Vitamin D, an unexpected helper in the fight against COVID-19?

Studies have shown that vitamin D can play a role in regulating immune function and reducing cytokine storms; randomized controlled clinical trials (prospective studies) have shown that there is a correlation between vitamin D levels and the severity of COVID-19 infection and mortality.

For ordinary people, sufficient vitamin D can be obtained by maintaining a reasonable diet and good living habits. Excessive supplementation may cause adverse drug reactions.

Written by | Veronica

After being infected with the novel coronavirus, young people with good basic health conditions may experience a week that is "unbearable to look back on", but fortunately, most people can rely on their own immunity to get through it. However, it is sad that many elderly people did not make it through the New Year.

In addition to vaccination, keeping healthy, and working hard to improve our own immunity, do we have any other helpers to fight the new coronavirus? The answer may be a little unexpected - it is vitamin D, which is familiar to us but often overlooked.

1

Is vitamin D deficiency related to COVID-19 infection?

Several studies have shown that vitamin D levels are correlated with COVID-19 infection. A meta-analysis based on 23 studies (total number of cases n=2692) showed [1] that vitamin D deficiency is associated with an increased incidence of severe COVID-19 infection and mortality, but the causal relationship between the two has not yet been confirmed.

An observational study in Barcelona[2] showed that among 4.6 million community residents who took cholecalciferol (vitamin D3) or calcifediol as prescribed by their doctors, those whose serum 25-hydroxyvitamin D (25OHD, the main form of vitamin D in the body) levels reached 30 ng/mL or above after treatment had a COVID-19 incidence, severe disease incidence, and mortality rate reduced by about half compared with those who did not take vitamin D supplements.

Another study conducted in 4,599 veterans in the United States showed [3] that when the patient's serum 25OHD level increased from 15 ng/mL to 60 ng/mL, the hospitalization rate due to COVID-19 infection could be reduced from 24.1% to 18.7% (p=0.009), and the COVID-19 mortality rate was reduced from 10.4% to 5.7% (p=0.001). This observational study is strong evidence of a causal relationship between serum 25OHD levels and the severity of COVID-19.

Most of the existing evidence comes from observational studies, while randomized controlled clinical trials (prospective studies) are direct evidence that vitamin D deficiency is associated with COVID-19 infection. In May 2022, a multicenter, randomized, controlled, non-blind, superiority clinical trial (total number of cases n=254) conducted in 9 medical centers in France was published [4]. It revealed for the first time that among high-risk populations, the high-dose (400,000 IU, IU is the international unit, 1 IU=0.025 μg) vitamin D3 group was compared with the standard-dose (50,000 IU) vitamin D3 group within 72 hours of COVID-19 infection. The high-dose group had a significantly lower mortality rate 14 days after infection (6% vs 11%, HR=0.33), but there was no significant difference in the 28-day mortality rate (15% vs 17%, HR=0.70). The researchers believe that if vitamin D is supplemented continuously rather than just once, long-term survival may be improved. In addition, compared with the standard-dose group, the high-dose group did not have an increase in drug side effects.

It is well known that vitamin D plays a key role in bone formation and blood calcium metabolism. It also plays many important roles in the body. Even before the outbreak of the COVID-19 pandemic, clinical studies have confirmed that low serum 25OHD levels are associated with an increased incidence of acute respiratory infections (including influenza virus infections) and community-acquired pneumonia [5].

In addition, multiple studies have shown that vitamin D deficiency is associated with the occurrence of many diseases, including infectious diseases, autoimmune diseases, coronary heart disease, diabetes, and cancer. These underlying diseases will increase the risk of severe COVID-19 infection and death, but some researchers believe that the more critical factor is the accompanying vitamin D deficiency rather than the underlying disease itself [6].

2

Do other vitamins have any effect on COVID-19?

In addition to vitamin D, are other vitamins related to COVID-19 infection? According to in vitro molecular studies and animal research models, multiple vitamins have the potential to resist COVID-19 infection, but there is a lack of clinical evidence to support this.

Vitamin A can stimulate the proliferation and differentiation of T cells, reduce oxygen free radicals and increase alveolar surfactant; vitamin B1 is involved in the metabolism of sugars, fats and proteins, and its deficiency can damage cell membrane function and induce inflammatory responses; vitamin C is related to the phagocytic function of macrophages, the chemotaxis of leukocytes and the proliferation and differentiation of T cells, and also has antioxidant function; vitamin E can delay "immune senescence". The functions of T cells, neutrophils and NK cells decline with age. Vitamin E can improve the function of immune cells and fight against oxygen free radicals[7].

Level 1 and 2 evidence-based medicine supports the use of vitamin B1, vitamin C, and vitamin D in the treatment of acute respiratory distress syndrome (ARDS) and sepsis, and the clinical manifestations of ARDS and sepsis are somewhat similar to those of COVID-19 infection. Current clinical research evidence shows that the role of vitamin C in COVID-19 infection remains uncertain and needs to be further confirmed by large sample size, well-designed randomized controlled trials [8]. However, there is still a lack of relevant clinical evidence for the role of vitamin A, vitamin B1, and vitamin E in COVID-19 infection.

3

Possible mechanism of vitamin D against novel coronavirus infection

Vitamin D plays a dual role in regulating the body's immune function. On the one hand, vitamin D can activate nonspecific immunity and enhance the body's antiviral ability; on the other hand, vitamin D can inhibit inflammatory responses and prevent the occurrence of cytokine storms.

Studies have shown[5] that vitamin D can enhance intercellular connections and strengthen the physical protective barrier of the skin and mucous membranes. In addition, vitamin D can induce the secretion of cathelicidin (also known as antimicrobial peptides) and defensins, preventing bacteria, fungi and viruses from invading cells while inhibiting viral self-replication. Vitamin D can also increase the expression of toll-like receptors (TLRs) [9], helping to identify invading microorganisms and activating nonspecific immune responses, which may play a role in resisting COVID-19 infection.

The cytokine storm caused by the massive secretion of inflammatory cytokines is one of the key factors leading to the development of severe COVID-19 infection. Vitamin D can inhibit the proliferation of type 1 helper T cells (Th1 cells), thereby reducing the secretion of pro-inflammatory cytokines such as interferon (IFN-γ), tumor necrosis factor (TNF-α), IL-1, and IL-6. At the same time, vitamin D can affect the differentiation of T cells, promote the transformation of type 17 helper T cells (Th17 cells, pro-inflammatory) to regulatory T cells (T-reg cells, anti-inflammatory), and promote macrophages to secrete anti-inflammatory cytokines such as IL-10. As a result, vitamin D can reduce the occurrence of cytokine storms and prevent or delay the development of COVID-19 infection into severe cases [5].

In addition, the role of vitamin D in fighting COVID-19 infection is also related to the ACE2 receptor. ACE2, or angiotensin-converting enzyme 2, is the main binding receptor for COVID-19-infected alveolar cells and intestinal epithelial cells. Vitamin D can increase the enzyme concentration of soluble ACE2[6]. Soluble ACE2 binds to COVID-19 and can reduce the content of free viruses, thereby reducing the chance of the virus binding to the ACE2 receptor on the cell surface and preventing viral invasion.

ACE2 plays an important role in the renin-angiotensin-aldosterone system (RAAS system), and can directly catalyze the metabolism of angiotensin 2 (Ang II) and reduce the content of Ang II. After the occurrence of COVID-19 infection, the body will downregulate the ACE2 receptors on the cell surface, resulting in an increase in Ang II levels. High levels of Ang II have a strong vasoconstrictive effect and can lead to acute respiratory distress syndrome (ARDS), myocarditis and acute kidney injury (AKI). High levels of vitamin D can increase soluble ACE2 on the one hand, and reduce the concentration of renin in serum on the other hand [10], thereby increasing the metabolism of Ang II, reducing the production of Ang II, and reducing tissue damage caused by COVID-19 infection.

At the same time, studies have shown[11] that vitamin D has a direct repair effect on damaged epithelial tissue and organ damage, and may have an anti-fibrotic effect. The above mechanism has been preliminarily confirmed in in vitro and animal experiments, but more clinical evidence is still needed to clarify the specific mechanism of vitamin D against COVID-19 infection in humans.

4

Vitamin D deficiency is very common in the population

About 20% of the vitamin D in the human body comes from daily diet (mainly dairy products and cod liver oil), and 80% comes from the effects of ultraviolet rays. Vitamin D is a steroid hormone. When we bask in the sun, 7-dehydrocholesterol in the human skin can be converted into vitamin D under the irradiation of ultraviolet rays (UVB).

Melanin is an indole-containing polymer produced by melanocytes, which determines the depth of our skin and hair color. Melanin can reduce the penetration of UVB, which reduces the incidence of skin cancer on the one hand, and reduces the production of vitamin D on the other hand. The melanin content of skin varies among different races, and the synthesis rate of vitamin D is also different. Generally speaking, vitamin D deficiency is more common among people of color.

It is estimated that about one billion people in the world suffer from vitamin D deficiency[12] . A population-based study of 40 countries showed [13] that more than 50% of the population suffer from vitamin D deficiency (serum 25OHD < 20ng/mL). In India, the number of people with vitamin D deficiency exceeds 70% of the total population, which may be related to their lifestyle habits. In Europe, this figure is about 40%, Canada is about 47%, and the United States is about 24% [14] . In China, the situation is also not optimistic. In 2009, a scholar reviewed the vitamin D nutrition data published in China over the past 20 years and found that 39.2% of the population suffers from vitamin D deficiency, including 80% of pregnant women and all newborns [15]. Over the past decade, the nutritional health awareness and nutritional level of the Chinese people have improved, but there is still a lack of large-sample population studies that can reflect the vitamin D nutritional status of the Chinese people.

Since the outbreak of the COVID-19 pandemic, people's lifestyles have undergone tremendous changes, with many people working from home and reducing outdoor activities. As the time spent in the sun decreases, the proportion of people with vitamin D deficiency may further increase. Compared with young people, the elderly are more susceptible to vitamin D deficiency. The main reason is that the content of 7-dehydrocholesterol in the skin of the elderly decreases, resulting in reduced vitamin D production; it is also related to factors such as less outdoor activities, unhealthy lifestyles (such as drinking), and decreased testosterone levels [16].

5

Do we need routine vitamin D supplementation?

Given its potential benefits, should we routinely use vitamin D to treat COVID-19 infections?

Clinical studies in France have shown[4] that oral high-dose vitamin D taken within 72 hours of being diagnosed with COVID-19 can reduce the 14-day mortality rate of high-risk patients (but does not change the 28-day mortality rate), and no increase in side effects was found. Another clinical study in Spain showed [17] that early supplementation with high-dose vitamin D can reduce the proportion of COVID-19 hospitalized patients admitted to the ICU. However, it should be noted that the research data so far are mostly based on the Delta strain, not the currently prevalent Omicron strain.

Many researchers believe that although the specific mechanism of action of vitamin D in fighting the new coronavirus infection needs further study, the regulatory effect of vitamin D on immune function has been confirmed. Given that vitamin D is highly safe, inexpensive, and easily available as a common drug, it is a good choice to add it to the treatment of new coronavirus infection in high-risk patients (currently, my country's "New Coronavirus Infection Diagnosis and Treatment Program (Trial Tenth Edition)" does not mention the addition of vitamin D treatment). However, in clinical application, attention should be paid to the use of drugs in special populations (such as drug metabolizing enzymes and receptor gene polymorphisms) and combined medications to avoid the occurrence of drug toxicity such as dehydration and hypercalcemia.

However, according to existing evidence, vitamin D supplementation is not very effective in treating the sequelae of COVID-19. On the other hand, vitamin D deficiency has been shown to be associated with fatigue and weakness in the general population [18] , which is precisely the most common sequelae of COVID-19. After infection with the new coronavirus, the expression of vitamin D receptor (VDR) in the cell nucleus is downregulated [6]. Therefore, vitamin D may play a greater role in the early stage of infection, but has limited effect in the later stage of infection. In addition to the new coronavirus, downregulation of VDR expression has also been reported in cytomegalovirus infection, hepatitis B virus infection, and hepatitis C virus infection.

So for ordinary people, is it necessary to regularly supplement vitamin D to prevent COVID-19? Vitamin D supplements are also a kind of medicine. If there is no vitamin D deficiency, excessive supplementation may cause adverse drug reactions. According to the recommendations of China's "Guidelines for the Application of Vitamin D and Adult Bone Health" [19] , people with serum 25OHD lower than 20ng/ml and the following high-risk factors are recommended to receive vitamin D supplementation:

1. Have risk factors for vitamin D deficiency, such as less outdoor activities, dark skin, etc.;

2. History of osteoporosis;

3. Use anti-resorptive drugs to treat bone diseases;

4. Use of anti-epileptic drugs or oral glucocorticoids;

5. Elevated serum parathyroid hormone.

If the serum 25OHD level is within the safe range, there is no need to supplement vitamin D. Adequate vitamin D levels can be maintained by increasing sunlight exposure and daily diet. Daily sunlight exposure time is preferably 10 to 30 minutes. Foods rich in vitamin D in the daily diet include animal liver, egg yolk, cod liver oil, dairy products, nuts and seafood.

According to the "Chinese Residents' Dietary Nutrient Reference Intake", adults are recommended to consume 10-15 μg of vitamin D, 2,600 units of vitamin A (male, 2,300 units for females), 1.4 mg of vitamin B1 (male, 1.2 mg for females), 100 mg of vitamin C, 23.4 units of vitamin E, and 800-1,000 mg of calcium per day. The recommended values ​​of the National Academy of Medicine of the United States are slightly different: adults are recommended to consume 15-20 μg of vitamin D, 3,000 units of vitamin A (male, 2,310 units for females), 1.2 mg of vitamin B1 (male, 1.1 mg for females), 90 mg of vitamin C (male, 75 mg for females), 22.4 units of vitamin E, and 1,000-1,200 mg of calcium per day.

References

[1] Oscanoa, TJ(2021) The relationship between the severity and mortality of SARS-CoV-2 infection and 25-hydroxyvitamin D concentration—a meta-analysis. Adv. Respir. Med. 2021, 89, 145–157.

[2] Oristrell, J. (2021) Vitamin D supplementation and COVID-19 risk: A population-based, cohort study. J. Endocrinol. Investig. 2021, 45, 167–179.

[3] Seal, KH(2022) Association of Vitamin D Status and COVID-19-Related Hospitalization and Mortality. J. Gen. Intern. Med. 2022, 37, 853–861.

[4] Annweiler C. (2022) High-dose versus standard-dose vitamin D supplementation in older adults with COVID-19 (COVIT-TRIAL): A multicenter, open-label, randomized controlled superiority trial. PLoS Med 19(5): e1003999.

[5] Ali, N. (2020) Role of vitamin D in preventing of COVID-19 infection, progression and severity. J. Infect. Public Health 2020, 13, 1373–1380.

[6] Barrea, L. (2022) Vitamin D: A Role Also in Long COVID-19? Nutrients 2022, 14, 1625.

[7] Jovic TH.(2020) Could Vitamins Help in the Fight Against COVID-19? Nutrients. 2020; 12(9):2550.

[8] Rs N.(2022) Vitamin C and its therapeutic potential in the management of COVID19. Clin Nutr ESPEN. 2022 Aug;50:8-14.

[9] Liu PT.(2006) Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006; 311(5768):1770–1773.

[10] Giménez VMM.(2020) Vitamin D-RAAS connection: an integrative standpoint into cardiovascular and neuroinflammatory disorders. Curr Protein Pept Sci. 21(Jun 6)

[11] Ahmad, S. (2020) Vitamin D and its therapeutic relevance in pulmonary diseases. J. Nutr. Biochem. 2020, 90, 108571.

[12] Lips, P. (2021) Trends in Vitamin D Status Around the World. JBMR Plus 2021, 5, e10585.

[13] Lips P.(2019) Current vitamin D status in European and Middle East countries and strategies to prevent vitamin D deficiency: a position statement of the European Calcified Tissue Society. Eur J Endocrinol. 2019; 180(4): p23–p54.

[14] Mohan M. (2020) Exploring links between vitamin D deficiency and COVID-19. PLoS Pathog 16(9): e1008874.

[15] Wu Guangchi. (2009) Vitamin D nutritional status of the Chinese population. Proceedings of the Academic Seminar on Progress in Maternal, Child and Adolescent Nutrition and the Promotion Conference of the Dietary Guidelines for Pregnant Women, Breastfeeding Mothers and Children Aged 0-6 Years Old, Chinese Nutrition Society, 2009.

[16] Zhang Chenyang et al. (2019) Current status and countermeasures of vitamin D deficiency in the elderly. Chinese Journal of New Drugs and Clinical Practice, 2019, 38(6): 328-332.

[17] Entrenas ME(2020) 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. J. Steroid Biochem. Mol. Biol. 2020, 203, 105751.

[18] Townsend, L. (2021) Investigating the Relationship between Vitamin D and Persistent Symptoms Following SARS-CoV-2 Infection. Nutrients 2021, 13, 2430.

[19] Liao Xiangpeng et al. (2014) Vitamin D and bone health application guide for adults (2014 standard version). Chinese Journal of Osteoporosis, 2014, 20(9): 1011-1025.

This article is supported by the Science Popularization China Starry Sky Project

Produced by: China Association for Science and Technology Department of Science Popularization

Producer: China Science and Technology Press Co., Ltd., Beijing Zhongke Xinghe Culture Media Co., Ltd.

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