FOR IMMEDIATE RELEASE
Orthomolecular Medicine News Service, Apr 9, 2020

by William B. Grant, PhD and Carole A. Baggerly

(OMNS Apr 9, 2020) There are two main reasons why respiratory tract infections such as influenza and COVID-19 occur in winter: winter sun and weather and low vitamin D status. Many viruses live longer outside the body when sunlight, temperature, and humidity levels are low as they are in winter [1].Vitamin D is an important component of the body’s immune system, and it is low in winter due to low solar ultraviolet-B (UVB) doses from exposure and the low supplement intakes of most. While nothing can be done about winter sun and weather, vitamin D status can be raised through vitamin D supplements.

Vitamin D has several mechanisms that can reduce risk of infections [2]. Important mechanisms regarding respiratory tract infections include:

• inducing production of cathelicidins and defensins that can lower viral survival and replication rates as well as reduce risk of bacterial infection
• reducing the cytokine storm that causes inflammation and damage to the lining of the lungs that can lead to pneumonia and acute respiratory distress syndrome.

Vitamin D deficiency has been found to contribute to acute respiratory distress syndrome, a major cause of death associated with COVID-19 [3]. An analysis of case-fatality rates in 12 U.S. communities during the 1918-1919 influenza pandemic found that communities in the sunny south and west had much lower case-fatality rates (generally from pneumonia) than those in the darker northeast [4].

To reduce risk of infection, it is recommended that people at risk of influenza and/or COVID-19 consider taking 10,000 IU/day (250 micrograms/day) of vitamin D for a few weeks to rapidly raise 25-hydroxyvitamin D [25(OH)D] concentrations, followed by at least 5000 IU/day. The goal should be to raise 25(OH)D concentrations above 40-60 ng/ml (100-150 nmol/l), taking whatever is necessary for that individual to achieve and maintain that level.

For treatment of people who become infected with COVID-19, higher vitamin D doses would be required to rapidly increase 25(OH)D concentrations.

Vitamin D is an inactive, pro-hormone which is also considered a seasonal, ‘conditional’ vitamin as vitamin D is not usually produced by the skin during the winter or when people are inside or covered up in the summer. Vitamin D is produced through the action of UVB radiation on 7-dehydrocholesterol in the skin followed by a thermal reaction. It then enters the blood stream and when it reaches the liver, it receives a hydroxyl group and becomes 25(OH)D. This is the circulating metabolite that is measured to determine vitamin D status [25(OH)D concentration]. This metabolite is essentially inert, but is converted in the kidneys to 1,25(OH)2D (calcitriol) for circulation in the blood, where it helps regulate serum calcium concentrations. Other organs can also convert 25(OH)D to calcitriol as needed, such as to fight cancer. Most of the effect of vitamin D is mediated by calcitriol entering vitamin D receptors (VDRs) attached to chromosomes in nearly every cell in the body, resulting in many genes being up- or down-regulated.

An adequate magnesium level is required for the activation of 25(OH)D [5]. Since many people in our modern society are deficient, along with supplements of vitamin D, magnesium supplements (300-400 mg/d, in citrate, chloride or malate form) should be considered. Data from voluntary participants in GrassrootsHealth.net’s 25(OH)D concentration measurement program found that taking magnesium supplements was equivalent to taking ~400 IU/d more vitamin D supplementation. [6]

While the initial classical role of vitamin D is to regulate calcium and phosphate absorption and metabolism, vitamin D has many non-skeletal effects. Many of the effects are known from observational studies in which serum 25(OH)D concentrations for those with or without specific diseases or conditions are compared statistically. Such studies generally find that concentrations above 30 to 50 ng/ml (75 to 125 nmol/l) are associated with lower risk of disease than concentrations below 10-20 ng/ml, such as cancer, cardiovascular disease, diabetes mellitus, etc. [7]. Two large-scale randomized controlled trials (RCTs) did find significant reductions in incidence and mortality rates for cancer and progression from prediabetes to diabetes in the secondary analyses [8].

At this point, what is needed are quickly developed public health studies to evaluate the effect on preventing COVID-19 in the populations that achieved the recommended serum concentrations. Another critically important project would be to evaluate the serum 25(OH)D concentrations of those who develop severe symptoms of COVID-19 infection. Achieved 25(OH)D concentrations should be measured.

Medical systems generally require randomized controlled trials (RCTs) that investigate effectiveness and risks before accepting what they consider a novel treatment. This requirement is problematic for vitamin D since most RCTs conducted to date have not followed Heaney’s guidelines for all nutrient studies:

Heaney’s guidelines [9], applied to vitamin D:

1. Basal 25(OH)D must be measured, used as an inclusion criterion for entry into study, and recorded in the report of the trial.
2. Vitamin D supplementation must be large enough to change vitamin D status and must be measured.
3. The change in 25(OH)D produced in those enrolled in the trials must be measured and recorded in the report of the trial.
4. The hypothesis to be tested must be that a change in 25(OH)D (not just a change in vitamin D intake) produces the sought-for effect.
5. Conutrient status must be optimized in order to ensure that the test nutrient is the only nutrition-related, limiting factor in the response

Open-label field trials based on Heaney’s guidelines have found significantly reduced risk of disease such as breast cancer [10].

Regarding the safety of high-dose vitamin D supplementation, the abstract of a recent article [11] stated:

“During this time, we have admitted over 4700 patients, the vast majority of whom agreed to supplementation with either 5000 or 10,000 IUs/day. Due to disease concerns, a few agreed to larger amounts, ranging from 20,000 to 50,000 IUs/day. There have been no cases of vitamin D3 induced hypercalcemia or any adverse events attributable to vitamin D3 supplementation in any patient.” In addition, many reviews have reported that vitamin D supplementation is safe.

The studies that aim to provide whatever intake is necessary to obtain a serum level between 40- 60 ng/ml (100-150 nmol/L) have shown a wide range of responses to a specific vitamin D intake. Thus, it is necessary to measure 25(OH)D concentrations at the start of vitamin D supplementation and after supplementing for a 2-3 months. Hypercalceima is the only significant risk [12], but generally does not occur below 150 ng/ml (375 nmol/l) and can be easily treated by stopping supplementation at that time.

The groups for whom it is most important to take vitamin D supplements during the current COVID-19 pandemic are health care providers and first responders. [13]

It should be noted that treatment of those with COVID-19 has several goals: (1) reduce the symptoms; (2) overcome the adverse effects of the infection such as impaired oxygen uptake due to pneumonia; (3) if possible, reduce survival and replication of the virus; (4) keep the patient alive long enough so that the body’s immune system can overcome the infection. As discussed in a recent review, the complex, integrated immune system needs multiple specific micronutrients, including vitamins A, D, C, E, B6, and B12, folate, zinc, iron, copper, and selenium, which play vital, often synergistic roles at every stage of the immune response. Micronutrients with the strongest evidence for immune support are vitamins C and D and zinc. Available evidence indicates that supplementation with multiple micronutrients with immune-supporting roles may modulate immune function and reduce the risk of infection [14]. Thus, more attention should be paid to supporting the immune system when treating COVID-19 patients.

Data from GrassrootsHealth.net volunteers underscores the interdependence of various supplements that affect immunity. Participants taking approximately 1000 mg/d vitamin C achieved a 25(OH)D concentration of 40 ng/ml with 586 IU/d lower vitamin D supplementation. [15]

Results for effects on 25(OH)D for vitamins B6, B12, K2, and calcium are available at GrassrootsHealth.net.

(William B. Grant, PhD, may be reached at [email protected] and Carole A. Baggerly at [email protected] )

References

1. Aldridge RA, Lewer D, Beale S, et al. (2020) Seasonality and immunity to laboratory-confirmed seasonal coronaviruses (HCoV-NL63, HCoV-OC43, and HCoV-229E): results from the Flu Watch cohort study [version 1; peer review: awaiting peer review] 30 March 2020. https://wellcomeopenresearch.org/articles/5-52/v1

2. Grant WB, Lahore H, McDonnell SL, Baggerly CA, French CB, Aliano JA, Bhattoa HP. (2020) Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients. 12: 988. https://www.mdpi.com/2072-6643/12/4/988

3. Dancer RC, Parekh D, Lax S, D’Souza V, Zheng S, Bassford CR, et al. (2015) Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS). Thorax. 70:617-624. http://thorax.bmj.com/cgi/pmidlookup?view=long&pmid=25903964

4. Grant WB, Giovannucci E. (2009) The possible roles of solar ultraviolet-B radiation and vitamin D in reducing case-fatality rates from the 1918-1919 influenza pandemic in the United States. Dermatoendocrinol. 1:215-219. http://www.tandfonline.com/doi/full/10.4161/derm.1.4.9063

5. Uwitonze AM, Razzaque MS. (2018) Role of magnesium in vitamin D activation and function. J Am Osteopath Assoc. 118:181-189. https://jaoa.org/article.aspx?articleid=2673882

6. GrassRoots Health Research Institute. (2020) Are both supplemental magnesium and vitamin K2 combined important for vitamin D levels? https://www.grassrootshealth.net/blog/supplemental-magnesium-vitamin-k2-combined-important-vitamin-d-levels

7. Rejnmark L, Bislev LS, Cashman KD, Eir¡ksdottir G et al. (2017) Non-skeletal health effects of vitamin D supplementation: A systematic review on findings from meta-analyses summarizing trial data. PLoS One. 12(7):e0180512. http://dx.plos.org/10.1371/journal.pone.0180512

8. Grant WB, Boucher BJ. (2019) Why secondary analyses in vitamin D clinical trials are important and how to improve vitamin D clinical trial outcome analyses – A comment on “extra-skeletal effects of vitamin D. Nutrients. 11(9). pii: E2182. https://www.mdpi.com/2072-6643/11/9/2182

9. Heaney RP. (2014) Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev.72:48-54. https://onlinelibrary.wiley.com/doi/pdf/10.1111/nure.12090

10.McDonnell SL, Baggerly CA, French CB, Baggerly LL, Garland CF et al. (2018) Breast cancer risk markedly lower with serum 25-hydroxyvitamin D concentrations ò60 vs < 20 ng/ml (150 vs 50 nmol/L): Pooled analysis of two randomized trials and a prospective cohort. PLoS One. 13(6):e0199265. http://dx.plos.org/10.1371/journal.pone.0199265

11. McCullough PJ, Lehrer DS, Amend J. (2019) Daily oral dosing of vitamin D3 using 5000 TO 50,000 international units a day in long-term hospitalized patients: Insights from a seven year experience. J Steroid Biochem Mol Biol. 189:228-239. https://www.ncbi.nlm.nih.gov/pubmed/30611908

12. Malihi Z, Wu Z, Lawes CMM, Scragg R. (2019) Adverse events from large dose vitamin D supplementation taken for one year or longer. J Steroid Biochem Mol Biol. 188:29-37. https://www.sciencedirect.com/science/article/abs/pii/S0960076018304692?via%3Dihub

13. Grant WB. (2020) Re: Preventing a covid-19 pandemic: Can vitamin D supplementation reduce the spread of COVID-19? Try first with health care workers and first responders. BMJ, 368:m810. https://www.bmj.com/content/368/bmj.m810/rr-42

14. Gombart AF, Pierre A, Maggini S. (2020) A review of micronutrients and the immune system-working in harmony to reduce the risk of infection. Nutrients 12(1). pii: E236. http://www.mdpi.com/resolver?pii=nu12010236

15. GrassRoots Health Research Institute. (2020) Is supplemental vitamin C important for vitamin D levels? https://www.grassrootshealth.net/blog/supplemental-vitamin-c-important-vitamin-d-levels

Related publications

Grant WB, Al Anouti F, Moukayed M. (2020) Targeted 25-hydroxyvitamin D concentration measurements and vitamin D3 supplementation can have important patient and public health benefits. Eur J Clin Nutr. 74:366-376. http://dx.doi.org/10.1038/s41430-020-0564-0

Grant WB, Boucher BJ, Bhattoa HP, Lahore H. (2018) Why vitamin D clinical trials should be based on 25-hydroxyvitamin D concentrations. J Steroid Biochem Mol Biol. 177:266-269. https://core.ac.uk/download/pdf/161069124.pdf

McNamara L. (2020) COVID-19: Fighting fear and the coronavirus pandemic with precautions and quality supplements. https://laddmcnamara.com/2020/03/13/covid-19-fighting-fear-and-the-coronavirus-pandemic-with-precautions-and-quality-supplements

Laird E, Kenny EA. (2020) Vitamin D deficiency in Ireland – implications for COVID-19. Results from the Irish Longitudinal Study on Ageing (TILDA). https://tilda.tcd.ie/publications/reports/pdf/Report_Covid19VitaminD.pdf

McCartney DM, Byrne DG. (2020) Optimisation of vitamin D status for enhances immune-protection against COVID-19. Irish Med J.113:P58. http://imj.ie/wp-content/uploads/2020/04/Optimisation-of-Vitamin-D-Status-for-Enhanced-Immuno-protection-Against-Covid-19.pdf

Schwalfenberg GK. (2020) Rapid Response: Covid 19, Vitamin D deficiency, smoking, age and lack of masks equals the perfect storm. BMJ, 368:m810. https://www.bmj.com/content/368/bmj.m810/rr-44

Wimalawansa SJ. (2020) Global epidemic of coronavirus – COVID-19: What we can do to minimize risks. Eur J Biomedical Pharmaceutical Sci. 7:432-438.

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維生素D補充劑可降低流感和COVID-19感染和死亡的風險

冬季發生諸如流感和COVID-19等呼吸道感染的主要原因有兩個：冬季的陽光和天氣以及低維生素D狀態。當冬天的陽光，溫度和濕度較低時，許多病毒會在體內存活更長的時間[1]。維生素D是人體免疫系統的重要組成部分，由於日照紫外線低，因此在冬季則較低。暴露（B）（UVB）劑量和大多數人的低補品攝入量。儘管對於冬季的陽光和天氣無能為力，但可以通過補充維生素D來提高維生素D的狀況。

維生素D具有多種降低感染風險的機制[2]。有關呼吸道感染的重要機制包括：

    誘導產生cathelicidins和防禦素，從而降低病毒存活率和復制率，並降低細菌感染的風險
    減少引起炎症和破壞肺內膜的細胞因子風暴，後者可導致肺炎和急性呼吸窘迫綜合徵。

維生素D缺乏症已導致急性呼吸窘迫綜合徵，這是與COVID-19相關的主要死亡原因[3]。對1918-1919年流感大流行期間美國12個社區的致死率的分析發現，南部和西部陽光明媚的社區的致死率（通常來自肺炎）要比較黑暗的東北部地區低得多[4]。

為了降低感染的風險，建議有流感和/或COVID-19風險的人考慮服用10,000 IU /天（250微克/天）的維生素D數週，以迅速增加25-羥基維生素D [25（ OH）D]濃度，然後至少每天5,000 IU。目標應該是提高25（OH）D的濃度至40-60 ng / ml（100-150 nmol / l）以上，並採取使該個人達到並維持該水平所需的一切。

為了治療感染了COVID-19的人，需要更高劑量的維生素D以迅速增加25（OH）D的濃度。

維生素D是一種不活躍的激素，也被認為是季節性的“有條件的”維生素，因為維生素D通常在冬天或人們在室內或夏天被遮蓋時，皮膚通常不會產生。維生素D是通過UVB輻射在皮膚中的7-脫氫膽固醇中產生的，然後進行熱反應而產生的。然後進入血液，到達肝臟後，它接受一個羥基並變成25（OH）D。這是測定維生素D狀態[25（OH）D濃度]的循環代謝物。這種代謝物基本上是惰性的，但會在腎臟中轉化為1,25（OH）2D（骨化三醇），以在血液中循環，從而幫助調節血清鈣濃度。其他器官也可以根據需要將25（OH）D轉化為骨化三醇，以抗擊癌症。維生素D的大多數作用是由鈣三醇進入人體幾乎每個細胞的染色體中附著的維生素D受體（VDR）介導的，導致許多基因被上調或下調。

25（OH）D的活化需要足夠的鎂水平[5]。由於現代社會許多人缺乏維生素D補充劑，因此應考慮鎂補充劑（檸檬酸鹽，氯化物或蘋果酸鹽形式的300-400 mg / d）。來自GrassrootsHealth.net的25（OH）D濃度測量程序的自願參與者的數據發現，服用鎂補充劑相當於每天多補充400 IU /天的維生素D。 [6]

維生素D最初的經典作用是調節鈣和磷酸鹽的吸收和代謝，而維生素D具有許多非骨骼作用。從觀察研究中可以了解許多影響，其中對有或沒有特定疾病或狀況的人的血清25（OH）D濃度進行了統計比較。此類研究通常發現，濃度低於30至50 ng / ml（75至125 nmol / l）的疾病風險要低於濃度低於10至20 ng / ml的疾病，例如癌症，心血管疾病，糖尿病等。 [7]。在二級分析中，兩項大型的隨機對照試驗（RCT）確實發現癌症的發生率和死亡率以及從糖尿病前期到糖尿病的發病率和死亡率顯著降低[8]。

此時，需要快速開展的公共衛生研究來評估在達到推薦血清濃度的人群中預防COVID-19的作用。另一個至關重要的項目將是評估出現嚴重COVID-19感染症狀的人的血清25（OH）D濃度。應測量達到的25（OH）D濃度。

3762/5000Character limit: 5000醫療系統通常需要隨機對照試驗（RCT），在接受他們認為新穎的治療方法之前，先對有效性和風險進行調查。由於迄今為止進行的大多數RCT均未遵循Heaney關於所有營養素研究的指南，因此該要求對於維生素D來說是個問題。

Heaney的準則[9]，適用於維生素D：

    必須測量基礎25（OH）D，用作進入研究的納入標準，並記錄在試驗報告中。
    補充維生素D必須足夠大才能改變維生素D的狀態，並且必須進行測量。
    必須對參加試驗的人員產生的25（OH）D的變化進行測量並記錄在試驗報告中。
    要檢驗的假設必須是25（OH）D的變化（不僅僅是維生素D攝入量的變化）產生了所希望的效果。
    必須優化輔助營養素狀態，以確保測試營養素是響應中唯一與營養相關的限制因素

根據Heaney指南進行的開放標籤現場試驗發現，患乳腺癌等疾病的風險大大降低了[10]。

關於大劑量補充維生素D的安全性，最近的一篇文章[11]的摘要指出：

“在這段時間裡，我們已經接納了4700多名患者，其中絕大多數同意每天補充5000或10,000 IU。由於疾病的考慮，一些人同意增加使用量，範圍從每天20,000到50,000 IU /天。沒有任何患者因維生素D3引起高鈣血症或任何因補充維生素D3而引起的不良事件。”此外，許多評論報告補充維生素D是安全的。

旨在提供所需攝入量以達到40-60 ng / ml（100-150 nmol / L）血清水平的研究表明，對特定維生素D攝入量的反應廣泛。因此，有必要在補充維生素D開始時和補充2-3個月後測量25（OH）D的濃度。高鈣血症是唯一的重大風險[12]，但通常不會在150 ng / ml（375 nmol / l）以下時發生，可以通過在此時停止補充來輕鬆治療。

在當前的COVID-19大流行期間，最重要的是服用維生素D補充劑的人群是醫療保健提供者和急救人員。 [13]

應當指出，對COVID-19的治療有幾個目標：（1）減輕症狀； （2）克服感染的不良影響，例如由於肺炎引起的氧氣吸收受損； （3）盡可能減少病毒的存活和復制； （4）使患者存活足夠長的時間，以使人體的免疫系統克服感染。正如最近的評論所討論的那樣，複雜的綜合免疫系統需要多種特定的微量營養素，包括維生素A，D，C，E，B6和B12，葉酸，鋅，鐵，銅和硒，它們起著至關重要的作用，通常具有協同作用在免疫反應的每個階段發揮作用。具有最強免疫力證據的微量營養素是維生素C，D和鋅。現有證據表明，補充多種具有免疫支持作用的微量營養素可以調節免疫功能並降低感染風險[14]。因此，在治療COVID-19患者時應更加註意支持免疫系統。

來自GrassrootsHealth.net志願者的數據強調了影響免疫力的各種補品的相互依賴性。服用約1000 mg / d維生素C的參與者通過補充586 IU / d較低的維生素D達到25（OH）D濃度為40 ng / ml。 [15]

維生素B6，B12，K2和鈣對25（OH）D影響的結果可從GrassrootsHealth.net獲得。