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Explaining the Research on Covid-19

Vitamin D

Can Vitamin D help against Covid-19?

Substantial evidence from scientific studies shows that vitamin D reduces risk of infection, of a severe case, and of death from Covid-19.

Vitamin D articles

* Vitamin D versus Covid-19: part one
* Vitamin D versus Covid-19: part two
* Vitamin D versus Covid-19: part three
* Fighting Covid-19: Vitamin D, Magnesium, Vitamin B12

* Vitamin D and Covid-19 Clinical Trials from ClinicalTrials.gov ongoing trials.

Vitamin D videos

* Vitamin D NOW for COVID-19 by Allan Mishra, MD and DareToBeVital.com
* Video: Does Vitamin D Protect Against COVID-19? by Dr. JoAnn E. Manson, MD, DrPH
* Dr. Mobeen Syed on immune system benefits of vitamin D
* Dr. Syed again on Vitamin D overview and description of an RCT
* Dr. Roger Seheult of MedCram on vitamin D

Vitamin D commentary

For more vitamin D commentary, see this article.

Summary

Having normal healthy blood levels of vitamin D reduces Covid-19 risks, including risk of infection [7, 8, 9, 11, 12, 14, 16, 23, 27], of having a severe case [1, 3, 4, 5, 15, 17, 20, 22, 24, 25, 26], of needing hospitalization, ICU care, and/or mechanical ventilation [2, 10, 14, 15, 21, 22, 24, 26], as well as the risk of dying from Covid-19 [4, 6, 7, 9, 12, 13, 17, 18, 19, 22, 24, 25, 28].

Experts recommend Vitamin D supplementation as a measure against Covid-19 [81, 83, 84], at a dosage of 10,000 IU per day for a few weeks or a month, reducing to 5,000 IU/day thereafter [81, 84]. Doses of 10,000 IU/day are necessary to raise vitamin D levels in 97.5% of the population to optimal levels; lower doses may not be effective in everyone [82]. Doses as high as 40,000 IU/day are unlikely to result in vitamin D toxicity [82].

Additional benefits of vitamin D. Studies have shown that a high intake of vitamin D reduces risk of respiratory tract infections [101], stroke [102], multiple sclerosis [103], rheumatoid arthritis [104], type 2 diabetes [105], breast cancer [106], prostate cancer [107], colon cancer [108], and all-cause mortality [109].

Vitamin D can be taken daily or once-a-week. A one-time bolus of 300,000 IU of vitamin D is safe [87, 90] and may be useful when vitamin D cannot be taken daily, or when someone becomes ill and needs to raise their vitamin D levels as quickly as possible. Calcifediol can be used in-hospital to treat patients with Covid-19 and low vitamin D [21].

Sunlight on skin can produce significant amounts of vitamin D, butt he amount of skin exposed must be more than the face and hands [89]. Face, hands, and arms exposed to sunlight is a minimum for reaching vitamin D normal levels [88, 89].

Other Vitamins

articles:
* Riboflavin (Vitamin B2) as an Inhibitor of Covid-19
* MATH+ Protocol for prophylaxis and mild cases (Vitamins D, C, B1)

videos:
* Dr. Mobeen Syed: Vitamin K Deficiency Leads to Poor COVID-19 Outcome

Vitamin D versus Covid-19, Studies

1. Alipio, Mark. “Vitamin D Supplementation Could Possibly Improve Clinical Outcomes of Patients Infected with Coronavirus-2019 (COVID-19).” SSRN 3571484 (9 April 2020).
Study Link | PDF Link

2. Lau, Frank H., et al. “Vitamin D insufficiency is prevalent in severe COVID-19.” medRxiv (28 April 2020).
Study Link | PDF Link

3. Daneshkhah, Ali, et al. “The Possible Role of Vitamin D in Suppressing Cytokine Storm and Associated Mortality in COVID-19 Patients.” medRxiv (2020).
Study Link | PDF Link

4. Davies, Gareth, Attila R. Garami, and Joanna C. Byers. “Evidence Supports a Causal Model for Vitamin D in COVID-19 Outcomes.” medRxiv (2020).
Study Link | PDF Link

5. De Smet, Dieter, et al. “Vitamin D deficiency as risk factor for severe COVID-19: a convergence of two pandemics.” medRxiv (2020).
Study Link | PDF Link

6. Raharusun, Prabowo, et al. “Patterns of COVID-19 Mortality and Vitamin D: An Indonesian Study.” (2020).
PDF file | PDF Link

7. Ilie, Petre Cristian, Simina Stefanescu, and Lee Smith. “The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality.” Aging Clinical and Experimental Research (2020): 1.
Study Link | PDF Link

8. D’Avolio, Antonio, et al. “25-hydroxyvitamin D concentrations are lower in patients with positive PCR for SARS-CoV-2.” Nutrients 12.5 (2020): 1359.
Study Link | PDF Link

9. Laird, E., et al. “Vitamin D and Inflammation: Potential Implications for Severity of Covid-19.” Ir Med J; Vol 113; No. 5; P81: 2020.
PDF file | PDF Link

10. Faul, J.L., et al. “Vitamin D Deficiency and ARDS after SARS-CoV-2 Infection.” Ir Med J; Vol 113; No. 5; P84: 2020.
PDF file | PDF Link

11. Meltzer, David O., et al. “Association of Vitamin D Deficiency and Treatment with COVID-19 Incidence.” medRxiv (2020).
Study Link | PDF Link

12. Li, Yajia, et al. “Sunlight and vitamin D in the prevention of coronavirus disease (COVID-19) infection and mortality in the United States.” (2020).
PDF file | PDF Link

13. Pugach, Isaac Z. and Pugach, Sofya “Strong Correlation Between Prevalence of Severe Vitamin D Deficiency and Population Mortality Rate from COVID-19 in Europe.” medRxiv (2020).
Study Link | PDF Link

14. Merzon, Eugene, et al. “Low plasma 25(OH) vitamin D3 level is associated with increased risk of COVID-19 infection: an Israeli population-based study.” medRxiv (2020). — Low vitamin D increased risk (adjusted OR) of infection with Covid-19 by 45% and of hospitalization for Covid by 95%.
Study Link | PDF Link

15. Panagiotou, Grigorios et al., “Low serum 25-hydroxyvitamin D (25[OH]D) levels in patients hospitalised with COVID-19 are associated with greater disease severity: results of a local audit of practice.” medRxiv (2020). Conclusion: “we found that patients requiring ITU admission [in the ICU] were more frequently vitamin D deficient than those managed on medical wards [on the floor], despite being significantly younger.”
PDF file Link | PDF Link

16. Chang, Timothy S., et al. “Prior diagnoses and medications as risk factors for COVID-19 in a Los Angeles Health System.” medRxiv (2020).
Study Link | PDF Link
~ Risk factors included vitamin D deficiency, which increased risk of COVID-19 diagnosis by 80% (OR 1.8 [1.4-2.2], p=5.7 x 10-6).

17. Maghbooli, Zhila, et al. “Vitamin D Sufficiency Reduced Risk for Morbidity and Mortality in COVID-19 Patients.” Available at SSRN 3616008 (2020).
Study Link | PDF Link
~ Vitamin D sufficiency reduced clinical severity and inpatient mortality.
* See this Expression of Concern by the editors of PLoS One

18. Panarese and Shahini, “Letter: Covid-19 and Vitamin D” Alimentary Pharmacology and Therapeutics, April 12, 2020.
Link to Letter | PDF Link
~ Covid-19 mortality increases with increasing latitude (by nation), and vitamin D blood levels decrease with increasing latitude. The authors propose that low levels of vitamin D increase Covid-19 mortality.

19. Carpagnano, Giovanna Elisiana, et al. “Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19.” Journal of Endocrinological Investigation (2020): 1-7. Study Link | PDF Link
~ “A survival analysis highlighted that, after 10 days of hospitalization, severe vitamin D deficiency patients had a 50% mortality probability, while those with vitamin D = 10 ng/mL had a 5% mortality risk (p = 0.019).”

20. Mardani, R., et al. “Association of vitamin D with the modulation of the disease severity in COVID-19.” Virus Research (2020): 198148. Study Link | PDF Link

21. Castillo, Marta Entrenas, et al. “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. Study Link | PDF Link

22. Radujkovic, et al. “Vitamin D Deficiency and Outcome of COVID-19 Patients.” Nutrients 2020, 12(9), 2757; Study Link | PDF Link
— “The present study demonstrates an association between VitD deficiency and severity of COVID-19.
VitD-deficient patients had a higher hospitalization rate and required more (intensive) oxygen therapy
and IMV. In our patients, when adjusted for age, gender, and comorbidities, VitD deficiency was
associated with a 6-fold higher hazard of severe course of disease and a ~15-fold higher risk of death.”

23. Israel, Ariel, et al. “The link between vitamin D deficiency and Covid-19 in a large population.” MedRxiv 9/7/2020. Study Link | PDF Link

24. Jae Hyoung Im, et al. “Nutritional status of patients with coronavirus disease 2019 (COVID-19).”
International Journal of Infectious Diseases. August 7, 2020. PDF Link | PDF Link

25. Gennari L, et al “Vitamin D deficiency is independently associated with COVID-19 severity and mortality” ASBMR 2020; Abstract 1023. Study Link | PDF Link

26. Baktash, Vadir, et al. “Vitamin D status and outcomes for hospitalised older patients with COVID-19.” Postgraduate Medical Journal (2020). Study Link | PDF Link
— “The main findings of our study suggest that older patients with lower serum concentrations of 25(OH)D, when compared with aged-matched vitamin D-replete patients, may demonstrate worse outcomes from COVID-19. Markers of cytokine release syndrome were raised in these patients and they were more likely to become hypoxic and require ventilatory support in HDU.” [HDU is high dependency unit]

27. Kaufman HW, et al. “SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels.” (2020) PLoS ONE 15(9): e0239252. Study Link | PDF Link
— Optimum vitamin D blood level for reducing Covid-19 infection was found to be in the 50’s (ng/ml). This is the first study to show that 25(OH)D at levels above 30 have additional benefits.

28. Brenner, Hermann, Bernd Holleczek, and Ben Schöttker. “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 12.8 (2020): 2488. PDF Link
— “Compared to those with sufficient vitamin D status, participants with vitamin D insufficiency and deficiency had strongly increased respiratory mortality, with adjusted hazard ratios (95% confidence intervals) of 2.1 (1.3-3.2) and 3.0 (1.8-5.2) overall, 4.3 (1.3-14.4) and 8.5 (2.4-30.1) among women, and 1.9 (1.1-3.2) and 2.3 (1.1-4.4) among men. Overall, 41% (95% confidence interval: 20-58%) of respiratory disease mortality was statistically attributable to vitamin D insufficiency or deficiency. Vitamin D insufficiency and deficiency are common and account for a large proportion of respiratory disease mortality in older adults, supporting the hypothesis that vitamin D3 supplementation could be helpful to limit the burden of the COVID-19 pandemic, particularly among women.”

29. Pepkowitz, Samuel H., et al. “Vitamin D Deficiency is Associated with Increased COVID-19 Severity: Prospective Screening of At-Risk Groups is Medically Indicated.” (2020). PDF File
— Persons hospitalized for Covid-19 were more than twice as likely to need ICU care if they had with vitamin D deficiency.

30. Mandal, Amit KJ, et al. “Vitamin D status may indeed be a prognosticator for morbidity and mortality in patients with COVID‐19.” Journal of Medical Virology. PDF Link
— Findings: “patients with low concentrations of 25OH-D (<or=30nmol/l) demonstrated clinically relevant, elevated markers of cytokine release syndrome and were more likely to become hypoxic and require ventilatory support."

31. Karahan and Katkat. “Impact of Serum 25(OH) Vitamin D Level on Mortality in Patients with COVID-19 in Turkey.” The journal of nutrition, health & aging (2020). PDF File

32. Faniyi, et al. “Vitamin D status and seroconversion for COVID-19 in UK healthcare workers who isolated for COVID-19 like symptoms during the 2020 pandemic.” medRxiv 6 Oct. 2020. PDF Link
— “Vitamin D deficiency is a risk factor for COVID-19 seroconversion for NHS healthcare workers especially in BAME male staff.”

33. Yılmaz, Kamil, and Velat Şen. “Is Vitamin D Deficiency a Risk Factor for Covid 19 in Children?.” Pediatric Pulmonology. Study Link
— “The symptom of fever was significantly higher in COVID‐ 19 patients who had deficient and insufficient vitamin D levels than in patients who had sufficient vitamin D level.”
— “Patients with COVID‐19 had significantly lower vitamin D levels 13.14 ng/ml than did the controls 34.81 ng/ml.”

34. Annweiler, C. et al. “Vitamin D and survival in COVID-19 patients: A quasi-experimental study.” The Journal of Steroid Biochemistry and Molecular Biology, 13 October 2020. Study Link
— Bolus vitamin D3 supplementation during or just before COVID-19 was associated with less severe COVID-19 and better survival rate in frail elderly.

Contrary Studies

61. Hastie, Claire E., et al. “Vitamin D concentrations and COVID-19 infection in UK Biobank.” Diabetes & Metabolic Syndrome: Clinical Research & Reviews (2020). Study Link
— This study used Vitamin D data from 2006 to 2010 and looked at whether those patients were more or less likely to become infected with Covid-19 “for the period 16th March 2020 to 14th April 2020.” At that early a date in the pandemic, when few persons were transmitting the disease, the risk of infection is much more likely to be related to being at high risk via profession or close association to an infected person by circumstance. It was not widespread enough for a factor like vitamin D blood levels to show up in the data. Also, the vitamin D levels were from 10 years or more before the date of infection. Finally, vitamin D has a much larger effect on disease severity than on infection.

Vitamin D versus Covid, Commentary

81. Grant, William B., et al. “Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths.” Nutrients 12.4 (2020): 988. Study Link
— “To reduce the risk of infection, it is recommended that people at risk of influenza and/or COVID-19 consider taking 10,000 IU/d of vitamin D3 for a few weeks to rapidly raise 25(OH)D concentrations, followed by 5000 IU/d…. For treatment of people who become infected with COVID-19, higher vitamin D3 doses might be useful.”

82. Garland, Cedric F., et al. “Vitamin D supplement doses and serum 25-hydroxyvitamin D in the range associated with cancer prevention.” Anticancer research 31.2 (2011): 607-611. Study Link
— “Results: Serum 25(OH)D rose as a function of self-reported vitamin D supplement ingestion in a curvilinear fashion, with no intakes of 10,000 IU/d or lower producing 25(OH)D values above the lower-bound of the zone of potential toxicity (200 ng/ml). Unsupplemented all-source input was estimated at 3,300 IU/d. The supplemental dose ensuring that 97.5% of this population achieved a serum 25(OH)D of at least 40 ng/ml was 9,600 IU/d. Conclusion: Universal intake of up to 40,000 IU vitamin D per day is unlikely to result in vitamin D toxicity.”

83. Charoenngam and Holick, “Immunologic Effects of Vitamin D on Human Health and Disease.” Nutrients 2020, 12(7), 2097; Study Link
— “It is therefore proposed that supplementation of vitamin D can reduce the risk and severity of COVID-19 infection.”

84. Sharma, Suresh K., et al. “Vitamin D: A cheap yet effective bullet against coronavirus disease-19–Are we convinced yet?.” National Journal of Physiology, Pharmacy and Pharmacology 10.7 (2020): 0-0.
Study Link
“Therefore, from reviewed literature, it seems fairly appropriate to suggest taking Vit-D at 10,000 IU/day as an adequate dose to enhance circulatory concentration of Vit-D into the optimal range of 40–60 ng/mL; after 1 month the dose can be reduced to 5000 IU/day to maintain serum levels.”

85. Kroll, Martin H., et al. “Temporal relationship between vitamin D status and parathyroid hormone in the United States.” PloS one 10.3 (2015): e0118108. Study Link
— Based on 3.8 million lab results of adults in the U.S.: “Vitamin D deficiency and insufficiency was common (33% <20 ng/mL; 60% <30 ng/mL)…. The percentage of patients deficient in 25(OH)D3 seasonally varied from 21% to 48%…."

87. Kearns, Malcolm, Jessica Alvarez, and Vin Tangpricha. “Large, single-dose, oral vitamin D supplementation in adult populations: a systematic review.” Endocrine Practice 20.4 (2014): 341-351.
— “This review recommends that vitamin D3 be used for supplementation over vitamin D2 and concludes that single vitamin D3 doses ≥300,000 IU are most effective at improving vitamin D status and suppressing PTH concentrations for up to 3 months.”

88. Robert P. Heaney, The Vitamin D requirement in health and disease; Journal of Steroid Biochemistry & Molecular Biology. doi:10.1016/j.jsbmb.2005.06.020

89. Alagöl, Faruk, et al. “Sunlight exposure and vitamin D deficiency in Turkish women.” Journal of endocrinological investigation 23.3 (2000): 173-177.

90. Liu, Guoqiang, Tianpei Hong, and Jin Yang. “A Single Large Dose of Vitamin D Could be Used as a Means of Coronavirus Disease 2019 Prevention and Treatment.” Drug Design, Development and Therapy 14 (2020): 3429.

Vitamin D versus Other Diseases

101. Martineau, Adrian R., et al. “Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data.” bmj 356 (2017).
Study Link
— Recommend daily or weekly dose, but not bolus dosing.

102. Marniemi et al., Dietary and serum vitamins and minerals as predictors of myocardial infarction and stroke in elderly subjects; Nutrition, Metabolism & Cardiovascular Diseases. Volume 15, Issue 3 , Pages 188-197, June 2005. Study Link

103. Munger et al., Vitamin D intake and incidence of multiple sclerosis; Neurology. January 13, 2004 vol. 62 no. 1, p. 60-65. Study Link

104. Merlino et al., Vitamin D intake is inversely associated with rheumatoid arthritis: Results from the Iowa Women’s Health Study; Arthritis & Rheumatism. Volume 50, Issue 1, pages 72-77, January 2004. Study Link

105. Pittas et al., Vitamin D and Calcium Intake in Relation to Type 2 Diabetes in Women; Diabetes Care. March 2006 vol. 29 no. 3 650-656. Study Link

106. Garland et al., Vitamin D and prevention of breast cancer: Pooled analysis; The Journal of Steroid Biochemistry and Molecular Biology, Volume 103, Issues 3-5, March 2007, Pages 708-711; Study Link

107. Garland et al., The Role of Vitamin D in Cancer Prevention; American Journal of Public Health. 2006 February; 96(2): 252-261. Study Link

108. Gorham et al., Optimal Vitamin D Status for Colorectal Cancer Prevention: A Quantitative Meta-Analysis; American Journal of Preventive Medicine. Volume 32, Issue 3 , Pages 210-216, March 2007; Study Link

109. Antonio, Leen, et al. “Free 25-hydroxyvitamin D, but not free 1.25-dihydroxyvitamin D, predicts all-cause mortality in ageing men.” 22nd European Congress of Endocrinology. Vol. 70. BioScientifica, 2020.