COVID 19 and Vitamin D

October 4, 2021

There are dozens of studies that show a correlation between COVID 19 and vitamin D deficiency, leading to increased incidence of COVID infection and mortality for those deficient in this essential vitamin.

Here we outline how the body absorbs vitamin D, why it is important, what factors affect vitamin D absorption and who is at risk of being Vitamin D deficient. Finally we analyze the different mechanisms through which Vitamin D effects COVID-19 and show dozens of studies that prove healthy vitamin D levels reduce the incidence of COVID: infection, hospitalizations and mortality.

Please Note: This article will be updated with new information as it becomes available and as time allows. Please bookmark and check back often, changelog at the bottom will highlight additions or edits.

Table of Contents

“Through its interactions with a multitude of cells, vitamin D may have several ways to reduce the risk of acute respiratory tract infections and COVID-19: reducing the survival and replication of viruses, reducing risk of inflammatory cytokine production, increasing angiotensin-converting enzyme 2 concentrations, and maintaining endothelial integrity.”

Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity

Although there is compelling evidence herein, there are also new studies published frequently, which look more into how vitamin D effects COVID infection and mortality. Considering Vitamin D is one of the safest vitamins available, supplementation is a low risk way to bolster your immune system and overall health during the pandemic.

vitamin d for covid 19 ivmstatus vdmeta c19vitamind 10-14-2021 dfpel
vitamin d for covid 19 ivmstatus vdmeta c19vitamind 10-14-2021 dfpel
vitamin d for covid 19 ivmstatus vdmeta c19vitamind 10-14-2021 dsplevels2
vitamin d for covid 19 ivmstatus vdmeta c19vitamind 10-14-2021 dsplevels2

Source c19vitamind.com with the help of vdmeta.com

How the Body Absorbs Vitamin D | Too much time indoors means not enough sun exposure

Methods of Vitamin D absorption into the body Diagram
Methods of Vitamin D absorption into the body | Diagram

The average person spends around 87% of their time indoors. That means most people are not even exposed to enough sunlight, to ensure adequate Vitamin D production. The main cause of deficiency is inadequate exposure to sunlight.

The National Human Activity Pattern Survey (NHAPS) | A resource for assessing exposure to environmental pollutants - Total time spent indoors 86.9%
The National Human Activity Pattern Survey (NHAPS) | A resource for assessing exposure to environmental pollutants – Total time spent indoors 86.9%

In addition, when people are outdoors, they are often covered in clothes, which further reduces sunlight absorption and consequently, Vitamin D production.

Sunlight above and below the 35th parallel

This is especially true for those living above the 35th parallel north and below the 35th parallel south, and even more so during the winter months in those geographical regions, where the cold climate keeps people indoors for longer periods and where daylight is significantly reduced.

Earth World Map - 35th parallel north and 35th parallel south - Differences in sunlight and Vitamin D across the word
Earth World Map – 35th parallel north and 35th parallel south.

In fact studies show that people above or below the 35th parallel, can’t really get enough Vitamin D by sun exposure alone during the wintertime.

“Sunlight exposure is the primary determinant of vitamin D status in humans and, particularly in northern latitudes from November to March, there are insufficient UV-B rays to produce vitamin D.

Demographic Differences and Trends of Vitamin D Insufficiency in the US Population, 1988-2004

Vitamin D Synthesis USA Heat Map

As you can see below, during the months of January and February, the sun is simply not close enough across the entire U.S. for vitamin D synthesis to happen and your body to obtain enough vitamin D. Of course, these are only two months out of the entire year, but there are many months where UVB rays will be hard to obtain, and you could become vitamin D deficient.

Note: If you live outside of the U.S., visit this Sun or Moon Altitude Table to determine how far the sun is from your location at any given time.

Source of images: www.epa.gov

Editorial: low population mortality from COVID-19 in countries south of latitude 35 degrees North supports vitamin D as a factor determining severity

An editorial shows that as you get further away from the equator (marked O on graph) we have less direct sunlight, and correspondingly the incidence of mortality from COVID-19 increases.

“When mortality per million is plotted against latitude, it can be seen that all countries that lie below 35 degrees North have relatively low mortality. Thirty‐five degrees North also happens to be the latitude above which people do not receive sufficient sunlight to retain adequate vitamin D levels during winter. This suggests a possible role for vitamin D in determining outcomes from COVID‐19. There are outliers of course—mortality is relatively low in Nordic countries—but there vitamin D deficiency is relatively uncommon, probably due to widespread use of supplements. 4 Italy and Spain, perhaps surprisingly, have relatively high prevalences of vitamin D deficiency. Vitamin D deficiency has also been shown to correlate with hypertension, 5 diabetes, 6 obesity 7 and ethnicity 8 —all features associated with increased risk of severe COVID‐19.”

low population mortality from COVID-19 in countries south of latitude 35 degrees North supports vitamin D as a factor determining severity

So although there are some outliers who are further from the equator and direct sunlight, but still have low mortality such as the Nordic countries, this is due primarily to widespread vitamin D supplementation.

Vitamin D, Seasonality and COVID 19

The Influenza rate is higher during winter time than summer [127]. Many scientists expected COVID-19 to also exhibit a seasonal trend. Several papers show evidence of monthly and seasonal variation for viral infections.

Flu Activity correlation to Sunlight and Avg Vitamin D per month

Studies show a direct correlation between low vitamins D levels and upticks in flu illness; evidence that sunlight exposure and it’s consequential vitamin d production, are essential to maintain a robust immune system, and ultimately a healthy body.

Peak Month of Fly Activity 1982-1983 through 2017-2018 with Average Vitamin D Level Per Month - Shows a correlation between low vitamin d levels and upticks of flu illness.
Peak Month of Fly Activity 1982-1983 through 2017-2018 with Average Vitamin D Level Per Month – Shows a correlation between low vitamin d levels and upticks of flu illness.

Global patterns in monthly activity of influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus: a systematic analysis

A 2019 study published Aug 2019 in the esteemed Lancet medical journal titled Global patterns in monthly activity of influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus: a systematic analysis performed a systematic analysis of global patterns in monthly activity of influenza virus, respiratory syncytial virus, parainfluenza virus and metapneumovirus.

The analysis analyzed 185 studies. It included 246 sites for influenza virus, 183 sites for respiratory syncytial virus, 83 sites for parainfluenza virus, and 65 sites for metapneumovirus.

Influenza virus had clear seasonal epidemics in winter months in most temperate sites but timing of epidemics was more variable and less seasonal with decreasing distance from the equator”

respiratory syncytial virus had clear seasonal epidemics in both temperate and tropical regions, starting in late summer months in the tropics of each hemisphere, reaching most temperate sites in winter months. “

Parainfluenza virus epidemics were found mostly in spring and early summer months in each hemisphere. Metapneumovirus epidemics occurred in late winter and spring in most temperate sites but the timing of epidemics was more diverse in the tropics.”

“The seasonality information has important implications for health services planning, the timing of respiratory syncytial virus passive prophylaxis, and the strategy of influenza virus and future respiratory syncytial virus vaccination.”

Global patterns in monthly activity of influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus: a systematic analysis

Global Seasonality of Human Seasonal Coronaviruses: A Clue for Postpandemic Circulating Season of Severe Acute Respiratory Syndrome Coronavirus 2?

A study published in OXFORD The Journal of Infectious Diseases Jul 21 2020 titled Global Seasonality of Human Seasonal Coronaviruses: A Clue for Postpandemic Circulating Season of Severe Acute Respiratory Syndrome Coronavirus 2? analyzed the global seasonality of human seasonal coronaviruses across 40 studies, representing 40 sites from 21 countries.

“For nearly all of these viruses, infection rates in northern mid and high latitudes
are highest from November through March. They examined correlations of meteorological conditions with coronavirus infections, finding the highest correlation with low temperature combined with high relative humidity.

Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity
Heat maps of global monthly activity of seasonal coronaviruses (sCoVs), influenza virus (IFV), and respiratory syncytial virus (RSV). For each site, the results of IFV and RSV for the same site were presented for comparison. The y-axis shows the countries where the data were from and the latitude of sites (references are shown in the Supplementary Appendix). Numbers on the right side denote the total number of sCoV cases. Six studies that did not report sCoVs (of all species) were excluded.
Global Seasonality of Human Seasonal Coronaviruses: A Clue for Postpandemic Circulating Season of Severe Acute Respiratory Syndrome Coronavirus 2? Figure 3. Heat maps of global monthly activity of seasonal coronaviruses (sCoVs), influenza virus (IFV), and respiratory syncytial virus (RSV). For each site, the results of IFV and RSV for the same site were presented for comparison. The y-axis shows the countries where the data were from and the latitude of sites (references are shown in the Supplementary Appendix). Numbers on the right side denote the total number of sCoV cases. Six studies that did not report sCoVs (of all species) were excluded.

The study also found that temperature and humidity plays a role in coronavirus seasonality

“Low temperature with higher relative humidity was found to be associated with higher proportion of sCoV cases“.

They point out that there are lessons to learn from Influenzas transition from a pandemic to a seasonal virus, which can help us to prepare for SARS-CoV-2s potential transition to a seasonal virus.

“One of the lessons learned from the history of influenza pandemics is its transition from pandemic to seasonal circulation and the replacement of existing strain(s) with the pandemic strain. Although it is not clear how the existing sCoVs initially emerged or whether they had previously replaced any viruses, understanding the global seasonality of sCoVs would undoubtedly offer some clues on the possible postpandemic circulating season of SARS-CoV-2 and contribute to the knowledge pool for the postpandemic preparedness for SARS-CoV-2.”

“The global seasonality of sCoVs provides a clue for the possible circulating timing of SARS-CoV-2 after the initial pandemic. A modeling study reported that SARS-CoV-2 will likely enter into regular circulation starting from 2021 or 2022 in the US and synchronize with sCoVs, if immunity to SARS-CoV-2 is not permanent [4]”

Correction: Absolute Humidity and the Seasonal Onset of Influenza in the Continental United States

Another study titled Correction: Absolute Humidity and the Seasonal Onset of Influenza in the Continental United States showed the role humidity plays in the seasonality of Influenza, which gives insight into a role it may also play in the seasonality of Coronaviruses such as COVID-19.

“The origin of seasonality in influenza transmission is both of palpable public health importance and basic scientific interest. Here, we present statistical analyses and a mathematical model of epidemic influenza transmission that provide strong epidemiological evidence for the hypothesis that absolute humidity (AH) drives seasonal variations of influenza transmission in temperate regions. We show that the onset of individual wintertime influenza epidemics is associated with anomalously low AH conditions throughout the United States.”

“The results indicate that AH affects both the seasonality of influenza incidence and the timing of individual wintertime influenza outbreaks in temperate regions. The association of anomalously low AH conditions with the onset of wintertime influenza outbreaks suggests that skillful, short-term probabilistic forecasts of epidemic influenza could be developed.”

Correction: Absolute Humidity and the Seasonal Onset of Influenza in the Continental United States

Low Temperature and Low UV Indexes Correlated with Peaks of Influenza Virus Activity in Northern Europe during 2010–2018

An article published Mar 1 2019 in MDPI, analyzed Low Temperature and Low UV Indexes Correlated with Peaks of Influenza Virus Activity in Northern Europe during 2010–2018. The study found that low temperature was the most important factor facilitating transmission, followed by solar UV radiation and low humidity.

The paper also noted that high humidity favors transmission in tropical and subtropical zones, in accordance with the findings in Global Seasonality of Human Seasonal Coronaviruses: A Clue for Postpandemic Circulating Season of Severe Acute Respiratory Syndrome Coronavirus 2?

According to data posted at WorldoMeter, COVID-19 case rates in Northern Europe peaked in spring, were very low in summer, then started rising in July (e.g., Spain), August (e.g., Italy) or September (e.g., the UK).

Vitamin D, geographical factors in COVID-19 Seasonality

“According to data posted at WorldoMeter, COVID-19 case rates in Northern Europe peaked in spring, were very low in summer, then started rising in July (e.g., Spain), August (e.g., Italy) or September (e.g., the UK).

At higher latitudes in the southern hemisphere, COVID-19 rates were very low through April, then started to rise in June and continued rising into October as in Argentina. On the other hand, in the tropical South American countries such as Brazil, COVID-19 rates started rising in April, peaking around early August then declined, in general agreement with other coronavirus infections. Of course, a number of factors help determine the case rate including the extent to which social distancing and mask wearing are practiced, when school attendance begins, and solar and meteorological factors. However, mortality rates were only high in the spring. Most likely the low mortality rates in September were due to the COVID-19 rates being highest for those aged 20 to 29 years [132]. Yet, with time, COVID-19 rates will increase among the elderly as well.”

Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity

Vitamin D and Metabolism

  • For more than a century, vitamin D deficiency has been suggested to increase susceptibility to infection.
  • Increased risk of respiratory tract infections (RTIs) in children with nutritional rickets
  • Vitamin D was considered of importance in the treatment of ruberculosis
  • Seasonality of RTI’s and low 25OHD levels during wintertime has been suggested to be the “seasonal stimulus”
  • If so, this is of major importance to public health, as RTI are a major contributor to mortality
  • Recent studies have provided further evidence of bitamin D as an important regulator of human immune function, as bitmain D may stimulate the innate immune response which provides front-line protection against infectious agents
  • The VDR has been shown to be expressed in different cells of the myeloid and lymphoid lineage and vitamin D may increase the expression of antimicrobial peptides in human monocytes and neutrophils
  • Particularly, vitamin D may enhance the expression of the human cathelicidin antimicrobial peptide (hCAP-18) which is of specific important in host defenses against respiratory tract pathogens.

Vitamin D and Age

“A comparison of the amount of previtamin D3 produced in the skin from 8-18-yr-old subjects with the amount produced in the skin from the 77- and 82-yr-old subjects revealed that aging can decrease by greater than twofold the capacity of the skin to produce previtamin D3”

JCI The Journal of Clinical Investigation

Vitamin D Insufficiency and Deficiency and Mortality from Respiratory Diseases in a Cohort of Older Adults | Study

A study on vitamin d levels and respiratory diseases observed 9940 Germans, 50-75 years old and did follow-ups up to 15 years later. The study stated vitamin D levels of 50 nmol/L were healthy, and levels under 30 nmol/L were unhealthy or deficient.

Scientists then followed them over a period of years, checked the death certificates after 15 years, and analyzed what they died from.

Figure 2. Kaplan Meier curves for deaths from respiratory diseases according to vitamin D
Survival from Respiratory mortality.

“Statistically, after adjustment for sex, age, season of blood draw, school education, smoking, BMI, physical activity, and fish consumption, 41% of the variability in respiratory mortality during this 15-year follow-up period was independently associated with 25(OH)D levels < 50 nmol/l”

Vitamin D Insufficiency and Deficiency and Mortality from Respiratory Diseases in a Cohort of Older Adults: Potential for Limiting the Death Toll during and beyond the COVID-19 Pandemic? (Nutrients)

They found that people with healthy vitamin D levels over 50 nmol/L had a better survival rate, in terms of respiratory mortality then those that had less than 30 nmol/L. In essence a statistically significant correlation between vitamin d levels and respiratory mortality.

It’s important to point out that there is a different between association and causation. In other words although low vitamin D levels are associated with higher respiratory mortality, that does not necessarily mean low vitamin D levels caused that disease (association vs causation)

Vitamin D and survival in COVID-19 patients: A quasi-experimental study

A “quasi-experimental study” titled Vitamin D and survival in COVID-19 patients: A quasi-experimental study analyzed vitamin D supplementation of residents in a French nursing home was conducted preceding and during a COVID-19 outbreak in the nursing home. Residents were normally given a bolus dose of 80,000 IU vitamin D3 every two to three months. COVID-19 affected many of the residents starting in March 2020.

Fifty seven of the residents, who had received 80,000 IU vitamin D3 in the preceding month, were included in the “intervention group” while nine who had not were included in the “comparator group”. The mean age of the residents was 87 _+ 9 years. The mean follow-up time was 36 +_ 7 days. Forty-seven (83%) of the intervention group survived compared to only four (44%) of the comparator group (p = 0.02). The fully adjusted HR for mortality according to vitamin D supplementation was 0.11 (95% CI, 0.03 to 0.48, p = 0.003).

Pharmacokinetics of a single, large dose of cholecalciferol

A clinical trial was conducted titled Pharmacokinetics of a single, large dose of cholecalciferol regarding bolus vitamin D dose (100,000 IU vitamin D3) supplementation involving 30 older (71 +_ 6 years) and ten younger (38 +_ 8 years) subjects and ten older controls (71 +_ 10 years). Baseline 25(OH)D was 27 +_ 8 ng/mL, rising to 42 +_ 9 ng/mL within six days, then falling in a linear fashion to 32 ng/mL after 70 days. Thus, bolus vitamin D3 supplementation monthly would be appropriate for nursing-home residents.

Vitamin D status and outcomes for hospitalised older patients with COVID-19

A study on Vitamin D status and outcomes for hospitalised older patients with COVID-19 published Aug 26 2020 analyzed 105 patients hospitalized with COVID-19 type symptoms.

The study found that SARS-CoV-2 positivity was linked with lower vitamin D levels (avg. 27nmol/L), while those who tested negative had healthy vitamin d levels (avg. 52nmol/L).

Vitamin D status and outcomes for hospitalised older patients with COVID-19 Fig. 1 - Flow chart, depicting recruitment of patients upon admission via the emergency department | COVID 19 and Vitamin D
Fig. 1 – Flow chart, depicting recruitment of patients upon admission
via the emergency department

In addition those with vitamin D levels over 30 nmol/L had lower peak d-dimers, which is considered to be a risk factor in blood cloths with COVID-19 infection. They also had a lower incidence of ventilator requirements.

In conclusion the study showed compelling evidence that potentially vitamin D levels are associated with a worse course or outcome of COVID-19 infection, in the hospital.

Vitamin D, Race & COVID 19

In the study below we observe that African American and Mexican Americans are more prone to Vitamin D deficiency, partly because dark skin pigmentation naturally absorbs less sunlight, as it is designed provide protection in areas with longer days and more intense prolonged, year round sun exposure. This makes deficiency even more pronounced in immigrants who move for example from somewhere like Africa to America or Canada.

Partly as result of skin pigmentation and lower 25(OH)D levels [15], African American and Hispanic individuals have higher COVID-19 case and death rates than European Americans [13,14]. But also other factors such as working and living in close proximity to many people and having higher rates of hypertension and other chronic diseases such as type II diabetes, often associated with COVID-19 [133] can confound the problem.

Vitamin D and Race - Racial differences in the relationship between vitamin D, bone mineral density, and parathyroid hormone in the National Health and nutrition Examination survey.
Vitamin D and Race – Racial differences in the relationship between vitamin D, bone mineral density, and parathyroid hormone in the National Health and nutrition Examination survey.

Vitamin D Production and Dark Skin Pigmentation

People whose ancestors come from sunny places have increased skin pigmentation (darker skin), to protect them from sunburn and other sun damage. this includes those whos ancestors are from Africa, the Middle East or South Asia.

The ability to produce vitamin D varies with the colour of a person’s skin. Those with increasingly darker skin naturally produce less Vitamin D from sunlight, and therefore have an increased risk of Vitamin D deficiency.

Vitamin D, Race and Immigrants

When people who are dark skinned, immigrate from a country along the equator to northern latitudes, the naturally shorter days and colder temperatures during the winter months, lead to reduced sun exposure, and consequently vitamin D deficiency.

Vitamin D World Map

People who are from Somalia for example are used to a climate with 12 months of warmth and sunshine, and they go outside every day for at least a couple of hours, which provides enough sunlight for the body to produce Vitamin D; even with darker skin. However Canada and much of America, does not provide the same climate for year round, daily sun-exposure. Instead we have short days with the sun low in the sky and long, harsh winters, which last 3-5 months.

Culture also plays a role this includes clothing, and the way society functions. For example some cultures may wear more clothing, resulting in less skin to sun exposure.

“The important role of culture, including places of worship, multigenerational households, and variation in social interactions might also have a role in increased risks of COVID-19”

Sharpening the global focus on ethnicity and race in the time of COVID-19

In Canada due to the more moderate weather and the structure of society, Canadians tend to spend a great deal of their day indoors: for work, school, and leisure time…as opposed to someone living in Hawaii who may be involved in more outdoor activities; there is of course exceptions.

COVID-19 and African Americans

An article published April 15, 2020 titled COVID-19 and African Americans collected and presented evidence of a very large disparity between COVID 19 infection rates and mortality among predominantly black communities and predominantly white communities. The article cited a publiciation in the Washington Post titled The coronavirus is infecting and killing black Americans at an alarmingly high rate which gathered and presented statistical data from Johns Hopkins University, state health departments and American Community Surveys on COVID-19 and black Americans.

Table African Americans by percentage of population and share of coronavirus deaths

“The Johns Hopkins University and American Community Survey indicate that to date, of 131 predominantly black counties in the US, the infection rate is 137.5/100 000 and the death rate is 6.3/100 000 [5]. This infection rate is more than 3-fold higher than that in predominantly white counties. Moreover, this death rate for predominantly black counties is 6-fold higher than in predominantly white counties. Even though these data are preliminary and further study is warranted, the pattern is irrefutable: underrepresented minorities are developing COVID-19 infection more frequently and dying disproportionately.”

COVID-19 and African Americans
The coronavirus is infecting and killing black Americans at an alarmingly high rate - Chart African Americans by county and share of coronavirus cases and deaths per 100k
Chart African Americans by county and share of coronavirus cases and deaths per 100k

It did not consider this an access to care problem

“Yes. The definition of a health care disparity is not simply a difference in health outcomes by race or ethnicity, but a disproportionate difference attributable to variables other than access to care [9]. Given the known risk factors for COVID-19 complications, the confluence of hypertension, diabetes, obesity, and the higher prevalence of cardiovascular disease among black persons may be driving these early signals.”

COVID-19 and African Americans

For a while the CDC only released COVID-19 figures by age and gender. However under mounting pressure from legislators, civic advocates and medical professionals, the CDC has now begun to include covid-19 hospitalizations by race and ethnicity in reports.

African-Americans Have a Higher Propensity for Death from COVID-19: Rationale and Causation | Study

A study was published on Jul 31 2020 titled African-Americans Have a Higher Propensity for Death from COVID-19: Rationale and Causation, found that certain race/ethnicities are more prone to COVID-19 infection from a multitude of factors.

It stated that African Americans have increased rates of social determinants predisposing them to COVID-19, such as lower income, education, and employment as well as higher rates of existing conditions such as diabetes, hypertension, cardiovascular disease, obesity, and lung disease. Those factors may help explain why black people and Hispanic people have 7% and 4% higher SARS-CoV-2 positivity rates, respectively, than white people at 30 ng/mL.

Nonetheless, the SARS-CoV-2 positive rate spread was much higher for black and Hispanic people than for white people near 20 ng/mL (18%, 16%, and 9%, respectively) than near 60 ng/mL (11%, 9%, and 5%, respectively), suggesting that vitamin D status plays a role in the increased COVID-19 rate for black and Hispanic people.

Association of Race With Mortality Among Patients Hospitalized With Coronavirus Disease 2019 (COVID-19) at 92 US Hospitals | Study

A study was published Aug 18 2020 titled Association of Race With Mortality Among Patients Hospitalized With Coronavirus Disease 2019 (COVID-19) at 92 US Hospitals analyzed over 11,000 patients with confirmed COVID-19 in hospital to show the different statistics between races and COVID-19 infection and mortality.

The study found no significant difference between black and white in-hospital patients in terms of COVID-19 mortality for those able to access hospital care, after adjusting for sociodemographic factors and comorbidities. This shows that sociodemographic factors and comorbidities play a significant role in COVID-19 mortality and may also play a role in Vitamin D deficiency due to lack of access to alternate vitamin D supplementation.

“Of 11 210 patients with confirmed COVID-19 presenting to hospitals, 4180 (37.3%) were Black patients and 5583 (49.8%) were men. The median (interquartile range) age was 61 (46 to 74) years. Compared with White patients, Black patients were younger (median [interquartile range] age, 66 [50 to 80] years vs 61 [46 to 72] years), were more likely to be women (2259 [49.0%] vs 2293 [54.9%]), were more likely to have Medicaid insurance (611 [13.3%] vs 1031 [24.7%]), and had higher median (interquartile range) scores on the Neighborhood Deprivation Index (−0.11 [−0.70 to 0.56] vs 0.82 [0.08 to 1.76]) and the Elixhauser Comorbidity Index (21 [0 to 44] vs 22 [0 to 46]). All-cause in-hospital mortality among hospitalized White and Black patients was 23.1% (724 of 3218) and 19.2% (540 of 2812), respectively. After adjustment for age, sex, insurance, comorbidities, neighborhood deprivation, and site of care, there was no statistically significant difference in risk of mortality between Black and White patients (hazard ratio, 0.93; 95% CI, 0.80 to 1.09).”

“in this study, mortality for those able to access hospital care did not differ between Black and White patients after adjusting for sociodemographic factors and comorbidities”

A study published in Mar of 2009 titled Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004 compared serum 25-hydroxyvitamin D (25[OH]D) levels from the Third National Health and Nutrition Examination Survey (NHANES III), collected during 1988 through 1994, covering 18 883 participants in NHANES III and 13 369 participants in NHANES 2001-2004.

It found evidence that racial and ethnic differences represent important implications for health disparities.

Racial/ethnic differences have persisted and may have important implications for known health disparities.”

The Perfect Storm: COVID-19 Health Disparities in US Blacks

Conceptualization of multifactorial risk for COVID-19. As with any complex disease, it is the aggregate result of many risk factors and exposures which determines one’s susceptibility to and manifestation of disease. Genetic risk is likely just one piece of the complicated landscape underlying the observed disparity in Black mortality rates. Here, we highlight three candidate genes (angiotensin converting enzyme 2, ACE2; acetylcholinesterase, AChE; interleukin-6, IL-6) based on their involvement in both environmental responses and comorbid conditions that are relevant to SARS-CoV-2 pathophysiology. Importantly, it is the interplay between key environmental exposures (stress; social determinants of health, SDH) and genetic predisposition for aspects of viral pathogenesis and/or comorbid disease (e.g., type 2 diabetes mellitus, T2DM; hypertension, HTN) that ultimately converges on COVID-19 manifestation and affects mortality

A study published Sep 23 2020 titled The Perfect Storm: COVID-19 Health Disparities in US Blacks basically stated that yes race does play a role through comorbidity risk in COVID-19 mortality. However it statyed that there are “multi-faceted influences of comorbidity risk” and therefore large scale studies are warranted, which must utilize the latest computational biology and machine learning to fully encompass the broad spectrum of biological and environmental interactions and genetic predisposition that contribute to differences in health outcomes.

“Persistent, low-level inflammation is a prevailing hallmark of most if not all chronic disease and considered responsible for health outcomes [93,94,95]. Juxtaposed with the robust cytokine-mediated disease etiology and underlying biopsychosocial factors demarcates the setting of a “perfect storm.” The accumulated works presented here merge the multi-faceted influences of comorbid risk, the emerging biomolecular etiology of CoV-2 pathogenesis, and the underlying preferences in heritable genetic predisposition, as a collective explanation of the observed disparities of COVID-19 deaths in NHBs.

Clearly, there are many complicated interactions between biological and environmental sources of risk for severe COVID-19 outcomes; large-scale research of vulnerable human populations is warranted to enable the identification and quantification of the key drivers for COVID-19 mortality. Studies of this nature may allow for the development of models which predict risk at the individual level (Fig. 2), where the nature of exposures (e.g., SDH, psychosocial stress) can be weighted alongside the effects of specific genetic risk loci (e.g., where A, B, and C may be variants in genes such as ACE2, AChE, and IL-6) in order to determine the likelihood and/or degree of adverse COVID-19 pathology upon exposure. While this theoretical “threshold” model of disease risk is a vast oversimplification, rapid advances in computational biology, facilitated by artificial intelligence, may enable researchers to capture nuanced interactions not shown in Fig. 2 in order to greatly enhance predictive power.

To conclude, ongoing research in the field of health disparities provides evidence that the persistent disproportion of disease for NHBs and other ethnic/racial minorities and underserved groups will not be eliminated without concerted efforts to address social determinants. It is also true that a conscientious view into biologically derived risk and its interconnections within the psychosocial and environmental realms is required to realize the full potential of the knowledge gained to stimulate progress in therapeutics for decreasing health disparities in NHBs and conquering this pandemic as well as improve health outcomes.”

Sharpening the global focus on ethnicity and race in the time of COVID-19

A study titled Sharpening the global focus on ethnicity and race in the time of COVID-19 was published May 30 2020 in the esteemed medical journal The Lancet. The study presented a strong argument for differences in COVID 19 infection rates and mortality for ethnic/racial minority groups.

It pointed out that minorities are more present in frontline jobs exposing them to COVID-19. They are also often segregated in overcrowded urban housing, centers and workplaces increasing the risks of COVID-19 infection and spread.

“Some people from ethnic/racial minority groups have been segregated in overcrowded urban housing centres and workplaces, the conditions of which can make physical distancing and self-isolation difficult, leading to increasing risks for the spread of COVID-19.”

The study pointed out that racial minorities are less likely to have health insurance and reduced access to health care, a significant factor in COVID-19 mortality.

“Health-care disparities are also likely to have a role in the high burden of COVID-19 among ethnic/racial minorities—eg, in the USA, Black or African American minorities and Hispanic groups are less likely to have health insurance, with consequent reduced health-care access and use.”

It also mentioned that culture plays a significant role

“The important role of culture, including places of worship, multigenerational households, and variation in social interactions might also have a role in increased risks of COVID-19”

They pointed out that comorbidities are more common in African and South Asian minority groups ie: stroke being more common in African populations in UK & USA. These comorbidities can contribute to differences in COVID-19 severity and mortality among certain minorities.

“Chronic conditions, especially diabetes, are comparatively common in African and South Asian minority groups in Europe and the USA. Stroke is more common in African populations in the UK and the USA, with moderate increased risk of coronary heart disease in South Asian groups compared with White populations. Other comorbidities including COPD, asthma, and infections such as tuberculosis might also be contributing to comparatively adverse outcomes in COVID-19.”

They mention that genetic differences in certain races can lead to higher risk profiles which may affect COVID-19 outcomes.

“the heterogeneity of ethnic/racial minority groups, whether African, Caribbean, South Asian (Indian, Pakistani, or Bangladeshi in the UK), Chinese, or other ethnicities, have diverse risk factor profiles, which might be important for COVID-19 outcomes.”

They continued stating that chronic diseases among minorities shows social and economic disadvantages for those groups.

“The high prevalence of chronic diseases in US and UK ethnic/racial minorities reflects social and economic disadvantages, and factors such as diet, cigarette smoking, alcohol use, and exposure to psychosocial stressors.”

They also mirrored other similar studies in stating that “very low serum concentrations of 25-hydroxyvitamin D are common in ethnic/racial minorities with darker skins in the UK and the USA.”

They go on to state that more studies are needed but that there is significant evidence COVID-10 mortality is higher among certain ethnic groups.

“After adjustment for age, Black men are 4·2 times more likely to have a COVID-19-related death and Black women are 4·3 times more likely than White ethnicity men and women in the UK”

After taking account of age and other sociodemographic characteristics and measures of self-reported health and disability, people of Bangladeshi, Pakistani, Indian, and mixed ethnicities also had a significantly increased risk of COVID-19-related death compared with those of White ethnicity

Sharpening the global focus on ethnicity and race in the time of COVID-19

Vitamin D deficiency in African Americans is associated with a high risk of severe disease and mortality by SARS-CoV-2

A letter published in the Journal of Human Hypertension showed significant evidence that Vitamin D deficiency in African Americans is associated with a high risk of severe disease and mortality by SARS-CoV-2. The mechanism proposed was reduced ACE2 due to vitamin D deficiency.

“the morbidity and mortality rates by COVID-19 in AA are the highest among many other populations, as well as the mortality rate is 6-fold higher compared with white people

Fig. 1: Imbalanced protective and harmful factors facing to COVID-19 infection in African Americans.

They continue that although comorbidities play a role, which are influenced by social influences such as socioeconomic status or environment…there are genetic differences that can also play a significant role in COVID-19 infection rates and mortality.

“There are many health disparities in AA like high incidence rates of obesity, diabetes, high blood pressure, cardiovascular and renal diseases, among others. The usual explanation for these differences is the low socioeconomic status and educational levels, the social environment, lifestyle habits, and less access to health care services. However, there are pieces of evidence that these non-favorable conditions are not enough, and there are other influential factors that may help to a better approach to the real problem, like some genetic polymorphism and epigenetic-driven changes “

Final Thoughts – Vitamin D, Race & COVID 19

In one study there was clear evidence that 25(OH) D levels were lower in certain minorities resulting in higher SARS-CoV-2 Positivity. If these ethnic minorities were to raise their mean serum 25(OH)D levels to a healthy 50 ng/mL they could significantly decrease their risk of COVID-19 infection, and mortality.

Black non-Hispanics with 25(OH)D< or = 20 ng/mL had a 19% SARS-CoV-2 positivity, Hispanics with 25(OH)D concentration = 21 ng/mL had 15% positivity, while white non-Hispanics with 25(OH)D concentrations near 26 ng/mL had a positivity near 8%. If black non-Hispanics had a mean 25(OH)D concentration near 26 ng/mL, it is projected that they would have a positivity of approximately 17%. Thus, the contribution of vitamin D status to positivity higher than for white non-Hispanics is 2%(19%–8%) ~20%, while that for Hispanics is 2%(15%–8%) to ~30%. Thus, while disparities in vitamin D status do not explain much of the ethnic/racial differences in SARS-CoV-2 positivity, if black non-Hispanics were to raise their mean serum 25(OH)D concentration to 50 ng/mL, they could lower risk by approximately 40%, Hispanics by ~50%, and white non-Hispanics by ~25%.

Another analysis of physician deaths in the UK showed that 18 of 19 doctors and dentists who died by 22 April 2020, were of black, Asian, and mixed ethnicity. Presumably, they were not of low socioeconomic status and had similar contact with patients as their white counterparts. They could have had low vitamin D status due to darker skin and/or vegetarian or vegan diets.

Vitamin D and BMI

There is a correlation between body mass index (BMI) and the bioavailability of vitamin D. This is because vitamin D is a fat soluble vitamin (it is stored in the fat). Therefore if you are overweight, your body can store more vitamin D, which means you will have less soluble vitamin D available for your body to use.

“Because humans obtain most of their vitamin D requirement from casual exposure to sunlight, the >50% decreased bioavailability of cutaneously synthesized vitamin D3 in the obese subjects could account for the consistent observation by us and others that obesity is associated with vitamin D deficiency. Oral vitamin D should be able to correct the vitamin D deficiency associated with obesity, but larger than usual doses may be required for very obese patients.”

Decreased bioavailability of vitamin D in obesity

As a result of this increased capacity, by overwieght individuals to store vitamin D, larger then normal doses of vitamin D may be required to reach optimal healthy blood levels of vitamin D.

Vitamin D, Hypertension and COVID 19

A meta-analysis of 34 studies titled Comorbidities and the risk of severe or fatal outcomes associated with coronavirus disease 2019: A systematic review and meta-analysis found that hypertension was a significant risk factor for several or fatal COVID-19 compared to non-severe/non-fatal COVID-19: OR = 3.2 (95% CI 2.5 to 4.1) [61]. Thus, prevalence of hypertension should have been considered when dividing patients into treatment and control groups.

Vitamin D and Vegan or Vegetarian Diets

In England, a study titled Plasma concentrations of 25-hydroxyvitamin D in meat eaters, fish eaters, vegetarians and vegans: results from the EPIC-Oxford study reported that vegans and vegetarians have 25(OH)D concentrations as much as 8 ng/mL lower than those of meat eaters.

“Plasma 25(OH)D concentrations were lower in vegetarians and vegans than in meat and fish eaters; diet is an important determinant of plasma 25(OH)D”

Plasma concentrations of 25-hydroxyvitamin D in meat eaters, fish eaters, vegetarians and vegans: results from the EPIC-Oxford study

Prof Roger Seheult Vitamin Ds role in prevention and treatment of COVID 19 (VIDEO)

Professor Roger Seheult, MD explains the important role Vitamin D may have in the prevention and treatment of COVID-19. Dr. Seheult illustrates how Vitamin D works, summarizes the best available data and clinical trials on vitamin D, and discusses vitamin D dosage recommendations.

Vitamin D Deficiency in Pregnant Women

Vitamin D deficiency is thought to be common among pregnant women. Regaining optimal levels of Vitamin D is critical for you and your baby.

“Large epidemiological studies reveal the high prevalence of vitamin D in women, including antenatal and lactating mothers.[3 , 4 , 5]”

“Vitamin D requirements are probably greater in pregnancy, as evidenced by physiologically higher 1,25-dehydroxy vitamin D levels seen in the second and third trimesters. While 1,25(OH) 2D levels do not correlate directly with 25 hydroxy vitamin D concentrations, the physiological rise in the active metabolite, the enhanced intestinal calcium absorption, and enhanced fetal requirement of calcium (250 mg/day in the third trimester) all point to the importance of vitamin D biology in pregnancy.[6]”

Vitamin D supplementation in pregnancy – US National Library of Medicine

“The daily upper safe limit for vitamin D has been set at 4000 IU by IOM and 10,000 IU by the Endocrine Society.[26 , 28]”

Vitamin D supplementation in pregnancy – US National Library of Medicine

“Vitamin D supplementation during pregnancy improves maternal vitamin D status and may reduce the risk of pre-eclampsia, low birthweight and preterm birth.”

World Health Organization

How to test vitamin D levels

You can obtain a lab test from your doctor, or you can order a mail in lab test from imaware mail-in vitamin d test for only $70 .They send you a small kit, it only requires a simple fingertip pin prick and a few droplets of your blood sent back to get a detailed report of your vitamin d levels. It’s cheaper and faster and just as accurate as your doctors lab ordered vitamin d tests. Take the test on a normal day that matches your average daily sun exposure to ensure accuracy.

Dr. Mercola Mail in Vitamin D tests

Dr. Mercola also provides Vitamin D, and combo Vitamin D mail-in test kits. They are fairly affordable and very accurate.

Simply follow the directions in the kit to collect a small blood sample, mail it in, and fill out a quick and easy online health questionnaire through GrassrootsHealth (which will take you 5 to 10 minutes to complete).

After filling out the questionnaire, you will receive an email when your test results are ready. This is usually within 7 to 10 days after receipt of your sample.

Vitamin D supplementation

Healthy blood levels of Vitamin D - Deficient <30 ng/mL. Insufficient 30-50 ng/mL. Optimal 51-70 ng/mL. Treatment for heart condition 71-100 ng/mL. Too high >100 ng/mL
Healthy blood levels of Vitamin D | Chart

There is no international standard for vitamin D supplementation dosage, however different countries have different recommendations from their cooresponding publis health authorities.

“The recommended daily intake of vitamin D ranges from 400 to 600 IU (by the IOM),[26] 400 IU (by the National Institute for Health and Clinical Excellence, United Kingdom),[27] and to 1500-2000 IU (by the Endocrine Society),[28] and 2000 IU (by the Canadian Society).[29] The daily upper safe limit for vitamin D has been set at 4000 IU by IOM and 10,000 IU by the Endocrine Society.[26 , 28]”

Vitamin D supplementation in pregnancy – National Institutes of Health

Supplementation of vitamin D can lead to fractures, and when taken with calcium supplements, it has been shown in some studies to be associated with a modest increase in Myocardial Infarction or arterial calcification.

  • Levels of 30-40 ng/mL are recommended for prevention of fractures
  • Levels over 150 ng/mL are associated with hypercalcemia
  • Some recommendations are 4,000 IU and others up to 10,000 IU
  • 20 minutes of normal sun exposure generates around 20,000IU of vitamin D. So some doctors even recommend up to 40,000IUs (which equals about 40 minutes of sun exposure). Obviously if you are getting less sun exposure due to your lifestyle and where you live, a higher dose may be required, as opposed to someone that for example, works outside in the sun all day.

“increasing evidence suggests that 30 ng/mL or even 40 ng/mL may be required for optimum health [19, 20, 21, 22, 23, 24, 25] Indeed, several authors argue that current recommended doses of vitamin D supplementation are woefully inadequate to meet higher serum 25(OH)D levels on a population level [22, 26,27,28]”

“Current recommendations for vitamin D supplementation are inadequate to address the growing epidemic of vitamin D insufficiency.””

Demographic Differences and Trends of Vitamin D Insufficiency in the US Population, 1988-2004

Recommended Dose for Pregnant Women

The Institute of Medicine (IOM) recommendations suggest a normal level of 20 ng/ml in pregnancy, while the Endocrine Society recommends 30 ng/ml or more.[24 , 25] but what IU dose of Vitamin D do I take to achieve those levels? Well results from a recent study found women taking 4,000 IU of vitamin D daily had the greatest benefits in preventing preterm labor/births and infections.

“Results of the recently conducted randomized controlled trial on vitamin D supplementation in pregnancy suggest a safe dose of 2000-4000 IU/day.[14 , 20 , 21 , 22]”

Vitamin D supplementation in pregnancy – National Institutes of Health

Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline

Lets take a close look at this study titled Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline which gives us some guidelines for Vitamin D supplementation.

AgeDose
0-6m1000 IU/d
6m-1y1500 IU/d
1y-3y2500 IU/d
4y-8y3000 IU/d
8y+4000 IU/d
Recommended Vitamin D Supplementation by age group

“We suggest that the maintenance tolerable upper limits (UL) of vitamin D, which is not to be exceeded without medical supervision, should be 1000 IU/d for infants up to 6 months, 1500 IU/d for infants from 6 months to 1 yr, at least 2500 IU/d for children aged 1–3 yr, 3000 IU/d for children aged 4–8 yr, and 4000 IU/d for everyone over 8 yr.However, higher levels of 2000 IU/d for children 0–1 yr, 4000 IU/d for children 1–18yr,and10,000 IU/d for children and adults19yr and older may be needed to correct vitamin D deficiency”

Evaluation, Treatment, and Prevention of Vitamin D
Deficiency: an Endocrine Society Clinical Practice
Guideline

Is body weight a factor in how much vitamin D you should supplement?

To answer just that question a study analyzed The importance of body weight for the dose response relationship of oral vitamin D supplementation and serum 25 (OH) D in over 17,000 healthy volunteers.

The pool of participants included existing 25 (OH) D levels of 4-158 ng/mL) and they supplemented with anywhere from 0-55,000 IU per day of vitamin D.

The study essentially found that the first 1,000IUs of supplemented vitamin D showed a huge increase in blood levels of vitamin D (4.8 ng/ml) but as the dosage increased up to 50,000 IU the blood levels of vitamin D did not increase nearly the same amount (as shown in the chart below)

The importance of body weight for the dose response relationship of oral vitamin D supplementation and serum 25 (OH) D in healthy volunteers - Charts.
The importance of body weight for the dose response relationship of oral vitamin D supplementation and serum 25 (OH) D in healthy volunteers – Charts

The study also showed that BMI played a role as well. Those that are overweight (BMI 26-30) had on avg 3 ng/ml less Vitamin D blood levels and vitamin. In addition it took 1.5x more supplemented vitamin D to get the same increase in vitamin D blood levels as a healthy individual.

Obese individuals had on avg 8 ng/ml less vit d levels and needed 3x more supplemented vit d to get the same increase in vitamin D blood levels as a healthy individual.

The effects of BMI on vitamin D are in large part because again, it is a fat soluble vitamin.

Vitamin D Fortification of Fluid Milk Products and Their Contribution to Vitamin D Intake and Vitamin D Status in Observational Studies

A review of Vitamin D Fortification of Fluid Milk Products and Their Contribution to Vitamin D Intake and Vitamin D Status in Observational Studies was published Aug 9 2018. It shows that in most countries Vitamin D fortified milk products are present. In Sweden an Canada it’s mandatory. In Norway and Finland it’s voluntary but everyone is doing it, so it’s almost as if it’s mandatory. And in United states it’s voluntary, and although some companies do fortify their products with Vitamin D, many do not.

Vitamin D Fortification of Fluid Milk Products and Their Contribution to Vitamin D Intake and Vitamin D Status in Observational Studies - Vitamin D fortification by country
Vitamin D Fortification of Fluid Milk Products and Their Contribution to Vitamin D Intake and Vitamin D Status in Observational Studies – Vitamin D fortification by country

Ireland does not have a formal vitamin D fortification strategy, and the COVID-19 pandemic, along with research of vitamin D’s positive impact on viral infection, has many countries re-evaluating their policy of mandatory vitamin D supplementation.

“Ireland does not have any formal vitamin D food policy – we practice a voluntary but not mandatory food fortification policy where food manufacturers can decide to fortify (or not) their food products with Vitamin D. The vitamin D status of those in ireland is lower than either the United States or Canada who have systemic (mass) vitamin D food fortification. However, vitamin D deficiency is not inevitable in older adults in ireland, and the ability to have sufficient vitamin D status year round is an achievable goal that many countries meet. For example, another European country – Finland (which is at a much higher latitude and therefore receives less sunshine than Ireland) has virtually eliminated vitamin D deficiency in it’s population with rates <1%. This is due in part to a successful food fortification and vitamin D supplement policy and educating the public and medical practitioners on the importance of vitamin D. This vitamin D success story demonstrates what could be achieved in Ireland.

Laird E, Kenna RA (2020) Vitamin D deficiency in ireland – implication for COVID-19 – results from the Irish Longitudinal Study on Ageing (TILDA). TILDA, Dublin.

Vitamin D Toxicity

In a study was published Sep 20 2018, titled Vitamin D Toxicity–A Clinical Perspective. The Endocrine society and the IOM (Institute of Medicine) both stated vitamin D toxicity is extremely rare and that concentrations of 25 (OH) would need to exceed 150 ng/mL (375 nmol/L) and additionally requires increased calcium intake. Ultimately they stated that vitamin D is one of the least toxic fat soluble vitamins).

In fact one scientists Dudenkov researched over 20,000 patients serum 25 (OH) D levels and found only one patient with a 25 (OH) D concentration of 364 ng/mL (910 nmol/L), who was diagnosed with hypercalcemia.

Another researcher Pietras reported on healthy individuals in a clinical setting receiving 50,000IU of vitamin D2 once every two weeks for up to 6 years, maintained safe 25 (OH) D concentrations of 40-60ng/ml (100-150 nmol/L) without any evidence of VDT or other side effects.

Canadian researcher Ekwaru found Canadian adults who ingested up to 20,000 IU of vitamin D3 per day had a significant increase of 25 (OH) D concentrations, up to 60ng/ml (150 nmol/L), but without any evidence of toxicity.

A study titled Factors associated with COVID-19-related death using OpenSAFELY was published in nature July 8 2020 analyzed 17 million patients totaling 10k COVID-19 deaths found those higher in age are more likely to die from COVID-19, with a direct correlation between age over 40 and likelihood of death from COVID-19 infection.

High risk groups include:

  • Males have a higher risk of death from COVID
  • As the obesity level goes up risk of death from COVID goes up
  • Mixed, South Asian, Black and other ethnicities have an increased chance of death from COVID as opposed to white ethnicities

Coincidently: old age, increased obesity and darker skin color were the same three things that put people at risk for Vitamin D deficiency. This shows that vitamin D may have a role in the mortality and morbidity of COVID-19.

A review of Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity

A review of 14 studies was published titled Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity headed by Dr. Mercola, which presented compelling evidence from multiple studies, that vitamin D can reduce the incidence of COVID-19 infection and when infected can significantly reduce lung damage through multiple mechanisms.

The role of vitamin D regarding ACE in response to SARS-CoV-2. ACE: angiotensin-converting enzyme.
Figure 2 The role of vitamin D regarding ACE in response to SARS-CoV-2. ACE: angiotensin-converting enzyme.

Vitamin D Helps Immune Cells Produce Antimicrobial Peptides

To oversimplify Vitamin D activates immune cell production of AMPs including cathelicidins and defensins, which are antiviral, antimicrobial and participate in a wide range of immune system activities, which include destruction of proteins that envelop viruses, and help block viral entry into your cells.

Source Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity

“Many studies have shown that vitamin D activates immune cells to produce AMPs, which include molecules known as cathelicidins and defensins [64, 65, 66, 67]. AMPs have a broad spectrum of activity, not only antimicrobial but also antiviral, and can inactivate the influenza virus [68]. The antiviral effects of AMPs are the result of, among other effects, the destruction of envelope proteins by cathelicidin [69, 70, 71].” See Figure

Figure 1. The cascade of events by the innate immune system in response to viral infections. Among the functions of AMPs (antimicrobial peptides) is chemotaxis, the movement of cells in response to a chemical stimulus, here macrophages, mast cells, monocytes, and neutrophils. Other effects include activation of the innate immune system, effects on angiogenesis, antiendotoxin activity, and opsonization (the molecular mechanism whereby pathogenic molecules, microbes, or apoptotic cells (antigenic substances) are connected to antibodies, complement, or other proteins to attach to the cell surface receptors on phagocytes and NK cells). LMS (lipopolysaccharide) --Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity | COVID 19 and Vitamin D
Figure 1. The cascade of events by the innate immune system in response to viral infections. Among the functions of AMPs (antimicrobial peptides) is chemotaxis, the movement of cells in response to a chemical stimulus, here macrophages, mast cells, monocytes, and neutrophils. Other effects include activation of the innate immune system, effects on angiogenesis, antiendotoxin activity, and opsonization (the molecular mechanism whereby pathogenic molecules, microbes, or apoptotic cells (antigenic substances) are connected to antibodies, complement, or other proteins to attach to the cell surface receptors on phagocytes and NK cells). LMS (lipopolysaccharide) —Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity

“Cathelicidins are a distinct class of proteins present in innate immunity of mammals. In humans, the primary form of cathelicidin is known as LL-37 [72]. LL-37 also blocks viral entry into the cell similarly to what is seen with other antimicrobial peptides [73].”

A brief review of interplay between vitamin D and angiotensin-converting enzyme 2: Implications for a potential treatment for COVID-19

A study titled A brief review of interplay between vitamin D and angiotensin-converting enzyme 2: Implications for a potential treatment for COVID-19, published on Jun 25 2020 found that SARS-CoV-2 tested positive less in those with vitamin D levels from 40-50 ng/mL, and stated that this may be due to the effect of vitamin D in reducing survival and replication of the virus by induction of cathelicidin and defensins as well as by increasing concentrations of free ACE2, thereby preventing SARS-CoV-2 from entering cells via the ACE2 receptor.

It also noted that a new strain D614G from Europe, which was introduced to New York from people traveling to Europe, has greater transmission, a genetic change which may account for somewhat higher SARS-CoV-2 positivity in the north, as opposed to reduced vitamin D in those regions being the sole cause.

Vitamin D Reduces Inflammatory Cytokine Production

To oversimplify, Vitamin D can reduce inflammatory cytokine production, which leads to reduced vascular injury, and consequently severity of the cytokine storm associated with COVID-19 infection.

“Elevated inflammation is an important risk factor for COVID-19 [16]. For example, much of the pathogenesis surrounding COVID-19 infection involves microvascular injury induced by hypercytokinemia, namely, by an important inflammatory cytokine—interleukin 6 (IL-6) [74,75]. Thus, it is useful to examine the role of vitamin D in reducing inflammation.

A number of reviews have suggested that one of the hallmarks of COVID-19 severity is the presence of a “cytokine storm” [76, 77, 78, 79]. The “cytokine storm” is defined as the state of out-of-control release of a variety of inflammatory cytokines [79]. Observational studies, however, have found that cytokine concentrations are elevated in COVID-19 patients compared to controls, but not as high as in some other diseases.”

Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity

Cytokine Levels in Critically Ill Patients With COVID-19 and Other Conditions | Study

A study In the Netherlands published Sep 3 2020 titled Cytokine Levels in Critically Ill Patients With COVID-19 and Other Conditions analyzed COVID-19 patients. The study split patients into groups: Septic shock, septic shock with ARDS, cardiac arrest (OHCA) and trauma. It then compared for each of these groups, proinflammatory cytokines tumor necrosis factor TNFalpha, IL-6 and IL 8 levels. It found evidence that COVID-19 patients have increased proinflammatory cytokines tumor necrosis factor TNFalpha, IL-6 and IL 8 levels.

“A study in the Netherlands compared cytokine levels in critically ill patients [80]. The study
involved 46 COVID-19 patients, 51 with septic shock with acute respiratory tract syndrome (ARDS), 15 with septic shock without ARDS, 30 with out-of-hospital cardiac arrest (OHCA), and 62 with trauma. Levels of (TNFalpha) for COVID-19 patients were lower than for septic shock patients but higher than for OHCA or trauma patients. Levels of IL-6 and IL-8 for COVID-19 patients were lower than for septic shock patients but comparable with those for OHCA and trauma patients.”

Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity

Characterization of the Inflammatory Response to Severe COVID-19 Illness | Review

A review published in the National Library of Medicine Sep 15 2020 titled Characterization of the Inflammatory Response to Severe COVID-19 Illness presented evidence that IL-6 concentrations were highly correlated with age-stratified COVID-19 deaths.

“A recent review examined whether IL-6 concentrations might affect the outcome of COVID-19 [75].The evidence presented included age-stratified IL-6 concentrations from a healthy Italian population were highly correlated with age-stratified Italian COVID-19 deaths, which in turn were highly correlated with age-stratified COVID-19 death rates in the UK.

The researchers also cited trials of vitamin D supplementation and its effect on IL-6 concentrations, of which eight of 11 showed a significant lowering of IL-6. People for whom a significant lowering was not found were healthy older adults, asthma patients, and prediabetic adults.

That review showed how IL-6 increases the severity of COVID-19 by upregulating angiotensin-converting enzyme 2 (ACE2) receptors and induction of macrophage cathepsin L. Cathepsin L mediates the cleavage of the S1 subunit of the coronavirus surface spike glycoprotein. That cleavage is necessary for coronavirus entry into human host cells, virus–host cell endosome membrane fusion, and viral RNA release for the next round of replication [81]”

Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity
Ireland Study on Cytokine Concentrations of Healthy Vs ICU COVID-19 patients | Study

The same study form Ireland also found ICU COVID-19 patients had much higher cytokine concentrations (IL-1, IL-6, IL-6 to IL-10 ratio, and tumor necrosis factor receptor superfamily member 1A – TNFR1) than stable COVID-19 patients, who were on par with healthy control groups.

A study from Ireland investigated cytokine concentrations of healthy controls, stable COVID-19 patients, ICU COVID-19 patients, and ICU community-acquired pneumonia patients. ICU-COVID-19 patients had the highest concentrations of IL-1, IL-6, IL-6 to IL-10 ratio, and tumor necrosis factor receptor superfamily member 1A (TNFR1). Stable COVID-19 patients had concentrations that were between the levels noted for healthy controls and those of ICU COVID-19 patients for all of the cytokines. ICU-community-acquired pneumonia patients had inflammatory cytokine concentrations between stable and ICU COVID-19 patients but higher IL-10 concentrations.

COVID-19-associated hyperinflammation and escalation of patient care: a retrospective longitudinal cohort | Study

A study posted on the Lancet Aug 21 2020 titled COVID-19-associated hyperinflammation and escalation of patient care: a retrospective longitudinal cohort study was conducted on 269 polymerase chain reaction (PCR)-confirmed COVID-19 patients admitted to two UK hospitals in March. The study found that COVID-19 patients with hyperinflammation were more at risk for escalation to respiratory support or death (40% with hyperinflammation died vs 26% who didn’t have hyperinflation.) This shows that hyperinflation is associated with COVID -19 severity and death. Therefore logically treatments which can reduce inflammation or hyperinflation can help reduce infection COVID severity and death rates, through inflammatory reducing mechanisms.

Hyperinflammation was defined as CRP concentration greater than 150 mg/L or doubling within 24 h from greater than 50 mg/L, or a ferritin concentration greater than 1500 ug/L. Ninety (33%) of the patients met the criteria for COV-HI at admission. Forty percent of COV-HI patients died compared to 26% of the non-COV-HI patients. Meeting the COV-HI criteria was significantly associated with risk of next-day escalation of respiratory support or death (hazard ratio = 2.24 (95% CI, 1.62 to 2.87)).”

Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity

Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study

Another study posted on the Lancet Sep 29 2020 titled Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study found that Vitamin D may can help with cytokinaemia associated with COVID-19, however it was unclear if it could help with some of the other mechanisms by which COVID-19 inflicts damage such as macrophage activation, haemotological dysfunction related to neutrophils and lymphocytes, coagulopathy or hepatic injury.

“The criteria included elevated temperature, macrophage activation (elevated ferritin), haemotological dysfunction related to neutrophils and lymphocytes, coagulopathy (elevated D-dimer), hepatic injury (elevated lactate dehydrogenase or aspartate aminotransferase concentration), and cytokinaemia (elevated IL-6, triglyceride, or CRP concentration). It is not clear whether vitamin D supplementation could affect any of these factors other than cytokinaemia.”

Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity

Other studies showing elevated cytokines with COVID-19 infection

  1.  Characterization of the Inflammatory Response to Severe COVID-19 Illness
  2. Coronavirus disease 2019 (COVID-19): cytokine storms, hyper-inflammatory phenotypes, and acute respiratory distress syndrome
  3. The possible pathophysiology mechanism of cytokine storm in elderly adults with COVID-19 infection: the contribution of “inflame-aging”

Why Cytokine Storm is Associated With Severe COVID-19 and Death

Essentially there are two primary mechanisms through which COVID-19 effects a cytokine storm 1. intravascular coagulation and 2. it affects endothelial cells leading to cell death, vascular leakage and induces a cytopathic effect on airway epithelial cells.

“There are several reasons why the cytokine storm is associated with severe COVID-19 and death [86,87]. As outlined in the review by Hojyo [86], the hypothesis that the main cause of death of COVID-19 is ARDS with cytokine storms can be explained by at least two reasons. One is intravascular coagulation as an important cause of multiorgan injury, which is mainly mediated by inflammatory cytokines such as IL-6 [88]. The other is that the SARS-CoV-2 virus affects endothelial cells, causing further cell death, which leads to vascular leakage and induces a cytopathic effect on airway epithelial cells [89].”

Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity

Vitamin D can limit RAS-Mediated Bradykinin Storm in COVID-19

Several recent publications looked at the role of bradykinin (BK) in the progression of COVID-19. In a report titled A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm stated:

“Jacobson used the Summit supercomputer at Oak Ridge National Lab in Tennessee; the second fastest supercomputer in the world. And in the summer of 2020 analyzed data on more than 40,000 genes from 17,000 samples from COVID-19 patients. The analysis revealed that SARS-CoV-2 actively upregulates ACE2 receptors in places where they’re typically expressed at low levels, including the lungs.”

“Additionally, an imbalance in RAS was also found, represented by decreased ACE in combination with increases in ACE2, renin, angiotensin, key RAS receptors, kininogen and many kallikrein enzymes that activate it, and both BK receptors, which produces a BK storm.

Since BK dilates blood vessels and increases permeability, excessive BK leads to fluid to soft tissue fluid accumulation. This leads to several adverse effects seen in COVID-19 patients, including on the heart, vascular system, pulmonary system, brain, and muscles

Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity

To oversimplify Renin which is found elevated in COVID-19 patients, plays a role in RAS imbalance, which together with other factors produces a Bradykinin Storm (BK). Vitamin D is a negative endocrine RAS modulator and inhibits renin expression and generation [40], thus disrupting the production of BK Storm.

“and it appears likely that vitamin D deficiency amelioration (improvement) would limit the COVID-19 BK storm. However, further investigation is needed to evaluate the role of vitamin D in this context”

Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity

COVID-19 and Type II Pneumocytes and Surfactants in the Lungs

“The type II pneumocytes in the lung are the primary target for coronaviruses because the ACE2 receptors to which the virus binds are highly expressed on those cells. One problem with COVID-19 is that it impairs the function of type II pneumocytes, which then decreases the surfactant concentration in the alveolar–air interface [90]. That is important because surfactant prevents the collapse of the alveoli.”

Essentially surfactant is essential during inhalation and exhalation to facilitate gas exchange across the alveoli wall. Without surfactant the alveoli can collapse, thus preventing your lungs from operating properly.

“Surfactant allows alveoli to stay open and compliant during both inhalation and exhalation. During inhalation, alveoli may collapse if they do not contain surfactant. If they collapse, gas exchange across the alveoli wall cannot occur. Without surfactant, each breath taken is like blowing up a collapsed balloon and then letting the air out of that balloon (lungs) and then doing it all over again with the next breath cycle. Simply put, having enough surfactant is necessary for alveoli to stay open and gas exchange to occur.”

“Another aspect of surfactant is its protein A (SP-A), which binds to influenza A viruses via its sialic acid residues and thereby neutralizes the virus [91]. Surfactant protein D clears influenza A from the lungs of mice [92]. There is some evidence that 1alpha,25(OH)2D increases surfactant production [93]. Such activity can be generalized to other viruses.”

Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity

Regulation of human pulmonary surfactant protein gene expression by 1α,25-dihydroxyvitamin D3 | Study

A study was published Oct 1 1005 titled Regulation of human pulmonary surfactant protein gene expression by 1α,25-dihydroxyvitamin D3 which showed evidence that 1alpha,25(OH)2D increases surfactant production.

Vitamin D, Angiotensin II, and ACE2 Receptors

The role of vitamin D regarding ACE in response to SARS-CoV-2. ACE: angiotensin-converting enzyme. | COVID 19 and Vitamin D
The role of vitamin D regarding ACE in response to SARS-CoV-2. ACE: angiotensin-converting enzyme.

“Angiotensin-converting enzyme (ACE) is part of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of bodily fluids. Angiotensin-converting enzyme 1 (ACE1) converts the hormone angiotensin I to the active vasoconstrictor angiotensin II [94]. Angiotensin II is a natural peptide hormone best known for increasing blood pressure through stimulating aldosterone [95] ACE2 normally consumes angiotensin I, thereby lowering its concentrations. However, SARS-CoV-2 infection downregulates ACE2, leading to excessive accumulation of angiotensin II. Cell cultures of human alveolar type II cells with vitamin D have shown that the SARS-CoV-2 virus interacts with the ACE2 receptor expressed on the surface of lung epithelial cells. Once the virus binds to the ACE2 receptor, it reduces its activity and, in turn, promotes ACE1 activity, forming more angiotensin II, which increases the severity of COVID-19 [96,97]. That effect may also be related to the vitamin D binding protein [98].

The vitamin D metabolite calcitriol increases expression of ACE2 in the lungs of experimental animals [99]. (Calcitriol has also been found to increase ACE2 protein expression in rat gmicroglia BV2 cells [100].) The additional ACE2 expressed as a consequence of vitamin D supplementation might reduce lung injury [101] because it can promote binding of the virus to the pulmonary epithelium. As mentioned, calcitriol also induces alpha-1-antitrypsin synthesis, which is vital for lung integrity and repair, by CD4+ T cells, which is required for the increased production of anti-inflammatory IL-10. Calcitriol should not be used to treat COVID-19 given the risk of hypercalcemia; however, vitamin D supplementation increases calcitriol concentrations [102] through its regulated conversion in the proximal tubules of the kidney and in extrarenal cells at the nuclear membrane.

High concentrations of angiotensin II may cause ARDS or cardiopulmonary injury. Renin, by contrast, is a proteolytic enzyme and a positive regulator of angiotensin II. Vitamin D is a potent inhibitor of renin. Vitamin D supplementation prevents angiotensin II accumulation and decreases proinflammatory activity of angiotensin II by suppressing the release of renin in patients infected with COVID, thus reducing the risk of ARDS, myocarditis, or cardiac injury [103]. Although vitamin D increases expression of ACE2, which promotes the binding of the virus, it prevents the constriction response of the lung blood vessel in COVID-19, as illustrated in Figure 2 [104] (permission to reuse granted by copyright holder). ARDS is also due to a variety of mechanisms, including cytokine storm, neutrophil activation, and increased (micro)coagulation, and it is likely that vitamin D supplementation would counter those mechanisms [105]. ARDS is responsible for approximately 70% of fatal COVID-19 cases [106].”

Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity

Vitamin D Reduces Risk of Endothelial Dysfunction

The endothelium is a layer of cells that line the blood and lymph vessels in the body, an area in which COVID-19 inflicts much of it’s damage.

Inflammation and coagulopathy are two hallmarks of severe COVID-19, which endothelial dysfunction plays a significant role in causing. A number of papers have discussed how vitamin D can reduce risk of ED.

Endothelial Dysfunction (ED) contributes to COVID-19-associated vascular inflammation and coagulopathy | Review

A review by Jun Zhang and colleagues, published Aug 12 2020 titled Endothelial dysfunction contributes to COVID-19-associated vascular inflammation and coagulopathy outlined how endothelial dysfunction (ED) contributes to COVID-19-associated vascular inflammation and coagulopathy. It identified Four stages of ED which contribute to inflammation and coagulopathy which are as follows:

  1. Stage 1 – Type I endothelial cell (EC) activation after infection by SARS-CoV-2 entering through the ACE2 receptor. That results in the loss of anticoagulant molecules.
  2. Stage 2 – Type II EC activation which leads to the de novo synthesis of procoagulant molecules.
  3. Stage 3 – endothelial apoptosis involving endothelial detachment and denudation of basement membrane.
  4. Stage 4 – endothelial necrosis.

Vitamin D deficiency in association with endothelial dysfunction: Implications for patients with COVID-19 | Review

Another review by Zhang and colleagues was published Sep 30 2020 in Reviews in Cardiovascular Medicine titled Vitamin D deficiency in association with endothelial dysfunction: Implications for patients with COVID-19 , which shows that vitamin D likely protects against ED by reducing oxidative stress and NF-kB activation.

1,25(OH)2D3 inhibits oxidative stress and monocyte adhesion by mediating the upregulation of GCLC and GSH in endothelial cells treated with acetoacetate (ketosis) | Study

A study published May 2016 titled 1,25(OH)2D3 inhibits oxidative stress and monocyte adhesion by mediating the upregulation of GCLC and GSH in endothelial cells treated with acetoacetate (ketosis) presented evidence for the following:

  1. 1,25(OH)2vitamin D inhibits ketone induced oxidative stress and monocyte adhesion in HUVEC.
  2. Beneficial effects of 1,25(OH)2vitamin D are impaired in cells that are deficient in glutathione.
  3. 1,25(OH)2vitamin D upregulates glutathione in a vitamin D receptor-dependent manner.

Vitamin D and Endothelial Function | Review

A review was published Feb 22 2020 titled Vitamin D and Endothelial Function which analyzed several studies to see the role that Vitamin D plays in Endothelial function.

“Vitamin D maintains endothelial function by reducing the production of reactive oxygen species as well as reducing proinflammatory mediators such as TNF-a and IL-6 and suppressing the NF-kB pathway”

Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity

Matrix Metalloproteinase 9 (MMP-9) and Lung Damage in COVID-19

MMP-9 plays a key role in Lung injury in acute lung diseases including in COVID-19 patients, and Vitamin D is vital to MMP-9 circulation. Therefore Vitamin D can help mitigate respiratory issues in severe COVID-19 infection.

“Matrix metalloproteinase-9 (MMP-9) is a member of the family of proteases that degrade extracellular matrix remodeling proteins. MMP-9 has been widely studied in acute lung injury
and acute lung disease”

Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity

ARDS is divided into three stages in which an initial inflammatory phase is followed by fibroproliferation, during which mesenchymal cells, in particular interstitial fibroblasts, migrate, replicate, and secrete extracellular matrix proteins such as collagen (3, 4). Unabated, this process can lead to established interstitial and intraalveolar fibrosis, the final phase.

Fibroproliferation Occurs Early in the Acute Respiratory Distress Syndrome and Impacts on Outcome

Matrix metalloproteinases in acute lung injury: mediators of injury and drivers of repair | Study

A study published in the EU Respiratory Journal (Vol 38 – Issue 4) titled Matrix metalloproteinases in acute lung injury: mediators of injury and drivers of repair elaborated on the role MMP-9 plays in Lung injury an acute lung diseases such as ARDS (Acute Respiratory Distress Syndrome.)

MMPs play a central role as both mediators and effectors of alveolar capillary membrane injury and repair in ALI/ARDS. Recent animal work and human studies demonstrate the role of inflammatory, mesenchymal and possibly epithelial cells that produce MMP-2, -3, -7, -8 and -9, in development of injury to the alveolar capillary membrane. Nonstructural ECM components important in chemotaxis such as syndecan-1/KC and MIP-1α have been shown to be important in mediating injury in experimental lung injury.”

rapid restitution of the epithelial barrier is likely to be important in limiting fibroproliferation. MMP-7 production by airway epithelium and degradation of syndecan-1 and E-cadherin has been shown to be important in facilitating cell migration in epithelial repair and MMP-9 production by DLECs has, more recently, also been demonstrated to be important in epithelial wound repair.

“targeting of MMP activity using broad-spectrum inhibitors has been shown to limit injury when used as a pre-injury treatment strategy and may also be of benefit when given early in the course of experimental lung injury”

Matrix metalloproteinases in acute lung injury: mediators of injury and drivers of repair

Distinct and early increase in circulating MMP-9 in COVID-19 patients with respiratory failure | Study

A study in Norway published Jun 27 2020 titled Distinct and early increase in circulating MMP-9 in COVID-19 patients with respiratory failure investigated correlations between respiratory failure and MMP-9 in 21 COVID-19 patients with respiratory failure in comparison with 7 COVID-19 patients without respiratory failure.

“Respiratory failure was defined as arterial partial pressure of oxygen to fraction of inspired oxygen ratio (P/F ratio) <40 kPa (300 mmHg), corresponding to the threshold in ARDS. The researchers found a significant inverse correlation of the P/F ratio with respect to the log10 (MMP-9) as well as significantly higher MMP-9 concentrations for P/F below the threshold than above it.”

Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity

Article Navigation Circulating MMP9, vitamin D and variation in the TIMP‐1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders? | Study

A study titled Article Navigation Circulating MMP9, vitamin D and variation in the TIMP‐1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders? published 2002 in the International Journal of Medicine, took a patient group of 171 healthy British Bangladeshi adults

“Vitamin D status was the sole determinant of circulating MMP-9 (inversely)
and an independent determinant of CRP (inversely)”

“Vitamin‐D insufficiency is associated with increased circulating MMP2,9 and CRP, correctable by supplementation. This finding provides a possible mechanism for tissue damage in chronic inflammatory conditions, including CHD and diabetes.”

Article Navigation Circulating MMP9, vitamin D and variation in the TIMP‐1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders?

1alpha,25-dihydroxyvitamin D3 inhibits matrix metalloproteinases induced by Mycobacterium tuberculosis infection | Study

A study titled 1alpha,25-dihydroxyvitamin D3 inhibits matrix metalloproteinases induced by Mycobacterium tuberculosis infection found that Mycobacterium tuberculosis induced the production of MMP-1, MMP-7, and MMP-10. MMP-9 gene expression, secretion and activity were significantly inhibited by 1a,25(OH)2D3 irrespective of infection.

“Matrix metalloproteinases (MMP) can degrade all components of pulmonary extracellular matrix. Mycobacterium tuberculosis induces production of a number of these enzymes by human macrophages, and these are implicated in the pathogenesis of pulmonary cavitation in tuberculosis. “

“1α,25(OH)2D3 significantly attenuated M. tuberculosis-induced increases in expression of MMP-7 and MMP-10, and suppressed secretion of MMP-7 by M. tuberculosis-infected PBMC. MMP-9 gene expression, secretion and activity were significantly inhibited by 1α,25(OH)2D3 irrespective of infection.”

“1α,25(OH)2D3 also induced secretion of IL-10 and PGE2 from M. tuberculosis-infected PBMC. These findings represent a novel immunomodulatory role for 1α,25(OH)2D3 in M. tuberculosis infection.”

1alpha,25-dihydroxyvitamin D3 inhibits matrix metalloproteinases induced by Mycobacterium tuberculosis infection

Vitamin D and COVID-19 Infection Positivity

Immunophenotype of COVID-19 and Vit D deficiency

The chart below shows an analysis of what COVID-19 looks like from a biochemical stand-point compared to what Vitamin D deficiency looks like. You will notice that COVID-19 and Vitamin D deficiency are identical with IL-6, Tumor necrosis factor alpha, gamma interferon, TH1 adaptive response, and coagulability (hypercoagulability), which were all elevated in both, and ACE2 expression was reduced in both conditions as well.

This doesn’t prove anything conclusively, but does give the idea that vitamin D may play a role in COVID-19.

Immunophenotype of COVID-19 and Vit D deficiency - COVID-19 and Vitamin D deficiency are identical with IL-6, Tumor necrosis factor alpha, gamma interferon, TH1 adaptive response, and coagulability (hypercoagulability), which were all elevated in both, and ACE2 expression was reduced in both conditions as well | COVID 19 and Vitamin D
Immunophenotype of COVID-19 and Vit D deficiency.

As well scientists note that during winter season, there are upticks in other types of infections such as rhinoviruses, influenza, and other viruses which shows that vitamin D may very well play role in many different types of viral infections.

However one thing that is very different in COVID-19 is this hypercoagulability which is much more pronounced then in other viruses.

Randomized trial of vitamin D supplementation to prevent season influenza A in schoolchildren

A japan study preformed a Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren analyzed 334 school children, which were given 1200 IU/d Vitamin D3 or they were given placebo and then they performed a nasal swab on the children to test for influenza a.

The study found that those who had the 1200 IU vitamin D3 had a 10.8% prevalence of influenza A, as opposed to the placebo group which had an 18.6% rate of influenza A infection. with 13 NNT (Number Needed to Treat.) which ultimately shows that the ability vitamin D supplementation in school children to reduce viral infection for influenza A is statistically significant. This is relevant to reducing COVID-19 viral infection as well.

A study was published on Sept 7 2020 which explored The link between vitamin D deficiency and Covid-19 in a large population. It analyzed 52,405 matched to 524,050 controls (sex, age, geographical region).

As the chart below shows that lower vitamin D levels are associated with increased SARS-CoV-2 infection, especially in females as denoted by the elevated red bars from 10-40 unit values of vitamin D, on the females chart

 The link between vitamin D deficiency and Covid-19 in a large population - Figure 2: Distribution of vitamin D measured in the blood between years 2010-2020 among individuals later infected with SARS-CoV-2 patients and the rest of the population | COVID 19 and Vitamin D
Figure 2: Distribution of vitamin D measured in the blood between years 2010-2020 among individuals later infected with SARS-CoV-2 patients and the rest of the population.

Low plasma 25(OH) vitamin D level is associated with increased risk of COVID-19 infection: an Israeli population-based study

A study published in the FEBS journal analyzed low plasma 25 (OH) vitamin D blood plasma levels, as an associated risk of increased COVID-19 infection. The study pooled 14,000 subjects with at least one test for COVID-19, and a previous vitamin D level on record.

6,000 subjects had to be excluded because they had no previous vitamin D level on record. However around 7,000 patients had both a COVID-19 test and a previous vitamin D level on record.

Study on low plasma 25 (OH) vitamin D blood plasma levels, as an associated risk of increased COVID-19 infection - Flow chart of the study design. Of 14 022 subjects, aged 2 months to 103 years, who were tested for COVID-19 infection, 1416 (10.1%) had at least one positive result; 12 606 (89.9%) had only negative results. After excluding the 6215 individuals without data on plasma 25(OH)D levels, the study sample composed of 7807 individuals. Also for this sample, the proportion of infected individuals was 10.02% (782/7807) for COVID-19-P, and 7025 (89.98%) for COVID-19-N | COVID 19 and Vitamin D Deficiency.
Flow chart of the study design. Of 14 022 subjects, aged 2 months to 103 years, who were tested for COVID-19 infection, 1416 (10.1%) had at least one positive result; 12 606 (89.9%) had only negative results. After excluding the 6215 individuals without data on plasma 25(OH)D levels, the study sample composed of 7807 individuals. Also for this sample, the proportion of infected individuals was 10.02% (782/7807) for COVID-19-P, and 7025 (89.98%) for COVID-19-N.

In an analysis of data (plotted on the left image – scatter graph) its of note that there was almost no senior age individuals 60-80yrs old that had high or healthy vitamin D levels.

The right flow chart shows that of the positive SARS-CoV-2 population, only a small amount had normal vitamin D levels, while the rest had low or ‘suboptimal levels of Vitamin D in their blood.

Left graph - (A) Distribution densities of plasma 25(OH) vitamin D levels (horizontcal axis) and age (vertical axis) among persons infected (A) and not infected (B) with COVID-19. The criterion for plasma vitamin D ‘suboptimal’ or ‘low’ status was < 30 ng/mL.
Right image - The likelihood of hospitalization due to COVID-19 according to two-risk factors: the low or high vitamin D levels and age groups, classified by: 0–25, 25–50, 50+ years. Most of the patients with the low vitamin D were COVID-19-P as shown on the scheme. | COVID 19 and Vitamin D Deficiency
Left graph – (A) Distribution densities of plasma 25(OH) vitamin D levels (horizontcal axis) and age (vertical axis) among persons infected (A) and not infected (B) with COVID-19. The criterion for plasma vitamin D ‘suboptimal’ or ‘low’ status was < 30 ng/mL.
Right image – The likelihood of hospitalization due to COVID-19 according to two-risk factors: the low or high vitamin D levels and age groups, classified by: 0–25, 25–50, 50+ years. Most of the patients with the low vitamin D were COVID-19-P as shown on the scheme.

The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality

Another study titled The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality published April 8th 2020 analyzed 20 European countries and their average vit D levels, COVID cases and Mortality.

What the study found was that the higher the vitamin D levels of that country, the lower the COVID 19 cases and mortality. Countries where the population had very high vitamin D levels above 50nmol/L experienced an almost 0 incidence of mortality from COVID-19.

25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2

A study published in Nutrients on May 7 2020 titled 25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2 (Nutrients) analyzed 107 patients hospitalized in Switzerland, testing vitamin D levels for those SARS-CoV-2 positive, and those who were not.

The study found that those who tested negative for SARS-CoV-2 in a PCR test had higher Vitamin D levels then those who tested positive for the infection.

SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels

A study published in the US Sep 17 2020 analyzed SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels on nearly 200,000 participants.

The study proved that vitamin D levels are inversely related with SARS-CoV-2 Positivity rate. Right below Vitamin D blood levels of 50 ng/mL SARS-CoV-2 infection rates rapidly increase.

SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels- Fig 1. SARS-CoV-2 NAAT positivity rates and circulating 25(OH)D levels in the total population.Smooth line represents the weighted second order polynomial regression fit to the data associating circulating 25(OH)D levels (x) and SARS-CoV-2 positivity rates (y) where: y = 0.2029–0.0052*x + 4.8e-05*x2; R2 = 0.96. SI conversion factor: 1 ng/mL = 0.400641 nmol/L | COVID 19 and Vitamin D
Fig 1. SARS-CoV-2 NAAT positivity rates and circulating 25(OH)D levels in the total population.Smooth line represents the weighted second order polynomial regression fit to the data associating circulating 25(OH)D levels (x) and SARS-CoV-2 positivity rates (y) where: y = 0.2029–0.0052*x + 4.8e-05*x2; R2 = 0.96. SI conversion factor: 1 ng/mL = 0.400641 nmol/L. 

Scientists analyzed data to see if geography, race age, or sex had any influence on this trend.

  1. Geography – Same correlation between lower vitamin D levels and increased risk of being SARS-CoV-2 positive. It did point out that higher rates of SARS-Cov-2 in Northern US above the 35th parallel vs the Central and southern states where it was relatively low.
  2. Race – Doesn’t matter what race you are. If you have lower vitamin D levels, you have increased risk of SARS-CoV-2 positivity. However darker skinned races did have a higher risk of SARS-CoV-2 positivity as opposed to lighter skinned races.
  3. Age – Age not a major factor. It did note that SARS-CoV-2 positivity is higher for <60 age groups than >60 age groups. Scientists already know infection is more prevalent among younger persons, however hospitalizations from COVID-19 infection are much higher for older populations.
  4. Sex – Sex is not a contributing factor; the trend remains. As vitamin d levels go down, SARS-CoV-2 positivity goes up.
Left column charts - Fig 2. SARS-CoV-2 NAAT Positivity Rates and Circulating 25(OH)D Levels, (A) by Latitude Region and (B) Predominately Black non-Hispanic, Hispanic, and White non-Hispanic Zip Codes. Smooth lines represent the weighted second order polynomial regression fit to the data associating circulating 25(OH)D levels (x) and SARS-CoV-2 positivity rates (y) where: Northern: y = 0.2544–0.0055*x + 5.2e-05*x2; R2 = 0.94. Central: y = 0.1745–0.0049*x + 4.7e-05*x2; R2 = 0.94. Southern: y = 0.1693–0.0052*x + 5.2e-05*x2; R2 = 0.90. Black non-Hispanic: y = 0.2948–0.0067*x + 5.8e-05*x2; R2 = 0.87. Hispanic: y = 0.2873–0.0083*x + 8.5e-05*x2; R2 = 0.95. White non-Hispanic: y = 0.1219–0.0021*x + 1.5e-05*x2; R2 = 0.92. SI conversion factor: 1 ng/mL = 0.400641 nmol/L | COVID 19 and Vitamin D
Left column charts – Fig 2. SARS-CoV-2 NAAT Positivity Rates and Circulating 25(OH)D Levels, (A) by Latitude Region and (B) Predominately Black non-Hispanic, Hispanic, and White non-Hispanic Zip Codes. Smooth lines represent the weighted second order polynomial regression fit to the data associating circulating 25(OH)D levels (x) and SARS-CoV-2 positivity rates (y) where: Northern: y = 0.2544–0.0055*x + 5.2e-05*x2; R2 = 0.94. Central: y = 0.1745–0.0049*x + 4.7e-05*x2; R2 = 0.94. Southern: y = 0.1693–0.0052*x + 5.2e-05*x2; R2 = 0.90. Black non-Hispanic: y = 0.2948–0.0067*x + 5.8e-05*x2; R2 = 0.87. Hispanic: y = 0.2873–0.0083*x + 8.5e-05*x2; R2 = 0.95. White non-Hispanic: y = 0.1219–0.0021*x + 1.5e-05*x2; R2 = 0.92. SI conversion factor: 1 ng/mL = 0.400641 nmol/L. 

Right column charts Fig 3. SARS-CoV-2 NAAT Positivity Rates and Circulating 25(OH)D Levels by (A) Age Group and (B) Sex. Smooth lines represent the weighted second order polynomial regression fit to the data associating circulating 25(OH)D levels (x) and SARS-CoV-2 positivity rates (y) where: Age <60: y = 0.2161–0.0058*x + 5.6e-05*x2; R2 = 0.94. Age ≥60: y = 0.1515–0.0030*x + 2.4e-05*x2; R2 = 0.91. Female: y = 0.1837–0.0045*x + 3.9e-05*x2; R2 = 0.94. Male: y = 0.2445–0.0068*x + 6.9e-05*x2; R2 = 0.94. SI conversion factor: 1 ng/mL = 0.400641 nmol/L. 

Vitamin D and COVID-19 severity and Mortality

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

A study was published on MDPI Oct 14 2021 which aimed to determine if low D3 is a result of infection or if deficiency negatively effects immune defense; consequently effecting COVID-19 mortality.

“strong evidence that low D3 is a predictor rather than just a side effect of the infection.”

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

The study analyzed “One population study and seven clinical studies” which “reported D3 blood levels pre-infection or on the day of hospital admission.” and found:

  1. “The two independent datasets showed a negative Pearson correlation of D3 levels and mortality risk (r(17) = −0.4154, p = 0.0770/r(13) = −0.4886, p = 0.0646).
  2. For the combined data, median (IQR) D3 levels were 23.2 ng/mL (17.4–26.8), and a significant Pearson correlation was observed (r(32) = −0.3989, p = 0.0194).”

“Regression suggested a theoretical point of zero mortality at approximately 50 ng/mL D3.”

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

In simple terms the meta-analysis found that D3 deficiency plays a role in COVID-19 infection; rather then COVID-19 infection causing Vitamin D deficiency. This is important because it supports that adequate vitamin D levels as a preventative measure against COVID-19 infection. In fact according to the study, it is theoretically possible to reach almost 0 COVID-19 mortality with blood levels of Vitamin D over 50ng/mL which equates to around 4,000-10,000 IUs supplemented daily (especially during the winter and cloudy days).

Dr. John Campbells review of the study | Video

Dr. John Campbell often preforms a concise and very straightforward review of studies on his YouTube channel.

Note: If you want to keep in the know regarding COVID-19, ide high recommend you subscribe to Dr. John Campbells YouTube Channel. Even the laymen will be able to grasp a basic understanding by watching his videos.

Dr. John Campbell review of 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 Part 1 Backup
Dr. John Campbell review of 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 Part 2 Backup

Patrick Holford – Flu Fighters Series – Other Approaches to COVID | Podcast

In this Podcast author of the Book Flu Fighters, Patrick Holford discusses with experts, Vitamin D and Ivermectin in prevention and early treatment of COVID-19.

A brief review of interplay between vitamin D and angiotensin-converting enzyme 2: Implications for a potential treatment for COVID-19

A study titled A brief review of interplay between vitamin D and angiotensin-converting enzyme 2: Implications for a potential treatment for COVID-19, published on Jun 25 2020 found that SARS-CoV-2 tested positive less in those with vitamin D levels from 40-50 ng/mL, and stated that this may be due to the effect of vitamin D in reducing survival and replication of the virus by induction of cathelicidin and defensins as well as by increasing concentrations of free ACE2, thereby preventing SARS-CoV-2 from entering cells via the ACE2 receptor.

It also noted that a new strain D614G from Europe, which was introduced to New York from people traveling to Europe, has greater transmission, a genetic change which may account for somewhat higher SARS-CoV-2 positivity in the north, as opposed to reduced vitamin D in those regions being the sole cause.

A meta-analysis of 25 RCT (Randomized controlled trials) studies on Vitamin D supplementation to prevent acute respiratory tract infections published in the British medical journal, analyzed if Vitamin D supplementation improved mortality in respiratory infections for non-COVID patients. The study results found that Vitamin D supplementation reduced the risk of acute ARI (Acute Respiratory illnesses).

“Our study reports a major new indication for Vitamin D supplementation: the prevention of acute respiratory tract infection. We also show that people who are very deficient in vitamin D and those receiving daily or weekly supplementation without additional bolus doses experienced particular benefit. Our results add to the body of evidence supporting the introduction of public health measures such as food fortification to improve vitamin d status, particularly in settings where profound vitamin D deficiency is common.

Vitamin D supplementation to prevent acute respiratory tract infections systematic review and meta-analysis of individual participant data (BMJ)

Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19

A study published in the New England Journal of Medicine May 20 2020, titled Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19, found during autopsies in patients with COVID-19, there was a 9 fold increase in blood clots in the lung tissue, when compared to autopsies of individuals without the infection.

Vitamin D deficiency in COVID-19: Mixing up cause and consequence

Scientists still had only shown that COVID-19 infection was associated with Vitamin D levels, not that low vitamin D levels caused COVID; it’s possible that SARS-CoV-2 infection may be causing vitamin D levels to go down.

In a letter to the editor titled Vitamin D deficiency in COVID-19: Mixing up cause and consequence published Nov 17 2020 scientists were able to prove that when somebody has an infection or is undergoing an immune response, plasma vitamin D levels did drop slightly (about 5 points).

However this was a modest drop, and does in no way prove COVID-19 specifically causes vitamin D deficiency, in those infected. It also only says that vitamin d levels can drop slightly in those only after infection, but does not address if low vitamin D levels can increase the incidence of infection.

Vitamin D deficiency in COVID-19: Mixing up cause and consequence - Plasma 25(OH)D levels (panel A) and cytokine concentrations (panel B) in response to LPS infusion in healthy volunteers. In panel A, data are depicted as individual datapoints and corresponding box-plots (whiskers: min-max), and dashed lines indicate median values at baseline (T = 0) and nadir (T = 2 and T = 3). P-value was calculated using Friedman test. *p < 0.05 vs. baseline, calculated using Dunn's post-hoc test. In panel B, data are presented as mean and SEM. Data of 9 subjects are shown in both panels | COVID 19 and Vitamin D
Plasma 25(OH)D levels (panel A) and cytokine concentrations (panel B) in response to LPS infusion in healthy volunteers. In panel A, data are depicted as individual datapoints and corresponding box-plots (whiskers: min-max), and dashed lines indicate median values at baseline (T = 0) and nadir (T = 2 and T = 3). P-value was calculated using Friedman test. *p < 0.05 vs. baseline, calculated using Dunn’s post-hoc test. In panel B, data are presented as mean and SEM. Data of 9 subjects are shown in both panels.

The argument for reverse causation

“…There is evidence that an acute-inflammatory disease state lowers
25(OH)D concentrations. A systematic review summarized results from eight studies reported between 1992 and 2013 regarding changes in 25(OH)D concentrations after acute inflammatory insult. Four studies involved surgery. One involving 19 patients undergoing cardiopulmonary bypass reported an 8 ng/mL drop in five minutes with return to near baseline after 24 h. Three involving knee or knee/hip arthroplasty or orthopedic surgery reported two-day decreases of 7 ng/mL, 4 ng/mL and 1 ng/mL for males, 3 ng/mL for females. There was no significant change for malarial infection and a one ng/mL decrease for acute pancreatitis. The largest decease was 15 ng/mL after three days for an injection of bisphosphonate. The nearest outcome to COVID-19 was malaria infection, for which no change was found. Thus, from these studies, it is unclear whether acute inflammation not associated with surgery results in reduction in 25(OH)D.

The argument against reverse causation

One argument Dr. Mercola made in the review is against “reverse causation”, was that infection and the inflammation it causes may cause the reduced Vitamin D levels.

“It can be argued that the association of low serum 25(OH)D concentrations with various diseases is due to “reverse causation”, i.e., that the disease state lowers the concentrations in proportion to the severity of the disease. That argument was made to explain why randomized controlled trials (RCTs) with vitamin D supplementation often fail to support observational studies reporting inverse correlations between 25(OH)D concentration and disease risk. However there are several counters to that argument.”

  1. Many vitamin D RCTs did not enroll participants with low 25(OH)D concentrations and did not supplement with sufficient vitamin D to produce a significant change in health outcome. Robert Heaney pointed out that vitamin D RCTs should be guided by serum 25(OH)D concentrations, not vitamin D dose.
  2. 25(OH)D concentrations used in prospective observational studies are obtained from blood drawn prior to the disease outcomes of interest. Only three observational studies were prospective studies with less than one year lag between blood draw and COVID-19 or SARS-CoV-2 positivity.

As you’ll see in this article below, many new studies have now shown that low blood serum levels of Vitamin D, is without a doubt directly related to increased COVID-19: infeciton rates, disease severity, hospitalization, ICU admission and mortality.

Vitamin D Supplementation in COVID-19 Patients: A Clinical Case Series | Study

A study titled Vitamin D Supplementation in COVID-19 Patients: A Clinical Case Series by Ohaegbulam and colleagues which involved four COVID-19+ patients in New York. Two, a male aged 41 years and a female aged 57 years, were given daily 50,000 IU vitamin D3 doses, whereas another two, males aged 53 and 74 years, were given five daily 1000 IU vitamin D3 doses. Baseline 25(OH)D concentration was between 17 and 22 ng/mL, whereas achieved 25(OH)D was 40 and 51 ng/mL for patients treated with high-dose vitamin D and 19 and 20 ng/mL for those treated with standard-dose vitamin D.

Biomarkers of inflammation were significantly reduced with high-dose treatment: CRP went from 31 to 2 mg/dL and from 17 to 8 mg/dL, compared with 13 to 22 mg/dL and 21 to 18 mg/dL for low-dose treatment; IL-6 went from 14 and 10 pg/mL to <5 pg/mL for high-dose treatment and from <5 and 6 pg/mL to <5 and 11 pg/mL for low-dose treatment.

The length of stay was 10 days for the high-dose patients and 13 and 14 days for the low-dose patients. The oxygen requirement went from zero and 15 L to zero for the high-dose patients and from 2 and 3 L to 2 and 7 L for the low-dose patients.

The strengths of this study include that high-dose vitamin D3 supplementation was used and that baseline and post-supplementation values for many parameters were measured. The main limitation was that only two patients were supplemented with high-dose vitamin D3.

Vitamin D Deficiency and Outcome of COVID-19 Patients

Another study on Vitamin D Deficiency and Outcome of COVID-19 Patients was published Sep 10 2020 also analyzed inpatient survival (hospitalized COVID-19 cases) with respect to vitamin D levels.

The study found those who had vitamin d blood serum levels >12 ng/mL (above) had a much better probability of survival vs those with levels under >12 ng/mL.

It also found a similar difference in survival probability for those >20 ng/mL vs those <20 ng/mL; although it was less of a difference to the 12 ng/mL sub-group.

Vitamin D Deficiency and Outcome of COVID-19 Patients - LEFT Graph - Cumulative incidence of invasive mechanical ventilation and/or death and probability of survival according to VitD status (<12 versus ≥12 ng/mL). (D) Survival probability according to VitD status in the inpatient subgroup. Abbreviations: CI, confidence interval; HR, hazard ratio; VitD, vitamin D.
RIGHT Graph - Figure A1. Cumulative incidence of invasive mechanical ventilation and/or death and probability of survival in patients with VitD < 20 versus ≥ 20 ng/mL. (D) Survival probability according to VitD status in the inpatient subgroup | COVID 19 and Vitamin D
LEFT Graph – Cumulative incidence of invasive mechanical ventilation and/or death and probability of survival according to VitD status (<12 versus ≥12 ng/mL). (D) Survival probability according to VitD status in the inpatient subgroup. Abbreviations: CI, confidence interval; HR, hazard ratio; VitD, vitamin D.
RIGHT GraphFigure A1. Cumulative incidence of invasive mechanical ventilation and/or death and probability of survival in patients with VitD < 20 versus ≥ 20 ng/mL. (D) Survival probability according to VitD status in the inpatient subgroup.

Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study

A study titled Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study.

Calcifediol is 25(OH)D3; the direct bioavailable formula which your body normally manufactures from vitamin D you ingest or absorb from sunlight. It is therefore different from normal Vitamin D supplements which are prepped to be metabolized by your body which then converts them to this form.

The study found that in the 2% of patients from intervention group (group with calcifediol treatment – dosed on days 1, 3 & 7) went to the intensive care unit vs 50% of the placebo group went to the intensive care unit.

Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study - Table 3
Requirements for admission to the Intensive Care Unit, in patients hospitalized with COVID-19 (treated or not with calcifediol) | COVID 19 and Vitamin D
Table 3
Requirements for admission to the Intensive Care Unit, in patients hospitalized with COVID-19 (treated or not with calcifediol)

In other words the study found that those who took calcifediol (direct bioavilable form of vitamin D) had a 25x lower incidence of Intensive Care Unit (ICU) admission during their hospitalization for COVID-19.

Cholecalciferol or Calcifediol in the Management of Vitamin D Deficiency | Study

A study out of Spain titled Cholecalciferol or Calcifediol in the Management of Vitamin D Deficiency was published Aug 29. Calcifediol [25(OH)D] is often used in Spain. It raises serum 25(OH)D concentration more quickly but does not last as long in the serum as a result of its lower lipophilia

In this study, 50 patients were given soft capsules of 0.532 mg of calcifediol on the day of admission, then 0.266 ng on day 3 and 7, and then weekly until discharge or admission to the intensive care unit (ICU). Thus, those in the treatment arm received approximately 130,000 IU of vitamin D during the first week, then approximately 33,000 IU/week thereafter. Serum 25(OH)D concentrations were not measured, but the calcifediol dose in the treatment arm was high enough to raise 25(OH)D concentration by approximately 20 ng/mL.

Forty-nine of the calcifediol-treated patients did not require the ICU, whereas 13 of the 26 not receiving that treatment did require the ICU. In addition, two of the patients admitted to the ICU died. The odds ratio (OR) for ICU in treated vs. control patients was 0.02 (95% CI, 0.002 to 0.17), which increased slightly when adjusted for hypertension and type 2 diabetes mellitus [OR = 0.03 (95% CI, 0.003 to 0.25)].

Vitamin D and survival in COVID-19 patients: A quasi-experimental study

A analysis in France of Vitamin D and survival in COVID-19 patients: A quasi-experimental study was published Oct 13 2020.

In France public health issues 80,000 IU Vit D every 2-3 months, on a random basis. So when people were admitted to the hospital with COVID -19 they checked 66 patients to see if they had received the 80,000 within 1 month prior to COVID 19 infection and which received the vit D further than 1 month prior to infection.

When analyzing this data the study found those who had received the vit D – 1 month prior (red line) had a much higher probability of survival, compared to those who received it longer then 1 month out (blue line).

 Vitamin D and survival in COVID-19 patients: A quasi-experimental study - Fig. 2 Kaplan-Meier estimates of the cumulative probability of participants’ survival according to the use of bolus vitamin D3 supplements during or just before
COVID-19 (n = 66). Red line intervention group who did get vit D in the previous 1 month prior to COVID-19 infection. Blue line control group who did not get vit D in the 1 month prior to COVID 19 infection | COVID 19 and Vitamin D
Fig. 2 Kaplan-Meier estimates of the cumulative probability of participants’ survival according to the use of bolus vitamin D3 supplements during or just before
COVID-19 (n = 66). Red line intervention group who did get vit D in the previous 1 month prior to COVID-19 infection. Blue line control group who did not get vit D in the 1 month prior to COVID 19 infection.

Effect of Vitamin D3 Supplementation vs Placebo on Hospital Length of Stay in Patients with Severe COVID-19

A study on the Effect of Vitamin D3 Supplementation vs Placebo on Hospital Length of Stay in Patients with Severe COVID-19 was published on Nov 12 2020 which analyzed 240 hospitalized patients, who received 200,000 IU of vitamin D3 or placebo.

The study concluded there was no differences in clinical outcomes including mortality or vent days. However the study had some faults…

  1. They only received a single dose of 200,000 IU of vitamin D3, where other studies specifically state that repeated daily or weekly doses of D3 are the most effective.
  2. Even in known working medications such as antibiotics, it is never distributed as a large single dose.
  3. The Vitamin D3 has to be metabolized in the liver to the 25 (OH), which can take some time. Meaning the severity of the infection can worsen before the vitamin d3 is converted to a form which the body can begin actively using.
  4. There is the possibility that the virus may effect the livers ability to metabolize Vitamin D3 or otherwise hamper it’s absorption, especially when it’s only given in one large, single dose.

Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomised, placebo-controlled, study

A more recent study from India titled Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomized, placebo-controlled, study analyzed 40 COVID-19 positive patients, 16 of which were given 60,000 IU vitamin D3 (oral nanoliquid) daily for 7 days and the control group of 24 was given a placebo. After 21 days they checked who was SARS-CoV-2 negative and was there any biomarker reductions.

The study found that at day 21 62.5% vs 20.8% were SARS-CoV-2 negative, in the intervention group (got the Vit D). As well Fibrinogen levels were significantly decreased in the intervention group.

In other words the study found those that received 60,000 IU’s of Vitamin D3 for 7 days had a roughly 3X lower SARS-CoV-2 positivity rate, compared to those who received placebo.

Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers

A study from India published Nov 19 2020 preformed an Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers, in a total of 154 individuals.

The study found that patients with blood serum levels of vitamin D above 20 ng/mL were more prevalent in the asymptomatic group (62) vs patients with vit. D levels under 20 ng/mL (29).

They also found those with higher vitamin D levels also had higher IL-6, TNF and ferritin levels (surrogate for inflammatory markers in COVID-19)

 Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers - Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers. Table 3 Inflammatory markers in relation to Vitamin D.
A (asymptomatic for 12 days) = 91
B (ICU Admission) = 63 | COVID 19 and Vitamin D
Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers. Table 3 Inflammatory markers in relation to Vitamin D.
A (asymptomatic for 12 days) = 91
B (ICU Admission) = 63

The study also analyzed fatality rates according to normal vitamin D levels vs deficient vitamin D levels and found that the fatality rate was much higher (21%) vs patients with a healthy vitamin D level (3.1%).

“When the fatality was compared on the basis of vitamin D deficiency, the fatality rate was 21% (19 patients died in 90 patients) among vitamin D deficient and 3.1% (2 patient died in 64) among patients with normal vitamin D level.”

Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers
Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers - Fatalities in normal Vitamin D vs Low Vitamin D | COVID 19 and Vitamin D
Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers – Fatalities in normal vit D vs Low vit D

They concluded:

“This all translates to increase morbidity and mortality in COVID-19 patients who are deficient in vitamin D. Keeping the current COVID-19 pandemic in view authors recommend administration of vitamin D supplements to population at risk for COVID-19.”

Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers

Conclusion

In conclusion vitamin D deficiency is an epidemic, with the highest frequency of individuals having deficient vitamin D blood levels from 25-45 25 (OH) D nmol/L, which are levels which make an individual more prone to viral infection and can increase severity of COVID-19 Infection.

There are numerous studies that show compelling evidence of Vitamin Ds benefits in preventing COVID infection, however there isn’t any current randomized control trial data that shows conclusively vitamin D is an effective COVID-19 treatment.

If you look at the risks of vitamin D supplementation against the potential benefits, it’s clear the Risk to Benefit ratio is high. Vitamin D is one of the safest vitamins to take as a supplement, with a very low chance of toxicity; only when taken in obscenely large doses of 200,000IU+ and usually when also supplemented with calcium.

For healthy individuals 18+ adults a vitamin D dose anywhere from 5,000 IU to 20,000 IU daily, can help raise blood levels of 25(OH) D to a healthy 50 ng/mL, ensuring a healthy Immune system that is able to reduce the incidence of viral infection, including that of COVID-19.

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