title: L-arginine and Vitamin D Adjunctive Therapies in Pulmonary Tuberculosis: A Randomised, Double-Blind, Placebo-Controlled Trial Vitamin D accelerates clinical recovery from tuberculosis: results of the SUCCINCT Study [Supplementary Cholecalciferol in recovery from tuberculosis]. A randomized, placebo-controlled, clinical trial of vitamin D supplementation in patients with pulmonary tuberculosis’ Vitamin D status and TB treatment outcomes in adult patients in Tanzania: a cohort study A single dose of vitamin D enhances immunity to mycobacteria. Why randomized controlled trials of calcium and vitamin D sometimes fail Vitamin D status and antimicrobial peptide cathelicidin (LL-37) concentrations in patients with active pulmonary tuberculosis. Effect of vitamin D supplementation in type 2 diabetes patients with pulmonary tuberculosis. High-dose vitamin D3 in adults with pulmonary tuberculosis: a double-blind randomized controlled trial.
abstract: 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 : Background Vitamin 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 . Methods Two hundred and fifty nine patients with pulmonary TB were r and omized to receive either 600,000 IU of Intramuscular vitamin D3 or placebo for 2 doses . Assessment s 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 . Results After 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 ) . Conclusions Supplementation 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 registration Clinical Trials.gov ; No. NCT01130311 ; URL : clinical Objectives Vitamin D is an immunomodulator and can alter response to tuberculosis ( TB ) treatment , though r and omised trials have been inconclusive to date . We present one of the first comprehensive analysis of the associations between vitamin D status and TB treatment , T-cell counts and nutritional outcomes by HIV status . Design Cohort study . Setting Outpatient clinics in Tanzania . Participants 25-hydroxyvitamin D levels were assessed in a cohort of 677 patients with TB ( 344 HIV infected ) initiating anti-TB treatment at enrolment in a multivitamin supplementation ( excluding vitamin D ) trial ( Clinical trials.gov identifier : NCT00197704 ) . Primary and secondary outcome measures Information on treatment outcomes such as failure and relapse , HIV disease progression , T-cell counts and anthropometry was collected routinely , with a median follow-up of 52 and 30 months for HIV-uninfected and HIV-infected patients , respectively . Cox and binomial regression , and generalised estimating equations were used to assess the association of vitamin D status with these outcomes . Results Mean 25-hydroxyvitamin D concentrations at enrolment were 69.8 ( ±21.5 ) nmol/L ( 27.9 ( ±8.6 ) ng/mL ) . Vitamin D insufficiency ( < 75 nmol/L ) was associated with a 66 % higher risk of relapse ( 95 % CI 4 % to 164 % ; 133 % higher risk in HIV-uninfected patients ) . Each unit higher 25-hydroxyvitamin D levels at baseline were associated with a decrease of 3 ( p=0.004 ) CD8 and 3 ( p=0.01 ) CD3 T-cells/µL during follow-up in patients with HIV infection . Vitamin D insufficiency was also associated with a greater decrease of body mass index ( BMI ; –0.21 kg/m2 ; 95 % CI −0.39 to −0.02 ) , during the first 8 months of follow-up . No association was observed  for vitamin D status with mortality or HIV disease progression . Conclusions Adequate vitamin D status is associated with a lower risk of relapse and with improved nutritional indicators such as BMI in patients with TB , with or without HIV infection . Further research is needed to determine the optimal dose of vitamin D and effectiveness of daily vitamin D supplementation among patients with TB RATIONALE Vitamin D was used to treat tuberculosis ( TB ) in the preantibiotic era . Prospect i ve studies to evaluate the effect of vitamin D supplementation on antimycobacterial immunity have not previously been performed . OBJECTIVES To determine the effect of vitamin D supplementation on antimycobacterial immunity and vitamin D status . METHODS A double-blind r and omized controlled trial was conducted in 192 healthy adult TB contacts in London , United Kingdom . Participants were r and omized to receive a single oral dose of 2.5 mg vitamin D or placebo and followed up at 6 weeks . MEASUREMENTS AND MAIN RESULTS The primary outcome measure was assessed with a functional whole blood assay ( BCG-lux assay ) , which measures the ability of whole blood to restrict luminescence , and thus growth , of recombinant reporter mycobacteria in vitro ; the readout is expressed as a luminescence ratio ( luminescence postinfection/baseline luminescence ) . IFN-gamma responses to the Mycobacterium tuberculosis antigens early secretory antigenic target-6 and culture filtrate protein 10 were determined with a second whole blood assay . Vitamin D supplementation significantly enhanced the ability of participants ' whole blood to restrict BCG-lux luminescence in vitro compared with placebo ( mean luminescence ratio at follow-up , 0.57 , vs. 0.71 , respectively ; 95 % confidence interval for difference , 0.01 - 0.25 ; p=0.03 ) but did not affect antigen-stimulated IFN-gamma secretion . CONCLUSIONS A single oral dose of 2.5 mg vitamin D significantly enhanced the ability of participants ' whole blood to restrict BCG-lux luminescence in vitro without affecting antigen-stimulated IFN-gamma responses . Clinical trials should be performed to determine whether vitamin D supplementation prevents reactivation of latent TB infection . Clinical trial registered with www . clinical trials.gov ( NCT 00157066 ) The importance of nutrients for promotion of health and prevention of disease has long been recognized . Nonetheless , scientists are still trying to delineate the optimal intakes of various nutrients and their potential benefits for different population s. To that end , evidence -based medicine ( EBM ) has been applied to the study of nutrition . EBM methods basically call for the use of r and omized controlled trials ( RCTs ) to establish causal connection between the intervention and any particular endpoint . This paper focuses on problems that arise in the use of RCTS to establish a causal link between nutrients and various clinical endpoints . While many RCTS of calcium and vitamin D have been positive , many others have been null . In this paper , we discuss the reasons why effective nutrient agents may be found to be ineffective in particular studies , giving examples of such null results , and focusing on the nearly universal failure to consider biological criteria in design ing RCTs . Our purpose is ( 1 ) to inform future study design so as to ensure that relevant biological facts are considered and ( 2 ) to aid in the interpretation of the abundant , but often inconsistent literature on this topic BACKGROUND Vitamin D insufficiency is common in industrialized and developing nations . Recent studies have shown that vitamin D insufficiency is associated with a higher risk of active tuberculosis .  Laboratory studies provided a mechanism for this link on the basis of findings that vitamin D metabolites regulate the expression of cathelicidin ( LL-37 ) , which is an endogenous antimicrobial peptide with activity against Mycobacterium tuberculosis . Little information is available on the clinical relation between vitamin D , LL-37 concentrations , and disease severity in patients with tuberculosis . OBJECTIVE The primary objective of the study was to evaluate the relation between vitamin D nutriture , serum LL-37 concentrations , and tuberculosis by using sample s stored in the Tuberculosis Trials Consortium serum repository . DESIGN We measured  25-hydroxyvitamin D [ 25(OH)D ] and LL-37 concentrations  in 95 serum specimens from patients with culture-confirmed pulmonary tuberculosis and correlated these concentrations to clinical and demographic variables . RESULTS The prevalence of  vitamin D insufficiency [ serum 25(OH)D concentration lt 30 ng/mL ] in patients with active tuberculosis was 86 % ( n = 95 ) with a mean baseline serum 25(OH)D concentration of 20.4 ng/mL. Factors associated with vitamin D insufficiency were black race and indoor lifestyle . The mean ( plusmn SD ) baseline LL-37 concentration was 49.5 plusmn 23.8 ng/mL. Higher LL-37 concentrations correlated with acid fast bacilli sputum smear positivity and weight gt 10 % below ideal body weight . Serum vitamin D status of the study subjects did not correlate with serum LL-37 concentrations . CONCLUSION More prospect ively design ed studies are needed to evaluate the clinical implication s of vitamin D insufficiency in patients with tuberculosis and the utility of circulating LL-37 as a potential biomarker in patients with active tuberculosis disease . The parent trial was registered at clinical trials.gov as NCT00023335 AIM Diabetes and vitamin D deficiency are widely prevalent in India . Studies have proven correlation between low vitamin D levels and pulmonary tuberculosis ( PTB ) and low vitamin D levels and insulin resistance . We evaluated the effects of vitamin D supplementation on type 2 diabetes mellitus patients with pulmonary tuberculosis ( PTB ) . METHODS Forty-five subjects ( M : F=34:11 ) were screened . Inclusion criteria were age > 15 years , newly diagnosed PTB cases with uncontrolled diabetes , serum vitamin D<20 ng/ml . The patients with vitamin D level<20 ng/ml were r and omly assigned to 2 groups . Group 1 subjects received oral cholecalceferol ( 60,000 units/week ) and calcium carbonate ( 1g/day ) along with anti tubercular treatment ( ATT ) , while group 2 subjects did not .  Sputum was checked at interval of 2 weeks for 12 weeks . Primary end point was time to achieve sputum smear conversion . RESULTS Fifteen patients having vitamin D>20 ng/ml were excluded . Age of the patients was 42.9±13.2 years and serum vitamin D levels were 18.4±15.3 ng/ml . Sputum smear conversion was 6 weeks in group 1 versus 8 weeks in group 2 ( p=0.067 ) . Glycated hemoglobin levels reduced from 11.1±1.3 to 7.7±0.9 in group 1 versus 10.3±1.2 to 7.8±1.1 ( p>0.1 ) . CONCLUSION Vitamin D can serve as adjuvant treatment of tuberculosis in diabetics with vitamin D deficiency . Further studies are required to vali date this observation and define a cut off for vitamin D level to prevent immunological alterations 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
target: 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: 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 .