Vitamin D deficiency and co-morbidities in COVID-19 patients - A fatal relationship?
NFS Journal (Official Journal of the Society of Nutrition and Food Science) https://doi.org/10.1016/j.nfs.2020.06.001
Hans K. Biesalski
Institute of Nutritional Sciences, University Hohenheim, D 70599 Stuttgart, Germany. biesal at t-online.de, biesal at uni-hohenheim.de.
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Table of contents
- Vitamin D effects
- Vitamin D and immune system
- Food sources
- Vitamin D deficiency
- Risk factors for severe courses of COVID-19
- The renin-angiotensin-system (RAS)
- RAS and SARS-CoV-2
- RAS and vitamin D deficiency
- Vitamin D, blood pressure, and COVID-19 mortality
- Vitamin D and cardiovascular diseases
- Vitamin D, obesity and type II diabetes
- Vitamin D and ARDS (adult respiratory distress syndrome)
- Cytokine storm: Vitamin D, SARS-CoV-2, and ACE2
- Kawasaki syndrome
- Therapeutic aspects
- References in PDF
- COVID-19 treated by Vitamin D - studies, reports, videos - VitaminDWiki
Infections of the respiratory tract are more frequent in the winter months and especially in the northern latitudes than they are in summer . This obviously also applies to the COVID-19 infectious disease that briefly spread all over the world in the winter months and became a pandemic [2,3]. A common feature of the winter months and the inhabitants of all countries north of the 42nd parallel is a hypovitaminosis D that frequently occurs during this period . In addition during cold temperature the virus will be more easily transmitted. This raises the question of whether an inadequate vitamin D supply has an influence on the progression and severity of COVID-19 disease.
A low vitamin D status, measured as the plasma level of the transport form of vitamin D, 25(OH)D,is widespread worldwide and is mainly found in regions of northern latitudes, but also in southern countries . In Europe, vitamin D deficiency is widely prevalent during the winter months and affects mainly elderly people and migrants. In Scandinavia only 5% of the population is affected by a low vitamin D status, in Germany, France and Italy more than 25%, particularly older people e.g. in Austria up to 90% of senior citizens [6,7]. In Scandinavian countries, the low incidence of vitamin D deficiency may be due to the traditional consumption of cod liver oil rich in vitamin D and A or to genetic factors resulting in higher synthesis of vitamin D in the epidermal layer . Taken together, low vitamin D status is common in Europe with the exception of the Scandinavian countries. The calculated COVID-19 mortality rate from 12 European countries shows a significant (P = .046) inverse correlation with the mean 25(OH)D plasma concentration .
This raises the question whether insufficient vitamin D supply has an influence on the course of COVID-19 disease? An analysis of the distribution of Covid-19 infections showed a correlation between geographical location (30-50° N + ), mean temperature between 5-11°C and low humidity . In a retrospective cohort study (1382 hospitalized patients) 326 died, Among them 70.6% were black patients. However, black race was not independently associated with higher mortality . An excess mortality (2 to sixfold have been described in African-Americans with average latitudes of their state of residence in higher latitudes (> 40) . The mortality of COVID-19 (cases/ million population) shows a clear dependence on latitude. Below latitude 35, mortality decreases markedly . Indeed, there are exceptions e.g. Brazil (tenfold higher than all other latin American countries - except mexico), however, the management of the pandemic may increase infection risk.
The skeletal and extra skeletal effects of vitamin D have recently been described in an extensive review . Vitamin D exerts a genomic and non-genomic effect on gene expression. The genomic effect is mediated by the nuclear vitamin D receptor (VDR), which acts as a ligand activated transcription factor. The active form 1,25(OH)2D binds to the VDR and in most cases heterodimerizes with the retinoid X receptor (RXR), whose ligand is one of the active metabolites of vitamin A, 9-cis retinoic acid. The interaction of this complex with the vitamin D responsive element can regulate the expression of target genes either positively or negatively . The non-genomic effects involve the activation of a variety of signaling molecules that interact with Vitamin D responsive element (VDRE) in the promoter regions of vitamin D dependent genes . Vitamins A and D are also of particlular importance for the barrier function of mucous membranes in the respiratory tract [17,18].
Vitamin D plays an essential role in the immune system . Vitamin D interferes with the majority of the immune systems cells such as macrophages, B and T lymphocytes, neutrophils and dendritic cells, which express VDR (for details  and Fig. 3). Cathelicidin, a peptide formed by vitamin D stimulated expression, has shown antimicrobial activity against bacteria, fungi and enveloped viruses, such as corona viruses [21,22]. Furthermore Vitamin D inhibits the production of pro- inflammatory cytokines and increases the production of anti-inflammatory cytokines .
The active metabolite of vitamin D in macrophages and dendritic cells, derived from the precursor 25(OH)D, leads to the activation of VDR, which, after RXR heterodimerization, results in the expression of various proteins of the innate and adaptive immune system (Treg cells, cytokines, defensins, pattern recognition receptors etc.) . Vitamin D exerts opposite effects on the adaptive (inhibition) and innate (promotion) immunsystem This correlates with an anti-inflammatory response and balances the immune response .
The active metabolite of vitamin D, 1,25(OH)2D3 can be formed in T and B lymphocytes and inhibits T cell proliferation and activation . This way, vitamin D may suppress T-cell mediated inflammation and stimulate Treg cells proliferation, by increasing IL-10 formation in DC cells, and thus enhance their suppressive effect [27,28].
There are only few dietary sources of vitamin D (cod liver oil, fat fish) that could satisfy the recommended daily allowance (15-20 ug/ day for adults). To reach such amount besides availability of dietary sources, vitamin D skin synthesis, which contributes to 80% in healthy individuals up to the age of 65, is important.
With the exception of mushrooms there are no plant sources of vitamin D. In particular wild mushrooms, which are grown in light. Sun- dried but not fresh mushrooms can contain between 7 and 25 ug/100 g of vitamin D2 , which is an important source  with a good shelf life  and comparable bioavailability to vitamin D3 . Vitamin D status can be significantly improved by fortified foods, as was shown in a meta-analysis .
Insufficient levels of vitamin D are caused by two main physiological causes: Low UVB exposure, especially in northern regions during the winter season  and in case of strong pigmentation, as well as decreased vitamin synthesis in the skin with aging . In addition a poor diet, low in fish and fortified food (if available) are the major reason for deficiency in old age and people living in poverty. Major risk groups , besides pregnant women and children under 5, include elderly, over 65 years, those with little or no sun exposure (full body coverage, little contact with the outside world) as well as people with dark skin, especially in Europe and the USA.
The vitamin D deficiency is a worldwide problem, which is not only observed in the northern countries, but increasingly also in the south. While in Europe, for example, deficits (< 30 nmol) are between 20 and 60% in all age groups, in Asia the figure for children is 61% (Pakistan, India) and 86% (Iran) [37,38].
Particularly critical is the number of migrants from Southern countries with insufficient vitamin D status (<25nmol/L) : e.g. Netherlands 51%, Germany 44% (in summer), UK 31% (end of summer) and 34% (autumn). In India, the number of adults with values < 25 nmol/L ranges from 20% to 96% depending on the region.
The half-life of 25(OH)D3 is about 15 days and that of 25(OH)D2 is between 13 and 15 days, due to the weaker affinity to the vitamin D binding protein . Consequently, longer periods of time indoor, e.g. in care homes or longer time in quarantine, pose risk for developing vitamin D deficiency.
Older age and co-morbidities are linked to an insufficient vitamin D supply. Over 60 years of age, a reduction in the synthesis of vitamin D in the skin becomes apparent, which further increases getting older . The precursor of vitamin D, 7-dehydrocholesterol in the skin declines about 50% from age 20 to 80 , and the elevation of cho- lecalciferol levels in serum following UVB radiation of the skin shows more than a 4-fold difference in individuals aged 62-80 yrs. compared with controls (20-30yrs) . This explains the high number of older individuals with an inadequate vitamin D status.
Based on a meta-analysis including 30 studies with 53,000 COVID- 19 patients, co-morbidities are risk factors for disease severity:
|Risk factor Odds ratio||95% CI|
|Old age > 50yrs||2.61||2.29-2.98|
|Chronic kidney disease||6.017||2.192-16.514|
Independent prognostic factors for COVID-19 related death:
|Risk factor||Relative risk||95% CI|
|Old age > 60||9.45||8.09-11.04|
Co-morbidities and old age show a relationship with Renin- Angiotensin-Aldosteron-System (RAS), vitamin D status and COVID-19 infection.
RAS plays an important role in maintaining vascular resistance and extracellular fluid homoeostasis. Fig. 1 summarizes the essential steps of this system.
Mainly in the juxtaglomerular apparatus of the kidney, but also in other tissues and cells, renin is formed, which cleaves the angiotensi- nogen secreted from the liver very selectively to the inactive form angiotensin I (Ang I). This decapeptide is then cleaved by a further protease the angiotensin-converting-enzyme (ACE) on the surface of the endothelial cells to the active angiotensin II (Ang II), which can bind to two different receptors AT1R or AT2R. Synthesis and secretion of renin in the kidney, as rate limiting enzyme of RAS, is stimulated by fluid volume, reduction of the perfusion pressure or salt concentration and by the sympathetic nervous system activity.
Renin synthesis and secretion is inhibited with increasing Ang II via an AT1R mediated effect and stimulated with decreasing Ang II . The stimulating effect on renin synthesis and secretion due to either low levels of Ang II or Ang II converting inhibitors (ACEI) or Ang II receptor blockers (ARB) is mediated through ligands that activate cAMP/PKA (Protein Kinase A) pathways (e.g. catecholamines, prostaglandins and nitric oxide) [45,46].
Ang II leads to the release of catecholamines and vasoconstriction. Via AT1R, Ang II increases aldosterone release and sodium reabsorption. Furthermore, binding to AT1R has pro-inflammatory and pro- oxidative effects and inhibits the action of insulin in endothelial and muscle cells. The latter can lead to a decrease in NO production in endothelial cells and thus will further increase vasoconstriction .
With the discovery of ACE2, a novel homologue of ACE, a transmembrane metallopeptidase with an extracellular ectodomain, the understanding of RAS manifold regulatory function was deepened (Review ). ACE2, a monocarboxypeptidase has been shown to cleave Ang I to Ang 1-9, and Ang II to Ang 1-7. This degradation can weaken the effect of Ang II at AT1R and thus counteract the pathological changes. While Ang 1-9 exerts a cardioprotective effect via AT2R , Ang 1-7 acts via the Mas Oncogene receptor. This counterbalances the effect of ANG II at AT1R and subsequently the “overstimulation” of the RAS and its pathological consequences . ACE2 is expressed in many organs, especially kidney and lung, and in the cardiovascular system in cardiomyocytes, cardiac fibroblasts, vascular smooth muscle and endothelial cells. It can counteract the effects of RAS, such as inflammation, vasoconstriction, hypertrophy and fibrosis, by degrading Ang I and Ang II, thus making them less available for the ACE/AngII/AT1 axis. At the same time ACE2 can strengthen the ACE2/ Ang 1-7/Mas axis which attenuates the proinflammatory RAS activation.
- Cardiac hypertrophy
- Bloodpressure Vasoconstriction Inflammation Catecholamines Cardiac hypertrophy
Fig. 1. In the classical RAS pathway Renin, expressed from the renin gene induces cleavage of Angiotensinogen to Angiotensin I which is converted to Angiotensin II via Angiotensin converting enzyme (ACE). Ang II activates the Angiotensin 1 receptor which results in an increase of blood pressure and further effects on the vascular system. In addition, Ang II suppresses renin synthesis via AT1R. To keep the system in balance a counter regulatory pathway exists. This pathway is activated through cleavage of Ang I to Ang1-9 via ACE2 or AT2R activation or Ang II to Ang1-7 which counter regulates via Mas receptor. This helps the system to stay within a homoeostatic balance, as long as the RAS activity is controlled.
Infection with SARS-CoV-2 causes the virus spike protein to come into contact with ACE2 on the cell surface and thus to be transported into the cell. This endocytosis causes upregulation of a metallopepti- dase (ADAM17), which releases ACE2 from the membrane, resulting in a loss of the counter regulatory activity to RAS . As a result, proinflammatory cytokines are released extensively into the circulation. This leads to a series of vascular changes, especially in the case of preexisting lesions, which can promote further progression of cardiovascular pathologies.
SARS-CoV-2 not only reduces the ACE2 expression, but also leads to further limitation of the ACE2/Ang 1-7/Mas axis via ADAM17 activation, which in turn promotes the absorption of the virus. This results in an increase in Ang II, which further upregulates ADAM 17. Thus a vicious circle is established turning into a constantly self-generating and progressive process. This process may contribute not only to lung damage (Acute respiratory distress syndrome - ARDS), but also to heart injury and vessels damage, observed in COVID-19 patients. Thus, previous lesions of the cardiovascular system represent a risk factor, since coexisting pathologies can progress as a result of the virus infection [52,53].
Several studies have shown increased plasma renin activity, higher Ang II concentrations and higher RAS activity as a consequence of low vitamin D status [54,55]. The same applies to the decreasing Renin activity with increasing vitamin D levels . There is an inverse relationship between circulating 25(OH)D and renin, which is explained by the fact that vitamin D is a negative regulator of renin expression and reduces renin expression by suppressing transcriptional activity in the renin gene promoter, thus acting as a negative RAS regulator to prevent overreaction In VDR knock out mice [57,58]. The 1,25(OH)2D induced repression of the renin gene expression is independent from Ang II feedback regulation.
Permanent increase of the renin levels with an increased Ang II formation has been described, suggesting that in vitamin D deficiency the expression and secretion of renin is increased at an early stage [59,60]. This results in increased fluid and salt intake and rise in blood pressure, that has been explained by an increase in renin and consecutive upregulation of the RAS in the brain .
Fig. 2 gives a short description of the impact of vitamin D on RAS.
In a small (open-label, blinded endpoint) study with 101 participants who received 2000 IU vitamin D3 or placebo over 6 weeks, a significant decrease in plasma renin activity and concentration was described .
The EVITA study examined the effect of vitamin D supplementation (4000IU/day) over 36 months . No relationship was found between blood levels of 1,25(OH)2D and various parameters of the RAS (renin, aldosterone) and vitamin D plasma levels increase. Rather, vitamin D supplementation led to an increase in renin in a subgroup that initially had a mild deficiency of vitamin D. The 25(OH)D value in these subgroups increased from 20.4 nmol/L to 83.7 nmol/L after 36 months. Renin from 859 mIU/L to 1656mIU/L. It cannot be excluded that these were rather toxic effects of a dose in the upper level range. However, the fact that blood levels increase naturally reduced the renin concentration become clear when looking at the placebo group with initial hypovitaminosis D (21.3 nmol/L) with a strong increase after 36 months (45.6 nmol/L). Renin decreases from the initial value of 507 to 430mIU/L after 36 months. According to this, a moderate suppressive effect of vitamin D is conceivable under physiological conditions and in particular in participants with a compensated vitamin D deficiency. The plasma level of renin and 1,25(OH)2D show a significant inverse correlation in hypertensive individuals . In a study on 184 normotensive participants, higher circulating Ang II levels were associated with decreasing 25(OH)D blood levels. After infusion of Ang II there was a blunted renal blood flow, both effects were considered RAS activation in the setting of lower plasma 25(OH)D .
Vitamin D supplementation leads to a reduction in blood pressure in patients with essential hypertension [66,67], and to a reduction in blood pressure, plasma renin activity and angiotensin II levels in patients with hyperparathyroidism [68,69]. Low vitamin D status may contribute to increased activity of the RAS and subsequent higher blood pressure. An inverse relationship between the concentration of the active metabolite 1,25(OH)2D3 and blood pressure has been described in hypertensive as well as normotensive individuals [70,71]. In a study using the mendelian randomization approach in 35 trials (146,581 participants) with four SNPs (Single Nucleotid Polymorphism), a causal relationship was shown between increasing 25(OH)D levels and decreased risk of hypertension in individuals with genetic variants leading to low Vitamin D plasma levels .
Depending on the study, the number of COVID-19 patients affected with hypertension was between 20 and 30% and the proportion of diabetics between 15 and 22% . Data from 5 studies in Wuhan (n:1458) reported 55.3% and 30.6% cases respectively of hypertension and of diabetes . 49% of the 1591 patients in ICUs in Italy (Lombardy), 1287 of whom needed respirators, had hypertension and were older than the normotensive ones .,
Hypertension, followed by diabetes (16.2%), was the most frequent concomitant morbidity in patients with severe course disease [76,77,78].
Vitamin D has multiple functions in the cardiovascular system and thus represents an important protective factor of endothelial, vascular muscle, and cardiac muscle cells . In a meta-analysis of 65,994 participants an inverse relationship between 25(OH)D vitamin D plasma levels (below 60 nmol/L) and cardiovascular events was shown . These findings have been confirmed by the Framingham and NHANES data [81,82]. As for the positive effects on respiratory diseases shown by vitamin D supplementation, also for cardiovascular disease positive effect was reported only if there was a vitamin D-deficit before supplementation.
- Fig. 3. Ang II leads to a series of pro-inflammatory stimuli in the immune system via the activation of AT1R. These include an increase in the expression of MCP-1 as well as the chemokine receptor CCR2, which lead to a massive infiltration of the endothelium with macrophages. The same applies to the activation, migration and maturation of dendritic cells (DC) and the antigen (Ag) presentation. The negative effect on T lymphocytes as well as on T regulatory cells further promotes a proinflammatory state. A number of other proinflammatory processes are triggered by AT1R and favor the development of inflammation, hypertension and diabetes. Vitamin D is considered to counteract this reaction by contributing to a normalization of immune function through a variety of processes. However, it should not be overlooked that most processes in the immune system initiated by vitamin D occur together with vitamin A 196.
In a large cohort of patients (n = 3296) referred to coronary angiography, a significant increase in plasma renin and angiotensin II was observed with decreased 25(OH)D and 1,25(OH)2D levels, but not with circulating aldosterone levels . Vitamin D plasma levels are an independent risk factor for CVD mortality. 92% of 1801 patients with metabolic syndrome, had a low vitamin D status (22.2% were severely deficient (25(OH)D < 25 nmol). CVD mortality and total mortality were reduced respectively by 69% and 75% in those with highest 25(OH)D levels (> 75nmol/L) .
CVD is considered an independent risk factor for fatal outcome in COVID-19 patients. The proportion of survivors with CVD was 10.8%, among non-survivors 20% . Disturbed coagulation, endothelial dysfunction and proinflammatory stimuli described as a result of a viral infection are considered to be among the major causes .
Obesity (BMI > 30 kg/m2) is often associated with low 25(OH)D plasma level [87,88]. Using a bi-directional genetic approach, 26 studies (42,024 participants - Caucasians from Northern Europe and America), including 12 SNPs, showed that higher BMI (Body Mass Index) leads to lower 25(OH)D plasma levels. The repeatedly discussed hypothesis that low 25(OH)D level leads to increased BMI could not be verified . Obesity is therefore another risk factor for an insufficient vitamin D status independent from age .
Low 25(OH)D plasma values are also found in diabetes II [91,92]. This is often associated with an increased risk of metabolic syndrome, hypertension and cardiovascular diseases [93,94]. One of the main causes could be insulin resistance, often found in connection with low vitamin D levels . This is well documented by the evaluation of observational and intervention studies using metabolic indicators. 10 out of 14 intervention studies showed a positive effect of Vitamin D on metabolic indicators . Vitamin D deficiency is therefore also considered to be a potential link between obesity and diabetes type II .
Via a short-loop feedback Ang II inhibits the further release of renin via AT1R.
If the renin secretion is not sufficiently inhibited, an overreaction of the RAS can lead to a further increase in blood pressure, increased sodium reabsorption, increased aldosterone secretion and thus increased insulin resistance . This overreaction is considered to be a major cause of the development of hypertension, diabetes and cardiovascular disease, especially in people with high BMI, since adipose tissue contributes to an overreaction of the RAS . Adiponectin synthesis in adipocytes counteracts most of these effects, however circulating levels are inversely related to BMI [100,101]. Vitamin D can regulate the formation and release of adiponectin [102,103]. Obese people often have low adiponectin and vitamin D levels and an inverse relationship between fat mass and vitamin D levels has been described . Therefore, vitamin D deficiency might explain RAS overreaction and following consequences .
In a small study on 124 IUC patients with SARS-CoV-2 it was found that obesity (BMI > 35 kg/m2) occurred in 47.6% of the cases and severe obesity (BMI > 35kg/m2) in 28.2% . In the latter case, 85.7% had to be mechanically ventilated invasively, 60 patients (50%) had hypertension, 48 of these (80%) had to be ventilated invasively. A study from Shenzhen, China also confirmed that obesity is a risk factor for severe course of disease. In a cohort of 383 patients with COVID-19, overweight patients (BMI 24-27.9) had 86% higher risk of developing pneumonia and obese patients (BMI > 28) had 142% higher risk of developing pneumonia compared to normal weight patients .
The main cause of death in COVID-19 patients is ARDS. Patients (without COVID-19) (mean age 62 Y) with ARDS (n:52) and those at high risk of ARDS (n:57) (esophagectomy) had low (27.6 nmol/L) to very low (13.7nmol/L) 25(OH)D blood levels as a sign for severe vitamin D deficiency .
ACE2 exerts a counter-regulation of the harmful effect of ACE. Ultimately, it would then be the balance between ACE and ACE2 that explains the reaction of the RAS. The ACE2 effect on the RAS is shown in experimental studies in which ACE2 knock out mice developed severe lung disease with increased vascular permeability and pulmonary edema . Over-expression or the use of recombinant ACE2 improves blood flow and oxygenation and inhibits the development of ARDS after LPS-induced lung damage [110,111].
The development of ARDS shows typical changes in membrane permeability of the alveolar capillary, progressive edema, severe arterial hypoxemia and pulmonary hypertension . The same changes can be achieved in animal experiments by injection of lipo- polysaccharides (LPS) . Vitamin D significantly attenuates the lung damage caused by LPS. LPS exposure leads to a significant increase in the pulmonary expression of renin and ANGII. This promotes the pro- inflammatory effects of the conversion of AngII via AT1R and suppresses ACE2 expression. The administration of vitamin D was able to reduce the increased renin and AngII expression and thus significantly lower the lung damage. The authors conclude that this may have been due to the reduction of the renin and ACE/AngII/AT1R cascade and the promotion of ACE2/Ang1-7 activity by vitamin D through its influence on renin synthesis.
Increased ACE and ANGII expression and reduced ACE2/Ang1-7 expression in lung tissue favors lung damage induced by ischemia reperfusion in mice . The ACE/Ang1-7 expression and the amount of circulating Ang 1 -7 was increased at the onset of ischemia and then decreased rapidly in contrast to the tissue concentration, while AngII increased. This suggests a dysregulation of local and systemic RAS. The application of recombinant ACE2 was able to correct the dysregulation and attenuate the lung damage, while ACE2 knock out increased the imbalance and was associated with more severe damage. Inhibition of the ACE/AngII/AT1R pathway or activation of the ACE2/Ang1-7 pathway have therefore been proposed as therapeutic options.
In rats with LPS-induced acute lung injury (ALI), the administration of vitamin D (calcitriol) was associated with a significant reduction in clinical symptoms of ALI. Calcitriol treatment led to a significant increase in the expression of VDR mRNA and ACE2 mRNA. VDR expression may have resulted in a reduction of angiotensin II, ACE2 expression in increased anti-inflammatory effects .
VDR is not only a negative regulator of renin, but also of NFkB , leading both to an increase in Ang II formation , which in turn promotes pro-inflammatory cascades. Furthermore SARS-CoV-2 infects T-lymphocytes  and the Covid-19 disease severity seems to be related to lymphopenia , which occurs in 83,2% of COVID-19 patients at hospital admission . Indeed, in a recent meta-analysis on 53.000 COVID-19 patients decreased lymphocyte count and increased CRP were highly associated with severity .
Regulatory T cells (Treg) play an important role in the development of ARDS . They can attenuate the pro-inflammatory effects of the activated immune system. Vitamin D increases the expression of Treg cells and supplementation of healthy volunteers results in a significant increase in Tregs . Vitamin D causes a reduction in pro-inflammatory cytokines by inhibiting B- and T-cell proliferation [124,125]. Inflammatory processes also play an important role in the development of hypertension and CVD [126,127]. Here, an interesting but so far not proven connection between vitamin D and RAS is found. T-cells have a RAS system, which contributes to the generation of reactive oxygen species (ROS) and the development of high blood pressure through the formation of Ang II . To what extent vitamin D in T cells is also a negative regulator of renin is not known, but could be one of the reasons for the anti-inflammatory effect .
In patients with a severe disease course (ARDS) a cytokine storm is assumed to be the underlying cause . SARS CoV-2 can lead to a downregulation of ACE2 in the lungs and to a shedding of the ectodo- main of ACE2. This soluble sACE2 shows enzymatic activity, but the biological role is unclear. The soluble form is believed to exert systemic influence on angiotensin II ; since SARS-CoV-2 induces shedding, it is assumed that sACE2 is directly related to the virus- induced inflammatory response .
Downregulation of ACE2 expression by SARS-CoV infection is associated with acute lung damage (edema, increased vascular permeability, reduced lung function) [ 133] and with RAS dysregulation leading to increased inflammation and vascular permeability. Inflammatory cytokines such as TACE (TNF-a-converting enzyme) induce increase shedding , which in turn can be also caused by spike protein of the virus, promoting virus uptake by ACE2 . Comparative studies on mortality rates in different countries and analysis of the relationship between vitamin D and CRP (as a marker of cytokine storm) plasma levels, concluded that.
risk factors for severity of the clinical course, predicted by high CRP and low vitamin D (<25 nmol) levels, were reduced by by 15.6% following vitamin D status normalization (>75nmol) . It is interesting to note that calmodulin kinase IV (CaMK IV) stimulates vitamin D receptor (VDR) transcription and interaction with co-activator SRC (steroid receptor coactivator) [ 137]. According to the authors, this would explain the linkage of the genomic and non-genomic membrane pathways of vitamin D. The calmodulin binding domain at ACE2  may explain why calmodulin inhibits the shedding of the ectodomain of ACE2 . It is also conceivable that vitamin D may show significant effects either by stimulating VDR-mediated transcription, or by mediating 1,25(OH)D calcium-dependent activity through CaMK II and phospholipase A .
Children and adolescents rarely show severe disease courses. A meta-analysis comprising 18 studies with 444 children under 10years of age and 553 between 10 and 19years of age, reported only one case of severe complication in a 13-year-old child. In North America, 48 cases of children (4.2-16.6 yrs) have been described with severe disease course. Independently of this, COVID-19 children have a clinical picture that has not been associated with usual acute clinical manifestations of SARS-CoV-2 infection, showing an unusually high proportion of children with gastrointestinal involvement, Kawasaki disease (KD) like syndrome, until now .
KD is an acute vasculitis which can lead to aneurysms of the coronary arteries and is considered the leading cause of acquired heart disease in children . A number of cases have been observed in recent weeks suggesting a relationship between Kawasaki syndrome and COVID-19 .
One reason probably relies upon ACE gene polymorphisms . In these polymorphisms there is a strong increase in ACE without affecting AngII plasma levels . There is a direct relationship between ACE polymorphism (with high ACE plasma levels) and the occurrence ofKD, according to a recent meta-analysis .
Irrespective of this, the disease occurs seasonally during the winter months in extratropical northern atmosphere and is often associated to respiratory tract infections . A KD associated Antigen was found in proximal bronchial epithelium in 10 out of 13 patients with acute KD and in a subset of macrophages of inflamed tissues . That strengthens the hypothesis that an infectious agent entering the respiratory tract, might be the cause of KD. Indeed, it was reported that children with KD were affected by respiratory diseases with HCoV: New Haven coronavirus . The authors concluded that there was a significant association between KD and HCoV-NH infection.
Just like current evidence suggest that vitamin D-deficiency is associated with increased risk of CVD, including hypertension, heart failure, and ischemic heart disease, patients with KD also show very low vitamin D levels. Children with KD (79) had significantly lower 25(OH) D levels (9.17 vs 23.3ng/ml) compared to healthy children of the same age .
Intravenous immunoglobulin (IVIG) has become the standard therapy for KD , with a good therapeutic response from young patients, of which only 10-20% need additional anti-inflammatory medication . In a study on 91 KD children, 39 of them with very low plasma vitamin D levels (< 20 ng/ml), showed immunoglobulin resistance compared to the rest of the children (n = 52) children with higher levels (> 20ng/ml) . Children with immunoglobulin resistance also have a higher incidence of coronary artery complications [154,155].
The relationship between ACE polymorphism and peripheral vascular disease is observed in Asians but not in Caucasians [156,157]. Furthermore the prevalence of KD in Japan (240/100,000) is 10 times higher than in North America (20/100,000) [158,159]. During February and April 2020, 10 cases of COVID-19 and KD were reported in Bergamo, Italy, corresponding to 30 times higher rate than the last 5 years incidence . The higher incidence of KD in Asian children (35.3 cases/100,000) as reported in California, may indeed indicate a more frequent ACE polymorphism in Asian population, followed by African-Americans (24.6/100,000) probably due to the fact that pigmentation reduces vitamin D production in the skin  compared to white children (14.7/100.000). From 189 children hospitalized between 1991 and 1998 136 (72%) of the children were African-American and 43 (23%) were white . It is conceivable that Vitamin D deficiency which activates the RAS, promotes the development and course of KD.
The aim of a therapy with vitamin D should be a normalization of the vitamin D status, preferably > 75 nmol/L. Basically, it can be assumed that a vitamin in physiological doses can do little more than remedy the symptoms or secondary manifestations of a deficiency. Vitamin D is a prohormone. Therefore, the question of correcting the status should be treated in the same way as for other hormones (e.g. thyroid hormone). Before starting therapy, the plasma level should be determined. This allows a dosage and therapy to be initiated that corresponds to the respective status. The analysis should be carried out especially in risk groups (Table 1) in order to be able to react adequately, especially in acute cases. The general recommendation to supplement with a recommended daily dose (800 IU) may apply to people who do not belong to a risk group, are healthy.
The vitamin D status is the basis for treatment with vitamin D. There are indeed, risk groups were a poor status can be expected.
As it is known that the amount of 25(OH)D circulating in the blood and less the active metabolite 1,25(OH)2D is a better indicator for a deficit, threshold values have been set here (Table 2).
Severe < 12.5 nmol/L < 5 ng/ml
Moderate 12.5-29 nmol/L 5-11.6 ng/ml
Mild 30.0-49 nmol/L 12-19.6 ng/ml
Sufficient > 50 nmol/L > 20ng/ml165
> 75 nmol/L > 30ng/ml166
Toxicity > 250 nmol/L > 100ng/ml
Table 2: Threshold levels to calculate deficiency ranges (25(OH)D)
A vitamin D status below 20 ng/ml or<50 nmol/L should be treated to achieve a minimum level of 30 ng/ml (75 nmol/L). Values around 75 nmol/L are considered optimal, with respect to the skeletal activities . Particularly in countries where vitamin D fortified foods are not available, the importance of an adequate supply should be emphasized. A sufficient vitamin D status can be achieved in the healthy populations following the recommendations and the thresholds of the plasma levels. In case of comorbidities related to the clinical development of COVID-19 there might be a higher need and therefore it is discussed to choose other recommendations for the adequate care of persons with chronic diseases [168,169].
The recommendations of the National Health Service UK are based on those of various professional associations. It should be noted that vitamin D therapy is contraindicated for patients with hypercalcemia or metastatic calcification. Suggested therapy should be used when low plasma levels and the following symptoms are present:
Proximal muscle weakness
Rib, hip, pelvis, thigh and foot pain (typical)
Risk factors for deficiency (NHS) .
Inadequate skin synthesis
Poor oral supply
Vegetarian or fish
Drugs: rifampicin, HAART-
Habitual sunscreen use
Institutionalized/housebound and people with poor mobility
Age > 65
CKD (eGFR < 60) 
So far, there is no experience on the use of vitamin D in COVID-19. The observation that a normal vitamin D status is important for the immune system as well as for the regulation of the RAS should, however, lead to a correction of the Vitamin D status if a deficiency is detected. Nevertheless, it should be borne in mind that high doses of
vitamin D also carry risks, as they can contribute to changes in VDR competence and thus have an inhibitory effect on immune function (Ref: Mangin M, Sinha R, Fincher K. Inflammation and vitamin D: the infection connection. Inflkamm Res 2014; 63: 803-811)
The importance of a vitamin D deficiency is shown by a recently published analysis of the COVID-19 deaths of 780 COVID-19 patients in Indonesia .
table 3 data of patients with COVID-19 related to vitamin D levels and disease outcome
|Vitamin D:||< 20ng/ml||20-30 ng/ml||> 30 ng/ml|
|Mean age||66.9±13.8||62.9 ± 14.7||46.6±12.6|
|Odds ratio |
Adjusted for age, sex and comorbidity
|10.12 (p < .001)||7.63(p < .001)|
The table illustrates that old age, comorbidities and vitamin D deficiency or insufficiency contributed to outcome of the disease.
Based on these data Vitamin D plasma level is an independent predictor of mortality.
VDRA are discussed to counteract the effect of imbalanced immune response and have suppressant effects on the RAS. Since VDRA have been observed to contribute to a significant reduction of inflammatory processes, they are increasingly used in immunosuppressive therapy to control TH1-related overreactions via interaction of VDRA with the chemokine CXCL10, a T cell chemoattractant chemokine . The induction of CXCL10 is an important step against bacterial and virus infections. However, sustained CXCL10 induction leads to amplified neuroinflammation in Coronavirus (JHMV) induced neurologic infection . CXCL10 is also considered a critical factor in ARDS. H5N1 influenza infection in mice resulted in increased CXCL10 secretion with a consequent inflamed neutrophils massive chemotaxis and a subsequent pulmonary inflammation . Following SARS-CoV-2 infection, CXCL10 and other chemo- and cytokines are upregulated . Anti CXCL10 antibodies have shown ARDS improvement following LPS induced lung injury with high CXCL10 levels .
Additionally evidence from animal models (diabetic nephropathy) has shown that VDRA block TGFft system in the glomerulus and thus abolish interstitial fibrosis . It is assumed that VDRA modulates increased RAS activity. Indeed, a clinical study on 281 patients (type II diabetes with albuminuria) revealed that VDR activator paricalcitol (19-nor-1,15-dihydroxyvitamin D2) led to a significant albuminuria reduction as well as a decrease in blood pressure despite increased salt intake, as a sign of decreased RAS activity ; effect that could not be achieved with losartan (ANG II receptor antagonist) .
Morphine medication is an essential part of treatment for COVID patients with severe ARDS. it is used early for dyspnea or pain and for shivers . Morphine, at doses similar to those used in humans, can lead to downregulation of VDR in human T cells and activation of RAS with renin upregulation and a threefold increase in Ang II production, resulting in increased reactive oxygen species (ROS) responsible for DNA damage and T cells apoptosis .
VDR agonist (EB1089) inhibits VDR downregulation, leading to RAS decreased activity, inhibition of morphine induced ANG II production, reduced ROS formation and lower DNA damage, thus inhibiting T-cell apoptosis . In addition, if Jurkat cells were pretreated with EB 1089 and Losartan, an Angiotensin II receptor antagonist (ARB) before incubation with morphine. The combination of the Vitamin D Receptor agonist and Losartan attenuated the morphine-induced ROS formation. Indeed, as an example ARB increase ACE2 expression  and Ang 1-7/Mas axis activation reduced ROS formation .
Spermidine is a metabolite of polyamines which are delivered through the diet and partially metabolized by colon bacteria from undigested proteins. Polyamines can influence macrophages development into pro-inflammatory or anti-inflammatory type by altering cellular metabolism and triggering mito- and autophagy . The capacity of spermidine to ensure proteostasis through the stimulation of the cyto- protective autophagy is acknowledged as one of its main features.
Recently, the effect of spermidine on autophagy in SARS-CoV-2 infected cells which results in inhibition of autophagy has been described . Since spermidine promotes autophagy, spermidine and other agents may be a therapeutic approach to SARS-CoV-2 infection.
With regard to the specific risk of elderly to develop severe course of SARS-CoV-2 infection, it is interesting to note that spermidine concentrations in organs and cells decline with age and resulting in a decrease of autophagy . Consumption of LKM512 yogurt increases spermidine synthesis in the gut in elderly . Whether that has any impact on supply of spermidine to enterocytes or other tissues remains to be elucidated. Spermin and spermidine but not putrescine another polyamine metabolite can activate VDR in vitro within their physiological intracellular concentrations . Vitamin D and VDR play an important role in autophagy. Vitamin D can induce autophagy similar to spermidine by inhibiting mTORC1 complex activation  and by increasing Beclin-1 expression, similar to spermidine .
A major limitation of al studies dealing with low levels of vitamin D and disease is the fact that there are only few studies, which show a causal relationship. Most studies show associations and data regarding the influence of COVID-19 on vitamin D status are missing. Furthermore, it should not be overlooked that many of the effects of vitamin D on genexpression in the immune system occur together with vitamin A. The effect of vitamin A deficiency in COVID-19 has not yet been investigated. However, vitamin A deficiency or combined deficiencies with vitamin D or other micronutrients exists not only in low income countries. .
An inadequate supply of vitamin D has a variety of skeletal and non- skeletal effects. There is ample evidence that various non-communicable diseases (hypertension, diabetes, CVD, metabolic syndrome) are associated with low vitamin D plasma levels. These comorbidities, together with the often concomitant vitamin D deficiency, increase the risk of severe COVID-19 events. Much more attention should be paid to the importance of vitamin D status for the development and course of the disease. Particularly in the methods used to control the pandemic (lockdown), the skin’s natural vitamin D synthesis is reduced when people have few opportunities to be exposed to the sun. The short half lives of the vitamin therefore make an increasing vitamin D deficiency more likely. Specific dietary advice, moderate supplementation or fortified foods can help prevent this deficiency. In the event of hospitalisation, the status should be urgently reviewed and, if possible, improved.
In the meantime, 8 studies have started to test the effect of supplementing vitamin D in different dosages (up to 200,000 IU) on the course of the COVID-19 disease. The aim is to clarify whether supplementation with vitamin D in different dosages has an influence on the course of the disease or, in particular, on the immune response, or whether it can prevent the development of ARDS or thromboses .
Declaration of Competing Interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgement: The author is grateful to the Society of Nutrition and Food Science e.V. (www.snfs.org) for defraying the open access publication charges for this article. My sincere thanks to Hellas Cena, University Pavia, Italy, for the critical reading of my manuscript and the excellent hints for strengthening the information contained therein. Ute Gola, Institute for nutrition and prevention, Berlin, Germany for valuable suggestions and advice.
Vitamin D is being used to fight COVID-19
- Doctors in Egypt’s quarantine hospitals to receive million Vitamin D doses: Ministry June 1
- Does anyone have details?
Intervention Clinical Trials
Intervention Trial Summary June 29
- 18) 200,000 IU Vitamin D when enter hospital, RCT Brazil Ending Dec 2020
- 17) Semi-activated Vitamin D given infrequently Spain
- 16) Semi-activated Vitamin D given daily for 60 days completion date March 2021
- no loading dose - so it will be unlikely to see any benefit in 30 days, Iran
- 15) 100,000 IU Vitamin D first day, 14 days of resveratrol
- US - Ohio, Recently test positive for COVID-19 but are not in hospital
- Note: Resveratrol greatly increases the amount of vitamin D getting to cells (VDR)
- 14) Iran 2,000 IU daily Complete March 2021
- 13) France, Nursing Home, daily 2,000 IU + Zinc
- 12) Argentina 500,000 IU Complete Dec 2020
- 11) US New Orleans 50,000 IU weekly +aspirin Complete Dec 2020
- 10) US Complete Nov 2020
- 9) Alberta, 100,000 IU first week Complete Dec 2020
- 8) Vitamin D Testing and Treatment for COVID 19 Study completion May 2021
- Supplement with 10,000 IU daily and unrealistically expect COVID-19 improvement in only 2 weeks (also look at 4 and 6 weeks)
- 7) Dr. Manson is planning a COVID-19 Vitamin D RCT for both prevention and treatment Medscape Video May 11
- In her video she recommends up to 2,000 IU of Vitamin D daily
- 6) VitaminDWiki is funding a Randomized Controlled Clinical Trial in Sri Lanka which may start in early June
- 400,000 IU of Vitamin D vs placebo to 1,000 people entering quarantine centers for 14 days
- See also Vitamin D trial with COVID-19 in Sri Lanka - interview May 16
- No trials have results of COVID-19 being prevented or treated by Vitamin D (but many are underway) May 1, 2020
- "Vitamin D: A rapid review of the evidence for treatment or prevention in COVID-19"
- 5) First RCT for Vitamin D and COVID-19 outside of China with enough Vitamin D - announced April 14
- Using 400,000 IU of Vitamin D in France for those >age 70 recently tested positive for COVID-19
- Dr. ANNWEILER had recently developed a way to estimate Vitamin D levels (only in the elderly) without a test
- 4) Spanish RCT using 25,000 IU probably not enough to make a difference
- 3) COVID-19 association with Vitamin D also being explored by Hollis and Wagner - April 2020
- 2) ?
- 1) Use 10,000 IU then 5,000 IU every few days to treat COVID-19 induced SARD Spain, April 30
- That small of a dose of vitamin D will be unlikely to show any benefit that late into the infection
Observational Clinical Trials
- 99 percent of the 380 Indonesians who died of COVID-19 had low vitamin D - May 2020
- All those with > 34 ng of Vitamin D survived
- All those with > 34 ng of Vitamin D survived
- Evaluation of the Relationship Between Zinc Vitamin D and b12 Levels in the Covid-19 Positive Pregnant Women posted May 29
- Exclusion Criteria: No vitamin D , Vitamin B12 or Zinc supplement use
- Clinical trial Arm1: Observe COVID-19 Deaths and Vitamin D levels in the UK trial completion June 2021
- Arm2: Measure Vitamin D of patients in general practices and see if they get COVID-19 in the next 6 months (prevention)
- Clinical trial observing Vitamin D levels of 500 people in Spain at entry into ICU and recording outcomes analysis to be completed July 2020
- Clinical trial to observe vitamin D levels of 100 COVID-19 Turks in hospital to be completed July 2020
- Bursa City Hospital, NCT04394390
- WHO 3 RCT for Vitamin D and COVID-19 as of May 27 (WHO not responding when asked for details)
- NCT04386044 Investigating the Role of Vitamin D in the Morbidity of COVID-19 Patients 10/05/2020
- NCT04334005 Vitamin D on Prevention and Treatment of COVID-19 29/03/2020
- ChiCTR2000029732 Impact of vitamin D deficiency on prognosis of patients with novel coronavirus pneumonia (COVID-19) 2020-02-10
- Clinical trial to measure Vitamin D status AND vitamin D genes of COVID-19 patients in Portugal Study completion date March 2021
- No intervention, hope they consider genes not noticed by Vit. D tests: such as Vitamin D Receptor, CYP27B1
Vitamin D Dosing Recommendations for COVID-19
- Portion of image from June 5 video (below)
- Commentary: Myths and facts on vitamin D amidst the COVID-19 pandemic Metabolism, June 2, FREE PDF, peer-reviewed publication
- "Preventive doses of vitamin D3 of 10,000 IU/day for 4 weeks followed by 5000 IU/day to reach a target 25(OH)D level of 100–150 nmol/L , and treatment doses >6000 IU/day in deficient individuals to reach a similar level and reduce disease progression , are suggested. ""
- Comment: Strange that the treatment dose is less than the prevention dose. Note treatment dose will take > 3 months to help
- Perhaps they meant the treatment dose to be 60,000 IU, not 6,000 IU
- Perspective: improving vitamin D status in the management of COVID-19 May 22 free PDF
- If low: 50,000 IU twice a week at the diagnosis (100,000 IU total)., then 50,000 IU taken once a week for the 2nd and 3rd weeks.
- Note: VitaminDWiki believes that this dosing is not large enough for prevention, much less treatment
- If low: 50,000 IU twice a week at the diagnosis (100,000 IU total)., then 50,000 IU taken once a week for the 2nd and 3rd weeks.
- COVID-19 might be prevented in 2 months by 50,000 IU weekly – May 12, 2020
- for people who have not been taking any vitamin D BusinessWorld May 22 - by Dr Renu Mahtani in videos below
- Vitamin D 60k IU twice a week for two weeks to be followed by 60k once a week for the next six weeks.
- or Vitamin D 60k IU daily for three days to be followed by 60k weekly for the total period of two months.
- Thus 480,000 IU total, No Vitamin D testing needed
Some people wanted improved immune systems, so took more vitamin D
- Sales of vitamin D supplements up 3000% after Public Health England recommendation May 14
- BBC reported a 6X decrease in % people dying of COVID-19 BBC June 16
- "Wonder if increased D ==> fewer % of COVID-19 patients ended up dying: 6% ==> 1%. Noted also in Italy
- Alternately, the decreased death rate of COVID-19 patients might be just due to more Vitamin D in the summer
- COVID-19 resulted in 3.7X decrease in Irish Very Low Weight Births (Vitamin D) - June 2020 Vitamin D sales had increased by 2500%
- I expect to find many other observations of:
- Fear of COVID-19 ==> Want to improve immune system ==> Take Vitamin D ==> Improved health
- Candidate health concerns for which people have probably have heard about Vitamin D include:
- Pregnancy, Asthma, Multiple Sclerosis, Parkinson's, and Cancer
- I expect to find many other observations of:
COVID-19 associated with Low Vitamin D
- 7X less likely to test COVID-19 positive if had more than 30 ng of Vitamin D (7,804 Israelis) - preprint July 3
- T1 Diabetic children with low vitamin D have COVID-19 problems (like diabetic adults) - preprint May 15
- COVID-19 deaths strongly correlated with percent having less than 10 ng of Vitamin D in a country– July 1 2020
- Pregnant women admitted to hospital with COVID-19 5X more often than non-pregnant women NYT June 24
- 31% vs 6%. Note: NYT article is confusing. Note: Vitamin D levels drop during pregnancy
- The role of vitamin D in reducing risk of COVID-19: a brief survey of the literature - June 9, 2020 in VitaminDWiki
- Evidence Supports a Causal Model for Vitamin D in COVID-19 Outcomes – June 3, 2020 in VitaminDWiki
- Founder of VitaminDWiki believes that Causal Modeling will replace many RCTs in the future
- BIG DATA is far faster and lower cost than RCTs while being able to consider far more interactions
- Model A: 16 predictions match observed data; 3 predictions cannot be determined.
- Founder of VitaminDWiki believes that Causal Modeling will replace many RCTs in the future
- Obese have major problems with COVID-19 - probably due to lower vitamin D and higher ACE2 June 5, 2020
- Low Vitamin D increased chance of COVID-19, unless supplement – May 13, 2020
- Researchers show potential link between vitamin D and coronavirus NBC News Madison Wisconsin May 22
- Reporting on the study from the University in that city - which is below
- Vitamin D for Covid-19? May 12 FREE PDF
- Perspective: improving vitamin D status in the management of COVID-19 European Journal of Clinical Nutrition May 12 FREE PDF
- Avoidance of vitamin D deficiency to slow the COVID-19 pandemic Martin Kohlmeier, BMJ, May 20 FREE PDF
- Vitamin D deficiency as risk factor for severe COVID-19: a convergence of two pandemics preprint May 5. updated May 18
- 186 patients. Lower Vitamin D levels associated with worse COVID-19 only for males
- Vitamin D levels : all males at same hospital in 2019, males in 2020 with COVID-19
- COVID-19 and vitamin D—Is there a link and an opportunity for intervention? Hrvoje Jakova, letter to the editor, May 1, FREE PDF
- [https://www.researchsquare.com/article/rs-30390/v1 |No COVID-19 patient in ICU had >20 ng, 4 had 12.5-20 ng, 13 had < 12.ng ] preprint May 22
- COVID-19 associated with low Vitamin D in more than 20 studies – May 21, 2020 BMJ reply
- Max Minute: How Much Does Vitamin D Help Against COVID-19? CBS News NYC Video May 19
- The Essential Role of Vitamin D in the Biosynthesis of Endogenous Antimicrobial Peptides May Explain Why Deficiency Increases Mortality Risk in COVID-19 Infections preprint May 16 (at least 10,000 IU daily)
- Vitamin D appears to play role in COVID-19 mortality rates Northwestern Univ. May 7
- "Patients with severe deficiency are twice as likely to experience severe complications, including death"
- "...statistical analysis of data from hospitals and clinics across China, France, Germany, Italy, Iran, South Korea, Spain, Switzerland, the United Kingdom (UK) and the United States."
- There are 2 concurrent pandemics – COVID-19 and Vitamin D deficiency – May 13, 2020
- Vitamin D Deficiency and ARDS after SARS-CoV-2 Infection Irish Medical Journal May 11
- Analysis of 36 COVID-19 patients: Vitamin D status: (nmol) ARDS 27, pneumonia 41;
- and, if <30 nmol. 3.2 X more likely to have intubation
Vitamin D levels are lower in those who test positive for COVID-19 -[doi:10.3390/nu12051359| Nutrients] May 09
- [https://articles.mercola.com/sites/articles/archive/2020/05/08/vitamin-d-level-correlated-to-covid19-outcomes.aspx?cid_source=dnl&cid_medium=email&cid_content=art1HL&cid=20200508Z1&et_cid=DM527863&et_rid=867359477 |Vitamin D Level Is Directly Correlated to COVID-19 Outcome] Mercola May 8
- Overview of many studies and video by Ivor Cummins
- [https://www.sciencedaily.com/releases/2020/05/200507131012.htm?utm_source=feedburner&utm_medium=email&utm_campaign=Feed%3A+sciencedaily%2Fhealth_medicine%2Fvitamin_d+%28Vitamin+D+News+--+ScienceDaily%29 |Vitamin D linked to low virus death rate in 20 countries in Europe] Science Daily May 7
- [https://doi.org/10.1101/2020.05.01.20087965 |Evidence Supports a Causal Model for Vitamin D in COVID-19 Outcomes] May 6 preprint
- Excellent extensive use of Causal Influence AI to discover associations.
- I have suspected that Causal Influence could be much better, far lower cost, and faster than the use of RCTs
- [https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3586555|Evidence of Protective Role of Ultraviolet-B (UVB) Radiation in Reducing COVID-19 deaths] preprint May 7
- "permanent unit increase in UVI is associated with a 2.2 % decline in daily growth rates of cumulative COVID-19 deaths [p < 0.01]
- as well as a 1.9 % decline in the daily growth rates of CFR [p < 0.05]
- 64 countries, 78 days, 6 UVI models
- [https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3593258#.XrE0oF1wSjU.twitter |Vitamin D Level of Mild and Severe Elderly Cases of COVID-19: A Preliminary Report] May 5
- 176 seniors in S. Asia - published in India
- Almost everyone with COVID-19 in a Louisiana ICU had low vitamin D – April 29, 2020
- COVID-19 mortality rate highest North of 35 degrees latitude (Vitamin D) – April 20, 2020
- COVID-19 was 19X more likely if low vitamin D (may be invalid data)– April 2020 Philippines
- The raw data has strange gaps in the vitamin D levels
- Research Suggests a Link Between Vitamin D Deficiency and COVID-19 Deaths May 5
- Indonesia preprint 13X if vitamin D insufficient,19X for patients who are vitamin D deficient.
- VitaminDWiki has requested but has not yet access to the raw data
- COVID-19 infections associated with very low vitamin D – Turin Italy – March 2020
- Experts criticise UK govt. for review of Vitamin D COVID-19 Nutragredients July 2
- "Shouldn't the best available proof be enough when it is better than doing nothing?"
- Nursing homes could reduce risk of COVID-19 with Vitamin D – June 30, 2020
- Hill's Criteria indicates that COVID-19 will be treated by Vitamin D - Annweiler June 8 2020
- Evidence that vitamin D is causally linked to COVID-19 outcomes using
- Vitamin D: A cheap yet effective bullet against coronavirus disease-19 – Are we convinced yet?
- June 5, FREE PDF
- How We can fix this pandemic in a month (Vitamin D: 20K IU for 14 days) – June 22, 2020 in VitaminDWiki
- COVID-19 1.9X more likely if Hypocalcemia (which is associated with low vitamin D) June 22, small study, FREE 17 page PDF
- Possible Role of Vitamin D in Covid-19 Infection in Pediatric Population Endocrinol Investigation June 15, FREE PDF
- Covid-19: Public health agencies review whether vitamin D supplements could reduce risk BMJ June 19
- The 2017 BMJ publication that concluded that vitamin D reduced the risk of ARDS was viewed 300,000 times since COVID-19 started.
- An RCT this Winter may be run by the UK to confirm the possibility
- Note: Many other RCTs are already underway - see the top of this section
- Vitamin D and Coronavirus Geriatric Nursing, June 18
- Vitamin D deficiency and co-morbidities in COVID-19 patients – A fatal relationship – June 7, 2020 in VitaminDWiki
- Does Vitamin D play a role in the management of Covid-19 in Brazil? April 2020 free PDF
- A strong role, but recommends against high doses such as 10,000 IU - no reason given
- Exploring the Links Between Coronavirus and Vitamin D NYT June 10
- A review of preprints, which does not look at on-line comments about about errors in a few of them.
- Apparently authored by a reporter, not a scientist
- Is Vitamin D One of the Key Elements in COVID-19 Days? June 2020, letter to editor, Turkey
- " Although there is a need for more research related to this subject, we think that supplementing vitamin D as a part of standard nutrition may be somewhat effective in providing clinical benefit"
- El rol de la vitamina D en la infección por SARS-CoV-2 Spanish June FREE PDF
- Is Vitamin D One of the Key Elements in COVID-19 Days? Letter to the editor of The journal of nutrition, health & aging - June 13
- YES, 20 references
- Vitamin D Levels and COVID-19 Susceptibility: Is there any Correlation? June 2 FREE PDF
- 4,000 IU for 2 months should help a lot. No data (yet) to support quickly fighting COVID-19 with loading doses
- Does Vitamin D play a role in the management of Covid-19 in Brazil? June 1, FREE PDF
- Recommends AGAINST 10,000 IU/day
- Supplementing with high doses of vitamin D could represent a promising alternative to prevent or treat COVID-19 infection June 1, peer reviewed ,FREE Spanish PDF
- 10,000 IU daily, 50,000 to 100,000 IU weekly
- Your Vitamin D Level Must Reach 60ng/mL Before the Second Wave Mercola June 1
- Founder of VitaminDWiki believes than 40 ng should be sufficient - based on ~40 studes
- Does vitamin D (and C) help with Covid-19 - May 2020 Germany
- Vitamin D deficiency and COVID-19 pandemic May 29 FREE PDF
- Patrick Zemb a Peter Bergmanb Carlos A.Camargo Jr c, Etienne Cavalier d, Catherine Cormier e, Marie Courbebaisse f, Bruce Hollis g, Salvatore Minisola h Stefan Pilz i, Pawel Pludowsk j, François Schmitt k, Mihnea Zdrenghea l, Jean-ClaudeSouberbielle m"
- Premorbid IL-6 levels may predict mortality from COVID-19 preprint, Morry Silberstein May 29 FREE PDF
- Vitamin D: A simpler alternative to tocilizumab for trial in COVID-19? Medical Hypotheses, Morry Silberstein July 2020 FREE PDF
- "Vitamin D lowers immune cell production of IL-6"
- "Vitamin D lowers immune cell production of IL-6"
- Does COVID-19 have a fear of hights? -(or just a fear of the increased VItamin D generated at high altitudes) WP May 31
- Cusco Peru (11,000 feet) - Vitamin D is not mentioned. yet there may be 50% more UVB-generated Vitamin D at that altiude
- "In one peer-reviewed study, published in the journal Respiratory Physiology & Neurobiology, researchers from Australia, Bolivia, Canada and Switzerland looking at epidemiological data from Bolivia, Ecuador and Tibet found populations living above 3,000 meters (9,842 feet) reported significantly lower levels of confirmed infections than their lowland counterparts"
- Reduced COVID-19 in Mexico is associated with higher UV or higher elevation (both of which are associated with higher vitamin D) preprint May 27
- Vitamin-D and COVID-19: Do Deficient Risk a Poorer Outcome? Lancet May 20
- Reviews many reports and includes the following comment by a researcher of "COVIDENCE UK, a study to investigate how diet and lifestyle factors might influence transmission of SARS-CoV-2, severity of COVID-19 symptoms, speed of recovery, and any long-term effect"
- "Despite his enthusiasm for the study, Martineau is pragmatic: “At best vitamin D deficiency will only be one of many factors involved in determining outcome of COVID-19, but it’s a problem that could be corrected safely and cheaply; there is no downside to speak of, and good reason to think there might be a benefit”.
- Should be cost-effective to use Vitamin D, Vitamin C and Curcumin to fight Covid-19 in India preprint May 22
- Fails to mention dose sizes or frequencies
- U.S. Rep. Glenn Grothman (Wisc.) wants the CDC to investigate if Vitamin D can fight COVID-19 May 22
- Letter: does vitamin D have a potential role against COVID-19 May 20
- Optimisation of Vitamin D Status for Enhanced Immuno-protection Against Covid-19 Irish Medical Journal, April 2020
- Lungs as target of COVID-19 infection: Protective common molecular mechanisms of vitamin D and melatonin as a new potential synergistic treatment Aug 2020
- both should help fight lung problems. Clinical Trials needed to see to discover dosing and benefits FREE PDF
- Mechanism of inflammatory response in associated comorbidities in COVID-19 PubMed literature Review May 12, free PDF
- "Vitamin D is highlighted as a potential therapeutic target, because in addition to acting on the immune system, it plays an important role in the control of cardiometabolic diseases"
- Vitamin D: A Low-Hanging Fruit in COVID-19? Medscape May 17
- Statements by a dozen doctors, such as Dr. Rosen: "I've been a huge skeptic from the get-go, and loudly criticized the data for doing nothing. I am surprised at myself for saying there might be some effect,"
- DOES VITAMIN D DEFICIENCY REALLY INCREASE RISK OF DEATH FROM COVID-19? Newsweek May 15
- Reviews about 10% of the items on this page
- Which fights COVID-19 more in the long-term - Vitamin D or Ultraviolet light Elemental+ May 13
- Note: Megadoses of Vitamin D can restore the immune system in days, whereas UV takes months
- Vitamin D and SARS-CoV-2 virus (Vitamin D should help) British Medical Journal May 13, 2020
- Unfortunately. the UK consensus is that 400 IU is enough to prevent or treat any health problem, including COVID-19
- The Possible Role of Vitamin D in Suppressing Cytokine Storm and Associated Mortality in COVID-19 Patients preprint April 30
- FoxNews May 7: China, France, Germany, Italy, Iran, South Korea, Spain, Switzerland, the UK and the US.
- Also reported on in Science Blogs and as The Vitamin That Reduces COVID Risk PSYBLOG May 30
- "Backman said this correlation might help explain the many mysteries surrounding COVID-19, such as why children are less likely to die. Children do not yet have a fully developed acquired immune system, which is the immune system’s second line of defense and more likely to overreact. Children primarily rely on their innate immune system,” Backman said. “This may explain why their mortality rate is lower.”
- "Not only does vitamin D enhance our innate immune systems, it also prevents our immune systems from becoming dangerously overactive"
- Role of vitamin D in pathogenesis and severity of COVID-19 infection preprint April 20
- Includes ACE2 discussion
- Perhaps solve the other pandemic: Vitamin D deficiency — to help beat Coronavirus? April 9, Joanneova - Australia 258 comments 10 days later
- Vitamin D reduces viral respiratory infections – editorial April 18, 2020 in VitaminDWiki
- Taiwan seniors have high vitamin D levels, perhaps that reduces the risk of COVID-19 outbreaks von Helden April 18
- Does Vitamin D Protect Us From Viral Infections? April 6
- Croatian, 17 references - probably does protect
- Deficient Vitamin D status might be a severe risk factor for COVID-19 DailyKos April 9
- The role of Vitamin D in the prevention of Coronavirus Disease 2019 infection and mortality April 8
- COVID-19: Vitamin D deficiency; and, death rates; are both disproportionately higher in elderly Italians, Spanish, Swedish Somali, and African Americans? April 7
- Vitamin D may be a COVID-19 Game-changer - BMJ April 6, 2020
- Vitamins C and D being considered as Coronavirus Treatments - April 7, 2020
- Preventing a COVID-19 pandemic with Vitamin D – Grant April 2020)
- COVID-19 and Vitamin D: Could We Be Missing Something Simple? Children's Health Defence April 9
- COVID-19 prompts awareness of deficiencies of Vitamin D, C and Magnesium - April 6 2020
- Vitamin D Supplements Could Reduce Risk of Influenza and COVID-19 Infection and Death - April 9, 2020
- Vitamin D should prevent COVID-19 (recommended dose takes 3 months to raise levels) - April 2020
- 97 year old woman with hypertension, diabetes, heart problems but with 75 ng of Vitamin D survived COViD-19 von Helden April 10
- Vitamin D supplementation could prevent and treat influenza, CORONAVIRUS, and pneumonia infections - March 2020
Higher levels of vitamin D result in fewer COVID-19 problems
- COVID-19 might be fought by 2 doses of Vitamin D (200,000-300,000 IU each) – Feb 2020 peer-reviewed publication
VIDEOS and PODCASTS
- High Fructose reduces Vitamin D needed to fight COVID-19 June 12, 2020 video, reviews many studies
- COMING OUT STRONGER FROM LOCKDOWN WITH VITAMIN D: A VITAMIN D MOVEMENT INITIATIVE Renu Mahtani and 3 others 13 minutes, June 5 - see her other video below.
- "It is not an optional supplement, It is a non negotiable cellular necessity" 40 ng minimum
- "Worrying about Vitamin D toxicity is like worrying about drowning when you are dying of thirst" Dr. Cannell
- Anecdote: 50,000 IU daily for 10 days given to people who live with person infected by COVID-19 ==> prevented infection
- Rhonda Patrick on Joe Rogan May 17
- Philippines: every standard deviation ==> 8 times more likely chance to have a mild
- Indonesia: only 4% of patients with sufficient vitamin D died.
- Blacks 2X as likely to die from COVID-19 than whites in England
- Daily or weekly vitamin D reduced the risk of acute respiratory infection by more than 50%
- Vitamin D normalizes ACE2 receptor levels in animals
- The Cheapest COVID-19 Therapy in the World May 24
- Doctor Mike Hansen - 2 nice videos discussing Vitamin D science and interaction with COVID-19
- COVID-19 - Do You Need to Start Getting This Vital Nutrient? Mercola May 31
- Video with Hollis, Wagner, and Baggerly of Vitamin D and COVID-19; a 2nd video of Wagner on the immune system
- Understanding—COVID-19: Actions For Mitigating Risks—Facts & Myths Sunil Wimalawansa, 90 minutes May 27
- Dr. Campbell (has daily COVID-19 videos) COVID-19 and Vitamin D May 9
- Dr. Coimbra: Vitamin D and COVID, 88 minutes in Portuguese May 1
- Click here for transcript in many languages
- COVID-19 and Vitamin D 30 minute updated May 12, excellent, Renu Mahtani
- previous version, taken down by YouTube, had 600,000 views, >2,000 comments
- for people who have not been taking any vitamin D she recommends Business World May 22
- Vitamin D 60k IU twice a week for two weeks to be followed by 60k once a week for the next six weeks.
- or Vitamin D 60k IU daily for three days to be followed by 60k weekly for the total period of two months.
- Could Vitamin D Help with COVID-19 April 9 India
- Vitamin D against Viral Infections: Antiviral Nutrition 2020 (excerpt 3) by Dr. Alex Vasquez March 6, 8 minutes
- Vitamin D for respiratory infections April 18 Rishi Desai CDC Viral Infections
- Could Vitamin D Help with COVID-19? April 6
- Vitamin D and Immunity, Lots of Evidence April 15 Dr. Campbell
- Vitamin D normalizes the ACE2, which is the attachment point for COVID-19 virus Dr. Patrick Video April 12
- Her video reviews about a dozen publications. Her description of the importance of vitamin D starts at 24:52
- Many videos by Sunil Wimalawansa April 12-- - , 5-10 minutes each
- He is starting a Randomized Controlled Trial in Sri Lanka for COVID-19 treatment by Vitamin D - not described in the videos
- 20: Vitamin D & COVID-19
- 21: How does vitamin D reduce COVID-19 infection?
- 22: What is ACE2 receptor, through which COVID-19 enters cells
- 23: How does COVID-19 kill us?
- 26: How does vitamin D reduce COVID-19 infection
- 44: What have we learned during the past 2 weeks on COVID-19?
- 45: How vitamin D help to attenuate COVID-19?
- 48: Herd immunity and the importance of testing
- 53 Reducing the severity of COVID-19 with vitamin D adequacy
- 54: Tropical countries, warm weathwer, and lower deaths due to COVID-19
- See also Video May 27 90 minute
- Dr. Eric Berg DC April 5 - one of his many vitamin D videos
- Take 100,000 IU of vitamin D, and again 3 months later to prevent COVID-19 Dr. Anderson March 22
Search Google Scholar for "COVID-19" "Vitamin D"
17,200 publications as of July 1, 2020
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