In light of current evidence,
to what extent do you agree with the
call for immediate widespread increased Vitamin D intakes to combat COVID-19
as argued in this open letter?

The scientific data showed that low vitamin D status have been related with low immune system. Low vitamin D status also correlated with the severity of COVID-19. Some experimental studies showed the benefit of vitamin D supplementation. There is a strong need of systematic review/ meta analysis in this topic.

Yes. My publication has over 1000 citations: Grant WB, Lahore H, McDonnell SL, Baggerly CA, French CB, Aliano JA, Bhattoa HP. Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients 2 April 2020, 12, 988. https://www.mdpi.com/2072-6643/12/4/988 Supported by this recent article: Association of Vitamin D Status and COVID-19-Related Hospitalization and Mortality. Seal KH, Bertenthal D, Carey E, Grunfeld C, Bikle DD, Lu CM.J Gen Intern Med. 2022 Jan 1:1-9. doi: 10.1007/s11606-021-07170-0. There are many diseases for which vitamin D reduces risk including cancer, cardiovascular disease, diabetes, other infectious diseases, etc. and all-cause mortality rate. The medical systems say they want to see successful vitamin D RCTs. RCTs have seldom supported the role of vitamin D in reducing risk of disease since they have been based on vitamin D dose (often low) rather than achieved vitamin D level: Critical Appraisal of Large Vitamin D Randomized Controlled Trials. Pilz S, Trummer C, Theiler-Schwetz V, Grübler MR, Verheyen ND, Odler B, Karras SN, Zittermann A, März W.Nutrients. 2022 Jan 12;14(2):303. doi: 10.3390/nu14020303. However, at least the U.S. health care system does not want vitamin D to be accepted since they obtain income and profit through treating disease, not preventing it. Thus, the demand for vitamin D RCTs is used as a roadblock to the acceptance of vitamin D. There are many vitamin D papers supporting vitamin D at pubmed.gov, scholar.google.com, VitaminDWiki.com, and Grassrootshealth.net

the scientific evidence has proven the intake of vitamin D can be beneficial to combat covid-19

Vitamin D effect and retinoid signaling mechanisms in COVID-19 Vitamin D (VitD), like VitA, is a steroid hormonal molecule important in many aspects of cellular physiology including bone metabolism, cell proliferation, regulation of innate and adaptive immunity, and preventive effect on cardiovascular and neurodegenerative diseases [321], [322]. It has been shown to modulate innate and adaptive immunity in a similar way as VitA does [323]. The role of VitD has been recognized in the prophylaxis and treatment of COVID-19 [324], [325]. At high doses, VitD has been shown to decrease the severity and provide therapeutic benefit in the treatment of COVID-19 [326]. However, VitD supplementation did not seem to be effective in hospitalized seriously ill COVID-19 patients [327], which we believe is due to the depleted retinol and subsequently dysregulated retinoid signaling mechanisms [315]. The lack of response to the supplementation of VitD in these severe COVID-19 patients may have well been due to the dysregulated retinoid signaling [327] because VitD exerts its effect through retinoid signaling mechanism [321]. In this sense, an optimum response would be accomplished when the proper signaling cascades through both of VitD and retinoids converge. VitD exerts its biological action through binding to its receptor VitD receptor (VDR) and activating downstream transcriptional activation [321], [328]. The VitD signaling converges with the retinoid signaling. VDR can heterodimerize with RXR and bind to VDR elements (VDRE) on the target genes [321], [322]. Binding of VitD to VDR/RXR heterodimers on the DNA recruits other regulatory factors to activate the transcription of the target genes [93], [94], [324], [329]. In this way, the VitD signaling converges with that of VitA through the use of common RXR in modulating the expression of downstream genes [94]. VDR is expressed in various immune cells including monocytes, dendritic cells, T and B cells [321], [323]. VitD exerts similar effect in immune cells as VitA does. In innate immune cells, it upregulates the expression of the PRR that leads to an increased innate immune response against infections [323], [330]. It also induces anti-inflammatory response through development of Tregs and suppresses development of Th17 cells, proinflammatory cytokines such as IL-17 and IL-23, and autoimmunity [330], [331]. A recent transcriptomic analysis shows that the metabolism and signaling of both VitD and RARs have been dysregulated in COVID-19 patients [315]. This study analyzed the transcriptomic data from bronchoalveolar lavage fluid (BALF) of COVID-19 patients and controls and showed that, in addition to the VitD signaling components, the retinoid signaling components were also downregulated in the lungs of COVID-19 patients [315]. Among the downregulated genes, were the expression of a large set of genes, including Vitamin D receptor (VDR), RXR, and CYP27A1. The RXR is an essential component of the VitD and retinoid signaling pathways [91], [92] while CYP27A1, a member of CYP450 protein family, is essential in metabolism of VitD and is strongly upregulated through activated retinoid signaling [315], [332]. This downregulation of CYP27A1 in these patients is a strong indication of dysregulated retinoid signaling. The majority of the downregulated genes were enriched in the immune cells. Among these genes, the top predictors belonged to NF-кB/cytokine signaling and cell cycle regulators [315]. Most of these genes are also regulated through retinoid signaling pathways indicating interdependence of the two signaling pathways. The therapeutic and prophylactic effect of VitD on COVID-19 appears to be through the retinoid signaling mechanism. Despite the large number of studies on VitD in the management and treatment of COVID-19, unfortunately, adequate clinical studies have not been conducted on VitA, which forms the basis of the retinoid signaling mechanism. The mechanism of retinoid signaling provided by VitA and VitD is intriguing, and more research is needed to identify their role in the pathogenesis of COVID-19. Therefore, a detailed investigation of the roles of VitA and VitD signaling mechanisms will be rewarding in understanding the pathogenesis, management, and treatment of COVID-19.Since vitamin D acts through retinoid signaling, it should mainly be given with vitamin A. The vitamin D receptor works by forming a dimer with the retinoid X receptor to show activity. If there is no vitamin A in the body, vitamin D will not be effective either. Since vitamin A is depleted in COVID-19, supplementation with vitamin D and vitamin A is particularly important for regulating the immune system in COVID-19.

Vitamin D’s role in immune response mechanisms appears to be regulated primarily by availability of 25(OH)D, induction of CYP27B1 in the antigen-presenting cells by the invading pathogens and, ultimately, by stimulation of 1,25(OH)2D in the immune system. Potential effects of 1,25(OH)2D by inducing antimicrobial peptides, recruitment of neutrophils, monocytes/macrophages, and dendritic cells, as well as by modulating the adaptive immune response would help to overcome the COVID-19. Importantly, vitamin D may suppress the cytokine storm by simultaneously enhancing the innate immune system and reducing the overactivation of the adaptive immune system. Hence, treatment with calcifediol at higher doses is recommended to prevent worse COVID-19 outcomes as an adjuvant therapy in the hospital. It is suported by an observational study conducted during the first European outbreak of the COVID-19 pandemic (Nogues X, et al. Calcifediol Treatment and COVID-19-Related Outcomes. J Clin Endocrinol Metab. 2021 Sep 27;106(10):e4017-e4027. ). It indicates that timely administration of calcifediol, a cheap, safe, an easily accessible drug, has the potential to control disease progression and avoid fatal outcomes.

Variuos observational and interventional studies, support using vitamin D for COVID-19 prophylaxis and treatment.

the letter seems to be quite subjective, expressing opinions rather than facts. It might be that there is sufficient data justifying an association of low D with increased covid-19 risks, but we should not forget that there is insufficient interventional data from well-designed clinical trials to support population-based recommendations to increase D. In addition, recommending daily supplementation of Vit D without prior or at least in short time testing of relevant concentrations can be a dangerous strategy.

I fully approve the principle of vitamine D daily intake (in function of the season) to avoid deficiency; obviously the benefits will go far beyond the relative protection again Covid. Bolus doses are in fact far less effective [LancetDiab&Endocr vol 9, iss 5, 276-292, May 1, 2021 / JGlobAntimicrobResist, 2020 Sep;22:133-134]. However prescribing the same posology for all is a just a start. I am presently on the verge of submitting a publication based on the relationship between weight and optimal posology for non-pregnant women. During the pregnancy, optimizing the supplementation could appear more subtle, as usual posology with maternal circulating levels < 30 ng/ml could be associated with asymptomatic hypercalcemia of the newborn in case of low birth weight.

in my view, there is sufficient data justifying an association of low D with increased covid-19 risks, but insufficient interventional data from well-designed clinical trials to support population-based recommendations to increase D

Current evidence is insufficient to prove if Vitamin D has a beneficial or preventive effect on COVID -19. Below is another study which showed vitamin D deficiency was not associated with a higher 30-day mortality in the hip fracture population co-infected with COVID-19 https://www.ej-med.org/index.php/ejmed/article/view/1159

Low serum 25-hydroxyvitamin D levels are linked to a longer viral clearance time and a higher likelihood of ICU admission in COVID-19 patients. Testing before giving suppluments is recommended.

Observational studies indicate that lower vitamin D levels are associated with worse covid19 outcome. Also, administration of vitamin D could ameliorate the SARS-CoV-2 infection. Infections and chronic inflammation reduce the level of vitamin D, so it is recommended to examine the levels of the 25OHD before infection occurs to get more precise data on this association. Randomized controlled trials on vitamin D application were not so convincing, however, level of this micronutrient is affected with many life factors and individuals with deficiencies should be recognized in those studies before the intervention for more clear results. It is recomended to test the level of vitamin D before supplementation.

Vitamin D is associated with biological activities of the innate and adaptive immune systems, as well as inflammation. In observational studies, an inverse relationship has been found between serum 25-hydroxyvitamin D (25(OH)D) concentrations and the risk or severity of coronavirus disease 2019 (COVID-19). Several mechanisms have been proposed for the role of vitamin D in COVID-19, including modulation of immune and inflammatory responses, regulation of the renin–angiotensin–aldosterone system, and involvement in glucose metabolism and cardiovascular system. Low 25(OH)D concentrations might predispose patients with COVID-19 to severe outcomes not only via the associated hyperinflammatory syndrome but also by worsening preexisting impaired glucose metabolism and cardiovascular diseases.

Vitamin D has been shown to have protective effects in common respiratory infections. The reports in COVID also suggests its protective action. Given that it is safe in smaller doses, I think that the global Vit D intake should be increased, esp. in deficient countries where Vit D augmentation to foods are not applied routinely. However, the replacement should not be in megadoses, such as >50,000 U/week. Such replacement may even be harmful for clinical outcomes. Vit D is better to be used regularly rather than huge loading doses.

Vitamin D can increase oxytocin function. Oxytocin has been proposed as a treatment for COVID-19. See references below: Vitamin D: Patrick RP, Ames BN. Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism. FASEB J. 2014 Jun;28(6):2398-413. doi: 10.1096/fj.13-246546. Epub 2014 Feb 20. PMID: 24558199. 'It has previously been shown that the genes encoding the oxytocin/neurophysin I prepropeptide (OXT) and the oxytocin receptor (OXTR) contain multiple putative VDREs (40). After examination of the VDRE sequences, we confirmed that OXT contains a proximal and 3 distal VDREs and OXTR has 1 distal VDRE (Table 1). Furthermore, these putative VDREs mostly appear to be consistent with transcriptional activation, suggesting that the vitamin D hormone would regulate both the production of the oxytocin hormone and the response to it (Table 1 and refs. 80, 157). The 4 different VDREs present in OXT likely modulate oxytocin production in different tissues. OXTR contains a putative VDRE that may be associated with activation (Table 1). Supporting evidence demonstrating that vitamin D regulates these oxytocin-related genes comes from data showing that the VDR colocalizes with oxytocin in hypothalamic neurons (158). Overall, these data suggest that vitamin D would modulate oxytocin synthesis as well as the response to the neuropeptide itself in different tissues, with important implications for benefiting social behaviors in ASD.' Oxytocin and COVID-19: TRPV1, Nrf2, and COVID-19: Could Oxytocin Have a Beneficial Role to Play? Diep P.-T. https://doi.org/10.1159/000521246 Consequences of pandemic-associated social restrictions: Role of social support and the oxytocin system Katharina Gryksa Inga D. Neumann https://doi.org/10.1016/j.psyneuen.2021.105601 Could oxytocin reduce autoimmune disease in COVID-19? Phuoc-Tan Diep and Véronique de Kok https://doi.org/10.1016/j.autrev.2021.102994 Covid and Oxytocin: Looking for Microbial Symbiosis Oleg V. Bukharin, Natalya B. Perunova, Phuoc-Tan Diep, Elena V. Ivanova https://doi.org/10.48037/mbmj.v8i10.1312 Are COVID-19 gastrointestinal symptoms due to oxytocin dysfunction? Mark Chapman, Phuoc-Tan Diep, Manal Atwan https://doi.org/10.48037/mbmj.v8i10.1310 Cardiovascular protective properties of oxytocin against COVID-19 Stephani C. Wanga and Yu-Feng Wang Life Sci. 2021 Jan 26 : 119130. doi: 10.1016/j.lfs.2021.119130 https://www.sciencedirect.com/science/article/pii/S0024320521001156 Oxytocin May be Superior to Gliptins as a Potential Treatment for Diabetic COVID-19 Patients Phuoc-Tan Diep SciMedicine Journal Doi: 10.28991/SciMedJ-2020-02-SI-10 https://scimedjournal.org/index.php/SMJ/article/view/181 Is there an underlying link between COVID-19, ACE2, oxytocin and vitamin D? Diep P Medical Hypotheses (2020) 110360 https://doi.org/10.1016/j.mehy.2020.110360 Hypothesis: Oxytocin is a direct COVID-19 antiviral Phuoc-Tan Diep, Khojasta Talash, Violet Kasabri Medical Hypotheses 145, 110329, 2020 https://doi.org/10.1016/j.mehy.2020.110329 Oxytocin as a Potential Adjuvant against COVID-19 Infection Pratibha Thakur, Renu Shrivastava and Vinoy Kumar Shrivastava, Endocrine, Metabolic & Immune Disorders - Drug Targets (2020) 20: 1. https://doi.org/10.2174/1871530320666200910114259 Can intravenous oxytocin infusion counteract hyperinflammation in COVID-19 infected patients? Benjamin Buemann, Donatella Marazziti and Kerstin Uvnäs-Moberg https://www.tandfonline.com/doi/abs/10.1080/15622975.2020.1814408?journalCode=iwbp20 Oxytocin's Anti-inflammatory and Pro-immune functions in COVID-19: A Transcriptomic Signature Based Approach Ali S. Imami et al. https://journals.physiology.org/doi/abs/10.1152/physiolgenomics.00095.2020 Oxytocin as a potential defence against Covid-19? Amélie Soumier and Angela Sirigu https://www.sciencedirect.com/science/article/pii/S0306987720306800?via%3Dihub Oxytocin, a possible treatment for COVID-19? Everything to gain, nothing to lose Phuoc Tan Diep, Benjamin Buemann, Kerstin Uvnäs-Moberg https://www.clinicalneuropsychiatry.org/download/oxytocin-a-possible-treatment-for-covid-19-everything-to-gain-nothing-to-lose-letter-to-the-editor-from-the-editordesk-commentary/

Vitamin D supplementation prevents acute respiratory infections as shown from randomized controlled trials. We have also shown that Calcitriol (Vit D3) alters the expression of most of the SARS-CoV-2 interacting human proteins, potentially interfering with the functions of 20 of 27 SARS-CoV-2 viral proteins.

Daily High dose vitamin D has significantly reduced the inflammatory markers in covid as published in a recent RCT.. It us zn objective evidence to show case the importance of vitamin D in mitigating the effects of covid.

I support recommendations of increased vitamin D. The opposition to it (and I'm thinking of Tim Spector - ZOE app) seems to fall into two categories: i) lack of evidence and ii) the outcome of studies largely focuses on bone health rather than immune function, Given the cheapness of vitamin D supplementation, the fact that cancer prevention measures have people covering themselves in factor 50 suncream all the time and that we can't make vitamin D for 4-6 months of the year anyway, surely its time for a pivotal randomised study to identify if vitamin D is beneficial or not.

Gaps in knowledge exist regarding the association that vitamin D administration will result in the improvement of COVID-19 patients; and the notion of whether vitamin D could be used for the treatment of COVID-19 patients is still a hypothesis. No study, to date, has established proof-of-concept or demonstrated a cause-effect relationship. Furthermore, vitamin D is not a harmless drug. Administration of high amounts of vitamin D without clinical correlation could result in toxicity and harmful consequences. Care in vitamin D replacement is warranted to avoid abnormalities in the calcium-vitamin D-parathyroid hormone (PTH) axis. Food sources and lifestyle factors should be encouraged. This will aid in improving the immune system, while also providing long-term health benefits till the time evidence is established regarding the role of vitamin D in the management of COVID-19. This also calls for large, multi-center, placebo-controlled clinical trials that study COVID-19 patients with different severity of the disease rather then open letter. Randomized clinical trial documentation of vitamin D supplementation being associated with a positive outcome in COVID-19 patients would provide an inexpensive and accessible addition to current treatment protocols. Establishment and validation of precise correlation of vitamin D in COVID-19 patients would serve as an inexpensive and accessible treatment option that is easy to disseminate to a larger population considerably rapidly as compared to other more complex interventions. Furthermore, the possible improvement of COVID-19 patients is just one aspect served by vitamin D. Its overall benefit on individuals’ and the community’s general wellbeing is substantial. Even though the COVID-19 related benefits of vitamin D have not been validated thus far, its supplementation to replace preexisting deficiency should be the cornerstone in patients suffering from COVID-19. Administration of vitamin D in already sufficient population should be held until discrete evidence has been established. Prospective, community-based studies are needed urgently to establish the efficacy of vitamin D supplementation as an inexpensive therapeutic tool to fight the ongoing pandemic.

Several studies demonstrate correlation between estimated or measured Vitamin D concentrations and COVID-19 severity. This VitD/morbidity correlation is also linked to other respiratory viral diseases and even chronic illness (prostate cancer). However, I am unsure about the use of VitD in a treatment or prevention protocol clinically. I think we need more RCTs to evaluate this potential. In particular, although a correlation appears to exist, it may be strongly influenced by selection bias. That is, much mortality and severity of disease has occurred in older/co-morbid populations, many of which may be selected for Vitamin D deficiency due to living conditions, disability, or other co-determinants such as nutritional status (e.g., residents of assisting-living facilities who are VitD deficient, those with co-morbid conditions that are VitD deficient, etc.). It is an intriguing hypothesis, but the need for more controlled studies is evident, in my view.

Huge body of evidence favor supplemental vitamin D3 having a preventative as well as therapeutic role in mitigation of viral illnesses causing influenza and pneumonia.

I recently wrote an invited chapter(1) summarizing the causal evidence with respect to the relationship between Covid-19 and vitamin D. My findings were inequivocal. There should now be no doubt that low vitamin D serum levels one of the major causes of severe Covid-19. When a person is exposed to the SARS-CoV-2 virus, low vitamin D causes an increase in susceptibility to disease, and increase in severity of disease, and an increase in mortality. The Open Letter was written relatively early in the pandemic, with respect to evidence(2). We now know, based upon infection prevention data, that target 25(OH)D levels should be at least 50ng/ml (125nmol/L), rather than 30ng/ml (75nmol/L). This means that the recommendations in the Open Letter are actually quite conservative. The Chapter also explains why concerns for vitamin D toxicity if supplements are recommended widely to the general public are unfounded. These and other issues are explored at length in this(3) recent podcast on the topic. 1. Benskin L. Chapter 4: THE INFLUENCE OF VITAMIN D ON COVID-19 OUTCOMES. In: Covid-19 and Nutraceuticals: A Guidebook [Internet]. Bohr Publishers and New Century Health Publishers, LLC; 2021. p. 63–108. (Lifestyle and Health Promotion). Available from: https://www.researchgate.net/publication/354376762_THE_INFLUENCE_OF_VITAMIN_D_ON_COVID-19_OUTCOMES_Chapter_4_of_Covid-19_and_Nutraceuticals_A_Guidebook_Bohr_Publishers_and_New_Century_Health_Publishers_LLC 2. Benskin L. A Basic Review of the Preliminary Evidence That COVID-19 Risk and Severity Is Increased in Vitamin D Deficiency. Frontiers in Public Health [Internet]. 2020 [cited 2021 Nov 25];8:513. Available from: https://www.frontiersin.org/article/10.3389/fpubh.2020.00513 3. Bret Weinstein. Vitamin D for Covid, What’s the Catch? - DarkHorse Podcast Gruff Davies and Linda Benskin [Internet]. 2021 [cited 2022 Jan 11]. Available from: https://youtu.be/8LFkWiNP1wQ

In our paper (10.3390/ijerph17155616, 'A Look Behind the Scenes at COVID-19: National Strategies of Infection Control and Their Impact on Mortality') and further publications, we concluded, that vitamin D intake is important in maintaining good immunity. However, a personalized approach has to be taken for every individual. Economical, sociological, environmental, cultural and environmental factors play a role on the serum 25-hydroxyvitamin D (25(OH)D) concentrations. Implementation of healthy lifestyle, together with individualized vitamin D supplementation can have a positive effect in global outbreaks. Breaking out of sedentary lifestyles can reduce obesity and co-morbidities resulting in less fatality rates in future pandemics. Increased health literacy in the population can improve the management and control of further global pandemics. A change to healthy lifestyle, with appropriate individualized vitamin D intake can increase mean serum 25-hydroxyvitamin D (25(OH)D) levels. However, this is a target, which can be achieved within few years of action. Far Eastern countries with experience of the SARS outbreak controlled the pandemic with the lowest number of COVID-19 fatalities. COVID-19 case and mortality counts in Europe are not directly dependent on temperature, mean age, or mean serum 25-hydroxyvitamin D (25(OH)D) levels, but on preparedness of countries’ health care systems and adequate public health strategies. Infection control measures in indoor environments are essential in viral transmission prevention and need to be taken into consideration. Indoor environments are interconnected with climatic conditions. Indoor climates are crucial to the control of the SARS-CoV-2 outbreak. Development of health care systems by increasing the number of hospitals, critical care units, and health care personnel are also key factors, and are particularly needed for the protection of the vulnerable and elderly population. The preparedness of the health care system includes stockpiles of appropriate and effective personal protection equipment (PPE), fast and reliable testing methods, and cluster and individual tracking of cases and their contacts. Recommendations of social distancing, personal hygiene, avoiding of gatherings, and mask wearing must be strictly followed even in indoor environments and household settings, particularly for the protection of those aged over 65 years. After all, Vitamin D intakes can improve partly the outcomes, but are not the only solution for avoiding high fatalities during future pandemics. They are just one of the tips of the icebergs available. Zehra Edis

There are data from multiple evidential strands which in isolation are imperfect, but which collectively support a compelling case for the role of low vitamin status in both increased risk and severity of SARS-CoV-2 infection. This view is supported by the application of Bradford Hill criteria for causality in the context of both infection and disease severity. The only reservation that I have in relation to the letter is the proposed dose. While I believe this needs to be (much) higher than those currently recommended, I believe a recommended dose of 50ug/d (2000 IU) should be the standard dose, with higher doses up to 100ug/d (4000 IU) recommended for those with likely or confirmed deficiency because of either poor cutaneous synthesis (older adults, those with darker skin) or disruptions to vitamin D metabolism (those with obesity or diabetes mellitus), rather than this 100ug/d (4000 IU/d) dose being the general adult population guideline.

There are multiple publications demonstrating that vitamin D sufficiency not only reduces risk of infectivity by COVID by more than 50% but it also substantially reduces morbidity and mortality for those who are infected also by as much as 50%. There is no downside to recommending that everyone improve their vitamin D status by taking a vitamin D supplement. It is reasonable to follow the guidelines of the Endocrine Society which recommends infants 400-1000 IUs, children 600-1000 IUs and adults 1500-2000 IUs daily. If you are obese you need 2-3 times more. Recent evidence suggests that there continues to be improvement in reducing risk for infection and morbidity and mortality when blood levels of 25-hydroxyvitamin D are increased up to 60 ng/mL. To reach this level for a normal weight adult would require 5000 IUs daily.

Although, there is a lack of evidence in supporting their utility among COVID-19 patients and further clinical trials need to be investigated, some micronutrients are an important concern, with promising beneficial use among COVID-19 patients. For example, the evidence of the advantageous use of vitamin D among COVID-19 patients is more powerful than that for other micronutrients. Recent observations showed that those who were vitamin D deficient had a 1.77 times greater significant risk of testing positive for COVID-19. According to a recent meta analysis (Ghasemian et al, 2021), most of the COVID-19 patients were suffering from vitamin D deficiency/insufficiency. Also, there is about three times higher chance of getting infected with SARS-CoV-2 among vitamin-D-deficient individuals and about five times higher probability of developing the severe disease in vitamin-D-deficient patients. Vitamin D deficiency showed no significant association with mortality rates in this population. Besides, an ecological study represented certain nutrients as having higher interest for COVID-19 patients, most importantly vitamins D, C, B12, and iron, associated with lower COVID-19 incidence and/or mortality. Importantly, the European Food Safety Authority (EFSA) evaluated and focused on six vitamins (D, A, C, Folate, B6, B12) and four minerals (zinc, iron, copper and selenium), essential for the normal functioning of the immune system, as evidenced by previous trials, promising for COVID-19 management and future treatment protocols. Many RCTs of which (Annweiler et al, 2020) and (Rastogi et al, 2020) showed the impact of high dose supplementation of 25-OHD on inflammatory markers related to COVID-19 infection. These RCTs, in addition to many, recommended between 60,000IU to 200,000IU per week.

Vitamin D increases from sun exposure have definitively correlated with improved outcomes. We do not make clinical decisions based on observational studies.

We need good quality prospective studies to be completely sure of the vitamin D benifical effects on Covid-19. However, the data currently available still strongly tsuggest vitamin D use in this setting

literature support vitamin d importance for proper immune system function. its role in covid19 is support in one of our research. However, always one question is in my mind: why the incidence and mortality of covid-19 is higher in winter & cold countries versus summer, tropical and equator countries , may be other contributing factor. also what is about those who are receiving ACEI & ARBs where the virus main effect

1) vitamin D deficiency / insufficiency remains prevalent throughout the globe. 2) given the essential role in numerous regulatory and immune processes, it's shorted sighted not to actively recommend vitamin D as reasonable strategy to promote overall health and wellness. 3) the unrelenting nature of the pandemic necessitates we employ a multi-pronged approach beginning at the individual-level.

No statistical inidication exists regarding Vitamin D and protection against COCID-19; this letter is quite subjetive and expresses opinions rather than fatcs; nonetheless, Vitamin D is important for other causes (e.e.g, rickets) and increasing Vitamin D intake together with other vitamins and other nutrients should help to disminish malnutrition worldwide.

It has not been evaluated thoroughly about the utility of Vitamin D against COVID-19. However, as per the literature, its usefulness in various contexts may have a beneficial effect but can't be mandated unless performed controlled studies. However, can be recommended for a good health perspective during this pandemic.

Vitamin D innige recommended dose is safe and inexpensive. It is not possible to complete large meaningful RCTs rapidly. Even a very small benefit would be useful in a pandemic. We know that a normal Vitamin D Level is necessary for normal function of the immune system.

The modulation of innate immune response caused by vitamin D is likely to prevent COVID-19 progressing to severe or critical phase, and to this extent it could be beneficial to have widespread increased vitamin D intake. However, it is not known whether increased vitamin D intake will interfere with the development of adaptive immunity following vaccination, and this aspect needs to be examined carefully.

Current evidence is insufficient to support this call. I kindly invite you to read the conclusions of the following studies. DOI: 10.5603/DEMJ.a2021.0024 and DOI: 10.5603/ARM.a2021.0037

Current scientific evidence is such that a benefit of vitD in the prevention or treatment of COVID-19 cannot be proved or refused. Several observational studies reported an inverse relation between vitD levels and risk of Sars-CoV-2 infection and disease severity, but reverse causality and residual confounding due to overlapping risk factors for vitD deficiency and COVID-19 cannot be definitively excluded. Few small intervention studies yielded mixed results, insufficient to guide on the use of vitD for COVID-19 treatment. Several randomized clinical trials on vitD supplementation to prevent or treat COVID-19 are in progress and will hopefully provide more information into the effectiveness and safety of vitD for COVID-19. A number of challenges however still hamper or delay drawing definitive conclusions. To cite just two: (i) large scale vaccination is reducing the event rate, making difficult the realization of adequately powered RCTs; (ii) dexamethasone, current standard of care in severe disease, and vitD share many intracellular pathways, with dexamethasone being more potent and thus mitigating adverse effects of vitD deficiency/masking potential benefits of vitD.

Though there are evidences that Vitamin D is a crucial component in building the immune system, overdosing on the other hand is also a concern. Sunlight has been known to be a good source of Vitamin D and in the tropics or countries close to the equator. This may account for low morbidity and mortality cases in these regions, however there are other factors that could contribute to observing low cases. For example, low testing rate, inadequate documentation of cause of death in these countries etc. Therefore, until we have sufficient data and RCTs to conclude the next line of action

Our recent work, DOI 10.1016/j.jsbmb.2021.105928 , support the position that vitamin D deficiency in patients with COVID-19 is correlated with an increased risk of hospital admission and the need for critical care, although vitamin D levels do not influence the rate of mortality. Further clinical research is required to expand the evidence base and include an analysis of comorbidities. Clinical trials performed to test these findings should be case-controlled and properly compared to test the relevance of vitamin D levels as a risk factor for infected patients and the application of vitamin D in therapy

The effect of vitamin D treatment on many diseases has been shown in the literature. Although the effect of vitamin d on covid is not known exactly, there is nothing to lose in its application.

While it is clear that low vitamin D is linked to severe cases of covid-19, it is still unclear what the best dosage is. Possibly the daily doses are those recommended in the open letter. Current scientific evidence does not show any significant adverse effects from vitamin D supplementation and brings the possibility of improving the patient's response to covid-19. Vitamin D supplementation is not a treatment 'against covid-19' but in favor of patients' health.

No time to wait for additional evidence. We need to protect our patients now!

A window exists in which significant number of adults could benefit from vitamin D supplementation because of the strong association between vitamin D status and a normally functioning immune system. This is especially important during the current pandemic and is particularly pertinent to older adults. Our group (Irish Covit-D Consortium (Nov 2020 position statement: 9 Irish medical experts from 'across Ireland’s leading universities)) recommend Vitamin D Intake 800-1000 IU (20-25 micrograms) / day, with higher monitored doses (e.g. 1500-2000 IU (37.5-50 micrograms) / day for vulnerable groups who have confirmed or likely low vitamin D status (e.g. those with obesity, darker skin, or in nursing homes or residential care).

Only in prevention as in other infecious disease

There is credible theoretic, epidemiological and some empirical evidence of benefit, not just for protection against covid-19 but also for other viruses, particularly influenza.

No RCT data yet but alot of circumstantial evidence that it will help.

Vitamin D need the sunlight to be fixed. And his effect can be covered by a number of individual and environmental factors.

I think balance is more effective in consumption

The magnitude of the effect is only minimal, and there aren't yet trials to confirm. We should be encouraging trials instead.

Reduced VD is a symptom in COVID-19 individuals, though the specific mechanism is unknown. At the moment, it is impossible to tell whether the human immune system fights the SARS-COV-2 virus, resulting in high consumption of VD; or whether the SARS-COV-2 virus interacts with VD, resulting in high consumption of VD. If the former is the case, VD can be gently supplemented. If the latter is the case, use caution when increasing with VD. If both of these case are present, VD should be supplemented according the condition patients. VD is more abundant in adipose tissue as natural cholecalciferol and is less abundant in muscle, serum, fat, and other tissues as 25(OH)D. However, because the present VD test is primarily a blood test, it cannot accurately characterize the distribution of VD loss in COVID-19 patients. It is advised to test immunological, muscle, blood, fat, and other tissues for VD and viral load during the autopsy of the COVID-19 deceased. Then it reaches a definitive conclusion using professional statistical analysis.

Arguments have been made that there is no clinical benefit to supplementing people who are already vitamin D sufficient. I agree, but this does not take into account the fact that high percentages of many populations are vitamin D deficient/insufficient and the downsides for broad vitamin D supplementation are far less than the potential benefits. Moreover, there is enough laboratory/preclinical/clinical/epidemiological evidence to support the potential benefits of broad supplementation. Based on clinical evidence, daily as opposed to weekly or bolus supplementation is best.

Correct the deficiency is a measured aiming not only to improve the immunological system to combat Covid-19 but also a need to restore the normal balance of bone and mineral homeostasis.

Bayesian logic: Assuming for the sake of argument that the evidence is in equipoise (which I don't think it is), what are the negative consequences of promoting it if it doesn't turn out to protect against covid-19 (small amount of money spent and bone health improved somewhat) versus the negative consequences of not promoting vitamin D if it does turn out to protect against covid-19 (millions of excess hospitalisations and tens of thousands of deaths). There is simply no comparison.

The existing evidence to date points out that vitamin D deficiency can worsen the prognosis of COVID-19. However, the use of vitamin D supplements in people without deficiency shows no evidence of protection against viral infection. Supplements are meant to correct deficiency, not prevent COVID-19.

I fully support the call and discuss more in depth evidence and recommendations on www.Fit4Pandemic.org

If the population would have a sufficiently high 25(OH)D level (>40 ng/dl), the whole COVID-19 problem plus influenza and many chronic diseases would be greatly reduced

Associations between vitamin D and COVID are almost entirely observational, a fact which is usually ignored by proponents of vitamin D supplementation. The same is true in many severe illnesses (cancer, dementia, heart disease) - low vitamin D is associated with disease, but there is no benefit whatsoever in actually replacing vitamin D (i.e. it is a third factor causing both the pathology and vitamin D deficiency). There is likely no benefit whatsoever from high dose vitamin D in acute illness and it is a distraction from treatments that actually benefit patients. There is a possible (very mild) benefit in disease prevention, if people are severely deficient (serum 25(OD)D less than 10ng/ml, or 25nmol/L), but there is almost no evidence that patients require a serum 25(OH)D of more than 20ng/mL (50mmol/L). Most studies showing benefits above this are funded by pharmaceutical companies or their affiliates, therefore subject to bias. Focussing on vitamin D in COVID detracts from other interventions that actually work (e.g. reducing obesity and smoking, and promoting vaccination) and falsely misleads members of the public that simply taking a multivitamin will be 'enough' to stop COVID.

Serum 25(OH)Vit-D level was not associated with in-hоsрitаl mortality in раtients with SАRS-СоV-2. Vitamin-D deficiency was more prevalent in younger age groups. [https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.27133]

Current evidence suggests that being well supplied with vitamin D lkeads to about a 50% reduction overall of risks of getting covid-19 , being hospitalized or dying from it,and, the last of these could be higher still using ccalcifediaol but not enogh data in yet to be sure of that point

Would not use bolus dosing

There are specific pathophysiologic mechanisms supporting the use of Vitamin D to combat COVID-19 - in addition to the general role for respiratory infections described prior to the pandemic. Some of this evidence can be found at: https://www.nature.com/articles/s41590-021-01080-3 https://www.sciencedirect.com/science/article/pii/S1567576920328976 There is clearly a need for ongoing work in this field, but it is worth noting anecdotally that widespread provision of a supplement that included Vitamin D in Uttar Pradesh (India) was accompanied by a reduction of daily case numbers from 34,000 in July 2021 to 100 at end December 2021. These were, presumably, delta, and there is not yet any evidence in relation to omicron, indicating the need for further research.

Correlation is not causation. Studies showing a correlation between measured serum vitamin D levels and any outcome are NOT proof of causation. Only randomised blinded, controlled clinical trials are able to prove this (mendelian randomisation studies also useful). Clinical trials of vitamin D supplementation have been negative or equivocal so far. Observational studies show a strong correlation between high vitamin D and low COVID mortality. if If vitamin D really was causally related, then intervention studies should show a strong effect- and they don't. QED.

Phosphate, whose status is managed by vitamin D, plays a key role in Covid-19. Ensuring an adequate phosphate status amongst others though an adequate vitamin D status, especially in categories at risk (obese, diabetic, older age/men, diuretics) can hence reduce covid-19 complications.

Vitamin D deficiency seems to be linked to increased susceptibility to all respiratory infections, so addressing this at a population-level should have a positive impact for COVID-19 and related diseases

All observational evidence for vitamin D is highly confounded. Mendelian randomization, which de-confounds these relationships show no support for vitamin D.

Interactions with vitamin K and calcium should be taken into account (doi: 10.1155/2017/7454376).

Our published work (DOI: 10.1002/prot.26198), based on in silico studies, was the first report to provide a scientific basis for the widely observed inverse correlation between Vit D levels and Covid-19 morbidity. Specifically, we reported that the human antimicrobial peptide LL-37 is structurally very similar to the N-terminal helix of ACE2, and that LL-37 docked well with the Receptor Binding Domain of SARS-CoV-2. Due to the striking shape similarity to NTH, LL-37, which freely circulates, could interfere with the binding of RBD to ACE2. LL-37 could bind to the RBD and prevent the virus from binding to ACE2 on cells. It is known that Vit D upregulates the expression of LL-37, so it is logical to interpret that effective Vit D levels could result in hampered binding of SARS-CoV-2 to cells. Considering the widely reported inverse correlation and our findings, I agree with the 'Open Letter'. Indeed, Vit D administration could help towards controlling the pandemic and governments should act now rather than waiting for the outcomes of clinical trials demonstrating that proactive Vit D supplementation can lower the rates of infection. The many inverse correlation studies are ground enough to carry out Vit D administration to reduce the morbidity. As mentioned in the Open Letter, Vit D deficiency is quite common. To make matters worse, people have been indoors more since the pandemic started, so many more people may have become deficient. Vit D should be administered in an amount known to be safe. The Probable Benefit to Probable Risk ratio appears to be very large and can be assessed using mathematical modeling and/or deep learning methods, to provide additional support for Vit D supplementation. As we are not doing further experimental work on LL-37:RBD interaction, it is desirable that such work be carried out by the scientific community.

I think the association COVID-19/vitamin D needs to be interpreted in a larger view. Several papers showed (way before the pandemic) that the majority of the population is vitamin D deficent. Given the biochemical property of vitamin D, it is obvious that a deficency will be associated with an increased probability of getting some respiratory tract infection (including COVID-19). In other word, if you have a deficiency, your body is less protected. Thus, it is obvious that is better to have a good level of vitamin d rather than a deficienncy. It's like asking: do you prefer to drive with flat tires or inflated to the right point? Personally I do not understand this debate related to COVID-19. We always suggested vitamin D intake (in winter) even before COVID-19. What's the difference now during the pandemic? Nothing, we still suggest to reach the correct level of vitamin D as you should always inflate your tires to right pressure.

I would like to point out that in December 2020 the Accademia di Medicina in Turin published a document in Italian (http://www.comune.torino.it/pass/salute/2020/12/07/vitamina-d-nella-prevenzione-e-nel-trattamento-del-covid-19- nuove-evidenze/) and then in English http://www.pharmadvances.com/vitamin-d-in-the-covid-19-prevention-and-treatment-emerging-evidence/) on which it was signed and shared by 156 Italian doctors and researchers in which the authorities are urged to spread the use of vitamin D for the production and therapy of COVID-19.-

D3 will help fighting Covid-19 and mitigiate the course of the disease, but alos enhance the success of vaccinations and mitigate their adverse effects. At > 75 ng/ml I personally (2 x Moderna, 1 time Eflueda (flu), 1 time Biontech) did not have any adverse effects oof the vaccination, not even a sore arm! BTW: I'm missing my name (Lorenz Borsche) on the list of invited. I obviously was invited b/c of https://doi.org/10.3390/nu13103596 LG LB

Vitamin D intake should be in a safe dosage as many authors claim from 2000 to 10000 IU. I absolutely agree with the opinion that vitamin D deficiency worsens the severity of coronavirus infection. And therefore, like most researchers, I adhere to the opinion of vitamin D intake, including for children

In order to reduce the risk of infection in populations at risk from influenza and/or COVID-19, An optimal level must be raised by a daily intake of 10 000UI/d over a few weeks in order to raise 25(OH)D concentrations rapidly, followed by 5000 IU/d. The goal should be to raise 25(OH)D concentrations above 69–80 ng/mL, with a blood control every 2 months.

Vitamin D supplementation is effective in the prevention against COVID-19 infection in both the initial and hyperinflammatory phase of the disease, as it effeciently modulates the immune response against SARS-COV2. Nevetheless, vitamin D, in severe SARS-CoV2 stage, should be administered with caution because it could stimulate or inhibit some cellular functions that could induce infectious tolerance (Ref. doi: 10.3390/nu12113512).

Low cut D is associated with obesity and metabolic syndrome. Obesity and MS are risk factors for worse COVID outcomes and so is low vit D in these people There is no strong evidence that supplementation of vit D improved outcomes

The dosage of 100 mcg is not safe, patient with undiagnosed sarcoidosis will be exposed to a life threatening cardiac arrest (see Calcium and Vitamin D in Sarcoidosis: Is Supplementation Safe?) In that article supplementation of 10 mcg was considered safe. However, the authorities should address the fact that in winter 30 to 50 % of their population have a vitamin d deficiency.

I think that only vitamine D is not enough; it is absolutely helpful but needs to be combined with other treatment to prevent serious Covid-19

Vitamin D status should not be considered as a stand-alone metric, as it is closely associated with many other variables that need to be taken into consideration (e.g. other dietary intake, ethnicity, socio-economic status). So although I do not fully agree with the open letter, I do partially agree as there are very few negative side effects at the dosages being recommended. I do think, however, that the problem is much bigger than the open letter suggests, and more studies that adjust for several relevant confounding variables need to be done urgently, but as it stands the evidence is nowhere near strong enough to warrant full agreement in this open letter.

Based on current research that I have read Vit D does not help to fight COVID infection. On th other hand patients with higher vitamin D levels before infection show lower rate of hospitalization and death compared to patients with vitamin D deficiency or insuficiency. Therefore, I belive vit D can be important thing to prevent serious COVID complication same as many other aspects of human health.

Current evidence is insufficient to support this call

Yes