Overcoming Infections Including COVID-19, by Maintaining Circulating 25(OH)D Concentrations Above 50 ng/mL

Introduction

The original SARS-CoV-2 virus and early variants, including the Delta, predominantly affected the lower respiratory tract.¹ Whereas, its recent mutants, especially Omicron and its subvariants, are up to ten-fold more infectious than the original SARS-CoV-2 but less lethal.² In addition, a a higher percentage of children are getting affected.^3,4 However, unlike SARS-CoV-2, Omicron affects both the lower and upper airway,⁵ impacts more on children and young adults,^4,6 and presents with less severe symptomatology even in those with co-morbid conditions.⁷ Through multiple gene mutations, Omicron variants have acquired sufficient changes of amino acids in Spike protein region, allowing immune evasion—resistance to COVID vaccines.^8–10

Individuals over 70 with pre-existing chronic pulmonary, cardiac, or renal diseases, hypertension, diabetes, or obesity, and those immune-suppressed, have a higher vulnerability to developing symptomatic COVID-19, experiencing complications, and a higher risk of death.^11,12 Most of those who develop complications have a weaker immune system, primarily due to chronic hypovitaminosis D. Characteristically, those who are vulnerable have low serum 25(OH)D and angiotensin-receptor coverting enzyme-2 (ACE-2) receptor concentrations.¹³ Vitamin D sufficiency rectifies the low concentrations of ACE-2.

Meanwhile, 20 to 40% of those who recover from COVID-19 develop longer-term complications.^14,15 These manifest as diverse syndromes, predominantly related to the central nervous system,¹⁶ with a high likelihood of dormant viruses.¹⁷ This post-COVID syndrome, also known as long-COVID, affects multiple systems and is a chronic process.¹⁶ Evidence suggests that those with low circulating 25(OH)D have a higher risk of acquiring post-COVID syndrome.^14,18

Progress in Managing COVID-19

Worldwide, people experienced varied COVID-19 pandemic-related situations, such as lockdowns and curfews in some countries to no restrictions in others, yet with similar clinical outcomes. Ironically, countries with the highest vaccine-booster uptakes like the USA, UK, and Isreal had higher hospitalization and death rates and outbreaks from SARS-CoV-2 than African countries with less than 10% vaccination. Populations were subjected to unprecedented contradictory advice from leading health organizations like the World Health Organization (WHO) and quasi-experts with conflicts of interest. Such confusion eroded people’s trust and confidence, and the consequent lack of compliance hampered the development of sound national policies and effective control of local outbreaks.

In mid-2020, despite uncertainties and unknowns, the United States government initiated by then president, Mr. Trump, a ten billion-dollar COVID-support program targeted free for larger pharmaceutical companies. This unique initiative of public funding subsidy, prioritized and kick-started the designing and manufacturing of COVID-19 vaccines.¹⁹ Several pharmaceutical companies leveraged this free-funding opportunity to develop COVID vaccines and antiviral agents against SARS-CoV-2, some of which effectively reduced the risks of severe complications and deaths from the original SARS-CoV-2 (https://www.nejm.org/coronavirus) but not for Omicron or the disease spread.

Meanwhile, the United States Food and Drug Administration (FDA) and regulatory bodies in other countries approved several diagnostic tests for SARS-CoV-2, such as polymerase chain reaction (PCR) and rapid antigen test (RAT) kits.²⁰ However, many of these diagnostic tests had high false positivity and negativity, reducing their diagnostic reliability. While the combination of PCR and RAT tests has improved specificity, but their usefulness remains questionable.²¹

Despite these advances, controversies arose about ways to prevent the spread of the disease, including wearing facemasks. Meanwhile, the regulator’s refusal to approve early preventative and therapeutic options using repurposed, cost-effective therapies for COVID-19 (eg, ivermectin and vitamin D), prevented effective control of COVID-19. In addition, contradictory advice from the WHO, the Centers for Disease Control (CDC), and governments, enfosed prolonged and unnecessary lockdowns that compounded the failures of health authorities. In parallel, pharma’s refusal to share COVID vaccine technology and provide raw material to manufacture vaccines to impoverished developing countries from generating and accessing vaccines. This was likely led to increased hospitalizations and deaths in early 2021 in middle-income and developing countries and prolonge the pandemic. This perspective focuses on the use of vitamin D for prevention and as an adjunct therapy for SARS-CoV-2 infection, complications, and to overcome cytokine storms.

Bioavailability and the Role of Vitamin D

Vitamin D deficiency is widespread in most populations. However, there is a high prevalence of hypovitaminosis D among underprivileged ethnic minorities, especially in those with darker skin color who live in temperate countries, and residents in nursing homes, disability centers, and prisons.^22–24 Multiple mechanisms related to benefts from vitamin D were reported to affect all body systems, especially the immune system. Considering the complexity, vitamin D deficiency should be defined as a convoluted clinical syndrome resulting from the “inability of circulatory D₃ and 25(OH)D to enter target cells due to inadequate circulatory concentrations”, preventing its intended biological functions.

The higher the fat mass, the higher the likelihood of more sequestration of vitamin D and 25(OH)D and increased catabolism of inactive metabolites—vitamin D and 25(OH)D,²⁵ resulting in a lower bioavailability of active component, 1,25(OH)₂D.²⁶ Chronic vitamin D deficiency contributes to or causes a variety of disorders. Examples include obesity, preventing weight loss, metabolic syndrome, autoimmune disease, and increased vulnerability to infections. Others have speculated reverse causation, as with infections like SARS-CoV-2, but there is no convincing evidence to support that.^27,28

Oral Doses of Vitamin D to Raise Serum 25(OH)D Concentrations

The relationship between doses of vitamin D and the serum 25(OH)D concentrations achieved is curvilinear. Increasing doses lessen the cumulative increases of serum 25(OH)D concentration. Figure 1 illustrates the relationships between the dose of vitamin D and serum 25(OH)D concentrations achieved in several studies. It demonstrates that the higher the intake lesser the percentage increase of circulatory 25(OH)D concentrations, reflecting lesser absorption and increased catabolism. Whereas those with higher serum 25(OH)D concentrations gained proportionately smaller increases than at lower range (despite some sequestration, but lasting for a shorter period), making it safer to take higher doses.

Figure 1 Illustrates the curvilinearity of the dose-response relationships between oral vitamin D and serum 25(OH)D concentrations in 22,215 healthy volunteers. It highlights the importance of not relying upon the administered vitamin D doses but on measured serum 25(OH)D concentration to make conclusions in clinical studies. A similar but exaggerated relationship exists between obesity (body weight/fat mss or BMI) and the serum 25(OHD concentrations achieved. Notes: Reproduced with modifications, from Ekwaru JP, Zwicker JD, Holick MF, Giovannucci E, Veugelers PJ. The importance of body weight for the dose response relationship of oral vitamin D supplementation and serum 25-hydroxyvitamin D in healthy volunteers. PLoS One. 2014. 9(11): p. e111265. Open Access29.

The above illustrations do not necessarily apply to the lower and higher circulatory 25(OH)D concentrations. These are, however, confounded by the concentrations of vitamin D binding protein (i.e., bioavailability) and sequestration of circulating D₃ and 25(OH)D into fat and muscle storage sites.^27,30,31 Consequently, the doses needed to raise serum 25(OH)D concentrations are higher with conditions associated with increased vitamin D binding protein (VDBP), the rate of catabolism of vitamin D metabolites, interfering components in the circulation, and in overweight and obese.

In contrast to, as seen with iodine, iron, and calcium supplementations, due to many reasons, food-based and fortification strategies for vitamin D have not been successful in preventing vitamin D deficiency. Besides bioavailability issues of vitamin D, the doses recommended by governments are up to ten times less than that needed to achieve the intended goals. In the case of food fortification, it is necessary to use three to four times higher than recommended. Therefore, using the correct quantities of vitamin D₃ and other immunoceuticals–micronutrients³² are necessary for fortifying dairy products, breakfast cereals, and other staple foods is a cost-effective strategy for preventing vitamin D micronutrient deficiencies.

Targeted supplementation or food fortifications are particularly relevant and effective for ethnic minorities with darker skin color, those in residential facilities, the elderly, and those with comorbidities.^22,33 As mentioned, the currently recommended amounts for food fortification globally, are insufficient: these should be increased by two-to-four-fold to achieve meaningful population-based intakes for disease prevention and improved clinical outcomes. Tangible increases and maintenance of serum 25(OH)D concentrations as mentioned above will significantly benefit vulnerable populations.

The Importance of Vitamin D on the Immune System

Formation of Vitamin D Metabolites and Their Significance

Vitamin D is generated from 7-dehydrocholesterol following exposure to solar UVB rays in the skin.^34,35 Skin-generated D₃, dietary (D₂ and D₃), and supplemental vitamin D₃ are primarily hydroxylated in mitochondria in the liver by the enzyme CYP2R1 to form 25(OH)D. Peripheral target cells, like immune cells, also have the 25-hydroxylase enzyme, which converts vitamin D to 25(OH)D. However, compared to the liver, the capacity is small.³⁶ Most vitamin D and 25(OH)D in the circulation are bound to VDBP and transported to the liver, renal tubular cells, storage tissues, and peripheral target tissue cells. In these cells, the enzyme CYP27B1 further hydroxylates 25(OH)D to form its most active metabolite, calcitriol [1,25(OH)₂D].³⁶

In proximal renal tubular cells, parathyroid cells, fat and muscle cells, vitamin D, and 25(OH)D are transported via an active megalin-cubilin-based endocytosis system.³⁷ This functional entry is essential for actively transporting both vitamin D and 25(OH)D from the circulation into fat, muscle, and renal tubular cells for either 1α-hydroxylation and/or for storage process. For example, renal tubular cells generate the hormonal form of calcitriol for its endocrine functions,^38,39 and muscle and fat cells sequestrate for storage.³⁷ The three most standard forms of vitamin D compounds and their circulatory concentrations are illustrated in Figure 2.

Figure 2 The molecular structures of three clinically relevant vitamin D metabolites, vitamin D, 25(OH)D, and 1.25(OH)2D, involved in the immune system, their circulatory half-lives, mean circulating concentrations, and respective cytochrome P450 (CYP) hydroxylating enzymes are illustrated. Most of the 25-hydroxylations of D2 and D3 occur in hepatocytes to form calcifediol (calcidiol). In contrast, calcitriol formed in the renal tubular cells and in peripheral target tissue cells as illustrated (note: serum concentration of calcitriol is about 900-fold less than calcifediol). Notes: Adapted from Wimalawansa, (S)J. Skeletal benefits, endocrine functions, and toxicity of vitamin D. J Endocrinol Diab, 2016. 3(3): p. 1–540.

In contrast, many other peripheral target cells do not have an active transportation system. Since the concentration of hormonal form—circulatory calcitriol is in pmol [in contrast to 25(OH)D and D₃ concentrations in nmol/l], thus, it is incapable of diffusing into peripheral target cells accross a concentration gradient. Therefore, targets like immune cells rely on the mentioned two precursor molecules—free D₃ and 25(OH)D in a concentration-dependent diffusion from the circulation and endocytosis of VDBP-bound components⁴¹ (see the section on genomic effects of calcitriol for more details). Whereas the musculoskeletal, calcium/phosphate metabolism, and parathyroid functions depend on hormonal calcitriol synthesized in renal tubular cells and secreted into the circulation, in conjuction with magnesium.

The circulatory 25(OH)D concentration above 15 ng/mL was reported sufficient for entry into renal tubular and parathyroid cells for 1α-hydroxylation of 25(OH)D to form calcitriol.^42,43 This is compatible with its hormonal functions on the musculoskeletal system.⁴⁴ In contrast, peripheral target cells like immune cells require serum 25(OH)D concentrations over 50 ng/mL (also a similar concentration of D₃) to enter immune cells to generate 1.25(OH)₂D intracellularly for their autocrine and paracrine signaling.^45–48

Therefore, a regular supply of vitamin D is necessary to maintain an adequate and stable circulatory D₃ and serum 25(OH)D concentrations above 50 ng/mL. Transfer of these precursors from the circulation into immune cells is vital for intracrine/autocrine and paracrine signaling, which is necessary for robust immune functions.^48–51 The circulatory half-life of vitamin D is about one day. However, following its hydroxylation into 25(OH)D, the half-life increased to 12 to 21 days, based on the individual’s vitamin D status. This is another scientific reason why a regular vitamin D supply is necessary to provide peripheral target cell activity with substrates.

Despite vast amounts of published data, many governments websites, such as NIH, NICE and SCAN, etc., and government-appointed bodies in UK and USA,^42,52 continue to recommend outdated vitamin D doses, between 400 and 800 IU/day [such as, Vitamin D - Health Professional Fact Sheet (nih.gov), last updated on April 28, 2022] that are unhelpful to the public.⁵³ These trivial doses fail to raise serum 25(OH)D concentrations meaningfully and have no tangible benefit on extra-renal targets like the immune cells and human physiological systems.

A 70 kg (non-obese), vitamin D sufficient or insufficient adult could raise their circulatory 25(OH)D to a steady above 50 ng/mL by consuming approximately 5000 IU/day (4000 to 7000 IU/day). However, in vitamin D deficiency, achieving this recommended therapeutic level would take a few months.⁴⁸ The latter is necessary to elicit robust immune responses.^48,54 Older adults, overweight and obese, those on anti-epileptic or retroviral therapies, or those with gastrointestinal absorption problems, require two to four times higher doses of vitamin D to maintain the mentioned 25(OH)D concentration.

In contrast to taking a few months to increase circulating 25(OH)D concentration, an upfront loading or a bolus dose administration of vitamin D can raise the circulatory 25(OH)D concentrations within three to four days.^36,55 However, in acutely ill patients, as in ICUs, increasing circulating 25(OH)D could take more than a week. Therefore, administering vitamin D, even with high doses, is unlikely to benefit severely ill patients in less than a week.⁴⁸ Because of this, such approaches should not be used in clinical studies or practice. Maintaining adequate serum D₃ and/or 25(OH)D concentrations provide the basis to enhance immune cell activity and reduce the risks of infections, especially from viral respiratory illnesses like COVID-19.⁵⁶

Sun Exposure Stimulates the Immune System

Casual sun exposure (or application of sunscreens before sun exposure) is insufficient to generate the daily requirement of vitamin D. On the other hand, daily sun exposure between 45 to 60 minutes with one-third of the skin surface open to direct summer-like sunlight, between 10.30 AM and 1.30 PM, can generate meaningful amounts of vitamin D: the quantity generated could vary between 2000 and 10,000 IU, dependent on the type of exposure, age, and the skin darkness—the melanin contents of the skin.

For some, exposure to the sun with 10-minute intervals is more practical. Times of the day outside mentioned above, early spring, late fall, and winter periods, the application of sunscreens prematurely, indoor sun exposure throug windoors, and for those with scarred skin (e.g., following burns) will not generate sufficient D₃ to raise vitamin D and 25(OH)D in the circulation, necessary to contribute to better immunity.^50,51

When one’s shadow is shorter than the height (a pratical guide) is the optimum time of the day for sun exposure. During this period, UVB rays reach the earth at an acute angle (zenith angle of sunrays), providing better skin penetration to generate vitamin D. The goal is to maintain individuals circulating 25(OH)D concentration above 50 ng/mL for better health, via sun exposure and/or vitamin D supplementation.^36–39,48

During viral epidemics, as with the current COVID-19 pandemic, it is recommended that non-obese adults (60 to 70 kg) take vitamin D supplementation between 4000 and 7000 IU/day or 50,000 IU once a week (preferably every 10th day).^50,51 While persons with bodyweight less than 60 kg could take lesser amounts (eg, <4000 IU daily, 25,000 IU once a week, or 50,000 IU once in two weeks), the obese and the elderly need two to four times more than the doses mentioned above. To raise circulatory D₃ and 25(OH)D concentrations within a few days for disease prevention and to reduce complications, one could use upfront loading or a bolus dose of vitamin D₃ between 100,000 and 400,000 IU.^1,54,57

Genomic Effects of Calcitriol

Calcitriol circulates in the blood in a concentration approximately 900-time less than D₃ and 25(OH)D (pmol vs nmol. Therefore, in the abscence of an energy-dependent mechanism, the concentration of circulatory calcitriol is too low (approximately 0.045 ng/mL) to enter immune cells. Therefore, hardly any hormonal form of calcitriol or orally administered calcitriol enters immune cells; consequently, there are no measurable effects on immunity. Besides its adverse effects from pharmacological doses of calcitriol, this is another reason why calcitriol should not administer as a therapeutic agent to overcome infections. The estimated intracellular concentration of calcitriol necessary for immune cells’ autocrine and paracrine signaling is approximately 1.0 ng/mL. This is more than 20 times higher than the average circulatory calcitriol concentration.^58,59

Intracellular calcitriol interacts with its receptors and migrates into the nucleus. These calcitriol/receptor complexes regulate the transcription of over 1000 genes. These enhance the transcription and the release of anti-inflammatory and antioxidant cytokines and suppresses the expression of inflammatory cytokines.^47,60–63 In addition, calcitriol initiates the synthesis of neutralizing antibodies and stabilizes epithelial and endothelial cells and gap-junctions, thus minimizing pathogen spread and fluid leakage into soft tissues.^59,64–66

Most peripheral target tissue cell functions, including immune responses, depending on locally synthesized calcitriol (eg, within immune cells) for their biological activity. Longer-term maintenance of circulating 25(OH)D concentrations above 50 ng/mL allows a constent supply of sufficient concentration of D₃ and calcifediol diffuse and endocytose into immune cells. This intracellularly generated calcitriol in target cells initiates intracrine/autocrine and paracrine signaling and related physiological functions.

As descrbed abive, most peripheral target cell-derived, end-organ-directed vitamin D functions are reliant on generating calcitriol intracellularly, as in the case with immune cells. Considering its broader benefits, lack of adverse effects, wide availability, and economical to use, healthcare workers should consider using vitamin D as a primary line of therapy for disease prevention and treatment and use it as an adjunct therapy to prevent infections/ sepsis—infections like COVID-19.^49,54,67,68

Vitamin D deficiency has been associated with many adverse clinical outcomes, such as increased risks of septicemia, and COVID-19-associated complications and the severity of infections.⁶⁹ Many studies have reported the importance of maintaining serum 25(OH)D concentration above 50 ng/mL, which is necessary to stimulate the immune system to overcome infections.^47,63,70 Figure 3 ilustrates summary data by Borsche L, et al,⁷⁰ from seven hospital studies. It showed a median baseline vitamin D₃ level of 23.2 ng/mL (range, 14.5–30.9 ng/mL) at their hospital admissions. These data are plotted with clinical outcomes (mortality coefficients), after correcting patient characteristics and combining data points. In Figure 3, the regression line of combined data crossed the zero 25(OH)D concentrations, baseline approximately 50 ng/mL (range 45–55 ng/mL).

Figure 3 Illustrates the Scatter plot and regressions of the individual and combined datasets. The data from seven hospital studies were plotted after correcting for patient characteristics. The correlation for the combined datasets intersects the axis at approximately 50 ng/mL, which suggests that this vitamin D3 blood level likely prevent excess mortality. Notes: Adapted from Borsche L, Glauner B, von Mendel J. COVID-19 mortality risk correlates inversely with vitamin D3 Status, and a mortality rate close to zero could theoretically be achieved at 50 ng/mL 25(OH)D3: results of a systematic review and meta-analysis. Nutrients 2021;13(10):3596. Open Access.70

These data are consistent with the circulatory vitamin D₃ concentrations of unsupplemented traditional hunter-gatherers reported to be between 45–50 ng/mL.^59,71,72 In Borsche L, et al study, mathematical regressions suggested that the minimum effective serum 25(OH)D concentrations is about 50 ng/mL (125 nmol/L).⁷⁰ Taken together, this and other data^59,71,72 suggest that when serum 25(OHD concentration is maintained above 50 ng/mL provides optimal immune protection against infections,^47,48,63 which would save lives from pathogenic microbes.

The above conclusions are further supported by a larger veteran administration study evaluating approximately two million patients, with 351,999 COVID-related deaths through 2020. Those who were vitamin D supplemented had a significant 28% reduction in symptomatic COVID-19 and a 33% decrease in 30-day mortality from COVID-19, compared to controls.⁷³ In this database, there were 343,094 cases and 14,981 known deaths from COVID, up to February 2021, with a Hazard Ratio (HR) = 0.67; 95% CI 0.59, 0.75. The authors estimated that proper doses of vitamin D would have reduced 69,000 cases and saved 4,900 lives of veterans from COVID-19.

As illustrated above, clinical studies overwhelmingly support the beneficial effects of vitamin D supplementation in reducing SARS-CoV-2 risk and preventing severe complications and deaths.^74–76 As illustrated in Figures 2 and 3, a robust immune system secondary to having a sustained serum 25(OH)D concentration above 50 ng/mL (125 nmol/L) minimizes infections to background levels of around 2.5%.⁷⁷

Immune Modulation by Calcitriol Generated Within Immune Cells

Vitamin D has profound, beneficial effects on the immune system’s activation and multiple mechanisms for stimulating the body’s immune defenses.^49,78 Higher circulatory D and 25(OH)D concentrations are associated with better immune functions and lesser inflammatory and oxidative activities.⁷⁹ These include the production of cathelicidin and defensins, which neutralize microbes, reduce microbial replication, prevent viruses from becoming attached to epithelial cells, and increase the rate of virus elimination.^49,80 A summary of the effects and the calcitriol-driven pathways of CD4—derived Th-immune cells are illustrated in Figure 4.

Figure 4 Illustrates the intracrine/autocrine pathways of immune modulation following calcitriol’s interactions with its receptors (CTR) in immune cells (eg, CD4+ T cells). Illustrates the effects of vitamin D (calcitriol) on immune cells, Th1, Th2, Th17, and Treg cells, and balances inflammation and anti-inflammatory in immune functions. The presence of adequate intracellular production of calcitriol suppresses the excess inflammatory reactions by immune cells while maintaining a healthy balance between the expression of inflammatory cytokines, such as IL-2, −8, −12, −17, −22, and TNFα, and the anti-inflammatory cytokines IL-1, −4, −5, −6, −10. Notes: Adapted from Bishop, (E) et al, Vitamin D and immune regulation: antibacterial, antiviral, anti-inflammatory.JBMR Plus. 2020;5(1):e10405. Open Access81.

Figure 4 above illustrates that the Th1 (inflammatory) phenomenon further accentuates inflammation and autoantibody formation but promotes the lymphocytes’ switch to the Th2 and Treg cells (anti-inflammatory) phenotype in response to intracellular intracrine signaling by calcitriol. With compliments, it modulates cell behavior, enables control of inflammation, and enhances autocrine functions. COVID-19 prevents the transformation of pro-inflammatory Th1 lymphocytes and Th17 to the anti-inflammatory Th2 and Treg status, maintaining their inflammatory status.^47,60,61,63 This also impairs the generation of protective antibodies by B-cells. In response to infections, the innate immune system releases cytokines to combat invading pathogens.

Figure 5 Coinciding of the flu season with the population’s lowest 25(OH)D concentration during the year—winter in those who live in the northern hemisphere. Mean values of retrospective data collected over six years are presented.

In contrast, maintaining circulatory 25(OH)D concentrations above 50 ng/mL facilitate favorable modulation of innate and adaptive immune responses. In addition, it reduces the expression of pro-inflammatory cytokines such as TNFα and IFNγ by Th1 cells, aiding the reduction of the hyper-immune status. Therefore, it is not surprising that vitamin D sufficiency reduces vaccination-associated adverse effects from viral Spike protein, autoimmune reactions, and increase vaccine’s efficacy. This is partly by preventing over-activations of the renin-angiotensin, controlling inflammation, and providing a better antibody response following vaccination.^76,82

Vitamin D, Viruses, and the Respiratory System

Hypovitaminosis D impairs immunity and increases vulnerability, particularly to respiratory viral infections,^{54,68,83–86} and increases the severity of infections.^87,88 The highest incidences and the severity of respiratory tract illnesses such as colds and influenza occur during winter when people’s serum 25(OH)D concentrations are the lowest.^89–91 All coronaviral diseases also exacerbate during the winter with the need for hospitalization.^92–94 Since the countries far from the equator have a higher prevalence of vitamin D deficiency, they have a higher incidence of winter-associated respiratory viral diseases (Figure 5).

Without effective UV rays, particularly in cold and dry climatic conditions, respiratory viruses remain infectious longer outside human bodies.^56,95,96 Despite these, during viral epidemics, maintaining a serum 25(OH)D concentration in individuals and communities greater than 50 ng/mL⁴⁵ would significantly reduce the risk of symptomatic infections, complications, and deaths.^68,97,98 This strategy is highly cost-effective. Children and younger adults have stronger innate immunity and cell-mediated acquired immunity (ie, the second line of defense) than the elderly, making them less vulnerable to developing complications from viral infections, including SARS-CoV-2, unless they are severely vitamin D deficiency. Therefore, vaccination cannot be justified in healthy children and younger males because of unacceptably high rates of adverse effects but minimum benefits.

Younger children with vitamin D deficiency are at a higher risk for developing symptomatic colds, partly due to close social interaction in schools and childcare centers. Children with severe vitamin D deficiency are at high risk for developing life-threatening conditions like Kawasaki-like syndrome, multi-system inflammatory syndrome, and COVID-19.⁹⁹

Associations Between Hypovitaminosis D and Known Risk Factors for COVID-19 Severity

Epidemiological, observational, and randomized controlled clinical studies (RCTs) have reported evidence of the protective effects of vitamin D against several common diseases, such as obesity, diabetes mellitus, asthma, and autoimmune diseases.^100–103 Different mechanisms have been proposed to explain the associations between hypovitaminosis D and the above disorders.^100,102

Common factors leading to vitamin D deficiency include insufficient exposure to sunlight due to predominant indoor work, sun avoidance behavior, impairment of the ability of the skin to generate vitamin D (eg, aging, scarred skin), decreased intestinal absorption of fat (impairing the absorption of fat soluble vitamins), impaired hydroxylation of D into 25(OH)D in the liver and to 1.25(OH)₂D in renal tubular cells and peripheral target cells. Supporting the above data, many studies reported that vitamin D supplementation has beneficial effects in mentioned groups.^101,102

Hypovitaminosis D Increases the Severity of Complications and Deaths

In most community-dwelling individuals, serum 25(OH)D concentrations range between 15 and 30 ng/mL;^104,105 thus, they are less protected from viral infections. Per person basis, countries with a higher percentage of people with vitamin D deficiency have higher healthcare costs. Their risks can be mitigated cost-effectively by maintaining the population serum 25(OH)D concentrations above 50 ng/mL, to sustain robust systems. Individuals with the mentioned therapeutic circulatory 25(OH)D concentrations have reduced incidence, severity, and complications from COVID-19.^50,106–108 Despite the availability of vast scientific literature, no government acknowledges or has implemented proactive approaches or issued guidelines on the above fundamentals to prevent infections and deaths from COVID-19 or other infections.

Therefore, in sepsis and acute infections like COVID-19, physicians need to take prompt, proactive actions to raise serum 25(OH)D concentration in their patients to activate their immune systems.^76,109,110 Intracellularly generated calcitriol in immune cells interacts with its receptor, enters the nucleus, and interacts with genes to modulate genes. These genomic interactions enhance the expression of immune protective functions, such as generation of antimicrobial peptides and antibodies, stimulate immune cells to destroy microbes, and decrease cytokines that cause inflammation and oxidation. Figure 6 illustrates pathways that calcitriol initiates its intracrine/autocrine and paracrine signaling in immune cells that cause immune protective actions.

Figure 6 When vitamin D and 25(OH)D enter peripheral target cells, like immune cells, these compounds are hydroxylated into 1.25(OH)2D (calcitriol) via abundant intracellular CYP2R1 and CYP27B1 enzymes.111 Immune cells also have ample CYP27B1 to covert 25(OH)D to,25(OH)2D and synthesize calcitriol receptors (CTR). The calcitriol-CTR complex translocates into the nucleus to modulate over 1000 biologically crucial genes after the interaction of calcitriol with CTR. Some expressed genes include anti-inflammatory and oxidant cytokines, antimicrobial peptides, antibodies, etc. The figure illustrates simplified calcitriol-mediated mechanistic pathways, leading to immune cells’ autocrine and paracrine signaling processes. Note that the renal tubular cell-derived hormonal form of calcitriol (the last row) has little or no effect on immune cells.

Prevention of Complications from Infections via Vitamin D

A cascade of events starts once calcitriol binds to its receptors (CTRs) in the cell cytosol. It migrates to the nucleus and combines with retinoid receptor RXR, where the complex interacts with target genes to modulate their expression and direct autocrine and paracrine signaling. In addition, the interactions of calcitriol/CTR complexes modulate the expression of specific cofactors and histones to expose upstream DNA response elements and up- or down-regulation of target genes.¹¹² These interactions and co-factors need adequate intracellular concentrations of magnesium and other micronutrient—components. As described below, the signaling modulates the immune system with obligatory biological and physiological actions crucial to combat pathogens and prevent autoimmunity.^46,47

Vitamin D Signaling Positively Modulates the Immune System

Immune modulation is initiated through the activation of the CTR pathway. Such activation down-regulates the expression of inflammatory cytokines and the oxidative stress pathways, while upregulating anti-inflammatory cytokines, activates immune cells—T and B cells, the macrophage, and dendritic cells—and enhances the production of antimicrobial peptides, facilitating infection control.¹¹³

Low pre-pandemic (i.e., prior to getting infected) vitamin D status is inversely related to increased risks of COVID-19 and its severity and complications^79,114 and other manifestations and associations between vitamin D status and COVID-19. Low serum 25(OH)D concentration on hospital admission could predict the need for intensive care use and correlate with higher COVID-related complications and deaths.^{61,79,115–117} In contrast, higher serum 25(OH)D concentrations lessen the severity of SARS-CoV-2 infections and reduce deaths by several folds (Figure 7).¹¹⁸

Figure 7 Post-estimation simulation of 25(OH)D concentrations using 15 and 50 ng/mL as the cut-offs predict an excess of four-fold higher mortality from COVID-19. Data were adjusted for age, sex, BMI, C-reactive protein, D-dimer, oxygen saturation, and chronic diseases, such as type 2 diabetes and chronic kidney disease. Notes: Adapted from Vanegas-Cedillo PE, Bello-Chavolla OY, Ramírez-Pedraza N et al. Serum vitamin D levels are associated with Iincreased COVID-19 severity and mortality independent of whole-body and visceral adiposity. Front Nutr. 2022;9:813,485118.

Not only does vitamin D improve immune functions,¹¹⁹ but it also substantially reduces the risk of viral and bacterial infections^118,120,121 and the risk of complications and deaths from COVID-19.¹¹⁸ Natural immunity and the protection derived from immunization could substantially reduce the viral spread and complications from COVID-19 and possibly could have eradicated the disease. However, no health administration used this low-cost strategy to overcome the pandemic. Despite the solid evidence demonstrating that vitamin D fulfiled the Bradford Hill criteria for causality, leading health authorities and governments continue to marginalize early therapies like vitamin D and ivermectin.

Studies reported that those who are PCR-positive for SARS-CoV-2 had a higher prevalence of severe hypovitaminosis D (i.e., below 12 ng/mL; p=0.004) compared with those with serum 25(OH)D concentrations higher than 24 ng/mL.¹²² Besides, the group with severe vitamin D deficiency had higher rates of complications and deaths.⁷⁹ Severe vitamin D deficiency is also associated with hyperinflammatory, hyper-reactive immune statuses¹²³ and cytokine storms,^124,125 causing acute respiratory distress syndrome (ARDS). It also increases the incidence and severity of autoimmune diseases.^126–128 While vitamin D₃ does not prevent a person from contracting COVID-19, it will significantly reduce symptomatic disease and complications,¹²⁹ and reduce deaths by 14-fold,⁷⁹ and the development of post-COVID syndrome.

Endothelial and Epithelial Barriers

In addition to increasing the expression of the antimicrobial peptides and promoting anti-infective functions of white blood cells and natural killer cells,¹³⁰ calcitriol stabilizes tight cell junctions in respiratory epithelia and vascular endothelia through non-canonical pathways. Vitamin D₃ improves epithelial and endothelial stability and reduces membrane porosity and vascular leak, independent of the calcitriol/CTR genomic path.¹³¹ These actions prevent fluid leakage, viral entry, and dissemination^132,133 and enhance macrophage-mediated destruction of microbes.⁶⁶

Besides, vitamin D deficiency impairs endothelial barriers leading to vascular fluid leakage into soft tissues and worsening infection.¹³¹ Similarly, the weakening of gap junctions and epithelial barriers, especially in the lung and blood-brain barrier, leads to the infiltration of viruses and the propagation of microbes.¹³⁴ These non-transcriptional mechanisms improve controlling infections, reduce inflammation, and prevent endothelial cells and epithelial cell damage-related embolization.

Mechanisms by Which Vitamin D Protects Cells from COVID-19

Receptors for angiotensin-converting enzyme-2 (ACE-2) and CD209L are expressed in most human tissue, inlcuding endothelial cells, pulmonary epithelial cells, the gastrointestinal tract, the brain, adipose tissue, the kidney, and the liver.^135,136 A higher concentration of ACE-2 receptors and CD209L is expressed in endothelial cells and pulmonary epithelial cells, making them a potential target for coronaviral entry. Replication of the SARS-CoV-2 virus damages endothelial cells, primarily via Spike proteins, causing microvascular thrombosis, myocarditis, and embolization¹³⁷ in COVID-19.^138,139

Similar adverse outcomes have been reported following vaccines due to Spike protein-related adverse interactions.^140,141 In either case, these can cause epithelial cell and lung damage, altering clotting mechanisms, impairing gas exchange, and causing hypoxia, viremia, effusion, pneumonia, and death. Therefore, stabilizing endothelial and epithelial cells should be investigated as a therapeutic target for preventing complications from SARS-CoV-2, in conjunction with vitamin D and magnesium adequacy.¹⁴²

Once SARS-CoV-2 enters human cells,¹⁴³ it downregulates ACE-2 receptors. Consequently, reduce the catabolism and hence accumulation of vasoconstrictor peptide, angiotensin-II.¹³⁷ The build-up of angiotensin-II in the circulation further stimulates the expression and release of inflammatory cytokines, increasing inflammation and oxidative stress, and cytokine storms.¹⁴⁴ Besides, excess angiotensin-II opposes the vasodilatory effects of angiotensin_(1–7), thus, increasing intravascular pressure causing pulmonary hypertension and edema, and increasing the risk of developing cytokine storm and ARDS.

Sufficient Vitamin D Doses for Improved Clinical Endpoints

Calcitriol is also involved in other regulatory and physiologic homeostatic activities. This depends on the adequate availability of D₃ and 25(OH)D steady concentrations in circulation.^46,47,70,128 Most importantly, intracellularly generated calcitriol in immune cells, through their intracrine mechanisms, reduces the risks of cytokine storms and acute viral-mediated lung injury in persons with COVID-19.^145,146

Population-wide vitamin D supplementation could prevent generalized inflammation and symptomatic disease, including cytokine storm,^138,139 and significanlty lessen the need for hospitalization. It reduces the severity and deaths from SARS-CoV-2 by more than 50%.¹⁴⁷ Therefore, considering the minimal costs and wide availability, lack of adverse effects at the recommended doses, and vitamin D intervention in the community and hospital admissions is a highly cost-effective.⁵¹

Since hypovitaminosis D significantly increases the risks of COVID-19-related complications, it is logical to raise individuals and the population’s serum 25(OH)D concentration to greater than 50 ng/mL. This can be achieved through adequate daily sun exposure and vitamin D supplementation. This level of vitamin D sufficiency will maintain a robust immune system, reduce the severity of infections, and improve associated health conditions.^1,76,148

Vitamin D on Renin-Angiotensin-Aldosterone Hormonal (RAS) Axis

Activating the renin-angiotensin-aldosterone axis (RAS) (especially production of renin and ACE1), leads to excess production of angiotensin-II, enhances the production of cytokines, worsens morbidity and mortality associated with sepsis-induced lung damage.^143,149 The actions related to RAS are intimately involved with the immune system. Excess angiotensin-II enhances inflammation and oxidative stress. In contrast, sufficient vitamin D suppresses RAS, increases ACE-2 enzyme and reduces angiotensin-II; thus, it reduces inflammation and oxidative stress and improves clinical outcomes from infections.

Coronaviral infections independently increase RAS activity that further propagates SARS-CoV-2 infection and survival in the body. Calcitriol regulates the RAS activity primarily by suppressing the expression of renin, the rate-limiting step of synthesis of angiotensin-II, working through cyclic AMP (cAMP)-dependent PKA signaling. Calcitriol also increases ACE-2 and, therefore, angiotensin_(1–7), reduces angiotensin-II concentration, and blocks the formation of the CRE-CREB-CBP complex.¹⁵⁰ These actions keep the RAS activity under control. In comparison, increased RAS activity in vitamin D deficiency, worsens complications and deaths from coronaviruses like SARS-CoV-2.¹⁵¹ In summary hypovitaminosis D negatively affects the RAS system, leading to complications, need for hospitalization, and increased risks of death.⁸¹

Hypovitaminosis D and low ACE-2 concentrations significantly increase symptomatic SARS-CoV-2-infections and synergistically increase vulnerability, severe complications, and higher mortality.^79,147,152 Coronaviral infections reduces ACE-2 concentration indirectly (as a viruses’ survival mechanism) via reducing the synthesis of ACE-2 and directly by utilization of ACE-2 in circulation. Prevention of catabolism of Angiotensin-II due to low ACE-2 enzyme creates multiple adverse effects. Therefore, via several mechanisms, vitamin D defiiency increases the vulnerability to SARS-CoV-2, its complications, and death. Whether higher concentrations of angiotensin II modulate, the cell-membrane-bound ACE-2 concentrations are unclear.

Complementary Immune Mechanisms

Low circulating D₃ and 25(OH)D cause a deficiency of the substrate, for the intracellular generation of calcitriol within immune cells. This impairs intracrine and paracrine signaling, thus, weakening the immune system.^153,154 The latter leads to overt pro-inflammatory responses, as seen in cytokine storms in COVID-19 and other severe infections. Children with serum 25(OH)D concentrations less than 10 ng/mL (i.e., severe vitamin D deficiency) infected with SARS-CoV-2, through similar mechanisms, causes Kawasaki-like disease and/or multi-system inflammatory syndrome that is associated with high mortality.^155–157

The presence of adequate D₃ and 25(OH)D in the circulation enables peripheral target cells to increase the synthesis of calcitriol and the expression of 1α-hydroxylase (CYP27B1) and 25-hydroxylase (CYP2R1) enzymes and the CTR (also known as VDR). This creates a conducive setting to synthesize both calcitriol and CTR within these cells. In contrast, vitamin D deficiency reduces the intracellular generation of calcitriol and CTR in immune cells, thus disrupting vital autocrine and paracrine signaling and weakening the innate and adaptive immune responses.

COVID Complications are Enhanced by Weakened Immunity

Weakened adaptive immune responses reduce the generation of antibodies and the effectiveness of memory cells and macrophages and impair the cytotoxic action of immune/killer cells against viruses. Consequently, exaggerated adverse responses could occur in hypovitaminosis D, following SARS-CoV-2 infection-associated over-activity of RAS and following COVID-immunization. This scenario diminishes the ability to form neutralizing antibodies and impairs the adaptive immune response. Consequently, adverse events are intensified in those with severe vitamin D deficiency following SARS-CoV-2 infection and immunization, including overt inflammation, autoimmune reactions, and pathological oxidative stress leading to systemic complications.

In addition, immune dysregulation further exacerbates the expression of pro-inflammatory cytokines and autoimmune reactions, host cell destruction, and vulnerability to hyper-inflammatory syndromes. This vicious cycle damages pulmonary epithelial cells causing hypoxia, fluid extravasation, pneumonia, and endothelial damage leading to coagulopathies, thrombocytopenia, and micro-embolisms.¹⁵⁸ These data illustrate the importance of vitamin D adequacy for preventing infection-related complications.

The deaths caused by SARS-CoV-2 are attributed to, among others, cytokine-driven storms causing ARDS,^135,159,160 primarily occurring in those with severe vitamin D deficiency (< 10 ng/mL). The latter initiates a vicious cycle, RAS-driven large quantities of angiotensin-II and expressing excessive amounts of inflammatory cytokines, causing tissue damage.^135,136 Such incidences and complications are highest among those with severe vitamin D deficiency.¹⁴⁷

The widespread inflammation and oxidative stress injure the pulmonary epithelial and vascular endothelial cells and their basement membranes. The endothelial abnormalities lead to micro-thrombosis and embolization, intravascular thrombosis, and dissemination of viruses and fluid leakage into soft tissues, including the lungs and brain.^138,139 Figure 8 illustrates broader pathways causing a vicious cycle by SARS-CoV-2 infection, and the sites and locations where vitamin D is likely to have favorable immune mechanisms to overcome infections like COVID-19.⁸¹ 8B illustrates the site of impacts from active vitamin D (calcitriol) in preventing and minimizing complications and adverse clinical outcomes from SARS-CoV-2.

Figure 8 (A) Summary of the pathological process initiated by SARS-CoV-2 viral infection leading to death. It illustrates the potential entry sites into the body via epithelial cells and mucous membranes. It also illustrates the renin-angiotensin axis (RAS) involvement and the development of acute respiratory distress syndrome and cardiovascular abnormalities, increasing the risks of death. (B) Illustrates the sites of interference of the negative vicious cycle initiated by the SARS-CoV-2 virus. Mechanistic sites that disrupt and stop the progression of the vicious cycle are shown in green crosses—interfering with the cellular entry of the virus, viral replication, down-regulation of the RAS, and preventing cytokine storm.

Correlation Between Vitamin D Status and COVID-19 Clinical Outcomes

The age-specific serum 25(OH)D concentrations in persons with COVID-19 in Italy, Spain, and France have revealed that severe complications and higher deaths were associated with those with severe vitamin D deficiency (<12 ng/mL).⁷⁹ The highest percentage ofdeaths occured in those with the lowest serum 25(OH)D concentration (e.g., less than 10 ng/mL), especially among those who are older than 70 years) with comorbidities. This groups had the highest number of severe complications and death.^57,161

Systematic reviews and meta-analyses have reported an inverse relationship between serum 25(OH)D concentrations (also supplemented vitamin D doses) and rates of symptomatic SARS-CoV-2 infections, severity, and mortality.^101,102,162 D’Ecclesiis et al¹⁶³ and other researchers concluded that vitamin D supplementation reduces the risk of severity and mortality by more than 50%. Larger daily doses and hence higher serum 25(OH)D concentrations are significantly associated with better clinical outcomes from SARS-CoV-2 infection:^{101,102,164,165} they could have been protected with vitamin D supplementation, as also illustrated in Figure 9.

Figure 9 Forest plot of risk estimates of severity for low vs high vitamin D levels. The association between serum 25(OH)D concentration and the severity of COVID-19 were evaluated regarding ICU admission (ventilated or intubated). Serum 25(OH)D was measured on admission to the hospital. Data demonstrated, on average, doubling of the risk of severity in subjects with hypovitaminosis D (SRR = 2.38, 95% CI: 1.53–3.70). Notes: Adapted from D’Ecclesiis O, Gavioli C, Martinoli C et al. Vitamin D and SARS-CoV2 infection, severity and mortality: A systematic review and meta-analysis.PLoS One. 2022; 17(7): e0268396. Open Access163.

Figure 9 is one of four graphs from D’Ecclesiis et al, which demonstrated that subjects with low serum 25(OH)D concentrations had doubled the risk of SARS-CoV-2 infection, higher severity and mortality from COVID-19, compared to a group with higher vitamin D, as reported previously by others.^67,166–168

COVID-19 is a Pandemic of Hypovitaminosis D

COVID-19 has become a pandemic among those with severe vitamin D deficiency, which causes the weakening of the immune systems, rendering them susceptible to symptomatic disease, complications, and death. This is also likely to be the case with other infectious epidemics. In these situations, data supports maintaining serum 25(OH)D concentrations above 50 ng/mL (125 nmol/L), significantly reducing infections and complications from viral disease, especially from respiratory viruses.^97,169 Beneficial effects from vitamin D supplementation are most visible in those with severe hypovitaminosis D.¹⁷⁰ No additional benefits are expected in those who are vitamin D sufficient.

In addition to sun exposure and vitamin D supplementation, food fortification programs are economical and practical for rectifying micronutrient efficiencies in specific groups and communities.³² It is particularly cost-effective when such measures target deficient populations and ethnic minority groups. Examples of similar successful targeted nutrient approaches include iodine supplementation to prevent goiters and folic acid and iron supplements during pregnancy.

The addition of other immunoceuticals–micronutrient supplementation, such as vitamins A, C, and K₂, magnesium, zinc, and selenium, essential fatty acids (eg, omega-3), nitric oxide donors, and resveratrol are likely to have a significant impact on the population, aiding to maintain a more robust immune system. Such cost-effective strategies would lead to better health, fewer absentees, higher productivity, and lesser healthcare cost.^171,172

Why is It Necessary to Target Serum 25(OH)D Concentration Above 50 ng/mL?

Good public health policies aim to minimize diseases, their complications, and the spread, cost-effectively. However, during the COVID pandemic, some of these principles were ignored by leading health authorities and governments, which led to chaos. Those who develop symptomatic disease and complications and die from infections have feeble immune systems. Therefore, maintaining a robust immune system is not only essential to protect the population during infectious pandemics like SARS-CoV-2 but also the most cost-effective way to control it.

Convincing evidence has been published that rapidly raising and maintaining vitamin D and/or serum 25(OH)D concentrations above the minimum required level of 50 ng/mL (125 nmol/L) would minimize infections-related adverse clinical outcomes.^46–48 Therefore, in such situations, in addition to preventing disease spread (eg, wearing effective face masks and social distancing), a broader goal should be to maintain mentioned circulatory 25(OH)D concentration in the population that would significantly improve clinical outcomes, including fewer hospitalizations and deaths, while mimizing healthcare costs.⁵⁰

If the goal is to achieve a population minimum serum 25(OH)D concentration of “40” ng/mL, 60% of people will be below the required serum 25(OH)D concentration of 50 ng/mL. Whereas, if the targeted minimum concentration is set for 30 ng/mL, more than 80% of the population will have serum 25(OH)D concentration below 50 ng/mL, due to the scatter of representation in the community. Consequently, such approaches are ineffective and unwise especially during infectious epidemics and pandemics. It would fail to maintain a robust immunity in the population that needs to overcome infections. This is a crucial reason for the community spread of SARS-CoV-2, its, severe complications and deaths from the current COVID pandemic.

Therefore, keeping individuals or the populations’ serum 25(OH)D concentration below 50 ng/mL as recommended by some as the lower limit, is unwise and undesirable.⁴⁸ During infectious epidemics or pandemics, there is no scientific justification for maintaining minimum serum 25(OH)D concentrations at 20, 30, or even 40 ng/mL, suggested as precautionary (and theoretical) principles by some. It would lead to serum 25(OH)D concentration of over two thirds of the population under the minimum necessary level of 50 ng/mL—disadvantage them by contracting infectious pathogens—both bacteria and viruses—therefore, it is counterproductive. Such a policy would enhance the spread of the viral illness, increase complications, hospitalizations, deaths, and associated costs.

Supporting Scientific Data

Three publications have addressed the issues of how to raise and maintain the needed physiological circulatory concentrations of 25(OH)D. Veugelers et al^29,173 and Huang (2021).¹⁷⁴ While the former recommended using body-weight-based dose calculations, the latter used a physiological-based pharmacokinetic model using baseline 25(OH)D concentration levels to obtain the desired dose of vitamin D.

The recent dose recommendations pulished (July 2022 in Nutrients) used practical clinical aspects, multiple data sets, and over two decades of extensive clinical experience and provided both bodyweight/BMI-based and serum 25(OH)D concentrations-based recommendations of appropriate vitamin D and calcifediol doses for children and adults.⁴⁸ These studies conclusively illustrated that the currently recommended vitamin D dosage of 400 to 800 IU/day for adults by most governments and some appointed bodies is grossly inadequate to raise serum 25(OH)D concentration to therapeutic levels and worthless for counteracting infections.^29,173–175

However, minimizing too-low and too-high circulatory 25(OH)D concentrations is necessary. Regarding this, Veugelers et al¹⁷³ have examined doses of 1885, 2802, and 6235 IU per day administered to those with average body mass index (BMI) and overweight and obese individuals (maintained between 23 and 68 ng/mL)-(defined as 58 to 171 nmol/L). They concluded that the standard recommended RDA is undesirable and recommended body-weight-based doses of optimal intakes.^29,173

Physiological studies with ED50 confirmed that both the baseline concentration, the daily or weekly oral doses, and the frequency of administration, influence the achievement of circulatory 25(OH)D concentration plateaus. They investigated 400 IU (10 μg) up to 50,000 IU (1250 μg) doses/day for 2 to 100 weeks of administration. Figure 10 illustrates the increase in serum 25(OH)D concentration vs baseline concentrations at each dose. A normalized increase in serum 25(OH)D was plotted against 25(OH)D baseline levels.^29,173

Figure 10 Illustrates mean ± SD and 95% (of 2.5th and 97.5 th percentiles are prepsented) prediction interval of serum 25(OH)D concentrations following vitamin D supplementation. The vertical axes provide serum 25(OH)D concentrations in nmol/L (left side) and ng/mL (right side). As the red arrow indicates, with a 5000 IU/day dose, serum 25(OH)D concentrations achieved were between 38 and 68 ng/mL, with a mean of 53 ng/mL with longer-term administration. The equation for The mean response for healthy individuals reported as Y = 51.9 + 17.7 *(1 - e-7.4*X) + 6.3 *X, in which Y denotes serum 25(OH)D (in nmol/L) and X, vitamin D supplementation (in 1000 IUs). Notes: Adapted from: Veugelers, PJ, Pham TM, Ekwaru JP. Optimal vitamin D supplementation doses that minimize the risk for both low and high serum 25-hydroxyvitamin D concentrations in the general population. Nutrients. 2015;7(12): 10,189–10,208173.

These data confirmed that for a 70 kg person consuming an average dose of 7000 IU/day, 97% maintain serum 25(OH)D concentration above 30 ng/mL, but 30% would be less than 50 ng/mL. Similarly, with a dose of 25,000 IU per week, only 50% of them would reach a serum 25(OH)D concentration above 50 ng/mL. In both scenarios, a significant proportion will have insufficient circulatory 25(OH)D concentration needed to overcome infections.²⁹ Figure 10 also illustrates the non-linearity of serum 25(OH)D concentrations in response to oral vitamin D doses and different plateau levels reached after different vitamin D doses in an average person.

Limitations of Systematic Reviews and Meta-Analyses

Several systematic reviews and meta-analyses have been published regarding vitamin D and COVID-19, with variable, non-confirmatory conclusions. Most RCTs and other clinical studies included in recent meta-analyses had significant methodological errors: poorly designed RCTs, study selection biases, and too fewer number of studies. Others have failed to address confounding variables, had inadequate sample sizes, and dramatic study group imbalances.

Because of poor-quality data from published studies and the heterogeneity of clinical studies included, outcomes and conclusions are consdered unreliable. For example, many RCTs failed to measure the baseline characteristics, especially serum 25(OH)D concentrations, the number of days from the onset of the clinical symptoms, have not included hard endpoints, severity between the interventional and control groups, etc.¹⁷⁶ Therefore, until data from adequate well-controlled RCTs are available, it is irrational to continue to republish meta-analyses on this subject.

Discussion

There are specific groups with a higher prevalence of vitamin D deficiency. These categories include (A) elderly with comorbidities, (B) over-weight, obese, or taking medications that enhance vitamin D catabolism, (C) darker skin persons living in temperate climatic, northern and southern hemispheres (D) institutionalized persons (e.g., prisons, nursing homes, disability centers), submarine crew members, and regular night shift workers, and (E) those who avoid sun exposure.

Consequently, they have a weaker immune system, thus, a higher risk of developing symptomatic diseases, severe complications, and death from infections like COVID-19. People belonging to these groups and those with chronic metabolic disorders such as diabetes, obesity, metabolic syndrome, chronic pulmonary hypertension, and cardiovascular and renal diseases have low serum 25(OH)D and low ACE-2 concentrations. Consequently, compared to the general public, they are at a higher risk of contracting infections, including COVID-19, and developing complications.

After excluding confounders, data from the past two years of COVID confirmed that death rates from COVID-19 of blacks, Asians, and ethnic minorities (BAEM)—those with darker skin color living in northern latitudes—were significantly higher than whites.¹⁷⁷ Socioeconomic factors, such as disparities in access to healthcare and economic status, play a role in the reported statistics related to COVID-19, but to a lesser extent than the prevelance of hypovitaminosis D.

During the COVID pandemic, lockdowns and curfews, reduced sun exposure, insufficient intake of nutritious food, and increased sedentary lifestyles led to an increased prevalence of malnutrition and hypovitaminosis D: further weakening the immune systems.^48,178 These collectively contributed to the increased prevalence of hypovitaminosis D and vulnerability to infection, complications, and deaths.^1,50

The relationships between serum 25(OH)D) concentrations and clinical outcomes from COVID-19 mentioned above fulfilled Bradford Hill’s criteria for causation, thus, no further RCTs are needed. Vitamin D deficiency predictably increased SARS-CoV-2-associated complications and deaths because of its adverse effects on the immune system.¹⁴⁷ Vitamin D supplementation breaks this vicious cycle through immune-mediated mechanisms, including suppressing inflammation, oxidative stress, and cytokine storm, as described above.^160,162,179 The link between severe vitamin D deficiency and COVID-19 complications is robust with a high effect size, including increased risks for cytokine storm, ARDS, needing ICU admission, assisted ventilation, and death.¹⁸⁰

Besides, hypovitaminosis D increases the risk of ARDS, lung damage, vascular abnormalities, blood clotting, and death.^135,136 Vitamin D stabilizes epithelial cells and cell gap junctions, especially in the lungs and vascular system, preventing fluid leakage into soft tissues and disseminating viruses. Moreover, it reduces microbial entry from the blood into tissues and the extracellular space, preventing viral spread, the occurrence of pulmonary edema, effusions, pneumonia, ARDS, and post-COVID syndrome.^138,159

In 2020/21, due to systematic failures—conflicting guidance and misleading policies by leading global health authorities, harmful lockdowns and enforcement of unjustifiable vaccine-mandates and worthless vaccine-passports by autocratic governments—that ignored early cost-effective therapies and disregarded the importance of vitamin D in immunity led to a “pandemic of hypovitaminosis D”. However, in 2022/23, with increased hospitalizations and deaths among those fully vaccinated and boostered surpassed unvaccinated, now it has become a “pandemic of vaccinated”.

Considering the value, cost-effectiveness, and lack of adverse effects from the recommended doses of vitamin D, each country must develop new educational and health guidelines, including safe sun exposure and vitamin D supplemental programs to strengthen immunity in individuals and the population, aiming to maintain it above 50 ng/mL (125 nmol/L). Alleviating vitamin D deficiency is the most cost-effective public health intervention one can provide to prevent any symptomatic infections and complications, and improve clinical outcomes from COVID-19 outbreaks. Astonishingly, no government or regulatory agency has yet to accept this principle and implement countrywide vitamin D supplementation programs to keep their citizens healthy. Whether this flagrant inaction is due to conflicts of interest and to maintain the “emergency use authorization” for patented medications and vaccines is yet to reveal.

Implementing vitamin D supplementation programs with community-based chronic disease management programs will positively impact health, prevent diseases and complications, reduce the need for hospitalization and intensive care admissions and reduce deaths from COVID-19 and other infectious diseases. Vitamin D supplementation initiatives to keep the population healthy are economical and potentially beneficial. This is a viable and highly cost-effective strategy for protecting vulnerable groups and populations with a high prevalence of vitamin D deficiency, such as the elderly, those with darker skin color, and institutionalized persons. This cost-effective approach reduces healthcare costs, reduces absenteeism, and minimizes opportunity costs.