Vitamin D in the COVID-19 era

UNIVERSITY OF SEVILLE VITAMIN D IN THE COVID-19 ERA Student: Mª de los Milagros Granados Palomo Academic year: 2020/2021 Tutors: Juan Dionisio Bautista Palomas Isabel María Moreno Navarro 1 University of Seville Faculty of Pharmacy MASTER'S DISSERTATION Vitamin D in the COVID-19 era Master in Professional Pharmacy Department of Biochemistry and Department of Toxicology Mª de los Milagros Granados Palomo July 12TH – Faculty of Pharmacy Academic year: 2020/2021 Tutors: Juan Dionisio Bautista Palomas and Isabel María Moreno Navarro Bibliographic review 1 2 INDEX ABSTRACT ……………………………………………………………………………………………………………………2 KEYWORDS ………………………………………………………………………………………………………………….2 RESUMEN …………………………………………………………………………………………………………………….3 PALABRAS CLAVE …………………………………………………………………………………………………………3 INTRODUCTION ……………………………………………………………………………………………………………5 o Prevalence of vitamin D deficiency and metabolism ……………………………………5 o Causes of vitamin D deficiency …………………………………………………………………….6 o Sources of vitamin D …………………………………………………………………………………..9 o Vitamin D Receptor and the many functions of vitamin D ………………………….12  Main function of vitamin D ………………………………………………………13  Other functions of vitamin D ……………………………………………………14 OBJECTIVES ……………………………………………………………………………………………………………….16 METHODOLOGY …………………………………………………………………………………………………………17 RESULTS AND DISCUSSION …………………………………………………………………………………………20 o Table 4: Revised and commented bibliography …………………………………………21 o COVID-19 Generalities ………………………………………………………………………………50 o Vitamin D and COVID-19 ……………………………………………………………………………51 o ¿A possible relation between vitamin D and COVID-19? …………………………….52 o Respiratory diseases and vitamin D …………………………………………………………..53 o Commentary about relevant papers included in Table 4 ……………………………54  Evidence that vitamin d supplementation could reduce the risk of influenza and covid-19 infections and deaths (Grant et al., 2020) ……54  25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2 (D’Avolio et al., 2020) …………………………56  “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” (Entrenas Castillo et al. 2020) ……………………………………………..57 o Veganism and vitamin D ……………………………………………………………………………58 CONCLUSIONS ……………………………………………………………………………………………………………61 REFERENCES ………………………………………………………………………………………………………………62 2 ABSTRACT The rapid global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2), the virus that causes coronavirus disease 2019 (COVID-19), has re-ignited interest in the possible role of vitamin D in modulation of host responses to respiratory pathogens. Indeed, vitamin D supplementation has been proposed as a potential preventative or therapeutic strategy. Recommendations for any intervention, particularly in the context of a potentially fatal pandemic infection, should be strictly based on clinically informed appraisal of the evidence base. In this narrative review, we examine current evidence relating to vitamin D and COVID-19 and consider the most appropriate practical recommendations. Although there are a growing number of studies investigating the links between vitamin D and COVID-19, they are mostly small and observational with high risk of bias, residual confounding, and reverse causality. Extrapolation of molecular actions of 1,25(OH)2- vitamin D to an effect of increased 25(OH)-vitamin D as a result of vitamin D supplementation is generally unfounded, as is the automatic conclusion of causal mechanisms from observational studies linking low 25(OH)-vitamin D to incident disease. Efficacy is ideally demonstrated in the context of adequately powered randomised intervention studies, although such approaches may not always be feasible. At present, evidence to support vitamin D supplementation for the prevention or treatment of COVID-19 is inconclusive. In the absence of any further compelling data, adherence to existing national guidance on vitamin D supplementation to prevent vitamin D deficiency, predicated principally on maintaining musculoskeletal health, appears appropriate. KEYWORDS Vitamin D, Vitamin D Receptor (VDR), hypovitaminosis, COVID-19, Vitamin D2 vegetarianism and veganism. 3 RESUMEN La propagación global rápida del síndrome respiratorio agudo severo coronavirus tipo 2 (SARS-CoV-2), responsable de la enfermedad del coronavirus 2019 (COVID-19), ha vuelto a despertar el interés del posible rol de la vitamina D en la modulación de la respuesta del hospedador ante patógenos respiratorios. De hecho, la suplementación con vitamina D se ha propuesto como estrategia de potencial preventivo o terapéutico. Las recomendaciones para cualquier intervención, especialmente en el contexto de una pandemia, deberían estar estrictamente basadas en evaluaciones clínicas informadas de la evidencia existente. En este trabajo se pretende examinar la evidencia actual que relaciona la vitamina D con el COVID-19 y considerar recomendaciones prácticas adecuadas. Aunque un número creciente de estudios investigan los vínculos entre la vitamina D y el COVID-19 se trata en la mayoría de los casos de estudios pequeños y observacionales de alto riesgo de parcialidad, confusión residual y causalidad inversa. La extrapolación de las acciones moleculares de la 1,25(OH)2-vitamina D a efecto de niveles incrementados de 25(OH)-vitamina D como resultado de la suplementación con vitamina D es generalmente sin fundamento, ya que se trata de la conclusión automática a la que se llega por los mecanismos causales obtenidos de estudios observacionales que enlazan niveles bajos de 25(OH)-vitamina D a la enfermedad incidente. La eficacia se demuestra en el contexto de estudios de intervención adecuados, aunque tal acercamiento no sea factible. En el presente, la evidencia parece apoyar la suplementación con vitamina D como prevención o tratamiento para el COVID-19. Ante la ausencia de datos más convincentes, la adherencia a las guías nacionales de suplementación de vitamina D para prevenir su deficiencia, normalmente enfocadas a mantener la salud del sistema músculo-esquelético, parece apropiada. PALABRAS CLAVE Vitamina D, Receptor de la Vitamina D (VDR), hipovitaminosis, COVID-19, Vitamina D2, vegetarianismo y veganismo. 4 5 INTRODUCTION Prevalence of vitamin D deficiency and metabolism Deficiency of vitamin D is very prevalent nowadays, being Europe one of the regions where this condition is higher, reaching 40% of people who are deficient and 13% who are severely deficient. The number of individuals who suffer from this hypovitaminosis varies depending on age, being the children and the elderly the ones whose prevalence is higher. It also depends on ethnicity, since Caucasians are the ones with lower levels of this micronutrient in their plasma (Amrein et al., 2020). For a brief historical outline, vitamin D was discovered in the beginnings of the XX century, being the existence of vitamins previously established by McCollum and Davis in 1913. Despite being identified as such, it was after discovered that it was a hormone since our body can synthesize it through the 7-dehydrocholesterol present in our skin (De Luca, 2016). 7-dehydrocholesterol transforms thanks to the sunlight, specifically UVB radiation, into previtamin D3 and it isomerizes into vitamin D3 or cholecalciferol later through a thermosensitive process (Bikle, 2014). For cholecalciferol to turn into vitamin’s D active form a hydroxylation needs to happen in the liver by hepatic cytochrome P-450s, obtaining 25- dihydroxyvitamin D3. The transport of vitamin D and its different forms through the organism is realized by the vitamin D binding protein (DBP). Then, this compound suffers another hydroxylation that this time takes place in the kidney and the result of this process is 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), which is the hormonal active form. This step can also happen in other types of cells, due to the presence of 1α-hydroxylase in them, under specific physiological circumstances such as pregnancy, but it serves as an autocrine/paracrine factor. Nevertheless, since a small intake through diet is necessary in order to reach the recommended daily ingest, we can still consider it as a vitamin instead of strictly a hormone (Brown et al., 2008; Christakos et al., 2015; De Luca, 2016; Lin et al., 2021; Mizobuchi, 2012). 1α-hydroxylase is highly regulated by dietary calcium and parathyroid hormone (PTH) along with other different factors in order to prevent a possible scenario of vitamin D intoxication. The inactivation of 1,25 12 Whole Food Vitamin D powder as a help to “maintain/support immune health” and “helps with immune function.” “Although we may not be able to fully prevent or treat an illness, it is still important to focus on daily eating patterns that are nutrient-rich with foods high in vitamins C and D, in addition to healthy lifestyle practices, such as practicing food safety, washing hands, staying active, getting enough sleep and taking care of one’s mental health to help support the immune system”. The requirements of vitamin D have changed since its discovery more than a hundred years ago. At the moment the recommended daily intake is 10 μg/day for all ages and 20-25 μg for premature children. The recommendation for people over seventy years old is 20 μg/day (Rodríguez-Rodríguez et al., 2019). Setting the daily dose to take is a key factor since the bioavailability of this vitamin depends on a significant number of factors, such as environment ones, malabsorption problems, use of certain medications or even genetics. This is why it is important to establish a daily intake and investigate the need to modify it if necessary. Vitamin D receptor and the many functions of vitamin D The importance of vitamin D for regulation of calcium and phosphate balance in musculoskeletal physiology is well established (Harvey et al., 2017). Vitamin D receptors are also expressed by many non-skeletal tissues suggesting a broader role for vitamin D in human health, particularly in modulating immune system activities (Bikle, 2014; Prietl et al., 2013). The vitamin D receptor (VDR) is a nuclear receptor with different functional domains. 1,25 D can do its actions by binding to VDR, forming a complex that dimerizes with the retinoid X receptor. This heterodimer then translocate to the nucleus where it binds vitamin D responsive elements that induce the expression of genes related to vitamin D (Aranow, 2011). This receptor can be found in many different tissues, which means that vitamin D deficiency has consequences beyond the ones that affect our skeletal system. Since the 13 VDR was discovered in almost every tissue of our body, along with nearly thousands of sites of union for the receptor in the genome, it’s interesting to explain some actions that vitamin D performs in our body (Bikle, 2014). Main function of vitamin D We can find vitamin D receptors on the intestine, inside enterocytes, where they develop the main role of vitamin D: regulation of calcium absorption on this level. This process is dependent on the union of vitamin D with its receptor inside the cells since this union stimulates the production of the channel responsible for the active transportation across the apical membrane. Then, calcium binds to a specific calciumbinding protein and exits the enterocyte across the basolateral membrane, ending in the bloodstream. All this process was discovered thanks to studies using the duodenum but it’s known that VDR is present along the entire intestine, both small and large. Also, the channel responsible for the transport of calcium into the cells is more abundant in the distant part of the intestine so it’s safe to assume this process occurs throughout the entire organ. Along with this process, calcium is also absorbed by paracellular transport, but the role of vitamin D is not clear and further studies are required (Christakos et al., 2015). On the kidneys, most calcium is absorbed independently of vitamin’s D presence but the rest is absorbed in the distant tube through active transport regulated by the presence of vitamin D and the parathyroid hormone (they increased the levels of the pertinent transporter in the membrane, just like happened in the intestine) (Christakos et al., 2015). Calcium and bone homeostasis are closely related. The role of vitamin D receptor is to stimulate bone resorption and to inhibit its mineralization when calcium concentration in plasma is low. This action, however, appears to be redundant since the inactivation of the receptor in mature osteoblasts and osteoclasts didn’t have any effects on the metabolism of the skeletal system. It’s necessary to develop more studies on this matter (Christakos et al., 2015). The parathyroid hormone (PTH) stimulates the liberation of calcium from the bone in a process dependant on the presence of vitamin D, not being able to do this process in 14 cases of deficiency. In the same way, without PTH vitamin D can’t elevate calcium levels in the bloodstream, unless the dietary intake of this mineral is very high (De Luca, 2016). Vitamin’s D role in the utilization of calcium (and also phosphorus), as said previously, is its main function. It helps to prevent diseases like rickets, osteoporosis and osteomalacia indirectly, rising blood levels of this mineral for its use when necessary. An incorrect supplementation of vitamin D can develop into toxic situations like hypercalcemia (Aguilar Shea et al., 2020; De Luca, 2016). Other functions of vitamin D Apart from its functions related to calcium and bone homeostasis, vitamin D forms part of many other different roles since its receptor can be found in most of the tissues in our body, as said before (Aguilar Shea et al., 2020). Vitamin D receptor also exists in cells that form part of the cardiovascular system, like myocytes, and plays a part in its functions. There are also receptors in the pancreatic beta cells and other target tissues for insulin, like the skeletal muscle tissue or the adipose tissue, and their activity is related to a better activity of those pancreatic cells, their protection against cells of the immune better sensitivity to insulin (Rodríguez- Rodríguez et al., 2019). Some studies relate the vitamin D - VDR axis with good homeostasis of the oral epithelium and its immunity since low levels of this vitamin are related to chronic peritonitis (Khammissa et al., 2018). Vitamin D plays a very important role in the immune system and participates in the regulation of innate and adaptive functions. On an innate level, monocytes and macrophages express the VDR, which exerts anti-inflammatory activity on an innate level. Dendritic cells also suffer from modulation by vitamin D, which causes changes in morphology and cytokine production (Martens et al., 2020). Vitamin D is also involved in the transcription of cathelicidin and defensin 4, peptides with antimicrobial activity (Aranow, 2011). Regarding adaptive immunity, vitamin D is involved in T-lymphocytes modulation both indirectly and directly. Indirectly, antigen-presenting cells are affected by vitamin D, which decreases their production. This develops into the regulation of lymphocytes T response, lowering their proliferation. Directly, when T lymphocytes are activated they 15 increase their number of vitamin D receptors and vitamin D inhibits the production of certain cytokines (Prietl et al., 2013). B-lymphocytes have VDR and 1α-hydroxylase which means vitamin D plays an important role in these cells. 1,25(OH)2D3 induces apoptosis of activated B lymphocytes, which prevents the generation of plasmatic cells and memory cells. Calcitriol also has antiproliferative effects, which was considered a role mediated by T helper cells. Regulation of these lymphocytes may be important in autoimmune diseases (Martens et al., 2020; Prietl et al., 2013). This involvement in the immune function may explain that vitamin D deficiency is involved a less vulnerability towards respiratory diseases and could have a potential role in the new coronavirus disease (Grant et al., 2020). 16 OBJECTIVES This revision aims to cover the following objectives: - Explore the prevalence of vitamin’s D deficiency in the world and the possible causes for this. - Explain the metabolism and synthesis of vitamin D. - Study different dietary sources for vitamin D, both from animal and vegetal origin. - Explore the relevance and functions of the vitamin D receptor (VDR) on different systems of the organism. - Give general information about the new SARS-CoV-2: symptoms, possible courses of the disease and recommended sanitary measures for its prevention. - Make a compilation of relevant articles that relate vitamin D with COVID-19 to ascertain a possible relation between them. - Explain how vitamin D deficiency may affect the vulnerability to certain respiratory diseases. - Explore the consequences of vegan diets over the individual vitamin D status. 17 METHODOLOGY All the information was searched in the Pubmed and Scopus data bases, different published articles related to the objectives of the review were found. Other information sources were consulted through the University of Seville online catalogue, FAMA such as books. The main criteria used for the inclusion of information in this revision were sources that were in either English or Spanish and with free open access through the resources of the University of Seville. Therefore, texts in other languages different from English or Spanish were excluded and so were the ones without open access. First, an information search was made to compile information about vitamin D and the VDR. This was carried out by using vitamin D as a keyword in FAMA, where books were consulted, and Pubmed and Scopus, where different relevant studies and reviews were found. To find information about 'vitamin D receptor' a new search was made using it as keyword in both Scopus and Pubmed resulting in several articles found about this issue Subsequently, a new search was done by using COVID-19 as keyword to search for information in different reviews and articles in Scopus and Pubmed. Next, different reviews and studies that related to these two topics (vitamin D and COVID) were explored so it was possible to collect relevant information about the relationship that exists mainly between low concentrations of 25(OH)D, which imply vitamin D deficiency, and the gravity or risk of infection of COVID-19. This compilation of articles and reviews were researched through Scopus following the search criteria “vitamin D” and “COVID” in the title, keywords or abstract. Among the results, the table included those whose abstracts were available so a brief comment about the contents could be made and checked out by everyone. The articles are placed from older to most recent (from December 2019 to June 2021) and language was not a conditional factor, as long as the abstract was in English. Then, three of the most cited ones in Scopus (one review and two studies) were selected to explain its contents and the conclusions that they arrived. 18 Table 3 “Search in data bases”: different number of articles present in the two main data bases used for this review and included in the table that contains information relating vitamin D and COVID-19. SEARCH PROFILE DATA BASE NUMBER OF ARTICLES Vitamin D (all open access) SCOPUS 45,937 COVID-19 (all open access) 118,202 Vitamin D and COVID 994 Vitamin D (all open access) PUBMED 29,931 COVID-19 (all open access) 113,107 Vitamin D and COVID 660 Figure 4: Schematic representation of data handling Records identified through database searching (n=75868) Scopus (n=45937), Pubmed (n=299131) All Open Access Records identified through database searching (n=231309) Scopus (n=118202), Pubmed (n=113107) All Open Access Vitamin D COVID-19 Records identified through database searching (n=1654) Scopus (n=994), Pubmed (n=660) Vitamin D and COVID-19 Studies included in the table (n=215) December 2019 – June 2021 Corrections, errors, notes, letters, no relation with the aim of the work abstract/authors not available excluded IDENTIFICATION SCREENING INCLUDED 19 Finally, a compilation of relevant information about the relation between vitamin D deficiency and respiratory diseases and the consequences of vegan diets on human health, mainly the nutritional state of the individual, was carried out and how this could affect the risk of getting COVID-19 or the gravity of the disease in case of contracting the illness. For the relation between respiratory diseases and vitamin D deficiency we used the terms “vitamin D” and “respiratory diseases” combined as search criteria in Scopus and them we used “veganism” and “vitamin D” to explore the possible implications of vegan diets over this particular nutrient also in Scopus. Papers were selected for inclusion in the work based on title and abstract screening followed by full text review, if appropriate. Further relevant studies were identified through cross referencing and author searches. With regards summarising evidence relating to vitamin D and non-COVID-19 acute respiratory infections, we selected the latest and most comprehensive systematic evidence reviews on the topic. 20 RESULTS AND DISCUSSION As can be observed from the Methodology section, this Review has involved an extensive bibliographic consultation that has led to the selection of 215 papers, which have been reviewed in detail and commented (Table 4). Of the 215 papers selected, 105 are research articles, 77 are Reviews and 33 are clinic trials. From obtained information, a quick analysis could lead us to conclude that hypovitaminosis D is an unfavourable factor against COVID-19 and viral infections; so supplementation with vitamin D would be beneficial. Which is generally true, but it requires a more detailed analysis. Of all the consulted publications in approximately 90% of them an association between vitamin D deficiency and COVID-19 is described. Since the aims of each article and review vary greatly from one to another it is very tedious and lacking in interest to classify every publication included into a specific category. A good part of them these papers claim that more evidence and studies or trials are necessary in order to prove the relevance of vitamin D in the current pandemic. This is due to the lack of proper randomized controlled trials and observational studies on this matter since this topic is very recent in the current state of affairs and all most of the trials carried out could be considerate inadequate because of, for example, imprecise homogeneity in the groups in which the participants are divided (some groups could have more individuals with certain comorbidities than others or even have different baselines of serum concentrations of vitamin D) spoil the results obtained. The rest of the articles found about this topic either deny an existent association or claim that proper studies and trials are needed before even claiming that there is a possible link between vitamin D and COVID-19. 21 Table 4: Revised and commented bibliography REFERENCE TITLE COMMENTARY Bonvecchio et al., 2019 Archivos Latinoamericanos de Nutrición Volume 69, Issue 4, Pages 259 - 273 Micronutrient recommendations for vulnerable groups in context of undernutrition, during the COVID-19 pandemic in Latin America. The potential impact of COVID-19 in Latin America could be decreased by following certain dietary measures, such as supplementation with vitamin C, D and zinc in adults. Palacios et al., 2019 Archivos Latinoamericanos de Nutrición Volume 69, Issue 4, Pages 242 - 258 Nutritional recommendations for healthcare and essential personnel exposed to COVID-19 in Latin America Supplementation of different micronutrients, including vitamin D, may prevent respiratory infections in adults. Pereira et al., 2020 Critical Reviews in Food Science and Nutrition DOI: 10.1080/10408398.2020.1841090 Vitamin D deficiency aggravates COVID-19: systematic review and meta-analysis Vitamin D deficiency was not associated with a higher risk of infection by COVID-19, but it was with the severity of the illness. Nayak et al., 2020 International Journal of Pharmaceutical Research Volume 12, Pages 2437 - 2448 Dietary supplementation and medication of vitamin c and vitamin d in covid-19 – a hypothesis Vitamin C and D play a role in reducing the risk of respiratory infection and other conditions that are associated with the current pandemic. Kerget et al., 2020 Tuberkuloz ve Toraks Volume 68, Issue 3, Pages 227 - 235 Evaluation of the relationship of serum vitamin d levels in covid-19 patients with clinical course and prognosis Quarantine has reduced exposure to sunlight to lower 25(OH)D levels. This status can be responsible for worse outcomes of COVID-19 Adami et al., 2020 Reumatismo Volume 72, Issue 4, Pages 189 - 196 Vitamin d and disease severity in coronavirus disease 19 (Covid-19) Prevalence of low levels of 25(OH)D is important due to its possible association with inflammatory response and respiratory failure in COVID-19 Jain & Parsanathan, 2020 Journal of the American College of Nutrition Pages 694 - 699 Can Vitamin D and L-Cysteine Co-Supplementation Reduce 25(OH)-Vitamin D Deficiency and the Mortality Associated with COVID-19 in African Americans? Vitamin D along with L-cysteine correct vitamin D deficiency, therefore, preventing the most severe consequences of the disease 28 Kenneth et al., 2020 Clinical Medicine, Journal of the Royal College of Physicians of London Volume 20, Issue 4, Pages E107 - E108 Does Vitamin D deficiency increase the severity of COVID- 19? Vitamin D reduces COVID-19 severity in different manifestations of the disease so supplements can reduce the impact of the pandemic. Aygun, 2020 Naunyn-Schmiedeberg's Archives of Pharmacology Volume 393, Issue 7, Pages 1157 - 1160 Vitamin D can prevent COVID-19 infection-induced multiple organ damage The immunomodulatory effects of vitamin D may have protective effects against symptoms of COVID-19 associated with the cytokine storm Anjum et al., 2020 Pakistan Journal of Medical and Health Sciences Volume 14, Issue 3, Pages 1184 - 1186 Examine the association between severe Vitamin D deficiency and mortality in patients with Covid-19 Vitamin D deficiency causes a major risk of mortality in individuals with COVID-19, especially those who are severely deficient. Ilie et al., 2020 Aging Clinical and Experimental Research Volume 32, Issue 7, Pages 1195 - 1198 The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality The number of COVID-19 cases was more abundant in countries where deficiency of vitamin D was more prevalent. Charoenngam & Holick, 2020 Nutrients Volume 12, Issue 7, Pages 1 – 28, Article number 2097 Immunologic effects of vitamin d on human health and disease Low levels of 25(OH)D in serum cause different immunerelated disorders, like respiratory diseases, so a proper intake of this vitamin is beneficial. Jayawardena et al., 2020 Diabetes and Metabolic Syndrome: Clinical Research and Reviews Volume 14, Issue 4, Pages 367 – 382 Enhancing immunity in viral infections, with special emphasis on COVID-19: A review Several micronutrients, such as vitamin D, may positively affect viral infections. They could be useful in both the prevention and treatment of COVID-19. Song et al., 2020 Chinese Pharmaceutical Journal Volume 55, Issue 13, Pages 1117 – 1121 Evidence-Based Evaluation of Vitamin C and D in the Treatment and Prevention of Acute Viral Respiratory Infectious Disease After evaluating the evidence that supports the treatment of COVID-19 with vitamin C and D due to their beneficial effects in other respiratory infections there was currently no evidence that supports their use for the current pandemic as proper treatment. 29 Alexander et al., 2020 Nutrients Volume 12, Issue 8, Pages 1 – 12, Article number 2358 Early nutritional interventions with zinc, selenium and vitamin D for raising anti-viral resistance against progressive COVID-19 Adequate supplementation of micronutrients can be useful in both prevention and outcome of COVID-19 so this ingest should be recommended especially in high-risk areas. Singh et al., 2020 Aging Clinical and Experimental Research Volume 32, Issue 8, Pages 1609 – 1612 Revisiting the role of vitamin D levels in the prevention of COVID-19 infection and mortality in European countries post infections peak It appears that there is a negative correlation between vitamin D levels and the number of COVID-19 cases but further studies are required with different subgroups. Tramontana et al., 2020 Endocrine Volume 69, Issue 2, Pages 237 – 240 The D-side of COVID-19: musculoskeletal benefits of vitamin D and beyond Adequate 25(OH)D levels in elderly patients are important to achieve good musculoskeletal and respiratory health in COVID-19 Martín Giménez et al., 2020 Life Sciences Volume 254, Article number 117808 Lungs as target of COVID-19 infection: Protective common molecular mechanisms of vitamin D and melatonin as a new potential synergistic treatment Vitamin D and melatonin could attenuate the pulmonary complications of COVID-19 thanks to their mechanisms against inflammation and oxidative stress. Brenner et al., 2020 Nutrients Volume 12, Issue 8, Pages 1 – 11, Article number 2488 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? Vitamin D3 may reduce COVID-19’s mortality since individuals with deficiency had higher mortality than those who did not. Xu et al., 2020 Journal of Translational Medicine Volume 18, Issue 1, Article number 322 The importance of Vitamin D metabolism as a potential prophylactic, immunoregulatory and neuroprotective treatment for COVID-19 Vitamin D has potential for prevention against COVID-19 so this review explores several functions and mechanisms Singh et al., 2020 Diabetes and Metabolic Syndrome: Clinical Research and Reviews Volume 14, Issue 5, Pages 1033 - 1035 Vitamin D deficiency in patients with diabetes and COVID- 19 infection Vitamin D deficiency is associated with the severity of COVID- 19 but there is not enough data related to diabetic patients about the effects of the vitamin on them. Slominski et al., 2020 Experimental Dermatology Volume 29, Issue 9, Pages 885 - 890 COVID-19 and Vitamin D: A lesson from the skin Vitamin D supplementation must be taken into consideration in the treatment of COVID-19 especially since the population more vulnerable to the disease is deficient. 30 Mohan et al., 2020 PLoS Pathogens Volume 16, Issue 9, Article number e1008874 Exploring links between Vitamin D deficiency and covid- 19 As an immunomodulator, is relevant to explore the actions of vitamin D against COVID-19, especially since there is no treatment available. Merzon et al., 2020 FEBS Journal Volume 287, Issue 17, Pages 3693 - 3702 Low plasma 25(OH) vitamin D level is associated with increased risk of COVID-19 infection: an Israeli population-based study Low levels of 25(OH)D present in the Israeli population seem to be an independent risk factor for COVID-19. Pizzini et al., 2020 Nutrients Volume 12, Issue 9, Pages 1 – 9, Article number 2775 Impact of vitamin d deficiency on covid-19—a prospective analysis from the covid registry Even if vitamin D deficiency is common among patients with COVID-19 there is not enough evidence that proves that it worsens the disease’s outcome. Shalayel et al., 2020 Pakistan Journal of Pharmaceutical Sciences Volume 33, Issue 5, Pages 2179 - 2186 Vitamin D is a potential inhibitor of COVID-19: In silico molecular docking to the binding site of SARS-CoV-2 endoribonuclease Nsp15 Vitamin D may act as an inhibitor of COVID-19 Nsp15 endoribonuclease binding sites so, its supplementation may be useful to fight the illness. Whittemore, 2020 American Journal of Infection Control Volume 48, Issue 9, Pages 1042 – 1044 COVID-19 fatalities, latitude, sunlight, and vitamin D Even though it seemed to be a correlation between a country’s latitude, vitamin D deficiency and COVID-19 fatality, further research is needed to confirm the relation. de las Heras et al., 2020 Antioxidants Volume 9, Issue 9, Pages 1 – 21, Article number 897 Implications of oxidative stress and potential role of mitochondrial dysfunction in covid-19: Therapeutic effects of vitamin d COVID-19 is associated with altered mitochondrial functionality and oxidative stress and vitamin D can help normalize these situations in the organism Macaya et al., 2020 Nutricion Hospitalaria Volume 37, Issue 5, Pages 1039 – 1042 Interaction between age and vitamin d deficiency in severe covid-19 infection Vitamin’s D deficiency is associated with severe cases of COVID-19 and this could be particularly important in the younger population Ohaegbulam et al., 2020 American journal of therapeutics Volume 27, Issue 5, Pages e485 - e490 Vitamin D Supplementation in COVID-19 Patients: A Clinical Case Series High dose supplementation of vitamin D is observed to improve the recovery from COVID-19. To ascertain the efficacy of this treatment further studies are needed. 31 Dos Santos et al., 2020 Archives of Endocrinology and Metabolism Volume 64, Issue 5, Pages 498 – 506 Reasons to avoid vitamin D deficiency during COVID-19 pandemic Vitamin D supplementation is recommended during the confinement to avoid deficiency but its positive effect against COVID remains unclear Maghbooli et al., 2020 PLoS ONE Volume 15, Issue 9, Article number e0239799 Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 Adequate levels of 25(OH)D modulate the immune response and may help to reduce the severity of the morbidities associated with COVID-19 Malek Mahdavi., 2020 Reviews in Medical Virology Volume 30, Issue 5, Article number e2119 A brief review of interplay between vitamin D and angiotensin-converting enzyme 2: Implications for a potential treatment for COVID-19 Vitamin D affects unbalanced RAS and ACE2 that happens during COVID-19 so it may have a therapeutic effect against the disease, restoring the balance and preventing lung damage Žerjavić, 2020 Medicus Volume 29, Issue 2, Pages 219 – 224 COVID-19 and vitamin d – is there a link? High dose vitamin D supplementation (up to 10,000 IU per day) should be prescribed to achieve antiviral respiratory effects against COVID-19 Isaia & Medico, 2020 Aging Clinical and Experimental Research Volume 32, Issue 9, Pages 1879 - 1881 Associations between hypovitaminosis D and COVID-19: a narrative review Cross-sectional analyses could not establish a clear relation between hypovitaminosis D and COVID-19, more studies are needed to explore the association between the two and if supplementation may help reduce the negative effects of the disease. Quesada-Gomez et al., 2020 Journal of Steroid Biochemistry and Molecular Biology Volume 202, Article number 105719 Vitamin D receptor stimulation to reduce acute respiratory distress syndrome (ARDS) in patients with coronavirus SARS-CoV-2 infections: Revised Ms SBMB 2020_166 Acute Respiratory Distress Syndrome (ARDS) may be aggravated by vitamin D deficiency so randomized clinical trials are in progress using vitamin D or oral calcifediol in patients with COVID-19 to see the possible benefits of supplementation. Kaufman et al., 2020 PLoS ONE Volume 15, Issue 9, Article number e0239252 SARS-CoV-2 positivity rates associated with circulating 25- hydroxyvitamin D levels SARS-CoV-2 positivity is strongly connected with low levels of 25(OH)D so it would be interesting to explore the effects of supplementation in reducing the risk of infection. 32 Meltzer et al., 2020 JAMA Network Open Volume 3, Issue 9, Article number e202019722 Association of vitamin D status and other clinical characteristics with COVID-19 test results Vitamin D deficiency is likely associated with an increased risk of COVID-19 in the cohort study, but randomized trials are necessary to determine the real effect of the vitamin over the disease. Benskin, 2020 Frontiers in Public Health Volume 8, Article number 513 A Basic Review of the Preliminary Evidence That COVID- 19 Risk and Severity Is Increased in Vitamin D Deficiency This review compiles information about the literature existing about vitamin’s D effect over COVID-19 and results in a positive view of the supplementation to reduce the risks associated with the disease. Zhang et al., 2020 Reviews in Cardiovascular Medicine Volume 21, Issue 3, Pages 339 - 344 Vitamin D deficiency in association with endothelial dysfunction: Implications for patients with COVID-19 The role of vitamin D deficiency in worsening the health of COVID-19 patients is still unclear so the review studies the role of vitamin D in endothelial health, which is relevant to the respiratory effects of SARS-CoV-2 Ali, 2020 Journal of Infection and Public Health Volume 13, Issue 10, Pages 1373 - 1380 Role of vitamin D in preventing of COVID-19 infection, progression and severity Even though there is a need for preventive measures against COVID-19 and some studies suggest vitamin D supplementation, there is not enough evidence that proves its protective role due to several other studies that disprove this statement. Annweiler et al., 2020 Maturitas Volume 140, Pages 24 – 26 Point of view: Should COVID-19 patients be supplemented with vitamin D? Positive results in the ongoing trials that study the effects of vitamin D supplementation against COVID-19 would encourage its use as a preventive measure. Pinzon et al., 2020 International Journal of Nutrition, Pharmacology, Neurological Diseases Volume 10, Issue 4, Pages 229 – 234 Coronavirus Disease 2019 (COVID-19) and Vitamin D Status: Is there any Opportunity for Intervention? The hospitalized patients due to COVID included in the study had deficient levels of vitamin D. Physicians should take these two factors into account. Rafiullah, 2020 American Journal of the Medical Sciences Volume 360, Issue 4, Pages 338 – 341 Can a Combination of AT1R Antagonist and Vitamin D Treat the Lung Complication of COVID-19? AT1R antagonists and vitamin D may protect against COVID by increasing ACE2 protein. ACE2 deficiency caused by the disease causes lung damage. 33 Taqarort & Chadli, 2020 Nutrition Clinique et Metabolisme Volume 34, Issue 3, Pages 211 – 215 Vitamin D and risk of acute respiratory infections: Influenza and COVID-19 Vitamin D stimulates the immune response and reduces negative responses of the immune system associated with the invasion of pathogens. Its deficiency could be linked to a higher risk of respiratory infections like COVID or influenza. Daneshkhah et al., 2020 Aging Clinical and Experimental Research Volume 32, Issue 10, Pages 2141 – 2158 Evidence for possible association of vitamin D status with cytokine storm and unregulated inflammation in COVID- 19 patients Vitamin D deficiency may be one of the causes for unregulated cytokine response in COVID-19 but the results of the study were insufficient to prove this claim. Goddek, 2020 International Journal of Infectious Diseases Volume 99, Pages 286 – 290 Vitamin D3 and K2 and their potential contribution to reducing the COVID-19 mortality rate Vitamin D3, vitamin K2 and magnesium supplements may prevent the long term health risk of the COVID-19 disease. Entrenas Castillo et al. 2020 Journal of Steroid Biochemistry and Molecular Biology Volume 203, Article number 105751 “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” A high dose of Calcifediol or 25-hydroxyvitamin D reduced the ICU admission of patients with COVID-19. Despite this, larger trials with properly matched groups are needed. Kara et al., 2020 British Journal of Nutrition Volume 124, Issue 7, Pages 736 - 741 'Scientific Strabismus' or two related pandemics: Coronavirus disease and vitamin D deficiency There is a severe vitamin D deficiency across the world and an association between this and mortality in COVID-19 is possible. Gündüz & Karaaslan, 2020 Annali Italiani di Chirurgia Volume 91, Issue 6, Pages 673 - 678 Covid-19 reminds us: Community vitamin d deficiency Comparing vitamin D status between people affected with COVID-19 and those who are not it is noticeable that those affected by the illness had lower levels in serum (In Italian). Mercola et al., 2020 Nutrients Volume 12, Issue 11, Pages 1 – 24, Article number 3361 Evidence regarding vitamin d and risk of covid-19 and its severity According to various observational studies, it seems to be a link between a deficiency in vitamin D and the risk of COVID- 19 infection. Supplementation of this vitamin as treatment or prevention could be useful, nevertheless, large scale randomized control trials are necessary on this matter. Hoong et al., 2020 Hormone and Metabolic Research Are Adequate Vitamin D Levels Helpful in Fighting COVID- 19? A Look at the Evidence There seems to be a link between COVID-19 and vitamin D levels so this association is worthy of exploration. 34 Volume 52, Issue 11, Pages 775 - 783 Bilezikian et al., 2020 European Journal of Endocrinology Volume 183, Issue 5, Pages R133 - R147 MECHANISMS in ENDOCRINOLOGY Vitamin D and COVID- 19 Vitamin D has the potential to intervene in the cytokine storm that causes some of the most serious complications of COVID- 19, like the ARDS. Moreover, it could have effects on the coagulopathy that can course with the illness. Tan et al., 2020 Nutrition Volume 79-80, Article number 111017 Cohort study to evaluate effect of vitamin D, magnesium, and vitamin B12 in combination on severe outcome progression in older patients with coronavirus (COVID-19) Supplementation with vitamin D, magnesium and vitamin B12 in older patients to prevent clinical deterioration and oxygen support. Annweiler et al., 2020 Nutrients Volume 12, Issue 11, Pages 1 – 12, Article number 3377 Vitamin d supplementation associated to better survival in hospitalized frail elderly covid-19 patients: The geriacovid quasi-experimental study Vitamin D supplementation in elder frail patients was showed to reduce the mortality of COVID-19 in this study. Mansur et al., 2020 Clinica e Investigacion en Arteriosclerosis Volume 32, Issue 6, Pages 267 – 277 Vitamin D high doses supplementation could represent a promising alternative to prevent or treat COVID-19 infection Vitamin’s D anti-inflammatory and immunomodulatory properties may be beneficial for COVID-19 but more clinical trials are necessary to validate the hypothesis. Mardani et al., 2020 Virus Research Volume 289, Article number 198148 Association of vitamin D with the modulation of the disease severity in COVID-19 Vitamin D has a modulating effect on lung injuries so its levels were measured, along with ACE concentrations and neutrophil to lymphocyte ratio, in patients with COVID-19 and their levels were altered comparing them to a control group. Annweiler et al., 2020 Journal of Steroid Biochemistry and Molecular Biology Volume 12, Issue 11, Pages 1 – 12, Article number 3377 Vitamin D and survival in COVID-19 patients: A quasiexperimental study Vitamin D3 supplementation taken during or just before COVID-19 was associated with a less severe course of the disease in frail elderly patients. 35 Silberstein, 2020 International Immunopharmacology Volume 88, Article number 106995 Correlation between premorbid IL-6 levels and COVID-19 mortality: Potential role for Vitamin D IL-6 are higher in COVID-19 patients. Since vitamin D is shown to lower the levels of this interleukin the prescription of this vitamin may be in order to prevent this situation. Im et al., 2020 International Journal of Infectious Diseases Volume 100, Pages 390 – 393 Nutritional status of patients with COVID-19 Deficiency of vitamin D or selenium is shown to decrease the immune system actions against COVID-19 and worsen the status of the disease. Lansiaux et al., 2020 Spatial and Spatio-temporal Epidemiology Volume 35, Article number 100362 Covid-19 and vit-d: Disease mortality negatively correlates with sunlight exposure Sunlight exposure may have a negative correlation with COVID-19 mortality due to its role in vitamin’s D synthesis. Malaguarnera, 2020 Nutrients Volume 12, Issue 11, Pages 1 – 19, Article number 3512 Vitamin d3 as potential treatment adjuncts for covid-19 The use of vitamin D supplementation in SARS-CoV-2 infection is supported by several observational studies since its actions may prevent severe respiratory effects. Padhi et al., 2020 International Immunopharmacology Volume 88, Article number 107001 Lower levels of vitamin D are associated with SARS-CoV-2 infection and mortality in the Indian population: An observational study There is an inverse correlation between 25(OH)D levels and SARS-CoV-2 infection rate but these observations need to be validated by more studies. Evans & Lippman, 2020 Cell Metabolism Volume 32, Issue 5, Pages 704 - 709 Shining Light on the COVID-19 Pandemic: A Vitamin D Receptor Checkpoint in Defense of Unregulated Wound Healing Paricalcitriol, a vitamin D analogue, has been proposed as infusion therapy against the cytokine storm that COVID-19 produces. Vitamin D and the inability of its receptor to activate can worsen respiratory syndrome. Bae & Kim, 2020 Molecules (Basel, Switzerland) Volume 25, Issue 22 Mini-Review on the Roles of Vitamin C, Vitamin D, and Selenium in the Immune System against COVID-19 Vitamin D, along with vitamin C and selenium, is discussed to have a great impact on the immune system. Their role in COVID-19 is explored in this review. Santaolalla et al., 2020 Frontiers in Physiology Volume 11, Article number 564387 Association Between Vitamin D and Novel SARS-CoV-2 Respiratory Dysfunction – A Scoping Review of Current Evidence and Its Implication for COVID-19 Pandemic A search was conducted about different studies to determine the relationship that may exist between COVID-19 morbidity and mortality and vitamin D deficiency. This review resulted 36 in the need for more observational studies to clearly establish the connection between the two elements. Murdaca et al., 2020 Clinical and Molecular Allergy Volume 18, Issue 1, Article number 23 Vitamin D and Covid-19: an update on evidence and potential therapeutic implications The mechanisms which through vitamin D reduces the risk and mortality of respiratory infections are diverse. Despite this, whether vitamin D is beneficial or not for COVID-19 prevention or treatment is not clear. Jain et al., 2020 Scientific Reports Volume 10, Issue 1, Article number 20191 Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers Levels of vitamin D are particularly low among COVID-19 patients and the inflammatory response is higher. This results in increased mortality of the disease, which could be prevented through supplementation. Pinzon at al., 2020 Tropical Medicine and Health Volume 48, Issue 1, Article number 102 Vitamin D deficiency among patients with COVID-19: case series and recent literature review In this study, all the participants who had COVID-19, had vitamin D deficiency. Supplementation may be beneficial thanks to the very few risk vitamin D has. Randomized control trials about this recommendation are needed. Griffin et al., 2020 Royal Society Open Science Volume 7, Issue 12, Article number 201912 Vitamin D and COVID-19: Evidence and recommendations for supplementation Even if there is no clear correlation between vitamin D deficiency and COVID-19 people who get hospitalized due to the illness should have the levels of the vitamin taken into consideration and the deficiency of the population should be treated. Grant et al., 2020 Nutrients Volume 12, Issue 12, Pages 1 – 19, Article number 3741 The benefits of vitamin D supplementation for athletes: Better performance and reduced risk of COVID-19 Aside from the benefits that vitamin D has for athletes in improving their condition, the supplementation may offer protection against COVID-19 thanks to its action against other respiratory diseases. Yılmaz & Sen, 2020 Pediatric Pulmonology Volume 55, Issue 12, Pages 3595 – 3601 Is vitamin D deficiency a risk factor for COVID-19 in children? Vitamin D values may be associated with COVID-19 since this study of the pediatric population showed that the two factors had a negative correlation. 37 Annweiler et al., 2020 Trials Volume 21, Issue 1, Article number 1031 COvid-19 and high-dose VITamin D supplementation TRIAL in high-risk older patients (COVIT-TRIAL): study protocol for a randomized controlled trial Vitamin D supplementation may be effective to improve the outcome of COVID-19. This article studies the effect of a single high dose of cholecalciferol versus a standard dose during 14 days (both oral). Vassiliou et al., 2020 Nutrients Volume 12, Issue 12, Pages 1 – 9Article number 3773, Low 25-hydroxyvitamin D levels on admission to the intensive care unit may predispose COVID-19 pneumonia patients to a higher 28-day mortality risk: A pilot study on a greek icu cohort Low levels of 25(OH)D upon ICU admission due to COVID-19 seem to be a predisponent factor for mortality according to this observational study. Ling et al., 2020 Nutrients Volume 12, Issue 12, Pages 1 – 16, Article number 3799 High-dose cholecalciferol booster therapy is associated with a reduced risk of mortality in patients with covid-19: A cross-sectional multi-centre observational study The aim of the study was to predict whether low levels of 25(OH)D could be used as a predictor for COVID-19’s mortality. Treatment with cholecalciferol seemed to reduce the risk associated with the disease but larger studies are necessary to determine both of these statements. Gonçalves et al., 2020 Clinical Nutrition ESPEN Volume 40, Pages 110 – 114 Prevalence of obesity and hypovitaminosis D in elderly with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) There is a high prevalence of ICU admission of elderly patients due to COVID-19 who have obesity and hypovitaminosis D in the study, so they suggest these two factors can be related to the severity of the disease and supplementation of the elderly population should be considered Name et al., 2020 Frontiers in Nutrition Volume 7, Article number 606398 Zinc, Vitamin D and Vitamin C: Perspectives for COVID-19 With a Focus on Physical Tissue Barrier Integrity Deficiency of Zinc, Vitamin D or Vitamin C compromises the immune system so supplementation of these nutrients may be in order during the pandemic to offer protection against the disease. Ahmed, 2020 Frontiers in Immunology Volume 11, Article number 590459 A Network-Based Analysis Reveals the Mechanism Underlying Vitamin D in Suppressing Cytokine Storm and Virus in SARS-CoV-2 Infection Vitamin D has antiviral effects and the potential for suppressing the cytokine storm that takes place in the organism during SARS-CoV-2 infection Boulkrane et al., 2020 Frontiers in Pharmacology Volume 11, Article number 604579 COVID-19 Disease and Vitamin D: A Mini-Review Supplementation of the high-risk population against COVID- 19 with vitamin D can be helpful in both the prevention and treatment of the disease. 44 Teymoori-Rad & Marashi, 2021 Reviews in Medical Virology Volume 31, Issue 2, Article number e2159 Vitamin D and Covid-19: From potential therapeutic effects to unanswered questions Vitamin D supplementation could be beneficial for COVID-19 in both treatment and prevention. Sulli et al., 2021 Nutrients Volume 13, Issue 3, Pages 1 – 13, Article number 717 Vitamin d and lung outcomes in elderly covid-19 patients Low levels of 25(OH)D were associated with more lung involvement in the new coronavirus disease. Detection of these low levels in younger patients with severe cases of the illness leads to thinking that it could be a determinant factor. Lohia et al., 2021 American Journal of Physiology - Endocrinology and Metabolism Volume 320, Issue 3 Exploring the link between vitamin D and clinical outcomes in COVID-19 There was no significant association found between low levels of vitamin D and mortality due to COVID-19 or more risk of its comorbidities. Lordan, 2021 Nutrients Volume 13, Issue 3, Pages 1 – 25, Article number 740 Notable developments for vitamin d amid the covid-19 pandemic, but caution warranted overall: A narrative review Patients with severe coronavirus disease tended to have vitamin D deficiency so maintaining good levels may have a positive influence on the disease. Griffin et al., 2021 Clinical Medicine, Journal of the Royal College of Physicians of London Volume 21, Issue 2, Pages E144 - E149 Perspective: Vitamin D supplementation prevents rickets and acute respiratory infections when given as daily maintenance but not as intermittent bolus: Implications for COVID-19 The role of vitamin D in respiratory diseases suggests a possible link between its deficiency and the current COVID- 19 pandemic. Supplementation should be taken into consideration. Annweiler & Souberbielle, 2021 Geriatrie et psychologie neuropsychiatrie du vieillissement Volume 19, Issue 1, Pages 20 – 29 Vitamin D supplementation and COVID-19: expert consensus and guidelines Hypovitaminosis D could be linked with severe cases of COVID-19 since a great percentage of individuals with this illness presented it (In French). Bleizgys, 2021 International Journal of Clinical Practice Volume 75, Issue 3, Article number e13748 Vitamin D and COVID-19: It is time to act Vitamin D deficiency is a grave global problem since it could be linked with severe cases of the new coronavirus deficiency. 45 Name et al., 2021 International Journal of Molecular Medicine Volume 47, Issue 3, Article number 4844 Vitamin D, zinc and glutamine: Synergistic action with OncoTherad immunomodulator in interferon signaling and COVID-19 (Review) Vitamin D, zinc and glutamine seem to regulate immune responses mediated by IFN signaling and this means they could have potential against COVID-19 Liu et al., 2021 International Journal of Infectious Diseases Volume 104, Pages 58 – 64 Low vitamin D status is associated with coronavirus disease 2019 outcomes: a systematic review and metaanalysis Vitamin’s D levels could be associated with an increased risk of COVID-19 infection but further studies are needed on this matter. De Smet et al., 2021 American Journal of Clinical Pathology Volume 155, Issue 3, Pages 381 - 388 Serum 25(OH)D Level on Hospital Admission Associated with COVID-19 Stage and Mortality In this study low levels of 25(OH)D upon admission were associated with increased mortality of COVID-19. Teshome et al., 2021 Frontiers in Public Health Volume 9, Article number 624559 The Impact of Vitamin D Level on COVID-19 Infection: Systematic Review and Meta-Analysis Low serum levels of 25(OH)D were associated with a higher risk of COVID-19 disease. Sufficient levels decreased said risk. Nie et al., 2021 Medicine Volume 100, Issue 9, Pages e24517 Oral high dose vitamin D for the treatment of diabetic patients with COVID-19: A protocol for systematic review and meta-analysis The authors of the article are going to carry out a study of how treatment with vitamin D affects diabetic patients infected with COVID-19. Feketea et al., 2021 Frontiers in Immunology Volume 12, Article number 648546 Vitamin D in Corona Virus Disease 2019 (COVID-19) Related Multisystem Inflammatory Syndrome in Children (MIS-C) Supplementation with 25-hydroxyvitamin D3 has favourable effects over Multisystem Inflammatory Syndrome in children, a grave complication of COVID-19. Hernández et al., 2021 Journal of Clinical Endocrinology and Metabolism Volume 106, Issue 3, Pages E1343 - E1353 Vitamin D Status in Hospitalized Patients with SARS-CoV- 2 Infection Levels of vitamin D were lower in patients with COVID-19 but there was no apparent relation between this and the severity of the disease. Murai et al., 2021 JAMA - Journal of the American Medical Association Volume 325, Issue 11, Pages 1053 - 1060 Effect of a Single High Dose of Vitamin D3on Hospital Length of Stay in Patients with Moderate to Severe COVID-19: A Randomized Clinical Trial A high dose supplementation of vitamin D hospitalized with COVID-19 reduced their hospital stay compared with those who received the placebo. 46 Meltzer et al., 2021 JAMA Network Open Volume 4, Issue 3, Article number e214117 Association of Vitamin D Levels, Race/Ethnicity, and Clinical Characteristics with COVID-19 Test Results The risk of COVID-19 was greater in black individuals with low vitamin D but no significant difference was found among white individuals. Guan, 2021 Chinese Journal of Endocrinology and Metabolism Volume 37, Issue 3, Pages 177 - 179 Can we use vitamin D to prevent and treat COVID-19? Vitamin D has the potential for treatment and prevention of the new coronavirus illness. The correction of the status of the vitamin is important (In Chienese). Akbar et al., 2021 Frontiers in Nutrition Volume 8, Article number 660420 Low Serum 25-hydroxyvitamin D (Vitamin D) Level Is Associated With Susceptibility to COVID-19, Severity, and Mortality: A Systematic Review and Meta-Analysis Low levels of 25(OH)D were associated with high mortality of COVID-19. Other factors that influenced were vitamin D and diabetes. Easty et al., 2021 Frontiers in Endocrinology Volume 12, Article number 644298 New Roles for Vitamin D Superagonists: From COVID to Cancer Vitamin D superagonist could play an important role that has not been studied yet against COVID-19 Dramé et al., 2021 Nutrients Volume 13, Issue 4, Article number 1339 Relation between vitamin d and covid-19 in aged people: A systematic review Vitamin D deficiency appears to be linked with an increased risk of COVID-19, especially in the elderly. It was also associated with worse outcomes of the disease. Tehrani et al., 2021 Clinical Nutrition ESPEN Volume 42, Pages 313 – 317 Evaluation of vitamin D levels in COVID-19 patients referred to Labafinejad hospital in Tehran and its relationship with disease severity and mortality There was no statistical difference between levels of vitamin D and COVID-19’s outcome. This deficiency affected patients with severe course of the disease. Carpagnano et al., 2021 Journal of Endocrinological Investigation Volume 44, Issue 4, Pages 765 – 771 Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19 Hypovitaminosis D is prevalent in COVID-19 patients and they have a higher risk of mortality. This deficiency could be a marker of the poor prognosis of the disease. Katz et al., 2021 Nutrition Volume 84, Article number 111106 Increased risk for COVID-19 in patients with vitamin D deficiency In this study, vitamin D deficiency was highly linked with a more severe case of the new coronavirus disease. 47 Charoenngam et al., 2021 Endocrine practice: official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists Volume 15, Issue 9, Article number e0239799 Association of Vitamin D Status With Hospital Morbidity and Mortality in Adult Hospitalized Patients With COVID- 19 There is an independent association between adequate levels of 25(OH)D and decreased risk of mortality from COVID-19 in the elderly and individuals without obesity. Piraux, 2021 Actualites Pharmaceutiques Volume 60, Issue 605, Pages 52 - 55 Interest of vitamin D in COVID-19 Vitamin’s D immunomodulatory effects may have potential against COVID-19, which explains the increased number of purchases and prescriptions of this vitamin. Abdollahi et al., 2021 Journal of Medical Virology Volume 93, Issue 4, Pages 2359 - 2364 The association between the level of serum 25(OH) vitamin D, obesity, and underlying diseases with the risk of developing COVID-19 infection: A case–control study of hospitalized patients in Tehran, Iran Vitamin D deficiency and obesity seem to be predisposing factor for the COVID-19 illness. Cereda et al., 2021 Clinical Nutrition Volume 40, Issue 4, Pages 2469 - 2472 Vitamin D 25OH deficiency in COVID-19 patients admitted to a tertiary referral hospital Low levels of 25(OH)D were highly prevalent among COVID- 19 patients but they weren’t associated with clinical outcomes of the disease. Angelidi et al., 2021 Mayo Clinic Proceedings Volume 96, Issue 4, Pages 875 - 886 Vitamin D Status Is Associated With In-Hospital Mortality and Mechanical Ventilation: A Cohort of COVID-19 Hospitalized Patients COVID-19 mortality and severity were inversely associated with vitamin D levels. Further observational studies about this are needed. Turrubiates-Hernández et al., 2021 International Journal of Molecular Medicine Volume 47, Issue 4, Article number 32 Potential immunomodulatory effects of vitamin D in the prevention of severe coronavirus disease 2019: An ally for Latin America (Review) Vitamin’s D immunomodulatory effects suggest that supplementation could help in the prevention of COVID-19 Giustina, 2021 Endocrine Volume 72, Issue 1 Hypovitaminosis D and the endocrine phenotype of COVID-19 Some consequences of COVID-19 infection could be influenced by an incorrect vitamin D status. 48 Pugach & Pugach, 2021 Wiener Klinische Wochenschrift Volume 133, Issue 7-8, Pages 403 - 405 Strong correlation between prevalence of severe vitamin D deficiency and population mortality rate from COVID- 19 in Europe Prevalence of vitamin D deficiency was associated with higher mortality due to COVID-19. Supplementation could be important in the treatment or prevention of the disease. Gaudio et al., 2021 International Journal of Environmental Research and Public Health Volume 18, Issue 7, Article number 3491 Vitamin D levels are reduced at the time of hospital admission in sicilian SARS-CoV-2-positive patients Sicilian patients with COVID-19 had low levels of vitamin D upon hospitalization but there is no clear evidence of a relationship between these two factors. Demir et al., 2021 Journal of Medical Virology Volume 93, Issue 5, Pages 2992 – 2999 Vitamin D deficiency is associated with COVID-19 positivity and severity of the disease A big part of COVID-19 positive patients had low levels of vitamin D so, maybe, increasing the levels could be a preventive measure against the disease. Jayawardena et al., 2021 Diabetes and Metabolic Syndrome: Clinical Research and Reviews Volume 15, Issue 3, Pages 757 – 764 Impact of the vitamin D deficiency on COVID-19 infection and morality in Asian countries Vitamin D deficiency is heavily associated with the risk of infection and mortality of COVID-19. Adequate levels seemed to have no relationship with the course of the disease. Tarazona-Santabalbina et al., 2021 Revista Espanola de Geriatria y Gerontologia Volume 56, Issue 3, Pages 177 – 182 VitaminD supplementation for the prevention and treatment of COVID-19: a position statement from the Spanish Society of Geriatrics and Gerontology Despite the lack of evidence about its efficacy against COVID- 19, daily vitamin D supplementation should be standardized as clinical practice. Alguwaihes et al., 2021 Aging Clinical and Experimental Research Volume 33, Issue 5, Pages 1415 – 1422 Severe vitamin D deficiency is not related to SARS-CoV-2 infection but may increase mortality risk in hospitalized adults: a retrospective case–control study in an Arab Gulf country Vitamin D deficiency is associated with a major risk of mortality due to COVID-19 but not with infection risk. Silberstein, 2021 European Journal of Pharmacology Volume 899, Article number 174031 COVID-19 and IL-6: Why vitamin D (probably) helps but tocilizumab might not Vitamin D could be more useful than tocilizumab in the downregulation of IL-6, which participates in the cytokine storm during COVID-19 Bassatne et al., 2021 Metabolism: Clinical and Experimental Volume 119, Article number 154753 The link between COVID-19 and VItamin D (VIVID): A systematic review and meta-analysis Low levels of 25(OH)D could be related to worse outcomes of COVID-19 but there is still no clear evidence on this matter. 49 Calcifediol supplementation may play a protective role over the disease. Petrelli et al., 2021 Journal of Steroid Biochemistry and Molecular Biology Volume 211, Article number 105883 Therapeutic and prognostic role of vitamin D for COVID- 19 infection: A systematic review and meta-analysis of 43 observational studies Low vitamin D values were associated with a higher risk of COVID-19 infection, severity and mortality. Ricci et al., 2021 Respiratory Research Volume 22, Issue 1, Article number 76 Circulating Vitamin D levels status and clinical prognostic indices in COVID-19 patients Assessing vitamin D levels could be useful as prognosis of COVID-19 infection. The deficiency of this vitamin seems to be related to severe cases of the disease. Al-Daghri et al., 2021 Journal of Translational Medicine Volume 19, Issue 1, Article number 166 Vitamin D status of Arab Gulf residents screened for SARS- CoV-2 and its association with COVID-19 infection: a multi-centre case–control study Individuals with low 25(OH)D in the Arab Gulf were related to SARS-CoV-2 positivity. However, other factors different than this seemed to be more relevant for COVID-19 so the relationship between vitamin D and the illness should be further studied. Walrand, 2021 Scientific Reports Volume 11, Issue 1, Article number 1981 Autumn COVID-19 surge dates in Europe correlated to latitudes, not to temperature-humidity, pointing to vitamin D as contributing factor Low levels of 25(OH)D seemed to be a contributing factor for the severity of the new coronavirus disease. Jevalikar et al., 2021 Scientific Reports Volume 11, Issue 1, Article number 6258 Lack of association of baseline 25-hydroxyvitamin D levels with disease severity and mortality in Indian patients hospitalized for COVID-19 25(OH)D levels upon hospital admission were not related to clinical outcomes of COVID-19 since treatment with cholecalciferol didn’t improve the conditions of the patients, comparing them to those who didn’t receive the treatment. 50 COVID-19 Generalities The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the pandemic that the world is currently experiencing for more than a year now. The first case originated in the Chinese province of Wuhan, from where the virus was then extended through the entire planet, in December of the year 2019 and by March of 2020 the situation was declared as a pandemic by the World Health Organization (Vabret et al., 2020; Wang et al., 2020). Like the rest of the virus of this family, SARS-CoV-2 causes an acute respiratory infection in the host which courses with a variety of symptoms like fever, cough and fatigue. These three are the ones that are more common and make the symptomatology very similar to other respiratory infectious pathologies but this disease can also develop in some patient’s dyspnoea in different degrees. Despite their similarities, COVID-19 has a greater chance to develop into severe cases in individuals without comorbidities that require more admissions of said patients to the ICU than in other diseases like pneumonia associated with influenza, even among young people (Cevik et al., 2020). COVID-19 can also cause gastrointestinal manifestations such as loss of the sense of smell and taste or diarrhoea and vomits. These extra-respiratory manifestations lead to think that the transmission of the virus could be faecal-oral besides through contact with droplets emitted by sick patients and that explain the contagion of people who are close to them. Some studies suggest airborne transmission as a possible means of transmission (Vabret et al., 2020; Wang et al., 2020). Even though in healthy individuals with a strong immune system the disease may course with no manifestations whatsoever, patients who have different comorbidities or whose health is somehow compromised may have a higher risk of contracting the ailment or develop severe cases of infection that can result in death. Some of the complications that were observed are acute stress respiratory syndrome, acute cardiac diseases or higher sensitivity to other infectious diseases. Besides, the absence of symptoms does not mean that a person cannot be a source of infection for the people that surround them. This is why is very important to adhere to the health recommendations to avoid getting the illness. It is important to notice that COVID-19 was discovered in other tissues 51 different from the respiratory like in the duodenum. This could be related to other means of transmission (Vabret et al., 2020; Wang et al., 2020). Among the preventive measures for COVID-19, we can find the following recommendations:  Avoid close contact with people out of your inner circle, guard security distance.  Wash your hands regularly with soap and water and use a hand sanitizer.  Use of mask to cover both mouth and nose.  Clean and disinfect surfaces that are touched frequently.  In case of need of cough or sneeze, cover yourself to avoid the spread of droplets (dos Santos, 2020). Vitamin D and COVID-19 The rapid global spread of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has renewed interest in the possible role of vitamin D in modulating the immune response to respiratory infections. Indeed, widespread vitamin D supplementation has been proposed as a preventative health measure (Cobbold, 2020). However, at present the evidence-base is of insufficient quality to support such recommendations. Importantly, while the active 1,25(OH)2-vitamin D form has been shown to have a role within the immune system (Aranow, 2011), evidence linking low 25(OH)D levels (the main circulating form, which correlates poorly to 1,25(OH)2- vitamin D) with increased risk or severity of COVID-19 has been inconsistent (Lanham-New et al., 2020). The non- COVID-19 literature contains numerous examples of 25(OH)D-morbidity associations which could be attributable to confounding or reverse causation (Harvey & Cooper, 2012). An example, demonstrated using Mendelian randomisation, is of the observational association between low 25(OH)D levels and obesity, which in causal analyses implicate obesity as driving lower 25(OH) D rather than the other way round (Vimaleswaran et al., 2013). Furthermore, 25(OH)D levels are determined by sunlight exposure to the skin, supplement use, diet, and comorbidity (since, in some clinical 52 contexts, 25(OH)D may be a negative acute phase reactant (Czarnik et al., 2018)). As such, vitamin D status is closely linked to general health and the potential for confounding in observational studies is high (Harvey and Cooper, 2012). While vitamin D, as cholecalciferol (vitamin D3) or ergocalciferol (vitamin D2), has a wide therapeutic window with a relatively low risk of toxicity, the easy availability of highdose supplements (particularly on the internet) may increase the likelihood of such rare events in the population (Rizzoli, 2021). A further consideration in the context of the current pandemic is the potential for adverse health behaviour resulting from a perception of protection gained from taking supplements. Thus, it is important that a strictly evidence-based approach, together with health economic assessment (which is beyond the scope of this review), underpin any health recommendations in relation to the use of vitamin D supplements to prevent or treat COVID-19. In this work, we review the scientific literature relating to vitamin D and respiratory infections, with a particular focus on COVID-19. A possible relation between vitamin D and COVID-19? It appears that the outbreak of COVID-19 happened when 25(OH)D levels in blood are low, which coincides with the seasons of the year when the solar radiation that reaches the Earth’s surface is at its minimum (Grant et al., 2020). It also seems that vitamin D deficiency contributes in the development of acute respiratory stress syndrome (SARS) and increases the fatal cases of the illness, which are related with age and the presence of chronic disease comorbidity (both of them related to low levels of the vitamin) (Meltzer et al., 2020). Another recent study (McCartney & Byrne, 2020) highlights the role of dipeptidyl peptidase-4 receptor (DPP-4/CD26) in the molecular virulence mechanism of closelyrelated COVID-MERS virus. In this respect, human DPP-4/CD26 has recently been shown to interact with the S1 domain of the COVID-19 spike glycoprotein, indicating that it may also be an important virulence factor in COVID-19 infection (Vankadari & Wilce, 2020). In this regard, DPP4/CD26 receptor expression has been shown to be significantly reduced in vivo upon correction of vitamin D deficiency (Vankadari & Wilce, 2020). 53 Based on this information, researchers call for vulnerable groups (elderly, hospitalizes patients, nursing home residents and others) to receive supplementation with 20- 50µg/d of vitamin D to enhance their resistance to COVID-19 (McCartney & Byrne, 2020; Griffin et al., 2020). Although this data does not prove the conclusion that vitamin D prevents COVID-19, its administration could contribute to prevent infections. Vitamin D will most likely be ineffective if given to sick patients; the possible beneficial effects will probably be as prevention, providing some sort of immune-boosting in susceptible individuals. Vitamin D will not be the key element to prevent the coronavirus pandemic, but it can contribute efficiently to prevent and/or difficult infections. More studies are needed to confirm this hypothesis to substantiate the benefits of vitamin D supplementation against infection, especially in the case of vegetarian and vegan patients who do not consume vitamin-D of animal origin. Respiratory diseases and vitamin D Respiratory tract diseases were responsible for more than 2 million deaths in 2013 and they are still a major health problem for the sanitary systems around the world. Different observational studies have detected a connection between low levels of calcitriol, also known as 1-α,25-dihidroxicolecalciferol (1,25-(OH)2D3), the active form of vitamin D, and greater susceptibility to respiratory infections. This could be explained since vitamin D is relevant in the synthesis of different peptides that have antimicrobial activity in the organism therefore, low levels of 25(OH)D in blood could lead to a lesser protective action against certain pathogens and an individual who is more prone to develop respiratory tract diseases (Martineau et al., 2017). It has been shown that vitamin D supplementation proved to have protective effects against infections but only in weekly and daily administration and not with bolus treatment (Martineau et al., 2017). The effects were also bigger in participants who had deficiency at the beginning of the study. As for why bolus treatment was inefficient in the study some of the reasons provided were that this form of administration causes fluctuations in serum calcitriol concentrations that are not observed in the other forms 60 appears that exerts a more effective bone remineralization than cholecalciferol and does not have a hipercalcemic effect in the organism. Therefore, obtaining mushrooms with high contents of vitamin D2 or its metabolites presents a very interesting approach not only for vegans but for omnivores as well (Falcon-García, 2019). 61 CONCLUSIONS  Vitamin D is essential for the proper function of the organism since it intervenes in different systems due to the presence of the vitamin D receptor in diverse tissues in the body.  There is a connection between a state of vitamin D deficiency and a greater vulnerability to respiratory diseases such as influenza. This may suggest a connection between this state and higher vulnerability to COVID-19.  There is a high prevalence of vitamin D deficiency in the world. Countries where the incidence of COVID-19 was greater may suggest that these situations could be related.  The vitamin D receptor is greatly extended through different tissues in the body and it is involved in very different functions.  The pandemic caused by SARS-CoV-2 calls for certain measures in order to achieve prophylaxis against the disease, especially in vulnerable population such as the elderly or patients with comorbidities.  From all the studies reviewed, there seems to be a relation between low vitamin D levels and a higher risk of COVID-19 infection, so its use as a prophylactic treatment should be considered. There is not enough evidence that indicates that vitamin D could be used as a treatment of the illness though.  Vitamin D supplementation can prevent different pathologies and it is safe enough to be administered to the general population.  People who follow vegan diets seem to have vitamin D deficiency, though this state is dependent on factors other than diet since individuals with an omnivore alimentation also present this deficiency.  The majority of existent vitamin D supplementation is from animal origin, which would be discarded by vegans. This opens the possibility of study the supplementation based of vitamin D2, for which mushrooms treated with UV radiation would be an interesting option. 62 REFERENCES  Aguilar Shea, A. L., Muñoz Moreno-Arrones, O., Palacios Martínez, D., & Vaño- Galván, S. (2020). Vitamin D for daily practice | Vitamina D para la práctica diaria. 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