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 Higher serum 25-hydroxyvitamin D concentrations are associated with active pulmonary tuberculosis in hospitalised HIV infected patients in a low income tropical setting: a cross sectional study High-dose vitamin D3 in adults with pulmonary tuberculosis: a double-blind randomized controlled trial. Zinc and vitamin A supplementation fails to reduce sputum conversion time in severely malnourished pulmonary tuberculosis patients in Indonesia Adjunctive micronutrient supplementation for pulmonary tuberculosis. Significant Effects of Oral Phenylbutyrate and Vitamin D3 Adjunctive Therapy in Pulmonary Tuberculosis: A Randomized Controlled Trial Micronutrient supplementation and T cell-mediated immune responses in patients with tuberculosis in Tanzania. L-arginine and Vitamin D Adjunctive Therapies in Pulmonary Tuberculosis: A Randomised, Double-Blind, Placebo-Controlled Trial
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 β-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 r and omized 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 r and omize 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 r and omized 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 r and omized 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 Background The inherent risk of developing tuberculosis ( TB ) in HIV- infected individuals is further enhanced by hypovitaminosis D. Interventions that offset HIV-associated immune deterioration potentially arrest disease progression and incidence of opportunistic infections including TB . Despite conflicting reports on association between vitamin D deficiency ( VDD ) and risk of TB , vitamin D ( VD ) supplementation remains a promising intervention . Methods We conducted a comparative cross-sectional study on 145 HIV+/pulmonary TB+ ( PTB ) and 139 HIV+/PTB− hospitalised patients to investigate association of vitamin D status and risk of PTB . Stratified r and om sampling was used to select archived serum specimens from participants enrolled in a r and omised controlled trial ( RCT ) conducted to investigate the impact of using a point-of-care urine lipoarabinomannan strip test for TB diagnosis . PTB status was confirmed using sputum smear microscopy , culture or GeneXpert MTB/RIF .  Serum 25-hydroxyvitamin D [ 25(OH ) D ] concentrations  were assayed by competitive chemiluminescent immunoassay prior to commencement of anti-TB treatment . Effect of VD status on duration of hospital stay and patient outcomes on follow up at 8 weeks were also investigated . Median serum 25(OH ) D concentrations were compared using Mann-Whitney test and covariates of serum VD status were assessed using logistic regression analysis . Results Overall VDD prevalence in the cohort was 40.9 % ( 95 % CI : 35.1–46.8 ) . Median serum 25(OH)D concentrations were significantly higher in HIV+/PTB+ group ( 25.3 ng/ml , IQR:18.0–33.7 ) compared to the HIV+/PTB− group ( 20.4 ng/ml , IQR:14.6–26.9 ) , p = 0.0003 . Patients with serum 25(OH ) D concentration ≥ 30 ng/ml were 1.9 times more likely to be PTB+ compared to those with serum 25(OH ) D concentrations < 30 ng/ml ( odds ratio ( OR ) 1.91 ; 95 % CI 1.1–3.2 ) . PTB-related death was associated with higher odds of having 25(OH ) D levels≥30 ng/ml . Age , gender , CD4 + count , combination antiretroviral therapy ( cART ) status , efavirenz based cART regimen and length of hospital stay were not associated with vitamin D status . Conclusions The finding of an association between higher serum 25(OH ) D concentrations and active PTB and TB-related mortality among hospitalised HIV-infected patients in the present study is at variance with the commonly reported association of hypovitaminosis and susceptibility to TB . Our findings though , are in concordance with a small pool of reports from other setting BACKGROUND Tuberculosis , including multidrug-resistant tuberculosis ( MDR-TB ) , is a major global health problem . Individuals with tuberculosis disease commonly exhibit vitamin D deficiency , which may adversely affect immunity and the response to therapy . OBJECTIVE We determined whether adjunctive high-dose vitamin D3 supplementation improves outcomes in individuals with pulmonary tuberculosis disease . DESIGN The study was a double-blind , r and omized , placebo-controlled , intent-to-treat trial in 199 individuals with pulmonary tuberculosis disease in Tbilisi , Georgia . Subjects were r and omly assigned to receive oral vitamin D3 [ 50,000 IUs ( 1.25 mg ) thrice weekly for 8 wk and 50,000 IU every other week for 8 wk ] or a placebo concomitant with st and ard first-line antituberculosis drugs . The primary outcome was the time for the conversion of a Mycobacterium tuberculosis ( Mtb ) sputum culture to negative . RESULTS Baseline characteristics between groups were similar . Most subjects ( 74 % ) were vitamin D deficient ( plasma 25-hydroxyvitamin D [ 25(OH)D ] concentration < 50 nmol/L ) . With vitamin D3 , plasma 25(OH)D concentrations peaked at ∼250 nmol/L by 8 wk and decreased to ∼125 nmol/L at week 16 . Adverse events and plasma calcium concentrations were similar between groups . In 192 subjects with culture-confirmed tuberculosis , an adjusted efficacy analysis showed similar median culture-conversion times between vitamin D3 and placebo groups [ 29 and 27 d , respectively ; HR : 0.86 ; 95 % CI : 0.63 , 1.18 ; P = 0.33 ) . Eight-week culture-conversion rates were also similar ( 84.0 % and 82.1 % for vitamin D3 and placebo , respectively ; P = 0.99 ) . CONCLUSION 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 clinical trials.gov at NCT00918086 Background A previous study showed that combination of zinc and vitamin A reduced sputum conversion time in pulmonary tuberculosis ( TB ) patients . Objective We studied the efficacy of which single micronutrient contributed more to the sputum conversion time . Methods In a double-blind r and omized community trial , newly sputum smear positive pulmonary TB patients were assigned r and omly to receive zinc , vitamin A , zinc + vitamin A or placebo on top of TB treatment . Patients were asked to deliver their sputum on weekly basis to measure positivity of the bacteria . Nutritional status , chest x-ray , hemoglobin , C-reactive protein ( CRP ) , retinol and zinc level were examined prior to , after 2 and 6 months of treatment . Results Initially , 300 patients were enrolled , and 255 finished the treatment . Most patients were severely malnourished ( mean BMI 16.5 ± 2.2 Kg/m2 ) . Patients in the zinc + vitamin A group showed earlier sputum conversion time ( mean 1.9 weeks ) compared with that in the other groups ; however the difference was not significant . Also , no benefit could be demonstrated of any of the used supplementations on clinical , nutritional , chest x-ray , or laboratory findings . Conclusions This study among severely malnourished TB patients , did not confirm that single or combined supplementation of zinc and vitamin A significantly reduced sputum conversion time or had other significant benefit OBJECTIVE To assess the effect of micronutrient supplementation on tuberculosis ( TB ) patient outcomes . MATERIAL AND METHODS The r and omized , double-blinded , placebo-controlled study was conducted in pulmonary TB patients undergoing directly observed treatment short course/ tratamiento acortado estrictamente supervisado ( TAES/ DOTS ) at IMSS in Ciudad Juarez , Chihuahua , Mexico , who were recruited during August 2005-July 2006 . Consecutive patients received zinc and vitamin A supplements or matched placebo for four months . Dietary intake , blood zinc and vitamin A , immune response ( IFN-gamma , TNF-alpha , and IL-10 mRNA ) , and sputum smear conversion were measured . RESULTS The proportion of micronutrient compared to placebo group subjects with a negative sputum smear by month 3 was significantly increased ( p= 0.03 ) . This occurred subsequent to increased TNF-alpha and IFN-gamma and decreased IL-10 observed at month 2 . Micronutrient supplementation appeared to accelerate the beneficial therapeutic effect of chemotherapy . CONCLUSIONS The earlier elimination of bacilli from sputum was associated with improved zinc status and Th1 immune response . The therapeutic effect of vitamin A was less evident Background Development of new tuberculosis ( TB ) drugs and alternative treatment strategies are urgently required to control the global spread of TB . Previous results have shown that vitamin D3 ( vitD3 ) and 4-phenyl butyrate ( PBA ) are potent inducers of the host defense peptide LL-37 that possess anti-mycobacterial effects . Objective To examine if oral adjunctive therapy with 5,000IU vitD3 or 2x500 mg PBA or PBA+vitD3 to st and ard chemotherapy would lead to enhanced recovery in sputum smear-positive pulmonary TB patients . Methods Adult TB patients ( n = 288 ) were enrolled in a r and omized , double-blind , placebo-controlled  trial conducted in Bangladesh . Primary endpoints included proportions of patients with a negative sputum culture at week 4 and reduction in clinical symptoms at week 8 . Clinical assessment s and sputum smear microscopy were performed weekly up to week 4 , fortnightly up to week 12 and at week 24 ; TB culture was performed at week 0 , 4 and 8 ; concentrations of LL-37 in cells , 25-hydroxyvitamin D3 ( 25(OH)D3 ) in plasma and ex vivo bactericidal function of monocyte-derived macrophages ( MDM ) were determined at week 0 , 4 , 8 , 12 and additionally at week 24 for plasma 25(OH)D3 . Results At week 4 , 71 % ( 46/65 ) of the patients in the PBA+vitD3-group ( p = 0.001 ) and 61.3 % ( 38/62 ) in the vitD3-group ( p = 0.032 ) were culture negative compared to 42.2 % ( 27/64 ) in the placebo-group . The odds of sputum culture being negative at week 4 was 3.42 times higher in the PBA+vitD3-group ( p = 0.001 ) and 2.2 times higher in vitD3-group ( p = 0.032 ) compared to placebo . The concentration of LL-37 in MDM was significantly higher in the PBA-group compared to placebo at week 12 ( p = 0.034 ) . Decline in intracellular Mtb growth in MDM was earlier in the PBA-group compared to placebo ( log rank 11.38 , p = 0.01 ) . Conclusion Adjunct therapy with PBA+vitD3 or vitD3 or PBA to st and ard short-course therapy demonstrated beneficial effects towards clinical recovery and holds potential for host-directed-therapy in the treatment of TB . Trial Registration clinical trials.gov Limited studies exist regarding whether incorporating micronutrient supplements during tuberculosis ( TB ) treatment may improve cell-mediated immune response . We examined the effect of micronutrient supplementation on lymphocyte proliferation response to mycobacteria or T-cell mitogens in a r and omized trial conducted on 423 patients with pulmonary TB . Eligible participants were r and omly assigned to receive a daily dose of micronutrients ( vitamins A , B-complex , C , E , and selenium ) or placebo at the time of initiation of TB treatment . We found no overall effect of micronutrient supplements on lymphocyte proliferative responses to phytohaemagglutinin or purified protein derivatives in HIV-negative and HIV-positive TB patients . Of HIV-negative TB patients , the micronutrient group tended to show higher proliferative responses to concanavalin A than the placebo group , although the clinical relevance of this finding is not readily notable . The role of nutritional intervention in this vulnerable population remains an important area of future research 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 r and omised , 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 Clinical Trials.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 Clinical Trials.gov . Registry number :
Conclusion Vitamin D supplementation showed no influence on the improvement of sputum smear-negative conversion rates and BMI , as well as the decrease in ESR
Background Vitamin D might be promising to serve as an adjunctive therapy for pulmonary tuberculosis ( TB ) .
However , the results remained controversial .
We conducted a systematic review and meta- analysis to evaluate the efficacy and safety of vitamin D in patients with pulmonary TB .