Vitamin D’s Impact on COVID-19
By Patrick Dixon, Head of Applied Sports Science at Amp Human

Summary
The role of vitamin D in the body’s immune response has become a key topic of interest during COVID-19. Vitamin D has been shown to regulate the immune response and deficiency in vitamin D is associated with an increased susceptibility to infection. The beneficial effects of supplementing vitamin D by those who are deficient may strengthen the immune response respiratory infections like the flu and COVID-19.
 
The Challenge of getting enough
Vitamin D deficiency is a major public health problem worldwide in all age groups, even in countries where it is assumed that climate and sun exposure is adequate and in countries where foods have been fortified[1]. Vitamin D is naturally present in foods like fatty fish and fish liver oils. Small amounts of vitamin D are also found in beef liver, cheese, and egg yolks with fortified foods providing most of the vitamin D in the American diet[2].  

Even with fortification though, the average person's daily intake from foods alone is substantially below the 600IU RDA according to the NIH. Furthermore, according to National Health and Nutrition Examination Survey (NHANES) data, the overall prevalence of vitamin D deficiency in the US is 41.6%, with the highest rates seen in African Americans (82.1%), followed by Hispanics (69.2%)[3]. Seasonality also plays a role in vitamin D status in that during the cooler months of the year, there is less direct sunlight and more time is spent indoors. This leads to less sun exposure and therefore creates less vitamin D naturally. 
 
How Vitamin D Supports Immunity
In 1981, Edgar Hope Simpson proposed that a “seasonal stimulus” and resulting sun exposure  may play a role in influenza outbreaks[4]. His idea was that the amount of sun exposure a person received was linked to incidence of influenza and the common cold. Years later, the link between sunlight, vitamin D status and immune function has been supported by a growing body of literature. 

Vitamin D acts as an immune system controller, preventing excessive inflammation and increasing the potential of macrophages which are responsible for detecting and destroying pathogens[5]. It also stimulates the immune response in the cells lining the respiratory tract where they play a major role in protecting the lungs from infection[5,6]. Studies show consistent associations between low vitamin D levels and sensitivity to acute respiratory tract infection[5,7.]  Vitamin D’s support of immune response to both viral and bacterial stimuli [8, 9, 10] suggests a potential mechanism by which Vitamin D may improve immune function. 
 
Enter the Novel Coronavirus
Human coronaviruses were first identified in the mid-1960s and represent a large family of viruses that can cause mild to moderate upper-respiratory tract illnesses, like the common cold. There are also 3 new strains of virus that have emerged in the past 2 decades, MERS, SARS and COVID-19, which present more serious symptoms and can lead to more severe outcomes[11].
Many of the symptoms of the common cold, influenza, pneumonia and COVID start off in the same way; fever, cough, shortness of breath, and fatigue.  But the body's ability to combat the infection is where things differ. In the pursuit of a treatment strategy for COVID-19, researchers have been looking at how vitamin D levels may relate to COVID-19 infection as well as the severity of symptoms in patients. 

The Best Research on Vitamin D and COVID-19
An upfront note: most of the studies to date are observational studies and data sets are analyzed soon after they are reported without waiting the normal peer review process. More research will be important to further define and validate the role that vitamin D plays with COVID-19.

Study 1: Symptom Severity
In a preprint letter on April 9, 2020, Mark Alipio presented some early data from the Philippines looking at vitamin D status and the severity of symptoms in 212 subjects[12].

Average vitamin D levels by severity of COVID-19 symptoms were 
- Mild: 31 ng/ml 
- Ordinary: 27 ng/ml
- Severe: 21 ng/ml
- Critical: 17 ng/ml

Interestingly, 86% of all cases among patients with normal vitamin D levels were mild, while 73% of cases among patients with vitamin D deficiency were severe or critical. Furthermore, as vitamin D levels increased, the odds of having a mild case compared to a severe case were 8 times greater, and the odds of having a mild case compared to a critical case were 20 times greater. All of the outcomes were statistically significant.  
Study 2: COVID Positive Rates
Michael F. Holick PhD, MD and his team from Boston University’s School of Medicine compared 190,000 blood samples in a retrospective study and found that SARS-CoV-2 positivity was strongly and inversely associated with circulating 25(OH)D (vitamin D) levels. This correlation appeared across latitudes, races/ethnicities, sexes, and age ranges and supports the need to explore the role of vitamin D supplementation in reducing the risk to an individual of COVID-19[13].

Meltzer et al. obtained data from 489 patients who had their vitamin D levels measured in the year before testing positive for COVID-19. The team found that the relative risk of testing positive for COVID-19 was 1.77 times greater in patients who were likely deficient compared to patients who were likely sufficient based on their previously recorded levels. The findings appear to support the role of vitamin D levels in COVID risk[14].
Study 3: Severe-Critical Cases
Another observational study by Karahan & Katkat, explored the relationship between mortality and 25(OH)D levels in COVID patients. They found that vitamin D insufficiency was present in 93% of the patients with severe-critical COVID-19 and that serum 25(OH) vitamin D was independently associated with mortality in COVID-19 patients[15]. See graphs below.
Study 4: Hospitalization & Death Rate
In a larger review paper, Pereira et al. selected 27 articles. In the analysis they found vitamin D deficiency was not associated with a higher chance of infection by COVID-19, but that severe cases presented 64% more vitamin D deficiency compared with mild cases and vitamin D insufficiency increased hospitalization and death rates. They observed a positive association between vitamin D deficiency and the severity of the disease[16.]

What Does It All Mean?
The available research around COVID-19, morbidity, and mortality continues to evolve as does our understanding of the role vitamin D plays in immune function. The strong correlation between vitamin D and the severity of COVID-19 symptoms suggests that daily vitamin D supplementation may be a simple, cost effective way to support immune function as it pertains to respiratory infections.

REFERENCES
1. Palacios C, Gonzalez L. Is vitamin D deficiency a major global public health problem?. J Steroid Biochem Mol Biol. 2014;144 Pt A:138-145.
2. Vitamin D: Fact Sheet for Health Professionals
https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/
3. Liu X, Baylin A, Levy PD. Vitamin D deficiency and insufficiency among US adults: prevalence, predictors and clinical implications. Br J Nutr. 2018 Apr;119(8):928-936.
4. Cannell, J.J., Zasloff, M., Garland, C.F. et al. On the epidemiology of influenza. Virol J 5, 29 (2008).
5. Cannell JJ, Vieth R, Umhau JC, et al. Epidemic influenza and vitamin D. Epidemiol Infect. 2006;134(6):1129-1140.
6. Sundaram ME, Coleman LA. Vitamin D and influenza. Adv Nutr. 2012;3(4):517-525. Published 2012 Jul 1.
7. Jolliffe DA, Griffiths CJ, Martineau AR. Vitamin D in the prevention of acute respiratory infection: systematic review of clinical studies. J Steroid Biochem Mol Biol 2013;136:321-9.
8. Hansdottir S, Monick MM, Hinde SL, Lovan N, Look DC, Hunninghake GW. Respiratory epithelial cells convert inactive vitamin D to its active form: potential effects on host defense. J Immunol 2008;181:7090-9.
9. Olliver M, Spelmink L, Hiew J, Meyer-Hoffert U, Henriques-Normark B, Bergman P. Immunomodulatory effects of vitamin D on innate and adaptive immune responses to Streptococcus pneumoniae. J Infect Dis 2013;208:1474-81.
10. Greiller CL, Martineau AR. Modulation of the immune response to respiratory viruses by vitamin D. Nutrients 2015;7:4240-70. 10.3390/nu7064240 
11. National Institute of Health: National Institute of Allergy and Infectious Disease. 
12. Vitamin D supplementation could possibly improve clinical outcomes of patients infected with Coronavirus-2019 (Covid2019)
13. Kaufman HW, Niles JK, Kroll MH, Bi C, Holick MF. SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels. PLoS One. 2020 Sep 17;15(9):e0239252.
14. Meltzer DO, Best TJ, Zhang H, Vokes T, Arora V, Solway J. Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results. JAMA Netw Open. 2020;3(9):e2019722.
15. Karahan, S., Katkat, F. Impact of Serum 25(OH) Vitamin D Level on Mortality in Patients with COVID-19 in Turkey. J Nutr Health Aging (2020).
16. Marcos Pereira, Alialdo Dantas Damascena, Laylla Mirella Galvão Azevedo, Tarcio de Almeida Oliveira & Jerusa da Mota Santana (2020) Vitamin D deficiency aggravates COVID-19: systematic review and meta-analysis, Critical Reviews in Food Science and Nutrition

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