Low vitamin D levels do not aggravate COVID-19 risk or death, and vitamin D supplementation does not improve outcomes in hospitalized patients with COVID-19: a meta-analysis and GRADE assessment of cohort studies and RCTs

Abstract Background The associations between vitamin D and coronavirus disease 2019 (COVID-19) infection and clinical outcomes are controversial. The efficacy of vitamin D supplementation in COVID-19 is also not clear. Methods We identified relevant cohort studies that assessed the relationship between vitamin D, COVID-19 infection and associated death and randomized controlled trials (RCTs) that reported vitamin D supplementation on the outcomes in patients with COVID-19 by searching the PubMed, EMBASE, and medRxiv databases up to June 5th, 2021. Evidence quality levels and recommendations were assessed using the GRADE system. Results Eleven cohort studies with 536,105 patients and two RCTs were identified. Vitamin D deficiency (< 20 ng/ml) or insufficiency (< 30 ng/ml) was not associated with an significant increased risk of COVID-19 infection (OR for < 20 ng/ml: 1.61, 95% CI: 0.92–2.80, I2 = 92%) or in-hospital death (OR for < 20 ng/ml: 2.18, 95% CI: 0.91–5.26, I2 = 72%; OR for < 30 ng/ml: 3.07, 95% CI: 0.64–14.78, I2 = 66%). Each 10 ng/ml increase in serum vitamin D was not associated with a significant decreased risk of COVID-19 infection (OR: 0.92, 95% CI: 0.79–1.08, I2 = 98%) or death (OR: 0.65, 95% CI: 0.40–1.06, I2 = 79%). The overall quality of evidence (GRADE) for COVID-19 infection and associated death was very low. Vitamin D supplements did not significantly decrease death (OR: 0.57, I2 = 64%) or ICU admission (OR: 0.14, I2 = 90%) in patients with COVID-19. The level of evidence as qualified using GRADE was low. Conclusions Current evidence suggested that vitamin D deficiency or insufficiency was not significantly linked to susceptibility to COVID-19 infection or its associated death. Vitamin D supplements did not significantly improve clinical outcomes in patients with COVID-19. The overall GRADE evidence quality was low, we suggest that vitamin D supplementation was not recommended for patients with COVID-19.

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Calcium and/or Vitamin D Supplementation for the Prevention of Fragility Fractures: Who Needs It?

Nutrients ◽

10.3390/nu12041011 ◽

2020 ◽

Vol 12 (4) ◽

pp. 1011 ◽

Cited By ~ 5

Author(s):

Ian R Reid ◽

Mark J Bolland

Keyword(s):

Vitamin D ◽

Bone Density ◽

Vitamin D Deficiency ◽

Nursing Home Residents ◽

Fragility Fractures ◽

Vitamin D Supplementation ◽

Community Dwelling ◽

Current Evidence ◽

Calcium Supplements ◽

Vitamin D Supplements

Vitamin D and calcium have different biological functions, so the need for supplementation, and its safety and efficacy, need to be evaluated for each separately. Vitamin D deficiency is usually the result of low sunlight exposure (e.g., in frail older people, those who are veiled, those with dark-skin living at higher latitudes) and is reversible with calciferol 400–800 IU/day. Calcium supplements produce a 1% increase in bone density in the first year of use, without further increases subsequently. Vitamin D supplements do not improve bone density in clinical trials except in analyses of subgroups with baseline levels of 25-hydroxyvitamin D <30 nmol/L. Supplementation with calcium, vitamin D, or their combination does not prevent fractures in community-dwelling adults, but a large study in vitamin D-deficient nursing home residents did demonstrate fracture prevention. When treating osteoporosis, co-administration of calcium with anti-resorptive drugs has not been shown to impact on treatment efficacy. Correction of severe vitamin D deficiency (<25 nmol/L) is necessary before use of potent anti-resorptive drugs to avoid hypocalcemia. Calcium supplements cause gastrointestinal side effects, particularly constipation, and increase the risk of kidney stones and, probably, heart attacks by about 20%. Low-dose vitamin D is safe, but doses >4000 IU/day have been associated with more falls and fractures. Current evidence does not support use of either calcium or vitamin D supplements in healthy community-dwelling adults.

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Implications of Vitamin D Research in Chickens can Advance Human Nutrition and Perspectives for the Future

Current Developments in Nutrition ◽

10.1093/cdn/nzab018 ◽

2021 ◽

Author(s):

Matthew F Warren ◽

Kimberly A Livingston

Keyword(s):

Vitamin D ◽

Vitamin D Deficiency ◽

Vitamin D Supplementation ◽

The Body ◽

Human Nutrition ◽

Vitamin D Metabolites ◽

Vitamin D Metabolism ◽

Related Research ◽

Vitamin D Intake ◽

Increased Risk

Abstract The risk of vitamin D insufficiency in humans is a global problem that requires improving ways to increase vitamin D intake. Supplements are a primary means for increasing vitamin D intake, but without a clear consensus on what constitutes vitamin D sufficiency, there is toxicity risk with taking supplements. Chickens have been used in many vitamin D-related research studies, especially studies involving vitamin D supplementation. Our state-of-the-art review evaluates vitamin D metabolism and how the different hydroxylated forms are synthesized. We provide an overview with how vitamin D is absorbed, transported, excreted, and what tissues in the body store vitamin D metabolites. We also discuss a number of studies involving vitamin D supplementation with broilers and laying hens. Vitamin D deficiency and toxicity are also described and how they can be caused. The vitamin D receptor (VDR) is important for vitamin D metabolism. However, there is much more that can be understood with VDR in chickens. Potential research aims involving vitamin D and chickens should explore VDR mechanisms which could lead to newer insights with VDR. Utilizing chickens in future research to help with elucidating vitamin D mechanisms has great potential to advance human nutrition. Finding ways to increase vitamin D intake will be necessary because the coronavirus 2019 disease (COVID-19) pandemic is leading to increased risk of vitamin D deficiency in many populations. Chickens can provide a dual purpose with addressing pandemic-caused vitamin D deficiency: 1) vitamin D supplementation gives chickens added value with possibly leading to vitamin D-enriched meat and egg products; and 2) chickens’ use in research provides data for translational research. Expanding vitamin D-related research in chickens to include more nutritional aims in vitamin D status has great implications with developing better strategies to improve human health.

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To Supplement or not to Supplement? The Rationale of Vitamin D Supplementation in Systemic Lupus Erythematosus

The Open Rheumatology Journal ◽

10.2174/1874312901812010226 ◽

2018 ◽

Vol 12 (1) ◽

pp. 226-247 ◽

Cited By ~ 1

Author(s):

Alessandra Nerviani ◽

Daniele Mauro ◽

Michele Gilio ◽

Rosa Daniela Grembiale ◽

Myles J. Lewis

Keyword(s):

Systemic Lupus Erythematosus ◽

Vitamin D ◽

Vitamin D Deficiency ◽

Lupus Erythematosus ◽

Clinical Manifestations ◽

Vitamin D Supplementation ◽

Current Evidence ◽

Systemic Lupus ◽

Vitamin D Receptors ◽

Vitamin D Levels

Background: Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease characterised by abnormal activation of the immune system, chronic inflammation and organ damage. Lupus patients are more prone to be vitamin D deficient. However, current evidence is not conclusive with regards to the role played by vitamin D in SLE development, progression, and clinical manifestations. Objective: Here, we will summarise the current knowledge about vitamin D deficiency prevalence, risk factors, molecular effects, and potential pathogenic role in SLE. We will focus on the link between vitamin D deficiency and lupus clinical manifestations, and on the clinical trials assessing the effects of vitamin D supplementation in SLE. Method: A detailed literature search was performed exploiting the available databases, using “vitamin D and lupus/SLE” as keywords. The relevant interventional trials published over the last decade have been considered and the results are reported here. Conclusion: Several immune cells express vitamin D receptors. Thus, an immunomodulatory role for vitamin D in lupus is plausible. Numerous observational studies have investigated the relationship between vitamin D levels and clinical/serological manifestations of SLE with contrasting results. Negative correlations between vitamin D levels and disease activity, fatigue, renal and cardiovascular disease, and anti-dsDNA titres have been described but not conclusively accepted. In experimental models of lupus, vitamin D supplementation can improve the disease. Interventional trials have assessed the potential therapeutic value of vitamin D in SLE, but further larger studies are needed.

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Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions

Endocrine Reviews ◽

10.1210/er.2018-00126 ◽

2018 ◽

Vol 40 (4) ◽

pp. 1109-1151 ◽

Cited By ~ 110

Author(s):

Roger Bouillon ◽

Claudio Marcocci ◽

Geert Carmeliet ◽

Daniel Bikle ◽

John H White ◽

...

Keyword(s):

Vitamin D ◽

Vitamin D Deficiency ◽

Human Subjects ◽

Osteoporotic Fractures ◽

Vitamin D Supplementation ◽

Current Evidence ◽

Elderly Subjects ◽

Vitamin D Status ◽

Hydroxyvitamin D ◽

25 Hydroxyvitamin D

AbstractThe etiology of endemic rickets was discovered a century ago. Vitamin D is the precursor of 25-hydroxyvitamin D and other metabolites, including 1,25(OH)2D, the ligand for the vitamin D receptor (VDR). The effects of the vitamin D endocrine system on bone and its growth plate are primarily indirect and mediated by its effect on intestinal calcium transport and serum calcium and phosphate homeostasis. Rickets and osteomalacia can be prevented by daily supplements of 400 IU of vitamin D. Vitamin D deficiency (serum 25-hydroxyvitamin D <50 nmol/L) accelerates bone turnover, bone loss, and osteoporotic fractures. These risks can be reduced by 800 IU of vitamin D together with an appropriate calcium intake, given to institutionalized or vitamin D–deficient elderly subjects. VDR and vitamin D metabolic enzymes are widely expressed. Numerous genetic, molecular, cellular, and animal studies strongly suggest that vitamin D signaling has many extraskeletal effects. These include regulation of cell proliferation, immune and muscle function, skin differentiation, and reproduction, as well as vascular and metabolic properties. From observational studies in human subjects, poor vitamin D status is associated with nearly all diseases predicted by these extraskeletal actions. Results of randomized controlled trials and Mendelian randomization studies are supportive of vitamin D supplementation in reducing the incidence of some diseases, but, globally, conclusions are mixed. These findings point to a need for continued ongoing and future basic and clinical studies to better define whether vitamin D status can be optimized to improve many aspects of human health. Vitamin D deficiency enhances the risk of osteoporotic fractures and is associated with many diseases. We review what is established and what is plausible regarding the health effects of vitamin D.

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Prevalence of 25-hydroxyvitamin D deficiency in subgroups of elderly persons with anemia: association with anemia of inflammation

Blood ◽

10.1182/blood-2010-09-309708 ◽

2011 ◽

Vol 117 (10) ◽

pp. 2800-2806 ◽

Cited By ~ 69

Author(s):

Todd S. Perlstein ◽

Reena Pande ◽

Nancy Berliner ◽

Gary J. Vanasse

Keyword(s):

Vitamin D ◽

Vitamin D Deficiency ◽

Serum Levels ◽

The Elderly ◽

Vitamin D Supplementation ◽

World Health ◽

Elderly Persons ◽

Increased Risk ◽

Health Organization ◽

Anemia Of Inflammation

AbstractAnemia and vitamin D deficiency are conditions that both result in significant morbidity and increase with age. The potential relationship between them remains poorly understood, particularly in the elderly. We used the Third National Health and Nutrition Examination Survey to examine the association of vitamin D deficiency with anemia subtypes in persons aged ≥ 60 years. Vitamin D deficiency was defined as serum levels < 20 ng/mL, and anemia was defined according to World Health Organization criteria. Vitamin D deficiency was associated with anemia prevalence independent of age, sex, or race/ethnicity (odds ratio, 1.47; 95% confidence interval, 1.06-2.05; P = .02) and varied significantly by anemia subtype (P overall = .003). The prevalence of vitamin D deficiency was 33.3% in the nonanemic population, 56% in anemia of inflammation (AI; P = .008), and 33.0% in unexplained anemia (P = .55). Non-Hispanic blacks had a 7-fold increased risk of AI compared with whites, and this was partially attenuated after adjusting for vitamin D deficiency. These data show that vitamin D deficiency is associated with specific subtypes of anemia in the elderly, especially in those with AI. Vitamin D may suppress inflammatory pathways, and studies to determine whether vitamin D supplementation ameliorates AI are warranted.

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Vitamin D Supplementation in Australia: Implications for the Development of Supplementation Guidelines

Journal of Nutrition and Metabolism ◽

10.1155/2014/374208 ◽

2014 ◽

Vol 2014 ◽

pp. 1-4 ◽

Cited By ~ 5

Author(s):

Kellie Bilinski ◽

Peter Talbot

Keyword(s):

Public Health ◽

Vitamin D ◽

Vitamin D Deficiency ◽

Vitamin D Supplementation ◽

Supplement Use ◽

The Past ◽

Threefold Increase ◽

Vitamin D Supplements ◽

Vitamin D Supplement ◽

Potential Public Health

High rates of vitamin D deficiency and testing have been reported in Australia, yet there are few reports regarding vitamin D supplement use. Australian wholesale sales data was obtained for vitamin D supplements for the period 2000–2011. There has been a threefold increase in supplement sales over the past decade, whereby over A$94 million supplements containing vitamin D in Australia were sold during the year 2010. There were eighty-nine manufacturers that produce a variety of 195 vitamin D products. The amount of vitamin D in these products varies considerably, from 40 to 1000 IU per unit, although supplements containing only vitamin D had the highest amount of vitamin D. There was a trend for sales to increase in winter months. Given the potential public health benefits of vitamin D, there is an urgent need for a better understanding of supplementation use and for the development of supplementation.

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No Evidence for an Association of Vitamin D Deficiency and Migraine: A Systematic Review of the Literature

BioMed Research International ◽

10.1155/2014/827635 ◽

2014 ◽

Vol 2014 ◽

pp. 1-5 ◽

Cited By ~ 7

Author(s):

Giuseppe Lippi ◽

Gianfranco Cervellin ◽

Camilla Mattiuzzi

Keyword(s):

Vitamin D ◽

Vitamin D Deficiency ◽

Web Of Science ◽

Case Reports ◽

Vitamin D Supplementation ◽

Current Evidence ◽

Cross Sectional ◽

Electronic Search ◽

Human Disorders ◽

Keywords Migraine

Vitamin D deficiency is associated with a number of human disorders, including cardiovascular disease, cancer, diabetes, frailty, and infections. Since an association between vitamin D and migraine has also been recently speculated, we performed an electronic search on Medline, Scopus, and Web of Science using the keywords “migraine” and “vitamin D,” “25OH-D” “cholecalciferol,” “ergocalciferol,” with no language or date restriction. The electronic search allowed identifying seven studies (3 observational, 2 cross-sectional, and 2 case reports). The two case reports, including four women, showed favourable effects of vitamin D supplementation on migraine severity, but these studies were small and not placebo controlled. As regards the three observational studies, vitamin D deficiency was observed in 13.2 to 14.8% of migraine patients, and these rates do not differ from those reported in the general population (i.e., vitamin D deficiency between 22 and 42%). The results of the two cross-sectional studies are even more controversial, since no association was found between vitamin D status and migraine in both trials. In conclusion, the current evidence suggests that the association between migraine and vitamin D lacks reliable scientific support.

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Are Indian obese children and adolescents at increased risk for Vitamin D deficiency?

Indian Journal of Medical Sciences ◽

10.25259/ijms_510_2020 ◽

2021 ◽

Vol 0 ◽

pp. 1-5

Author(s):

Aashima Dabas ◽

T. Aravind ◽

Sangeeta Yadav ◽

Mukta Mantan ◽

Smita Kaushik

Keyword(s):

Vitamin D ◽

Vitamin D Deficiency ◽

Vitamin D Supplementation ◽

Obese Children ◽

Indian Children ◽

Hydroxyvitamin D ◽

Increased Risk ◽

High Risk Factor ◽

25 Hydroxyvitamin D ◽

Obese Subjects

Objectives: Obesity has been mentioned as a high risk factor for Vitamin D deficiency (VDD) requiring supplementation in Indian children. Material and Methods: Forty obese and age-matched non-obese subjects (age 5–18 years) were assessed for lifestyle parameters, metabolic profile, and serum 25-hydroxyvitamin D (25OHD). VDD was defined as serum 25OHD < 12 ng/mL. Results: Mean 25OHD was comparable among obese and controls (15.0 ± 9.95 and 15.1 ± 4.79 ng/mL; P = 0.97) with VDD seen in 82% of cases and 85% of controls. Pubertal cases had lower 25OHD values than prepubertal obese cases (10.78 ± 4.69 and 17.2 ± 11 ng/mL; P = 0.06). Mean duration of physical activity (<2 h/week) and screen time (>2 h/day) was similar across prepubertal and pubertal groups and between obese and controls. Obesity was not associated with risk for VDD among cases and controls (odds ratio 0.83, 95% C.I. 0.25–2.7, P = 0.76). Conclusion: Obese pubertal subjects were more at risk for VDD than prepubertal subjects. Routine Vitamin D supplementation to obese Indian children may be considered during adolescence.

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Nutritional Supplementation of Naturally Occurring Vitamin D to Improve Hemorrhagic Stroke Outcomes

Frontiers in Neurology ◽

10.3389/fneur.2021.670245 ◽

2021 ◽

Vol 12 ◽

Author(s):

Rani Ashouri ◽

Madison Fangman ◽

Jordan Brielmaier ◽

Zoe A. Fields ◽

Natalie Campo ◽

...

Keyword(s):

Vitamin D ◽

Vitamin D Deficiency ◽

Hemorrhagic Stroke ◽

Delayed Cerebral Ischemia ◽

Vitamin D Supplementation ◽

Dietary Vitamin ◽

Stroke Incidence ◽

Stroke Outcomes ◽

Increased Risk ◽

The Impact

Vitamin D deficiency, if left untreated, is associated with bone disorders, cardiovascular damage, and an increased risk of ischemic stroke. While there are various nutritional options for the natural intake of vitamin D, we hope to elucidate the potential mechanisms dietary vitamin D may play in hemorrhagic stroke pathology. This scoping review outlines findings from studies relevant to the biochemical activity of vitamin D, the impact of vitamin D deficiency on hemorrhagic stroke outcomes, and the potential benefit of nutritional vitamin D on hemorrhagic stroke outcomes. Here, we analyze the relevant factors that can lead to vitamin D deficiency, and subsequently, a higher risk of hemorrhagic stroke incidence with worsened subsequent outcomes. The neuroprotective mechanisms through which vitamin D works to attenuate hemorrhagic stroke onset and post-stroke outcomes have not yet been thoroughly examined. However, researchers have proposed several potential protective mechanisms, including reduction of blood brain barrier disturbance by inhibiting the production of reactive oxygen species, mitigation of inflammation through a reduction of levels of proinflammatory cytokines, and prevention of cerebral vasospasm and delayed cerebral ischemia following subarachnoid hemorrhage and intracerebral hemorrhage. While more research is needed and there are limitations to vitamin D supplementation, vitamin D as a whole may play a significant role in the dynamics of hemorrhagic stroke. Further research should focus on expanding our understanding of the neuroprotective capacity and mechanisms of vitamin D, as well as how vitamin D supplementation could serve as an effective course of treatment of hemorrhagic strokes.

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Low Vitamin D Levels Predict Mortality in Ankylosing Spondylitis Patients: A Nationwide Population-Based Cohort Study

Nutrients ◽

10.3390/nu12051400 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1400

Author(s):

Niv Ben-Shabat ◽

Abdulla Watad ◽

Aviv Shabat ◽

Nicola Luigi Bragazzi ◽

Doron Comaneshter ◽

...

Keyword(s):

Vitamin D ◽

Cohort Study ◽

Ankylosing Spondylitis ◽

Vitamin D Deficiency ◽

Vitamin D Supplementation ◽

Health Maintenance ◽

Increased Risk ◽

Vitamin D Levels ◽

All Cause Mortality

In this study, we aimed to examine the effect of vitamin D deficiency on all-cause mortality in ankylosing spondylitis (AS) patients and in the general population. This is a retrospective-cohort study based on the electronic database of the largest health-maintenance organization in Israel. AS patients who were first diagnosed between 2002–2007 were included. Controls were matched by age, gender and enrollment-time. Follow-up continued until death or end of study follow-up on 1 July 2019. Laboratory measures of serum 25-hydroxyvitamin-D levels during the entire follow-up period were obtained. A total of 919 AS patients and 4519 controls with a mean time of follow-up of 14.3 years were included. The mean age at the time of enrollment was 52 years, and 22% of them were females. AS was associated with a higher proportion of vitamin D deficiency (odds ratio 1.27 [95% confidence-interval (CI) 1.03–1.58]). In AS patients, insufficient levels of vitamin D (<30 ng/mL) were significantly associated with increased incidence of all-cause mortality (hazard ratio (HR) 1.59 [95% CI 1.02–2.50]). This association was more prominent with the decrease in vitamin D levels (< 20 ng/mL, HR 1.63 [95% CI 1.03–2.60]; <10 ng/mL, HR 1.79 [95% CI 1.01–3.20]) and among male patients (<30 ng/mL, HR 2.11 [95% CI 1.20–3.72]; <20 ng/mL, HR 2.12 [95% CI 1.19–3.80]; <10 ng/mL, HR 2.23 [95% CI 1.12–4.43]). However, inadequate levels of vitamin D among controls were not associated with an increased all-cause mortality. Our study has shown that vitamin D deficiency is more common in AS patients than controls and is linked to an increased risk for all-cause mortality. These results emphasize the need for randomized-controlled trials to evaluate the benefits of vitamin D supplementation as a secondary prevention of mortality in patients with chronic inflammatory rheumatic disease.

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