Vitamin D, 25-hydroxyvitamin D3, and Immunity
Vitamin D, 25-hydroxyvitamin D3, and Immunity
- Vitamin D is an essential nutrient, with recommended dietary intakes defined by expert authorities.
- Vitamin D deficiency is a widespread problem in the U.S., and specific population groups are more likely to suffer from deficiency (e.g. African Americans, the elderly [particularly those in institutional settings such as nursing homes], and individuals who are obese).
- Vitamin D is well-understood to support the immune system, including the defense against viral infections.
- Supplementation with vitamin D has been demonstrated to reduce the incidence of acute respiratory tract infections.In addition, data from around the world indicate that low vitamin D status correlates with increased incidence and severity of, and mortality from, COVID-19.
- A recent study of over 190,000 people in the United States confirms that low vitamin D status strongly correlates with increased rates of infection with SARS-CoV-2, the virus that causes COVID-19.This finding was consistent regardless of age, gender, race/ethnicity, or latitude.
- Supplementation to improve vitamin D status and support immunity is recommended by experts in nutrition and immunity.However, optimization of vitamin D status can take months with the currently available forms of vitamin D.
- 25-hydroxyvitamin D is a metabolite of vitamin D that is present in food, is the predominant form of circulating vitamin D, and is the form that healthcare professionals measure to determine an individual’s vitamin D status.
- 25-hydroxyvitamin D3 is approximately three times as effective vitamin D3 in optimizing vitamin D status, and can do so much more rapidly.
- 25-hydroxyvitamin D3 has a long history of safe consumption in foods.
- At present, 25-hydroxyvitamin D3 is not available as a dietary supplement in the United States.If it were available, 25-hydroxyvitamin D3 could more rapidly and effectively optimize vitamin D status and support immune function.
Supporting an effective immune system is a fundamental way to reduce the risk and consequence of infection. It well understood that nutrition is important to support immunity, and that adequate intake of both macronutrients and micronutrients helps ensure an optimal immune response to infection. Several vitamins, including vitamins A, B6, B12, C, D, E, and folate play fundamental and complementary roles in supporting immunity [1,2]. Deficiency or insufficiency in any of these vitamins can negatively affect immune function and can increase the susceptibility to infection.
Vitamin D is an essential, fat soluble vitamin that historically has been associated with bone health, but it also plays fundamental roles in supporting the immune system. There are multiple forms of vitamin D. Vitamin D3 (also called cholecalciferol) can be obtained through the diet from a variety of sources, including fatty fish, egg yolks, and in fortified foods, such as milk. It is also synthesized in the skin upon exposure to UVB light. Vitamin D2 (also called ergocalciferol) is found primarily in mushrooms, plants, and yeast . Following synthesis in the skin or dietary intake, both forms of vitamin D are transported to the liver, and are hydroxylated to form 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2, respectively. (Collectively, the two forms together are referred to simply as 25-hydroxyvitamin D, also known as calcifediol or calcidiol.) 25-hydroxyvitamin D3 is also found in certain foods, particularly animal products such as meat, liver, and eggs. 25-hydroxyvitamin D is the predominant circulating form of vitamin D found in the bloodstream, and is the form measured by medical professionals to determine a person’s vitamin D status. Ultimately, 25-hydroxyvitamin D is further hydroxylated in the kidney to 1α,25-dihydroxyvitamin D, or calcitriol, the active form of vitamin D .
A wide variety of immune cells have vitamin D receptors that, once engaged, profoundly alter cellular function. Vitamin D supports the differentiation of monocytes to macrophages, as well as the phagocytic and killing capacities of these macrophages; stimulates the expression of antimicrobial proteins in neutrophils, monocytes, natural killer cells, and in epithelial cells, including those that line the respiratory tract; modulates the secretion of inflammatory cytokines; and impacts antibody production and the activities of various T cell subsets [1,4,5].
From a clinical perspective, low vitamin D status, as measured by blood concentrations of 25-hydroxyvitamin D, is associated with an increased rate of infections, and in particular respiratory tract infections [5–7]. Respiratory tract infections are a major cause of illness and death globally, as illustrated both by seasonal influenza and the current COVID-19 pandemic. In the United States alone, the CDC estimates that influenza has been responsible for between 140,000 – 810,000 hospitalizations and 12,000 – 61,000 deaths annually since 2010 . As of mid-October, the US has experienced 8 million cases of COVID-19, and over 217,000 deaths .
Several meta-analyses in recent years have concluded that vitamin D supplementation can reduce the risk of respiratory tract infections and both adults and children [10–14]. In 2017, Martineau and colleagues published a systematic review and meta-analysis of individual participant data (n = 10,933 from 25 randomized, double blind, placebo controlled trials), that investigated the impact of vitamin D supplementation on the incidence of acute respiratory tract infections (ARTI) . For those individuals taking vitamin D supplements on either a daily or weekly basis, there was a 19% reduction in in those experiencing at least one ARTI. The impact was greatest in those participants who were deficient in vitamin D (defined in this study as 25-hydroxyvitamin D levels below 25 nmol/L), as these individuals experienced a 70% reduction.
More recently, a rapidly growing body of evidence indicates that vitamin D status also is associated COVID-19 outcomes. Several publications have reported that lower blood 25-hydroxyvitamin D levels are associated with higher rates of COVID-19 incidence, severity, and/or mortality in both Europe and Israel [15–18]. These data were confirmed in a recent study of over 190,000 Americans . This paper showed that lower blood levels of 25-hydroxyvitamin D were strongly associated with increased rates of positivity in COVID-19 tests. (Tests measured the presence of the SARS-CoV-2 virus, using nucleic acid amplification assays from any one of four providers with US FDA Emergency Use Authorization). In this study, individuals with deficient blood 25-hydroxyvitamin D levels had a 54% higher rate of positivity in their COVID-19 tests than those who had adequate levels. Specifically, those who were deficient (<20 ng/mL in this study) had a 12.5% positive rate, while those who were adequate (30 – 34 ng/mL) had an 8.1% positive rate. Those individuals with higher blood levels of 25-hydroxyvitamin D (≥55 ng/mL) had a positive rate of only 5.9%. Importantly, this relationship between 25-hydroxyvitamin D status and infection rate persisted regardless of age, gender, race/ethnicity, or latitude. In addition, several clinical trials are ongoing globally to directly assess the impact of vitamin D on COVID-19.
Collectively, these data strongly suggest that optimizing vitamin D status may be critical to help support the immune system, and to reduce the incidence and the severity of acute respiratory tract infections, including COVID-19. Unfortunately, few foods are rich in vitamin D, and synthesis in the skin is limited substantially in the elderly, those with darker skin, those who live in northern latitudes, and for everyone during the winter months [20,21]. Studies show that approximately 95% of American adults and 87% of children who do not take vitamin D supplements consume less than the Estimated Average Requirement (EAR) of vitamin D through their diets [22,23]. Not surprisingly, then, vitamin D insufficiency and deficiency is widespread. [24–26]. A recent study based on NHANES data of over 26,000 adults concluded that, based on thresholds established by the Endocrine Society, approximately 70% of adults are insufficient or deficient for vitamin D . Insufficiency and deficiency are higher in populations that are at-risk for increased severity and/or mortality of COVID-19, including African Americans, the elderly (particularly those in institutional settings such as nursing homes, and patient populations), and the obese [20,21,25,27,28]. Furthermore, certain widespread genetic polymorphisms are associated with a substantially elevated risk of vitamin D deficiency [29–31]. This situation represents a true public health crisis, and the FDA considers vitamin D to be a nutrient of public health concern .
Therefore, a growing number of experts in nutrition and immunity recommend vitamin D supplementation [2,4,14,33–36]. Although supplementation with currently available forms of vitamin D is a safe and inexpensive way to improve vitamin D status, it can be slow. Optimizing blood 25-hydroxyvitamin D levels with vitamin D can take several weeks or even months to accomplish [37–41]. This long timeline can be undesirable, especially given the current COVID-19 pandemic, the upcoming influenza season, and as people spend more time indoors during the winter.
As discussed, 25-hydroxyvitamin D is found in food, and is the primary circulating form of vitamin D. This form, particularly 25-hydroxyvitamin D3, has been assessed relative to vitamin D3 regarding its ability to improve vitamin D status. Several clinical trials in adults, including in elderly and obese populations, have demonstrated that 25-hydroxyvitamin D3 is approximately three times more effective than vitamin D3 at raising vitamin D status on an equal weight basis [37–45]. Moreover, supplementation with this form results in a far more rapid increase in vitamin D status, reducing the time to achieve optimized circulating 25-hydroxyvitamin D levels from up to months to just days or weeks [37–41,43]. The positive impact of 25-hydroxyvitamin D on optimizing vitamin D status is even more pronounced in obese people, which is estimated at an incidence of more than 40% of U.S. adults [44,46].
Recently, these results with 25-hydroxyvitamin D are further supported by emerging clinical data in COVID-19 patients. A small pilot clinical study in Spain reported that hospitalized COVID-19 patients receiving therapeutic levels of 25-hydroxyvitamin D in addition to their standard care were significantly less likely to require admission to the Intensive Care Unit .
Together, the totality of data indicate that provision of 25-hydroxyvitamin D3 as a dietary supplement could rapidly optimize the vitamin D status of Americans, thereby supporting their immune systems and reduce the incidence and severity of COVID-19.
The safety of 25-hydroxyvitamin D3 has been demonstrated. As described above, 25-hydroxyvitamin D3 is natural and is found in foods, and thus has a long history of safe consumption. 25-hydroxyvitamin D is the predominant form of circulating vitamin D, and is measured by healthcare professions to determine an individual’s vitamin D status. Clinical studies with exposure levels well above the intended use as a dietary supplement have also been conducted and support safety of use. While not yet available as a dietary supplement in the U.S., 25-hydroxyvitamin D3 is available to consumers in Australia.
In conclusion, vitamin D inadequacy is a widespread problem in the U.S. and globally. Experts in nutrition and immunity conclude there is a need to support optimal vitamin D status. This conclusion is supported by the data demonstrating that vitamin D supplementation reduces the incidence of ARTI, and the emerging data that sufficient vitamin D status may help limit the incidence and severity of COVID-19. Supplementation with currently available forms of vitamin D is effective at improving vitamin D status, but can be slow. If available, other forms of vitamin D, particularly 25-hydroxyvitamin D3, could more rapidly and effectively optimize vitamin D status and support immune function.
- Gombart, A.F.; Pierre, A.; Maggini, S. A Review of Micronutrients and the Immune System–Working in Harmony to Reduce the Risk of Infection. Nutrients 2020, 12, 236, doi:10.3390/nu12010236.
- Calder, P.C.; Carr, A.C.; Gombart, A.F.; Eggersdorfer, M. Optimal Nutritional Status for a Well-Functioning Immune System Is an Important Factor to Protect against Viral Infections. Nutrients 2020, 12, 1181, doi:10.3390/nu12041181.
- Dietary reference intakes: calcium, vitamin D; Ross, A.C., Institute of Medicine (U. S.), Eds.; National Academies Press: Washington, DC, 2011; ISBN 978-0-309-16394-1.
- Charoenngam, N.; Holick, M.F. Immunologic Effects of Vitamin D on Human Health and Disease. Nutrients 2020, 12, 2097, doi:10.3390/nu12072097.
- Cannell, J.J.; Vieth, R.; Umhau, J.C.; Holick, M.F.; Grant, W.B.; Madronich, S.; Garland, C.F.; Giovannucci, E. Epidemic influenza and vitamin D. Epidemiol. Infect. 2006, 134, 1129–1140, doi:10.1017/S0950268806007175.
- Ginde, A.A.; Mansbach, J.M.; Camargo, C.A. Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Archives of internal medicine 2009, 169, 384–390.
- Jat, K.R. Vitamin D deficiency and lower respiratory tract infections in children: a systematic review and meta-analysis of observational studies. Trop Doct 2017, 47, 77–84, doi:10.1177/0049475516644141.
- U.S. Centers for Disease Control Disease Burden of Influenza Available online: https://www.cdc.gov/flu/about/burden/index.html#:~:text=While%20the%20im…. (accessed on Aug 26, 2020).
- Johns Hopkins University COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University Available online: https://gisanddata.maps.arcgis.com/apps/opsdashboard/index.html#/bda7594… (accessed on Oct 16, 2020).
- Bergman, P.; Lindh, Å.U.; Björkhem-Bergman, L.; Lindh, J.D. Vitamin D and Respiratory Tract Infections: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. PLoS ONE 2013, 8, e65835, doi:10.1371/journal.pone.0065835.
- Charan, J.; Goyal, J.P.; Saxena, D.; Yadav, P. Vitamin D for prevention of respiratory tract infections: A systematic review and meta-analysis. Journal of Pharmacology and Pharmacotherapeutics 2012, 3, 300, doi:10.4103/0976-500X.103685.
- Autier, P.; Mullie, P.; Macacu, A.; Dragomir, M.; Boniol, M.; Coppens, K.; Pizot, C.; Boniol, M. Effect of vitamin D supplementation on non-skeletal disorders: a systematic review of meta-analyses and randomised trials. The Lancet Diabetes & Endocrinology 2017, 5, 986–1004, doi:10.1016/S2213-8587(17)30357-1.
- Rejnmark, L.; Bislev, L.S.; Cashman, K.D.; Eiríksdottir, G.; Gaksch, M.; Grübler, M.; Grimnes, G.; Gudnason, V.; Lips, P.; Pilz, S.; et al. Non-skeletal health effects of vitamin D supplementation: A systematic review on findings from meta-analyses summarizing trial data. PLOS ONE 2017, 12, e0180512, doi:10.1371/journal.pone.0180512.
- Martineau, A.R.; Jolliffe, D.A.; Hooper, R.L.; Greenberg, L.; Aloia, J.F.; Bergman, P.; Dubnov-Raz, G.; Esposito, S.; Ganmaa, D.; Ginde, A.A.; et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ 2017, 356, doi:10.1136/bmj.i6583.
- Ali, N. Role of vitamin D in preventing of COVID-19 infection, progression and severity. Journal of Infection and Public Health 2020, S1876034120305311, doi:10.1016/j.jiph.2020.06.021.
- Panagiotou, G.; Tee, S.A.; Ihsan, Y.; Athar, W.; Marchitelli, G.; Kelly, D.; Boot, C.S.; Stock, N.; Macfarlane, J.; Martineau, A.R.; et al. Low serum 25‐hydroxyvitamin D (25[OH]D) levels in patients hospitalized with COVID‐19 are associated with greater disease severity. Clin Endocrinol 2020, cen.14276, doi:10.1111/cen.14276.
- Merzon, E.; Tworowski, D.; Gorohovski, A.; Vinker, S.; Golan Cohen, A.; Green, I.; Frenkel Morgenstern, M. Low plasma 25(OH) vitamin D level is associated with increased risk of COVID‐19 infection: an Israeli population‐based study. FEBS J 2020, febs.15495, doi:10.1111/febs.15495.
- Ilie, P.C.; Stefanescu, S.; Smith, L. The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clin Exp Res 2020, 32, 1195–1198, doi:10.1007/s40520-020-01570-8.
- Kaufman, H.W.; Niles, J.K.; Kroll, M.H.; Bi, C.; Holick, M.F. SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels. PLoS ONE 2020, 15, e0239252, doi:10.1371/journal.pone.0239252.
- Linus Pauling Institute Micronutrient Information Center (Oregon State University) Vitamin D Available online: https://lpi.oregonstate.edu/mic/vitamins/vitamin-D#risk-factors-deficiency (accessed on Oct 16, 2020).
- Holick, M.F. High Prevalence of Vitamin D Inadequacy and Implications for Health. Mayo Clinic Proceedings 2006, 81, 353–373, doi:10.4065/81.3.353.
- Reider, C.A.; Chung, R.-Y.; Devarshi, P.P.; Grant, R.W.; Hazels Mitmesser, S. Inadequacy of Immune Health Nutrients: Intakes in US Adults, the 2005–2016 NHANES. Nutrients 2020, 12, 1735, doi:10.3390/nu12061735.
- Bailey, R.L.; Fulgoni, V.L.; Keast, D.R.; Lentino, C.V.; Dwyer, J.T. Do Dietary Supplements Improve Micronutrient Sufficiency in Children and Adolescents? The Journal of Pediatrics 2012, 161, 837-842.e3, doi:10.1016/j.jpeds.2012.05.009.
- Hilger, J.; Friedel, A.; Herr, R.; Rausch, T.; Roos, F.; Wahl, D.A.; Pierroz, D.D.; Weber, P.; Hoffmann, K. A systematic review of vitamin D status in populations worldwide. British Journal of Nutrition 2014, 111, 23–45, doi:10.1017/S0007114513001840.
- Liu, X.; Baylin, A.; Levy, P.D. Vitamin D deﬁciency and insufﬁciency among US adults: prevalence, predictors and clinical implications. Br. J. Nutr. 2018, 119, 928–936.
- CDC Second National Report on Biochemical Indicators of Diet and Nutrition in the U.S. Population 1999 2002; CDC, 2012; pp. 1–495;.
- U.S. Centers for Disease Control Coronovirus Disease 2019 (COVID-19): People at Increased Risk Available online: cdc.gov/coronavirus/2019-ncov/need-extra-precautions/index.h… (accessed on Oct 16, 2020).
- Allain, T.J.; Dhesi, J. Hypovitaminosis D in Older Adults. Gerontology 2003, 49, 273–278, doi:10.1159/000071707.
- Wang, T.J.; Zhang, F.; Richards, J.B.; Kestenbaum, B.; Meurs, J.B. van; Berry, D.; Kiel, D.P.; Streeten, E.A.; Ohlsson, C.; Koller, D.L.; et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. The Lancet 2010, 376, 180–188, doi:10.1016/S0140-6736(10)60588-0.
- Slater, N.A.; Rager, M.L.; Havrda, D.E.; Harralson, A.F. Genetic Variation in CYP2R1 and GC Genes Associated With Vitamin D Deficiency Status. Journal of Pharmacy Practice 2017, 30, 31–36, doi:10.1177/0897190015585876.
- Yao, P.; Sun, L.; Lu, L.; Ding, H.; Chen, X.; Tang, L.; Xu, X.; Liu, G.; Hu, Y.; Ma, Y.; et al. Effects of Genetic and Nongenetic Factors on Total and Bioavailable 25(OH)D Responses to Vitamin D Supplementation. The Journal of Clinical Endocrinology & Metabolism 2017, 102, 100–110, doi:10.1210/jc.2016-2930.
- U.S. Department of Health and Human Services Food and Drug Administration Use of the Term “Healthy” in the Labeling of Human Food Products: Guidance for Industry. 2016, 6.
- Brenner, H.; Holleczek, B.; Schöttker, B. Vitamin D Insufficiency and Deficiency and Mortality from Respiratory Diseases in a Cohort of Older Adults: Potential for Limiting the Death Toll during and beyond the COVID-19 Pandemic? Nutrients 2020, 12, 2488, doi:10.3390/nu12082488.
- Martineau, A.R.; Forouhi, N.G. Vitamin D for COVID-19: a case to answer? The Lancet Diabetes & Endocrinology 2020, 8, 735–736, doi:10.1016/S2213-8587(20)30268-0.
- Calder, P.C. Nutrition, immunity and COVID-19. BMJNPH 2020, 3, 74–92, doi:10.1136/bmjnph-2020-000085.
- Mitchell, F. Vitamin-D and COVID-19: do deficient risk a poorer outcome? The Lancet Diabetes & Endocrinology 2020, 8, 570, doi:10.1016/S2213-8587(20)30183-2.
- Cashman, K.D.; Seamans, K.M.; Lucey, A.J.; Stocklin, E.; Weber, P.; Kiely, M.; Hill, T.R. Relative effectiveness of oral 25-hydroxyvitamin D3 and vitamin D3 in raising wintertime serum 25-hydroxyvitamin D in older adults. American Journal of Clinical Nutrition 2012, 95, 1350–1356, doi:10.3945/ajcn.111.031427.
- Bischoff-Ferrari, H.A.; Dawson-Hughes, B.; Stöcklin, E.; Sidelnikov, E.; Willett, W.C.; Edel, J.O.; Stähelin, H.B.; Wolfram, S.; Jetter, A.; Schwager, J.; et al. Oral supplementation with 25(OH)D3 versus vitamin D3: Effects on 25(OH)D levels, lower extremity function, blood pressure, and markers of innate immunity. J Bone Miner Res 2012, 27, 160–169, doi:10.1002/jbmr.551.
- Graeff-Armas, L.A.; Bendik, I.; Kunz, I.; Schoop, R.; Hull, S.; Beck, M. Supplemental 25-Hydroxycholecalciferol Is More Effective than Cholecalciferol in Raising Serum 25-Hydroxyvitamin D Concentrations in Older Adults. The Journal of Nutrition 2019, 150, 73–81, doi:10.1093/jn/nxz209.
- Jetter, A.; Egli, A.; Dawson-Hughes, B.; Staehelin, H.B.; Stoecklin, E.; Goessl, R.; Henschkowski, J.; Bischoff-Ferrari, H.A. Pharmacokinetics of oral vitamin D3 and calcifediol. Bone 2014, 59, 14–19, doi:10.1016/j.bone.2013.10.014.
- Vaes, A.M.M.; Tieland, M.; de Regt, M.F.; Wittwer, J.; van Loon, L.J.C.; de Groot, L.C.P.G.M. Dose–response effects of supplementation with calcifediol on serum 25-hydroxyvitamin D status and its metabolites: A randomized controlled trial in older adults. Clinical Nutrition 2017, doi:10.1016/j.clnu.2017.03.029.
- Barger-Lux, M.J.; Heaney, R.P.; Dowell, S.; Chen, T.C.; Holick, M.F. Vitamin D and its Major Metabolites: Serum Levels after Graded Oral Dosing in Healthy Men. Osteoporos Int 1998, 8, 222–230, doi:10.1007/s001980050058.
- Quesada-Gomez, J.M.; Bouillon, R. Is calcifediol better than cholecalciferol for vitamin D supplementation? Osteoporosis International 2018, doi:10.1007/s00198-018-4520-y.
- Di Nisio, A.; De Toni, L.; Sabovic, I.; Rocca, M.S.; De Filippis, V.; Opocher, G.; Azzena, B.; Vettor, R.; Plebani, M.; Foresta, C. Impaired Release of Vitamin D in Dysfunctional Adipose Tissue: New Cues on Vitamin D Supplementation in Obesity. The Journal of Clinical Endocrinology & Metabolism 2017, 102, 2564–2574, doi:10.1210/jc.2016-3591.
- Navarro-Valverde, C.; Sosa-Henríquez, M.; Alhambra-Expósito, M.R.; Quesada-Gómez, J.M. Vitamin D3 and calcidiol are not equipotent. The Journal of Steroid Biochemistry and Molecular Biology 2016, 164, 205–208, doi:10.1016/j.jsbmb.2016.01.014.
- U.S. Centers for Disease Control Adult Obesity Facts Available online: https://www.cdc.gov/obesity/data/adult.html#:~:text=The%20prevalence%20o…. (accessed on Oct 16, 2020).
- Castillo, M.E.; Entrenas Costa, L.M.; Vaquero Barrios, J.M.; Alcalá Díaz, J.F.; Miranda, J.L.; Bouillon, R.; Quesada Gomez, J.M. Effect of Calcifediol Treatment and best Available Therapy versus best Available Therapy on Intensive Care Unit Admission and Mortality Among Patients Hospitalized for COVID-19: A Pilot Randomized Clinical study. The Journal of Steroid Biochemistry and Molecular Biology 2020, 105751, doi:10.1016/j.jsbmb.2020.105751.