Department of Medicine. University of Seville

Introduction
The intervention of vitamin D in our immune system activity led to the study of this hormone’s effect on SARS-CoV-2 infection from the start of the pandemic. Published studies have already been analyzed in other chapters of this special edition. Some societies and scientific and health institutions have considered this topic, and based on these reflections, offer recommendations to the health community. In this chapter, we present a brief overview.

Spanish Society for Bone Research and Mineral Metabolism
(SEIOMM)
As a professional group concerned specifically with the study of bone metabolism and osteoporosis and, therefore, a national reference, a compulsory position document1 was carried out into the current evidence regarding the role of vitamin D in the context of COVID-19. Published in December 2020, the expert document raised the following questions:
1. Is there a relationship between vitamin D deficiency and corona virus infection risk?
2. Is there a biological explanation for this association?
3. Can administration of vitamin D to deficient individuals prevent infection or alter its severity?
4. What is the risk/benefit ratio of its administration?
After analyzing the published studies and their results, the following responses were:
1. Although not all the data are uniform, there does seem to be a relationship, not necessarily causal, between vitamin D deficiency and the incidence and mortality from COVID‐19.
2. Vitamin D can play a protective effect thanks to:
‐ Maintaining the integrity of the epithelium.
‐ Stimulation of the production of antimicrobial peptides.
‐ Reducing the inflammatory response.
‐ Modification of the relationship between ACE/ACE2 by increasing the expression of ACE2.
3. The evidence to indicate the administration of vitamin D in preventing or treating COVID-19 is scarce and presents many limitations. Experts indicate that, at this time, the threshold of vitamin D that must be reached to achieve the objective, the most suitable metabolite or the doses that must be used are unknown. Due to the lack of sufficient clinical evidence then, they refrain from recommendations in this regard.
4. Pending the publication of clinical trials that confirm or negate its usefulness, the risk/benefit ratio could be favorable to the use of vitamin D in compassionate use (off-label) in the prevention and treatment of COVID‐19 in patients at risk, in which it might be reasonable to prevent or treat the deficiency, given the known beneficial effect on immunity and respiratory infections.

International League of
Associations for Rheumatology
(ILAR)
In April 2020, the International League of Associations for Rheumatology published a document2 in which, from the point of view of the rheumatologist, potential targets for COVID-19 treatment were analyzed.
After a brief introduction to the epidemiology of the disease, the risk factors for severe COVID-19 and the clinical manifestations that can mimic other rheumatic diseases, the authors focus on potentially useful drugs for its treatment. Among them, they address treatment with vitamin D supplements. They deem it reasonable to think that vitamin D can boost immunity and help the body in its fight against COVID-19 and its aggressive effects on all organs and systems. Thus, in subjects with laboratory-confirmed vitamin D deficiency, particularly the elderly, obese, those with dark skin, and those living in high latitudes, treatment with high doses of vitamin D should be considered.
Given its protective effects, experts suggest that in subjects at risk with chronic diseases (cancer, cardiovascular disease, respiratory tract infections, diabetes and hypertension), vitamin D supplementation is associated with an increase in serum levels of 25(OH) vitamin D above 50 ng/ml (125 nmol/l) could substantially reduce the incidence and severity of COVID-19, although they note that more clinical trials and cohort studies are urgently needed to assess its efficacy (and the of other preventive and curative agents) before professional societies can make evidence-based recommendations.

National Institute for Health
and Care Excellence
(NICE)
The UK’s National Institute for Health and Care Excellence (NICE) published its brief guidelines on COVID-19 and vitamin D on December 17, 2020[3]. They offer a series of recommendations on the need to maintain adequate vitamin D levels in the population, especially due to the periods of confinement that prevented sun exposure. But they also recommend that researchers delve into the preventive and therapeutic role of vitamin D in COVID-19.
Among the recommendations, we would highlight:
1. The population (adults, youth, and children over 4 years of age; including pregnant women) should be encouraged to maintain bone and muscle health if sun exposure is poor (for whatever reason) by taking daily supplements of vitamin D (400 IU per day) throughout the year. They should also be taken, regardless of sun exposure, by people with very dark skin due to their low production of vitamin D from the sun; infants from birth to one year of age (in doses between 340 to 400 IU) if they are breastfed or are taking formulas not fortified with vitamin D; children from 1 to 4 years; those whose medical condition implies a lower production of vitamin D.
2. In the autumn-winter months (those that correspond in each hemisphere), these supplements should be taken due to the low production of vitamin D in these times (the entire population).
3. Vitamin D supplementation alone should not be offered for the prevention or treatment of COVID-19, except as part of a clinical trial, due to the limited evidence available at that time.

Spanish Society of Geriatrics and Gerontology
(SEGG)
The SEGG published more recently (in February 2021) a position paper[4] in which the role of vitamin D as a modulator of immunity was analyzed, later focusing on its possible actions in COVID-19. They review the studies published to date, and based on them, make the following recommendations for elderly patients hospitalized for COVID-19:
1. Vitamin D should be administered daily until adequate levels are reached and maintained during the hospital stay, since vitamin D behaves as a negative acute phase reactant and consumption by the patient may occur during the course of treating the infection.
2. Although there is no evidence regarding specific doses in the elderly, they recommend their standardization. First of all, vitamin D levels must be determined at the time of hospital admission, and, if necessary, supplementation with vitamin D, suggesting a unique protocol based on experts’ opinions. They indicate the recommended doses of both cholecalciferol and calcidiol. The administration of cholecalciferol is recommended in any situation, regardless of the basal levels of 25(OH) vitamin D, and even in the absence of analytical determination. However, calcidiol is only recommended if at the time of diagnosis of COVID-19 we have levels determined and, in addition, these are below 20 ng/ml. In case of obesity or malabsorption, higher doses than those recommended by the authors should be considered.
3. The goal of vitamin D treatment should be to achieve adequate 25(OH) vitamin D levels as quickly as possible and maintain them for at least 3 months.
4. Finally, they recommend paying attention to possible vitamin D toxicity due to the administration of high doses of supplements, especially hypercalcaemia, so blood calcium levels should be monitored regularly during administration.

Vitamin D for all
An open letter published at the end of 2020[5], signed by more than 200 experts and opinion leaders in vitamin D from multiple countries is noteworthy.
It requests that governments and medical groups worldwide increase immediate, widespread determination of vitamin D levels in the population, given the possible benefits that this strategy could have in the fight against COVID-19. The authors highlight the role of vitamin D on immune function, noting that increasing vitamin D levels could help reduce infections, hospitalizations, ICU admissions and deaths from COVID-19.
In order to optimize 25 (OH) vitamin D levels above 30 ng/ml in the adult population, experts recommend an intake of 4,000 IU/day of cholecalciferol (or at least 2,000 IU) without the need for determination of levels, given that this amount is widely recognized as safe by international regulatory authorities such as the European Food Safety Authority (EFSA).

Conclusion
In conclusion, the scientific-health community’s recommendations to maintain adequate vitamin D levels in the population in the fight against COVID-19 is well known. Research continues into its implications in the pathogenesis, prevention and treatment of the infection. This demonstrates the importance that vitamin D has for the health of the population.

Conflicto de intereses: El autor declara no tener conflicto de intereses.

1. Pérez Castrillón JL, Casado E, Corral Gudino L, Gómez Alonso C, Peris P, Riancho JA. COVID-19 y vitamina D. Documento de posición de la Sociedad Española de Investigación Ósea y del Metabolismo Mineral (SEIOMM). Rev Osteoporos Metab Miner. 2020;12(4):155-9.
2. Misra DP, Agarwal V, Gasparyan AY, Zimba O. Rheumatologists’ perspective on coronavirus disease 19 (COVID-19) and potential therapeutic targets. Clin Rheumatol. 2020;39:2055-62.
3. COVID-19 rapid guideline: vitamin D. London: National Institute for Health and Care Excellence (UK); 2020 Dec 17. www.nice.org.uk/guidance/ng187.
4. Tarazona-Santabalbina FJ, Cuadra L, Cancio JM, Roca Carbonell F, Pérez-Castejón Garrote JM, Casas-Herrero A, et al. Suplementos de vitamina D para la prevención y el tratamiento de la COVID-19: declaración de posición de la Sociedad Española de Geriatría y Gerontología. Rev Esp Geriatr Gerontol. 2021;56(3):177-82.
5. Over 200 Scientists & Doctors Call for Increased Vitamin D Use To Combat COVID-19. https://vitamindforall.org/ letter.pdf. Consultado en: Octubre 2021.