Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment

Calcidiol, the major circulating metabolite of vitamin D, supports induction of pleiotropic antimicrobial responses in vitro. Vitamin D supplementation elevates circulating calcidiol concentrations, and thus has a potential role in the prevention and treatment of infection. The immunomodulatory effects of administering vitamin D to humans with an infectious disease have not previously been reported. To characterize these effects, we conducted a detailed longitudinal study of circulating and antigen-stimulated immune responses in ninety-five patients receiving antimicrobial therapy for pulmonary tuberculosis who were randomized to receive adjunctive high-dose vitamin D or placebo in a clinical trial, and who fulfilled criteria for per-protocol analysis. Vitamin D supplementation accelerated sputum smear conversion and enhanced treatment-induced resolution of lymphopaenia, monocytosis, hypercytokinaemia, and hyperchemokinaemia. Administration of vitamin D also suppressed antigen-stimulated proinflammatory cytokine responses, but attenuated the suppressive effect of antimicrobial therapy on antigen-stimulated secretion of IL-4, CC chemokine ligand 5, and IFN-α. We demonstrate a previously unappreciated role for vitamin D supplementation in accelerating resolution of inflammatory responses during tuberculosis treatment. Our findings suggest a potential role for adjunctive vitamin D supplementation in the treatment of pulmonary infections to accelerate resolution of inflammatory responses associated with increased risk of mortality.

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Vitamin D: Immuno-modulation and tuberculosis treatment

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2014-0386 ◽

2015 ◽

Vol 93 (5) ◽

pp. 377-384 ◽

Cited By ~ 23

Author(s):

Paramasivam Selvaraj ◽

Murugesan Harishankar ◽

Kolloli Afsal

Keyword(s):

Vitamin D ◽

Vitamin D Supplementation ◽

Sputum Smear ◽

Vdr Gene ◽

Dihydroxyvitamin D ◽

Resistant Tuberculosis ◽

Vdr Gene Polymorphisms ◽

Infected Cells ◽

High Doses

Tuberculosis (TB) is a major global health problem and often coincides with vitamin D deficiency. High doses of vitamin D were widely used to treat TB during the pre-antibiotic era. Vitamin D exerts its action through vitamin D receptor (VDR), and VDR gene polymorphisms are associated with susceptibility or resistance to tuberculosis as well as sputum smear and culture conversion during anti-TB treatment. In-vitro studies have revealed that 1,25-dihydroxyvitamin D3 enhances innate immunity by increased expression of various antimicrobial peptides, including cathelicidin, and induction of autophagy of the infected cells thus restricts the intracellular growth of Mycobacterium tuberculosis in macrophages. On the other hand, vitamin D has been shown to suppress the pro-inflammatory cytokine response and enhance the anti-inflammatory response. Supplementation with vitamin D in concert with treatment for TB may be beneficial with respect to minimizing the excessive tissue damage that occurs during the active stage of tuberculosis disease. Several clinical trials have evaluated vitamin D supplementation as an adjunct therapy in the treatment for tuberculosis. However, results are conflicting, owing to variations in dose regimens and outcomes. Further investigations are needed to find the optimal concentration of vitamin D for supplementation with standard anti-TB drugs to optimize treatment, which could help to effectively manage both drug-sensitive and drug-resistant tuberculosis.

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Old wine in new bottles: vitamin D in the treatment and prevention of tuberculosis

Proceedings of The Nutrition Society ◽

10.1017/s0029665111003326 ◽

2011 ◽

Vol 71 (1) ◽

pp. 84-89 ◽

Cited By ~ 52

Author(s):

Adrian R. Martineau

Keyword(s):

Vitamin D ◽

Vitamin D Deficiency ◽

Low Cost ◽

Vitamin D Supplementation ◽

Treatment And Prevention ◽

Research Priority ◽

Increased Risk ◽

Dosing Regimens ◽

Randomised Controlled

Tuberculosis (TB) is a major cause of mortality, responsible for 1·68 million deaths worldwide in 2009. The global prevalence of latentMycobacterium tuberculosisinfection is estimated to be 32%, and this carries a 5–20% lifetime risk of reactivation disease. The emergence of drug-resistant organisms necessitates the development of new agents to enhance the response to antimicrobial therapy for active TB. Vitamin D was used to treat TB in the pre-antibiotic era, and its active metabolite, 1,25-dihydoxyvitamin D, has long been known to enhance the immune response to mycobacteriain vitro. Vitamin D deficiency is common in patients with active TB, and several clinical trials have evaluated the role of adjunctive vitamin D supplementation in its treatment. Results of these studies are conflicting, reflecting variation between studies in baseline vitamin D status of participants, dosing regimens and outcome measures. Vitamin D deficiency is also recognised to be highly prevalent among people with latentM. tuberculosisinfection in both high- and low-burden settings, and there is a wealth of observational epidemiological evidence linking vitamin D deficiency with increased risk of reactivation disease. Randomised controlled trials of vitamin D supplementation for the prevention of active TB have yet to be performed, however. The conduct of such trials is a research priority, given the safety and low cost of vitamin D supplementation, and the potentially huge public health consequences of positive results.

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The Effect of Yearly-Dose Vitamin D Supplementation on Muscle Function in Mice

Nutrients ◽

10.3390/nu11051097 ◽

2019 ◽

Vol 11 (5) ◽

pp. 1097 ◽

Cited By ~ 2

Author(s):

Alan Hayes ◽

Emma Rybalka ◽

Danielle A. Debruin ◽

Erik D. Hanson ◽

David Scott ◽

...

Keyword(s):

Vitamin D ◽

Muscle Function ◽

Vitamin D Supplementation ◽

Fatigue Properties ◽

Direct Result ◽

High Dose ◽

Early Recovery ◽

Increased Risk ◽

Risk Of Falls ◽

Yearly Dose

Supplementation with vitamin D helps to alleviate weakness and fatigue seen with deficiency. However, large bolus doses appear to worsen the risk of falls. Whether this occurs as a direct result of muscle weakness is currently unknown. Thus, the aims of this study were to examine the muscle function following administration of high doses of vitamin D. Given the safety issues associated with bolus doses, experiments were conducted on C57BL6 mice. Mice at eight weeks of age with otherwise normal levels of vitamin D were supplemented for four weeks with a high dose (HIGH; n = 12) of vitamin D (20000 IU/kg food) designed to provide a year’s worth of vitamin D. These mice were compared to another group who received that same yearly dose in a single bolus i.p. injection (YEAR; n = 12). Mice provided with standard mouse chow, which contained 1000 IU/kg food, and injected with the vitamin D vehicle were used as controls (CON; n = 16). Force and fatigue properties of hind limb fast- and slow-twitch muscles were measured. CON animals ingested vitamin D consistent with typical human supplementation. HIGH animals consumed significantly more food than the CON animals, such that they ingested more than a year’s worth of vitamin D in four weeks. Despite this, there were few differences in the muscle function compared with CON. YEAR animals demonstrated lower absolute and relative forces in both muscles compared to the HIGH animals, as well as lower force during fatigue and early recovery. Large bolus doses of vitamin D appear to have detrimental effects on the skeletal muscle function, likely being a contributor to increased risk of falls observed with similar doses in humans. Mice ingesting the same amount over four weeks did not demonstrate the same deleterious effects, suggesting this may be a safe way to provide high vitamin D if required.

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Vitamin D as an Adjunctive Treatment to Standard Drugs in Pulmonary Tuberculosis Patients: An Evidence-Based Case Report

Advances in Preventive Medicine ◽

10.1155/2019/5181847 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Diajeng Ayesha Soeharto ◽

Diana Ashilah Rifai ◽

Stella Marsudidjadja ◽

Aisha Emilirosy Roekman ◽

Chadijah Karima Assegaf ◽

...

Keyword(s):

Vitamin D ◽

Adjunctive Therapy ◽

Conversion Rate ◽

Vitamin D Supplementation ◽

Adjunctive Treatment ◽

Current Evidence ◽

Sputum Smear ◽

Evidence Based ◽

Sputum Conversion

Background. Vitamin D has a prominent role in the body’s innate immunity as it is important in the maintenance of macrophages and monocytes and its function in defending against infections.In-vitrostudies have established vitamin D’s potential role in tuberculosis (TB) infection, in that it restrictsMycobacterium tuberculosisgrowth, thus implying the potential benefit of vitamin D as an adjunctive treatment for TB. However, clinical trials and reviews have contradicting findings regarding the true clinical efficacy of adjunctive vitamin D, particularly in reducing the sputum conversion rate (SCR).Objective. This study aims to update the current evidence regarding vitamin D supplementation as an adjunctive treatment in achieving the smear sputum conversion rate (SCR) among pulmonary TB patients.Method. A comprehensive search was conducted in October 2018 in PubMed-NCBI, MEDLINE-OVID, SCOPUS-Elsevier, and Cochrane. The selection of studies was done as per the predetermined inclusion and exclusion criteria of this EBCR and resulted in the inclusion of 11 eligible studies (8 RCTs and 3 systematic reviews). The selected studies were then critically appraised for their validity, importance, and applicability according to the CEBM (Centre for Evidence-Based Medicine) appraisal tools.Results. Overall, most of the trials showed no statistically significant changes in terms of the proportion of TB patients with a negative sputum smear conversion in the group treated with an adjunctive therapy vs. the group treated with standard antituberculosis therapy alone. Only one trial showed significant results, which was conducted in a population of TB patients with vitamin D deficiency. Furthermore, overall the reviews showed no significant change in the 8-week sputum smear conversion after treatment within the group given vitamin D in comparison to those who were not.Conclusion. Vitamin D as adjunctive therapy in TB patients shows no clinical improvement in terms of sputum conversion to antituberculosis management.

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Effect of Monthly High-Dose Vitamin D Supplementation on Acute Respiratory Infections in Older Adults: A Randomized Controlled Trial

Clinical Infectious Diseases ◽

10.1093/cid/ciz801 ◽

2019 ◽

Vol 71 (2) ◽

pp. 311-317 ◽

Cited By ~ 9

Author(s):

Carlos A Camargo ◽

John Sluyter ◽

Alistair W Stewart ◽

Kay-Tee Khaw ◽

Carlene M M Lawes ◽

...

Keyword(s):

Older Adults ◽

Vitamin D ◽

Clinical Trials ◽

Controlled Trial ◽

Vitamin D Supplementation ◽

High Dose ◽

Randomized Controlled ◽

Increased Risk ◽

High Dose Vitamin

Abstract Background Although adults with low vitamin D status are at increased risk of acute respiratory infection (ARI), randomized controlled trials of vitamin D supplementation have provided inconsistent results. Methods We performed a randomized, double-blinded, placebo-controlled trial of 5110 adults aged 50–84 years. In 2011–2012, participants were randomized to an initial oral dose of 200 000 IU vitamin D3 followed by 100 000 IU monthly (n = 2558) or placebo (n = 2552) until late 2013 (median follow-up, 1.6 years). Participants reported upper and lower ARIs on monthly questionnaires. Cox models analyzed time to first ARI (upper or lower) by treatment group. Results Participants’ mean age was 66 years and 58% were male; 83% were of European/other ethnicity, with the rest Maori, Polynesian, or South Asian. Mean (SD) baseline blood 25-hydroxyvitamin D [25(OH)D] level was 63 (24) nmol/L; 25% were <50 nmol/L. In a random sample (n = 441), vitamin D supplementation increased mean 25(OH)D to 135 nmol/L at 3 years, while those on placebo remained at 63 nmol/L. During follow-up, 3737 participants reported ≥1 ARI: 74.1% in the vitamin D group versus 73.7% in the placebo group. The hazard ratio for vitamin D compared with placebo was 1.01 (95% CI, 0.94, 1.07). Similar results were seen in most subgroups, including those with baseline 25(OH)D <50 nmol/L and in analyses of the upper/lower components of the ARI outcome. Conclusions Monthly high-dose vitamin D supplementation does not prevent ARI in older adults with a low prevalence of profound vitamin D deficiency at baseline. Whether effects of daily or weekly dosing differ requires further study. Clinical Trials Registration Australian New Zealand Clinical Trials Registry, identifier ACTRN12611000402943.

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24 A Retrospective Review of Vitamin D Levels and Dosing in Burn Center Patients

Journal of Burn Care & Research ◽

10.1093/jbcr/irab032.029 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

pp. S21-S21

Author(s):

Sara Calder ◽

Asia N Quan ◽

Suzanne C Osborn ◽

Karen J Richey ◽

Curt Bay ◽

...

Keyword(s):

Vitamin D ◽

Retrospective Chart Review ◽

Vitamin D Insufficiency ◽

Infectious Complications ◽

Vitamin D Supplementation ◽

High Dose ◽

Weekly Dose ◽

Burn Patients ◽

Increased Risk ◽

Vitamin D Levels

Abstract Introduction The potential consequences of vitamin D insufficiency/deficiency (I/D), include increases in ICU length of stay, organ dysfunction, infectious complications, and mortality. Burn patients, in particular, may be at increased risk of vitamin D I/D due to bleeding, systemic inflammatory response syndrome, increased utilization of vitamin D by injured tissues, compromised vascular integrity, fluid shifts, and leakage of vitamin D binding protein (VDBP) and albumin. The purpose of this study is to determine the incidence of vitamin D I/D and evaluate the institutional vitamin D dosing regimen. Methods A retrospective chart review was performed of all adult patients from January 1, 2018 through December 31, 2019 who received cholecalciferol and had at least one vitamin D hydroxy level during their hospitalization. Vitamin D level was drawn on admission, then weekly thereafter. Patients found to be I/D were initiated on high dose vitamin D supplementation and then adjusted based on the weekly levels. The therapeutic goal for vitamin D supplementation was set at 50 ng/ml. Results Three hundred and sixteen patients met criteria for review. Of those patients, 293 patients (93%) were vitamin D I/D. The magnitude of vitamin D deficiency was strongly positively correlated with %TBSA burn size (p< 0.001). Mean time to reach therapeutic vitamin D levels following initiation of supplementation was 19 days with an average weekly dose of 142,877 international units cholecalciferol. Many patients were discharged prior to reaching therapeutic levels. Time to reach therapeutic levels was also positively correlated with increasing burn size (p< 0.05). Conclusions Vitamin D I/D is present is over 90% of burn patients and the degree of I/D was profound. Additionally, vitamin D I/D was not easily corrected, taking almost 3 weeks to reach therapeutic levels using an aggressive supplementation regimen. Further studies documenting the clinical consequences of vitamin D I/D and development of evidence-based supplementation dosing regimens are warranted.

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667 A Retrospective Review of Vitamin D Levels and Dosing in Burn Center Patients

Journal of Burn Care & Research ◽

10.1093/jbcr/iraa024.283 ◽

2020 ◽

Vol 41 (Supplement_1) ◽

pp. S178-S179

Author(s):

Sara Calder ◽

Asia N Quan ◽

Suzanne Osborn ◽

Virginia Nisbet ◽

Karen J Richey ◽

...

Keyword(s):

Vitamin D ◽

Vitamin D Deficiency ◽

Total Body Surface Area ◽

Retrospective Chart Review ◽

Vitamin D Supplementation ◽

High Dose ◽

Burn Patients ◽

Burn Center ◽

Increased Risk ◽

Vitamin D Levels

Abstract Introduction The potential consequences of vitamin D insufficiency/deficiency (I/D) in critically ill patients include: increased ICU length of stay, organ dysfunction, infectious complications, and mortality. Burn patients, in particular, may be at increased risk of vitamin D I/D due to bleeding, systemic inflammatory response syndrome, increased utilization of vitamin D by injured tissues, compromised vascular integrity, fluid shifts, and leakage of vitamin D binding protein (VDBP) and albumin. The purpose of this study is to determine the incidence of vitamin D I/D and evaluate the institutional vitamin D dosing regimen. Methods A retrospective chart review was performed on all adult patients from January 1, 2018 through December 31, 2019 who received cholecalciferol and had at least one 25-hydroxy vitamin D level during their hospitalization. Vitamin D level was drawn on admission, then weekly thereafter. Patients found to be I/D were initiated on high dose vitamin D supplementation and then adjusted based on the weekly levels. The therapeutic goal for vitamin D supplementation was set at 50 ng/ml. Results Three hundred and sixteen patients met criteria for review. Of those patients, 293 patients (93%) were vitamin D I/D. The magnitude of vitamin D deficiency was strongly negatively correlated with increasing % total body surface area (TBSA) burn size (p< 0.001). Mean time to reach therapeutic vitamin D levels following initiation of supplementation was 19 days, requiring an average of 116,125 units cholecalciferol weekly. Time to reach therapeutic levels was also positively correlated with increasing burn size (p< 0.05). Many patients, however, were discharged prior to reaching therapeutic levels. Conclusions Vitamin D I/D is present in over 90% of burn center patients and the degree of I/D was profound. Additionally, vitamin D I/D was not easily corrected, taking almost 3 weeks to reach therapeutic levels using an aggressive supplementation regimen. Further studies documenting the consequences of vitamin D I/D and development of evidence-based supplementation dosing regimens are warranted. Applicability of Research to Practice This study documents common and severe vitamin D deficiency in burn patients, and difficulty in correcting this deficiency.

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