Low vitamin D status is becoming more common worldwide. The prevalence of vitamin D deficiency (VDD) was found to be 28.9 % and vitamin D insufficiency (VDI) 41% in a subset of 26,010 US adults surveyed as part of the ongoing National Health and Nutrition Examination Survey (NHANES) 2001-2010. Those who were African American, less educated, of lower socioeconomic status, smokers, physically inactive, obese and infrequent milk consumers demonstrated a higher prevalence of VDD and VDI. ¹ Worldwide, many countries report a high prevalence of low vitamin D status. The percentage of individuals with VDD or serum 25(OH)D <30 nmol/L (or 12 ng/ml) is estimated to be 7.4% in Canada, ² 13% in Europe³ and as high as >20% of the population in India, Tunisia, Pakistan and Afghanistan. ^3,4 However, certain populations are more at risk for becoming deficient than others. For example, individuals with chronic diseases especially of the liver, kidney and heart, anyone with diseases that lead to malabsorption such as Crohn’s disease, hospitalized patients, and anyone with reduced exposure to sunlight. ^5,6 Older adults, individuals with existing conditions, obese individuals, diabetics and those taking certain medications are particularly at risk. Older adults, especially those that are institutionalized, are at increased risk due to decreased sun exposure, decreased ability to synthesize vitamin D in the aging skin, ⁷ decreased intake and possibly a greater number of medications. Medications such as antiseizure medications, glucocorticoids, rifampin and supplements such as St. John’s Wort may increase the risk of vitamin D deficiency. ⁸ 

Vitamin D is a fat soluble vitamin that humans get from the diet, sunlight and supplements. It is not a single compound but is a family of similar compounds with slightly different side chains. There are two major forms of vitamin D: vitamin D2 and D3. Vitamin D2 or ergocalciferol is the most common form and an important dietary source that is synthesized by plants and also used to fortify foods like milk, orange juice and cereals. Most mammals can convert vitamin D2 to vitamin D3. Vitamin D3, also called cholecalciferol, is the form that can be made by the human body from cholesterol and is naturally found in cod liver oil, oily fish, and is often found in dietary supplements. D3 is the active part of 1,25-dihydroxycholecalciferol (1,25(OH)2D), which is responsible for the biological functions of vitamin D. ¹ 

With no supplementation, about 80% of vitamin D3 is synthesized in the skin and 20% is obtained from the diet. With regular sun exposure, a healthy diet, and healthy kidneys, many people can make the vitamin D they need. However, most people are not regularly exposed to the sun and diets vary. The absorption of Vitamin D from food sources is dependent upon the presence of long chain fats and bile salts. Dietary vitamin D first goes to the liver then the kidney converts it to its active form and distributes the active form throughout the body. Because it is synthesized and released from , the kidneys, and the fact that there are vitamin D receptors in many tissues makes vitamin D a “hormone-like” vitamin. ¹ 

Vitamin D is delivered throughout the body on vitamin D binding protein and must bond with a vitamin D receptor (VDR) to enact its biological effects. These receptors are located throughout the body and explain why vitamin D is important for so many functions in the body. ² For example, VDR has been found in cells of the intestinal epithelium, renal tubules, parathyroid gland cells, skin (keratinocytes), mammary epithelium, pancreas (beta islet cells), pituitary gland, skeleton (osteoblasts and chondrocytes), immune system (monocytes, macrophages, and T-lymphocytes), and germ tissues. The tissues with the highest VDR content are intestine, kidney, parathyroid gland, and bone, all of which are associated with maintenance of calcium homeostasis. ³ 

Vitamin D was first known for its role in bone development and maintenance. It plays a key role in the metabolism of calcium and phosphorus, two important minerals for bone integrity. Vitamin D stimulates the cells of the small intestine to produce a calcium binding protein called calbindin, which increases calcium absorption. When blood calcium levels decline, vitamin D stimulates the production of calbindin to increase calcium absorption from food. In addition, when blood levels of calcium fall, vitamin D stimulates the kidneys to conserve calcium by decreasing urinary excretion. Vitamin D has many other important functions. It plays a key role in maintaining immune health, oral health, muscle health and strength, for regulating gene transcription and promoting protein synthesis. ¹ These functions have received more research attention in recent years due to the findings that vitamin D receptors (VDR) and the vitamin D activating enzyme 1-α-hydroxylase (CYP27B1) are found in many cells outside the bone and kidney including the muscles, the intestine and some immune cells. This suggests the biologically active form of vitamin D, 1,25(OH)2D, can influence immunity and health in multiple ways. ^1-3 

Most days we go about our routines completely unaware that our immune systems are always working, recognizing, fighting and adapting to foreign invaders that might be bacteria, viruses, fungi… .anything foreign to our bodies. However, in 2020 we likely became more aware than ever of the importance of our immune systems in health, well-being and survival. But what exactly is the immune system? Well, it is quite complex and impacts many aspects of illness and health. One researcher said it well, “The main functions of body’s immune system are to protect the host against infection from pathological microorganisms, to clear damaged tissues, and to provide constant surveillance of malignant cells that grow within the body. Additionally, the immune system develops appropriate tolerance to avoid unwanted response to healthy tissues of self or harmless foreign substances. There is considerable heterogeneity (differences) among individuals in the vigor of their immunological function, largely owing to factors such as genetics, environment, lifestyle, nutrition, and the interaction of these factors.” ¹  

Vitamin D has profound effects on the immune system and has antibacterial and antiviral effects. ² Vitamin D deficiency is associated with an increased risk of developing viral and bacterial infections. ^3,4 The connection between vitamin D and immunity was first reported when it was identified that important immune cells like macrophages and dendritic cells, referred to as “antigen-presenting” cells, actually make the active form of vitamin D. Further studies demonstrated that epithelial cells like those found in skin, lung and the intestinal lining also convert vitamin D to its active form. This suggested that these cells could be influenced by vitamin D, which may be very important in respiratory diseases. ² Overall, there are two parts to the immune system: the innate and adaptive immune responses which will be discussed below. The evidence is stronger for the role of vitamin D in the innate immune system, but promising for adaptive immune system function as well. ⁵ It is important to note that innate and adaptive immunity overlap and work together. For example, vaccines have been developed based on what scientists have learned about the complexities of our immune systems. Vaccines are designed to initiate an innate immune response, which then activates an antigen specific adaptive immune response. ⁶ It is important to clarify the difference, first let’s discuss innate immunity. 

Innate immunity is the human body’s first defense against infection. It includes physical barriers including the skin, mucus and lining of the lungs and intestines, as well as cells with receptors that quickly recognize pathogens. The role of Vitamin D in the regulation of this line of defense was initially discovered during research for the treatment of leprosy and tuberculosis. Vitamin D reinforces the barrier provided by epithelial cells, enhances the cell’s ability to produce 1,25 (OH)2D at the site of infection, increases other key defenses of innate immunity and decreases inflammatory markers. ¹ Vitamin D is known to prevent the overproduction of certain inflammatory agents, cytokines, and enhances the bacterial fighting ability of a class of immune cells, called macrophages. ²

The adaptive immune system is also called the acquired immune system. It is the body’s second defense against infection. Unlike the innate immune system, it fights against pathogens or antigens very specifically, but it takes longer to develop. It is activated by exposure to pathogens, and it is able to learn about the pathogen and adjust the immune response accordingly. It can be thought of as an immunological memory. It is the type of memory that is created by vaccines so that exposure to a specific pathogen causes our immune system to recognize and specifically target it. ¹ 1,25(OH)2D has an inhibitory, anti-inflammatory, effect on the adaptive immune system. ² When cells of the adaptive immune system, called T and B cells, are activated by pathogens, the number of VDR on their surfaces is increased, which then upregulates up to 500 vitamin D responsive genes that influence the adaptive immune cell response. This is thought to play a protective role in autoimmune disorders and to decrease the inflammatory response. ^3,4

Observational studies report consistent independent associations between low serum concentrations of 25-hydroxyvitamin D (the major circulating vitamin D metabolite) and susceptibility to acute respiratory tract infection. In an analysis of 25 studies, vitamin D supplementation reduced the risk of acute respiratory tract infection among over 11,000 subjects who were supplemented. Daily or weekly supplementation benefitted the subjects more than just a large single dose. Those that were most deficient benefitted the most. ¹

While scientists have not yet determined an exact answer to this question,  many studies suggest a potential connection between vitamin D and COVID-19 and mechanisms to explain the connection have been proposed. It is established that inflammation and what is called a cytokine storm, which is when an infection triggers your immune system to flood your bloodstream with inflammatory proteins called cytokines, play a critical role in COVID–19 patient outcomes. This dramatic inflammatory reaction can kill tissue and damage organs. Adequate vitamin D levels as well as a healthy balanced diet, particularly the Mediterranean Diet, have been identified as beneficial to offset this inflammatory response. Additionally, vitamin D may exhibit antiviral effects by interfering with viral replication and through its immunomodulatory and anti-inflammatory properties. ¹ In addition, Vitamin D administration impacts several other molecular mechanisms that are protective against lung infection in COVID-19. ²  Vitamin D supports the ability of macrophages (a type of white blood cell) to mature and that prevents them from releasing too many inflammatory molecules such as cytokines. 

Recent publications have suggested potential mechanisms to explain why vitamin D plays a beneficial role in COVID-19, some are summarized here. 

• Vitamin D reduces the risk of microbial infection and death. 
• Vitamin D supplementation has shown favorable effects in viral infections including influenza and HIV. 
• Vitamin D is a negative endocrine renin-angiotensin system (RAS) modulator. 
• Vitamin D increases expression and concentration of certain genes and receptors – thereby having a potential protective role against acute lung injury and acute respiratory distress syndrome. ^3,4 

Vitamin D goes through several transformations before the human body can use it. The first occurs in the liver where vitamin D is converted to 25-hydroxyvitamin D, also called calcidiol [25(OH)D]. The amount of 25(OH)D in the blood is a good indication of how much Vitamin D the body contains. Vitamin D status is determined by measuring serum levels of 25(OH)D. While there is not complete agreement on the exact levels to diagnose insufficiency, most experts agree that between 20 and 125 nmol/L is ideal for bone health. Levels higher than 150 nmol/L can be detrimental. Low concentrations of serum 25(OH)D (<30 nmol/L) are associated rickets and osteomalacia, conditions characterized by softened and weakened bone. Higher concentrations of serum 25(OH)D above the deficiency range, yet not sufficient, are associated with bone mineral depletion and susceptibility to fractures. ^1,2,3 The National Academy of Medicine-recommends the following: at risk of deficiency [serum 25(OH)D <30 nmol/L (<12 ng/mL)], at risk of inadequacy [serum 25(OH)D 30–49 nmol/L (12–19 ng/mL)], sufficiency [serum 25(OH)D 50–125 nmol/L (20–50 ng/mL)], and concentrations of possible concern [serum 25(OH)D >125 nmol/L (>50 ng/mL)]. ⁴ Vitamin D deficiency can be caused by many factors including decreased intake, inadequate exposure to sunlight, living at high latitudes, winter season, having respiratory disease such as asthma, obesity, diabetes and even some medications can lead to deficiency. ^5-7 Vitamin D deficiency is a major health concern because it has been linked to depression, fatigue, muscle aches, increased risk of respiratory infections, autoimmune disorders, osteoporosis, osteomalacia, osteoarthritis, increased risk of infection and some cancers. ^5-7

Vitamin D comes from 3 potential sources: food, sunlight-dependent production in the skin and supplements. There are very few natural food sources; plants contain ergocalciferol (vitamin D2) and fatty fish (salmon, mackerel, sardines, cod liver oil) and some types of mushrooms (Shiitake), especially if sun-dried, contain cholecalciferol (vitamin D3). Because it is not easily obtained from food, manufacturers in many countries, including the US and Canada, have regulation that requires fortification of commonly consumed foods, such as milk, orange juice, other dairy products and cereals with vitamin D. Dietary supplements also contribute to intake and are of extra importance in the large population that is not regularly exposed to sunlight and/or who do not consume enough from food. ¹

One of the many unique characteristics of vitamin D is that the body can make it from sunlight. Cholesterol combines with ultraviolet rays from sunlight and is converted to a precursor form of vitamin D. Through a series of steps, it is ultimately converted to the active form of vitamin D. Even though humans can theoretically make all of the vitamin D they need, it is still advisable to consume vitamin D from food and/or dietary supplement sources because few people have sufficient exposure to sunlight. Anything that interferes with exposure to sunlight, especially UVB sunlight, can potentially impair sunlight-stimulated vitamin D production. UVB rays are not very strong at latitudes above 35 °N in the winter, so sufficient amounts of vitamin D cannot be made from sunlight exposure during the winter months at higher latitudes. Clothing, sunscreen and skin melanin levels also impair sunlight-induced vitamin D production. People with darker skin require longer exposure to the sun to make the same amount of vitamin D as individuals with less melanin. ¹ Because the use of sunscreen is critical important for skin health, it is important to consider sources of vitamin D beyond sunlight as well.

The Institute of Medicine recommends a dietary intake of Vitamin D of 600 IU/day for all ages over 1 year (and for pregnant and lactating women), with increases to 800 IU/day for individuals over 71 years. ¹ Few people are able to obtain enough vitamin D from food sources alone, therefore supplementation is very important. ² How much to supplement is less clear and will vary based on vitamin D status. Deficient individuals will need a different supplemental strategy than those who are not deficient. As you read through the various studies and information regarding vitamin D, you will notice varying approaches to dosing individuals identified to be deficient. For many years it was common to provide what is called a bolus, or large single dose, it was easy and efficient, but it was determined to be less effective and to be associated with increased risk of falls and other issues. It then became more common to provide daily or weekly doses, and sometimes in individuals who are in intensive care or severely deficient, a large single dose is used along with daily or weekly supplementation. There is no agreed upon dose globally, recommendations typically range from 400-2000 IU/day and your doctor may recommend more. However, a common dose of 1000 IU or 25 μg of vitamin D3, has been identified to be safe and effective. ² It has been reported that a daily vitamin D dose of 800 IU can achieve a target 25(OH)D level of at least 50 nmol/L (or 20 ng/mL) in most healthy individuals, and 2000 IU is sufficient to achieve a level of at least 75 nmol/L (or 30 ng/mL). ³

Toxicity is rare, and vitamin D is very safe at wide ranges of intake. However, growing consumer awareness of vitamin D has led to increased supplementation and intake making potential toxicity more of a possibility. In addition, there have been global public health campaigns to fortify common foods like dairy products, which increases total vitamin D consumption. High concentrations of serum 25(OH)D or free 1,25(OH)2D, when serum 25(OH)D exceeds 375 nmol/l (or 150 ng/ml), causes high calcium in the blood and urine and is typically associated with high calcium intake or genetic abnormalities in vitamin D metabolism. Vitamin D is a fat soluble vitamin so if levels increase to toxic levels, they will stay elevated for up to 18 months. Therefore, although it is very rare and one would have to consume a lot of vitamin D to reach toxic levels, it is advisable to stay within recommended intake ranges or follow the doses recommended by your healthcare practitioner. ¹