB patients were abnormal and that the triglyceride concentration was significantly higher in DQY patients (P = 0.0252). Our study is the first to acquire the microarray expression profiles of lncRNAs and mRNAs and analyze pathway enrichment in PYD, HFYD, and DQY patients with TB. CONCLUSIONS: Our analyses of the expression profiles of lncRNAs and mRNAs may represent a novel method to explore the biological essence of TCM syndromes of TB.

Effect of 1,25-dihydroxyvitamin D3 on the expression of mannose receptor, DC-SIGN and autophagy genes in pulmonary tuberculosis.

1,25-dihydroxyvitamin D3 [1,25(OH)2D3] is a powerful immuno-modulator, which enhances expression of antimicrobial peptides and induces autophagy in monocytes/macrophages. Since 1,25(OH)2D3 increases the phagocytic potential of monocytes/macrophages, we have explored the effect of 1,25(OH)2D3 on the expression of receptors such as mannose receptor (CD206) and DC-SIGN (CD209) as well as autophagy genes such as ATG5 and Beclin-1 (BECN1) in monocytes/macrophages of healthy controls (HCs) and pulmonary tuberculosis (PTB) patients with and without cavitary disease. Peripheral blood mononuclear cells (PBMCs) were isolated from 40 HCs and 40 PTB patients and were cultured for 72 h with Mtb in the presence or absence of 1,25(OH)2D3 at 10(-7) M concentration. 1,25(OH)2D3 significantly upregulated the expression of mannose receptor, ATG5 and BECN1; whereas DC-SIGN expression was suppressed in Mtb infected cells of both study groups (p < 0.05). The 1,25(OH)2D3-induced expression of CD206, ATG5 and BECN1 genes was lower in PTB patients compared to HCs, whereas expression of these genes was impaired in PTB patients with cavitary disease. Moreover, the relative expression of ATG5 and BECN1 was positively correlated with monocyte/macrophage phagocytosis and cathelicidin antimicrobial peptide gene expression in HCs and PTB patients (p < 0.05). Our study results suggest that vitamin D supplementation in PTB patients without cavitary disease could enhance innate immune functions and may help to control intracellular growth of mycobacteria in macrophages.

A novel role of Yin-Yang-1 in pulmonary tuberculosis through the regulation of the chemokine CCL4.

Mycobacterium tuberculosis (M. tb) is the etiological agent of pulmonary tuberculosis (TB); this disease remains a worldwide health problem. Yin-Yang-1 (YY1) plays a major role in the maintenance and progression of some pulmonary diseases, including pulmonary fibrosis. However, the role of YY1 in TB remains unknown. The aim of this study was to elucidate the role of YY1 in the regulation of CCL4 and its implication in TB. We determined whether YY1 regulates CCL4 using reporter plasmids, ChIP and siRNA assays. Immunohistochemistry and digital pathology were used to measure the expression of YY1 and CCL4 in a mouse model of TB. A retrospective comparison of patients with TB and control subjects was used to measure the expression of YY1 and CCL4 using tissue microarrays. Our results showed that YY1 regulates the transcription of CCL4; moreover, YY1, CCL4 and TGF-ß were overexpressed in the lung tissues of mice with TB during the late stages of the disease and the tissues of TB patients. The expression of CCL4 and TGF-ß correlated with YY1 expression. In conclusion, YY1 regulates CCL4 transcription; moreover, YY1 is overexpressed in experimental and human TB and is positively correlated with CCL4 and TGF-ß expression. Therefore, treatments that decrease YY1 expression may be a new therapeutic strategy against TB.

Effects on type 2 diabetes complicated with pulmonary tuberculosis: regiment of insulin, isoniazid, rifampicin, pyrazinamide and ethambutol versus the regiment plus Qi-boosting and Yin-nourishing decoction of Traditional Chinese Medicine.

OBJECTIVE: To observe the clinical effect on type 2 diabetes mellitus (T2DM) complicated with pulmonary tuberculosis (TB) of insulin, isoniazid, rifampicin, pyrazinamide and ethambutol (conventional medication) administered together with Qi-boosting and Yin-nourishing decoction derived from Traditional Chinese Medicine (TCM). METHODS: A total of 60 patients with T2DM complicated with pulmonary TB were randomly and equally divided into positive control group and treatment group. The control group was treated with Western conventional regiment (WCR): insulin, isoniazid, rifampicin, pyrazinamide, and ethambutol, whereas the treatment group was given both WCR and Qi-boosting and Yin-nourishing decoction prepared from TCM. RESULTS: After the treatment, 20 (66.7%) and 11 (36.7%) cases showed sputum bacteria negative conversion in the WCR plus TCM group and WCM group respectively (P < 0.05). A total of 25 (83.3%) and 18 (60%) cases showed improvement in lung lesion in the WCR plus TCM group and WCM group respectively (P < 0.05). Compared with WCR group, fasting plasma glucose and 2-hour postprandial blood glucose levels in the WCR plus TCM group significantly decreased (P < 0.05 and P < 0.01, respectively). CONCLUSION: Qi-boosting and Yin-nourishing decoction combined with the Western medication showed better curative effect in treating T2DM complicated with pulmonary TB compared with the group using the conventional Western Medicine alone.

Computational pharmacokinetics/pharmacodynamics of rifampin in a mouse tuberculosis infection model.

One critical approach to preclinical evaluation of anti-tuberculosis (anti-TB) drugs is the study of correlations between drug exposure and efficacy in animal TB infection models. While such pharmacokinetic/pharmacodynamic (PK/PD) studies are useful for the identification of optimal clinical dosing regimens, they are resource intensive and are not routinely performed. A mathematical model capable of simulating the PK/PD properties of drug therapy for experimental TB offers a way to mitigate some of the practical obstacles to determining the PK/PD index that best correlates with efficacy. Here, we present a preliminary physiologically based PK/PD model of rifampin therapy in a mouse TB infection model. The computational framework integrates whole-body rifampin PKs, cell population dynamics for the host immune response to Mycobacterium tuberculosis infection, drug-bacteria interactions, and a Bayesian method for parameter estimation. As an initial application, we calibrated the model to a set of available rifampin PK/PD data and simulated a separate dose fractionation experiment for bacterial killing kinetics in the lungs of TB-infected mice. The simulation results qualitatively agreed with the experimentally observed PK/PD correlations, including the identification of area under the concentration-time curve as best correlating with efficacy. This single-drug framework is aimed toward extension to multiple anti-TB drugs in order to facilitate development of optimal combination regimens.

Effect of 1,25-dihydroxy vitamin D3 on cathelicidin expression in patients with and without cavitary tuberculosis.

1,25-dihydroxy vitamin D3 (1,25(OH)2D3) is a potent immuno-modulator which induces LL-37, the active peptide of cathelicidin, and restricts the growth of Mycobacterium tuberculosis (Mtb) in human macrophages. In the present study, we investigated the effect of 1,25(OH)2D3 on cathelicidin antimicrobial peptide (CAMP) expression in healthy controls (HCs) and pulmonary tuberculosis (PTB) patients. Peripheral blood mononuclear cells (PBMCs) from 50 HCs and 35 PTB patients were cultured for 72 h either with Mtb alone or Mtb with 1,25(OH)2D3 at 10(-7) M concentration. 1,25(OH)2D3 significantly up regulated the macrophage phagocytosis, CD14, CAMP gene expression and hCAP18 protein in HCs and PTB patients (p < 0.05). A significant positive correlation was observed between macrophage phagocytosis and CAMP gene expression in both the study groups (p < 0.05). Moreover, 1,25(OH)2D3 up regulated CAMP gene expression was more prominent in PTB patients without lung cavity (less severe form of disease) as compared to patients with cavitary TB (severe form of disease) (p < 0.05). The present study suggests that vitamin D may be used as an adjunct to anti-TB treatment and may be useful for a quicker recovery from less severe forms of TB disease.

L-arginine and vitamin D adjunctive therapies in pulmonary tuberculosis: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Vitamin D (vitD) and L-arginine have important antimycobacterial effects in humans. Adjunctive therapy with these agents has the potential to improve outcomes in active tuberculosis (TB). METHODS: In a 4-arm randomised, double-blind, placebo-controlled factorial trial in adults with smear-positive pulmonary tuberculosis (PTB) in Timika, Indonesia, we tested the effect of oral adjunctive vitD 50,000 IU 4-weekly or matching placebo, and L-arginine 6.0 g daily or matching placebo, for 8 weeks, on proportions of participants with negative 4-week sputum culture, and on an 8-week clinical score (weight, FEV1, cough, sputum, haemoptysis). All participants with available endpoints were included in analyses according to the study arm to which they were originally assigned. Adults with new smear-positive PTB were eligible. The trial was registered at ClinicalTrials.gov NCT00677339. RESULTS: 200 participants were enrolled, less than the intended sample size: 50 received L-arginine + active vitD, 49 received L-arginine + placebo vit D, 51 received placebo L-arginine + active vitD and 50 received placebo L-arginine + placebo vitD. According to the factorial model, 99 people received arginine, 101 placebo arginine, 101 vitamin D, 99 placebo vitamin D. Results for the primary endpoints were available in 155 (4-week culture) and 167 (clinical score) participants. Sputum culture conversion was achieved by week 4 in 48/76 (63%) participants in the active L-arginine versus 48/79 (61%) in placebo L-arginine arms (risk difference -3%, 95% CI -19 to 13%), and in 44/75 (59%) in the active vitD versus 52/80 (65%) in the placebo vitD arms (risk difference 7%, 95% CI -9 to 22%). The mean clinical outcome score also did not differ between study arms. There were no effects of the interventions on adverse event rates including hypercalcaemia, or other secondary outcomes. CONCLUSION: Neither vitD nor L-arginine supplementation, at the doses administered and with the power attained, affected TB outcomes. REGISTRY: ClinicalTrials.gov. Registry number: NCT00677339.

Rationale and design of a randomized controlled trial of the effect of retinol and vitamin D supplementation on treatment in active pulmonary tuberculosis patients with diabetes.

BACKGROUND: The association between pulmonary tuberculosis (PTB) and diabetes mellitus (DM) has been previously attracted much attention. Diabetes alters immunity to tuberculosis, leading to more frequent treatment failure in TB patients with DM. Moreover, TB and DM often coincide with micronutrients deficiencies, such as retinol and vitamin D, which are especially important to immunity of the body and may influence pancreas ß-cell function. However, the effects of retinol and vitamin D supplementation in active TB patients with diabetes on treatment outcomes, immune and nutrition state are still uncertain. We are conducting a randomized controlled trial of vitamin A and/or D in active PTB patients with DM in a network of 4 TB treatment clinics to determine whether the supplementation could improve the outcome in the patients. METHODS/DESIGN: This is a 2×2 factorial trial. We plan to enroll 400 active PTB patients with DM, and randomize them to VA (2000 IU daily retinol); VD (400 IU daily cholecalciferol); VAD (2000 IU daily retinol plus 400 IU cholecalciferol) or control (placebo) group. Our primary outcome measure is the efficacy of anti-tuberculosis treatment and ameliorating of glucose metabolism, and the secondary outcome measure being immune and nutrition status of the subjects. Of the first 37 subjects enrolled: 8 have been randomized to VA, 10 to VD, 9 to VAD and 10 to control. To date, the sample is 97.3% Han Chinese and 91.9% female. The average fasting plasma glucose level is 12.19 mmol/L. DISCUSSION: This paper describes the design and rationale of a randomized clinical trial comparing VA and/or VD supplementation to active pulmonary TB patients with DM. Our trial will allow rigorous evaluation of the efficacy of the supplementation to active TB and DM therapy for improving clinical outcomes and immunological condition. This detailed description of trial methodology can serve as a template for the development of future treatment scheme for active TB patient with DM. TRIAL REGISTRATION: ChiCTR-TRC-12002546.

Iron status predicts treatment failure and mortality in tuberculosis patients: a prospective cohort study from Dar es Salaam, Tanzania.

BACKGROUND: Experimental data suggest a role for iron in the course of tuberculosis (TB) infection, but there is limited evidence on the potential effects of iron deficiency or iron overload on the progression of TB disease in humans. The aim of the present analysis was to examine the association of iron status with the risk of TB progression and death. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed plasma samples and data collected as part a randomized micronutrient supplementation trial (not including iron) among HIV-infected and HIV-uninfected TB patients in Dar es Salaam, Tanzania. We prospectively related baseline plasma ferritin concentrations from 705 subjects (362 HIV-infected and 343 HIV-uninfected) to the risk of treatment failure at one month after initiation, TB recurrence and death using binomial and Cox regression analyses. Overall, low (plasma ferritin<30 µg/L) and high (plasma ferritin>150 µg/L for women and>200 µg/L for men) iron status were seen in 9% and 48% of patients, respectively. Compared with normal levels, low plasma ferritin predicted an independent increased risk of treatment failure overall (adjusted RR = 1.95, 95% CI: 1.07 to 3.52) and of TB recurrence among HIV-infected patients (adjusted RR = 4.21, 95% CI: 1.22 to 14.55). High plasma ferritin, independent of C-reactive protein concentrations, was associated with an increased risk of overall mortality (adjusted RR = 3.02, 95% CI: 1.95 to 4.67). CONCLUSIONS/SIGNIFICANCE: Both iron deficiency and overload exist in TB patients and may contribute to disease progression and poor clinical outcomes. Strategies to maintain normal iron status in TB patients could be helpful to reduce TB morbidity and mortality.

Nitric oxide production in the exhaled air of patients with pulmonary tuberculosis in relation to HIV co-infection.

BACKGROUND: Nitric oxide (NO) is essential for host defense in rodents, but the role of NO during tuberculosis (TB) in man remains controversial. However, earlier observations that arginine supplementation facilitates anti-TB treatment, supports the hypothesis that NO is important in the host defense against TB. Local production of NO measured in fractional exhaled air (FeNO) in TB patients with and without HIV co-infection has not been reported previously. Thus, our aim was to investigate levels of FeNO in relation to clinical symptoms and urinary NO metabolites (uNO). METHODS: In a cross sectional study, FeNO and uNO were measured and clinical symptoms, chest x-ray, together with serum levels of arginine, tumor necrosis factor alpha (TNF-alpha) and interleukin 12 (IL-12) were evaluated in sputum smear positive TB patients (HIV+/TB, n = 36, HIV-/TB, n = 59), their household contacts (n = 17) and blood donors (n = 46) from Gondar University Hospital, Ethiopia. RESULTS: The proportion of HIV-/TB patients with an increased FeNO level (> 25 ppb) was significantly higher as compared to HIV+/TB patients, but HIV+/TB patients had significantly higher uNO than HIV-/TB patients. HIV+ and HIV-/TB patients both had lower levels of FeNO compared to blood donors and household contacts. The highest levels of both uNO and FeNO were found in household contacts. Less advanced findings on chest x-ray, as well as higher sedimentation rate were observed in HIV+/TB patients as compared to HIV-/TB patients. However, no significant correlation was found between FeNO and uNO, chest x-ray grading, clinical symptoms, TNF-alpha, IL-12, arginine levels or sedimentation rate. CONCLUSION: In both HIV negative and HIV co infected TB patients, low levels of exhaled NO compared to blood donors and household were observed. Future studies are needed to confirm whether low levels of exhaled NO could be a risk factor in acquiring TB and the relative importance of NO in human TB.

Effect of vitamin E and selenium supplementation on oxidative stress status in pulmonary tuberculosis patients.

BACKGROUND AND OBJECTIVE: Increased production of reactive oxygen species secondary to phagocyte respiratory burst occurs in pulmonary tuberculosis (TB). The present study evaluated the efficacy of vitamin E-selenium supplementation on oxidative stress in newly diagnosed patients treated for pulmonary TB. METHODS: A double-blind, placebo-controlled trial including patients with newly diagnosed TB was conducted. The intervention group (n = 17) received vitamin E and selenium (vitamin E: 140 mg alpha-tocopherol and selenium: 200 microg) and the control group (n = 18) received placebo. Both groups received standard anti-TB treatment. Assessment of micronutrient levels, oxidative markers and total antioxidant capacity were carried out at baseline and 2 months after the intervention. RESULTS: Malondialdehyde levels were significantly reduced in the intervention group (P = 0.01), while there was minimal reduction in the control group. The mean plasma level of total antioxidants was increased significantly (P = 0.001) in both the intervention and the control groups. CONCLUSION: A 2-month intervention with vitamin E and selenium supplementation reduces oxidative stress and enhances total antioxidant status in patients with pulmonary TB treated with standard chemotherapy.

16alpha-Bromoepiandrosterone restores T helper cell type 1 activity and accelerates chemotherapy-induced bacterial clearance in a model of progressive pulmonary tuberculosis.

BALB/c mice with pulmonary tuberculosis develop a T helper cell type 1 response that peaks at 3 weeks, temporarily controlling bacterial growth. Then bacterial proliferation recommences, accompanied by increasing interleukin (IL)-4 levels and decreasing interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and inducible nitric oxide synthase (iNOS) levels. These changes mimic those in the human disease. In a previous study, administration of dehydroepiandrosterone (DHEA) beginning on day 60 after infection reversed these changes and protected the mice. However, DHEA is suboptimal for human use, partly because it is readily metabolized into sex steroids. 16alpha-Bromoepiandrosterone (EpiBr; 16alpha -bromo-5alpha -androstan-3beta-ol-17-one) is a synthetic adrenal steroid derivative that does not enter sex steroid pathways. In the present study, when tuberculous BALB/c mice were treated with EpiBr 3 times/week beginning on day 60, inhibition of bacterial proliferation and increased expression of TNF-alpha, IFN-gamma, and iNOS were observed, although decreased expression of IL-4 was also observed. Moreover, when given as an adjunct to conventional chemotherapy, EpiBr enhanced bacterial clearance. Trials for the use of EpiBr in the treatment of human tuberculosis are now justified.

Nutrient partitioning during treatment of tuberculosis: gain in body fat mass but not in protein mass.

BACKGROUND: Tuberculosis is an important cause of wasting. The functional consequences of wasting and recovery may depend on the distribution of lost and gained nutrient stores between protein and fat masses. OBJECTIVE: The goal was to study nutrient partitioning, ie, the proportion of weight change attributable to changes in fat mass (FM) versus protein mass (PM), during antimycobacterial treatment. DESIGN: Body-composition measures were made of 21 men and 9 women with pulmonary tuberculosis at baseline and after 1 and 6 mo of treatment. All subjects underwent dual-energy X-ray absorptiometry and deuterium bromide dilution tests, and a four-compartment model of FM, total body water (TBW), bone minerals (BM), and PM was derived. The ratio of PM to FM at any time was expressed as the energy content (p-ratio). Changes in the p-ratio were related to disease severity as measured by radiologic criteria. RESULTS: Patients gained 10% in body weight (P < 0.001) from baseline to month 6. This was mainly due to a 44% gain in FM (P < 0.001); PM, BM, and TBW did not change significantly. Results were similar in men and women. The p-ratio decreased from baseline to month 1 and then fell further by month 6. Radiologic disease severity was not correlated with changes in the p-ratio. CONCLUSIONS: Microbiological cure of tuberculosis does not restore PM within 6 mo, despite a strong anabolic response. Change in the p-ratio is a suitable parameter for use in studying the effect of disease on body composition because it allows transformation of such effects into a normal distribution across a wide range of baseline proportion between fat and protein mass.

The effect of glucosaminylmuramyl dipeptide injection to mice on the course of tuberculous infection and in vitro superoxide anion production.

Immunotherapy as an adjunct to chemotherapy is of interest for optimizing therapeutic regimens for tuberculosis. In this context, we investigated the influence and mode of action ofglucosaminylmuramyl dipeptide (GMDP) in mouse experimental models. Intermittent injections of GMDP to Mycobacterium tuberculosis-infected mice reduced the viable bacilli in the lungs, but increased the counts in the spleens at 16 weeks, but not at earlier harvests after infection. Injections of GMDP selectively ameliorated also in the lungs the spontaneous relapse of infection following chemotherapy. The mode of GMDP action was examined in respect of superoxide anion production. The O2 production by phorbol myristate-induced peritoneal macrophages in vitro was reduced by preinjection of mice with 100 microg of GMDP. Notably, this outcome contrasts and can also override the previously known enhancing effect of MDP on O2- production. The inhibitory activity of GMDP became even more pronounced when testing macrophages from Mycobacterium bovis BCG-infected mice. However, these results do not explain readily the grounds for the contrasting effects of GMDP on the growth patterns of tubercle bacilli in the lungs and spleens. Although the observed effects on bacillary counts have been modest, such action of GMDP could represent a beneficial adjunct to suitably formulated chemotherapeutic regimens.