"Vitamin D and COVID-19"

There have recently been advances in the treatment of COVID-19. Clinical trials support intervention with steroids and antiviral drugs to shorten both the length and severity of illness. Vitamin D has also been suggested as both a prevention and treatment but as yet all positive evidence is indirect. However, the strength of the evidence has prompted several authorities to recommend Vitamin D supplementation on a population level. Vitamin D deficiency is easily treatable by supplements, which are very safe^[1].

Vitamin D is known as the sunshine vitamin being made by the action of sunlight on our skin. People living in higher latitudes tend to have lower levels of Vitamin D and increased mortality from COVID-19. In addition Vitamin D deficiency is more common in obese individuals, people with type 2 diabetes, hypertension, and most strikingly amongst ethnic minorities in Europe and North America, all of whom have higher mortality rates from COVID-19

According to the Royal Society, Vitamin D deficiency is associated with an increased risk of both respiratory viral infections and inflammatory conditions. Vitamin D has an important regulatory role in the human immune system, so a deficiency of Vitamin D is likely to cause immune dysregulation, which may reduce the first line of our defence against COVID-19^[2].

Charles Bangham, professor of immunology at Imperial College London and co-author of the Royal Society paper, said: “I started from quite a sceptical position, doubting whether vitamin D was going to play an important role in COVID-19, but I am now convinced that there is strong evidence that people who are deficient in vitamin D are more susceptible to acute respiratory tract infections^[3].”

Many countries have recommendations for use of vitamin D supplements. UK Government advice during the COVID-19 pandemic is that everyone should consider taking 10 micrograms (400iu) of vitamin D a day because they might not be getting enough from sunlight if they're indoors most of the day. Six medical societies from across the globe are also emphasizing the importance of individuals obtaining the daily recommended dose of vitamin D, especially given the impact of the COVID-19 pandemic on outdoor time. They felt the need to clarify the recommendations for clinicians. Central to the guidance is the recommendation to directly expose the skin to sunlight for 15 - 30 minutes per day, while taking care to avoid sunburn.

In Hong Kong with social distancing measures in place, particularly the closure of pools and beaches, it may be hard to achieve adequate daily sun exposure. This being the case individuals and families may wish to supplement with Vitamin D. According to Public Health England there are many brands, and formulations of vitamin D supplements that may have different recommended doses^[4]. This can make deciding which supplement to take difficult without health professional advice. If in doubt a blood test for Vitamin D status is readily available in Hong Kong and can allow your Doctor to guide your supplementation with Vitamin D.

References

1. Rhodes, J., Subramanian, S., Laird, E., Griffin, G., Kenny, R. (2020) Perspective: Vitamin D deficiency and COVID-19 severity –plausibly linked by latitude, ethnicity, impacts on cytokines,ACE2 and thrombosis. Journal of Internal Medicine. doi.org/10.1111/joim.13149

2. The Royal Society (2020) Vitamin D and COVID-19.Retrieved July 27, 2020, from https://royalsociety.org/-/media/policy/projects/set-c/set-c-vitamin-d-and-covid-19.pdf

3. Cookson, C. (2020). Vitamin D promoted as potential defence against coronavirus. Retrieved July 27, 2020, from https://www.ft.com/content/932920f9-f9ae-414a-940f-602169ee620f

4. McCall, B. (2020). Medical Societies Advise on Vitamin D in Midst of COVID-19. Medscape. Retrieved July 27, 2020 from https://www.medscape.com/viewarticle/933715

5. NICE (2020). COVID-19 rapid evidence summary: Vitamin D for COVID-19 Retrieved July 27, 2020 from https://www.nice.org.uk/advice/es28/chapter/Key-messages

"The First Clinical Trial to Support Vitamin D Therapy For Covid-19"

[Updated 27 Sept] Oral calcifediol reduced ICU admission for Covid-19 from 50% to 2%. And key questions about the trial answered.

Astudy from Spain finally presents the first clinical evidence for the use of vitamin D to treat Covid-19. The study, “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,” was published in The Journal of Steroid Biochemistry and Molecular Biology on 29 August. It is called a pilot because the sample size is small, but its randomization and prospective design still make it a robust research.

 

What the study did and found

Researchers randomly allocated 76 cases of Covid-19 into oral calcifediol (50 patients) or no-calcifediol control (26 patients) groups on the day of the hospital admission. Oral calcifediol was given at high doses at 0.532 mg on the first day and then at 0.266 mg on the third and seventh day, and then weekly until discharge or admission to the intensive care unit (ICU).

Calcifediol, also called 25-hydroxyvitamin D3 (vitamin D3), is the main metabolite (effector) of vitamin D. All patients also received the best available standard care at that time, which was hydroxychloroquine plus azithromycin.

Results revealed that 13 out of 26 patients (50%) in the control group were admitted to ICU, and two died in the end. In the calcifediol group, only one out of 50 (2%) required ICU admission, and none died.

Both calcifediol and control groups had similar baseline characteristics in terms of age, sex, comorbidities (lung, cardiovascular, and kidney diseases, type 2 diabetes, and immunosuppression), and clinical biomarkers of disease severity (oxygen levels, C-reactive protein, interleukin-6, ferritin, D-dimer, lactate dehydrogenase, and lymphocyte count). The only difference is that the control group had a higher prevalence of hypertension than the calcifediol group (57.69% vs. 24.19%).

Results revealed that 13 out of 26 patients (50%) in the control group were admitted to ICU, and two died in the end. In the calcifediol group, only one out of 50 (2%) required ICU admission, and none died. These results were statistically significant, equating to a 93% reduction in odds of ICU admission after adjusting for possible confounders (e.g., hypertension).

“Although this was a small trial, the ICU results are so dramatic that they are statistically highly significant,” stated a featured letter in The BMJ, a top-tier medical journal, in response to this clinical trial.

A few more questions about the study

1. What does the study not tell us?

All patients received standard care. Thus, it is not known if calcifediol would be effective on its own. And calcifediol is a medical drug used to treat parathyroid problems, so it is unclear if normal vitamin D supplementation would achieve the same effect.

Calcifediol is also 3.2-fold more effective than native vitamin D3 supplements in restoring low blood levels of vitamin D3.

The researchers also did not measure the vitamin D3 levels of the patients, but they were probably deficient based on prior population data. Still, it remains uncertain if vitamin D3 levels would affect the efficacy of calcifediol treatment for Covid-19. And other possible confounders in this study that the researchers did not measure are obesity, ethnicity, and socioeconomic status.

2. Why calcifediol over native vitamin D3?

Calcifediol is the actual hormonal effector of vitamin D3. Upon contact with sun rays (UV-B spectrum), the skin makes vitamin D3, which can also be taken as a supplement. The liver then converts vitamin D3 into 25-hydroxyvitamin D3, also called calcifediol or calcidiol that has wide-ranging effects on the immune system and other physiological systems. In this sense, calcifediol is a better biomarker for the body’s stores of vitamin D3.

Calcifediol is also 3.2-fold more effective than native vitamin D3 supplements in restoring low blood levels of vitamin D3. Because normal vitamin D3 needs to undergo liver processing first, which is not required for calcifediol. Another perk of calcifediol is its higher intestinal absorption rate.

Source (CC BY): Šimoliūnas et al. (2019). Bioavailability of Different Vitamin D Oral Supplements in Laboratory Animal Model.

Healthy vitamin D status associates with a regulated immune system — characterized by increased B-cells and T-cells but decreased systemic inflammation, disease severity, and mortality…

3. Is the study in line with prior clinical evidence?

The clinical trial from Spain provided the strongest evidence to date that vitamin D3 therapy could work for Covid-19. These results support prior cohort and observational studies that found low vitamin D3 levels (calcifediol) in the blood as an independent risk factor for severe Covid-19, as discussed further here:

Low Vitamin D Levels as a Risk Factor for Greater Covid-19 Severity

Evidence from cohort studies, an observational study, meta-analyses, and reviews.

medium.com

Low vitamin D3 status not only increases the risk of greater Covid-19 severity but of positive diagnosis as well. In a September paper in JAMA involving 489 Covid-19 patients, those likely deficient in vitamin D3 had a 1.77-times increased risk of testing positive for Covid-19 than those with likely sufficient levels. The term ‘likely’ is used because vitamin D3 levels were measured one year before Covid-19 testing.

This result agrees with a previously published study paper where researchers found that, in a sample of 107 Covid-19 cases in Switzerland, those tested positive had significantly lower vitamin D3 levels (median 11.1 ng/ml) than those tested negative (22.0 ng/ml) for SARS-CoV-2. And this time, vitamin D levels were measured three days after the testing.

A more recent study of 235 Covid-19 patients discovered that healthy vitamin D status associates with a regulated immune system — characterized by increased B-cells and T-cells but decreased systemic inflammation, disease severity, and mortality — even after adjusting for confounders such as age, sex, BMI, smoking, and comorbidities.

4. How does vitamin D3 help fight Covid-19?

From a mechanistic standpoint, vitamin D3 and Covid-19 both target similar physiological systems — namely the renin-angiotensin system (RAS) and immune system.

A recent breakthrough has uncovered that Covid-19 kills by bradykinin storm, in addition to the cytokine storm. The RAS regulates blood pressure and fluid volume and breaks down bradykinin. According to the bradykinin hypothesis, SARS-CoV-2 dysregulates the RAS via its interaction with the angiotensin-converting enzyme 2 (ACE2) receptor. This leads to the accumulation of bradykinin, which makes blood vessels leaky. This poses multiorgan consequences; for example, it causes leakage of fluid and immune cells into the lungs and breakdown of the blood-brain-barrier.

From a mechanistic standpoint, vitamin D3 and Covid-19 both target similar physiological systems — namely the renin-angiotensin system (RAS) and immune system.

The research team that formulated the bradykinin hypothesis then proposes vitamin D as a potential treatment for Covid-19. This is because vitamin D is one of the very few hormones that regulates the RAS and prevents bradykinin accumulation. Vitamin D also acts as an immunomodulator that keeps inflammation at bay while supporting functions of B-cells and T-cells, which are essential in fighting infections and generating immunological memory. For instance, T-cells must have their vitamin D receptor (VDR) activated to ‘wake up’ form their inactive state.

Short abstract

Finally, there is a pilot randomized controlled trial that supports vitamin D3 therapy for Covid-19. Oral calcifediol reduced the risk of ICU admission by 93% compared to no calcifediol in Covid-19 patients. Specifically, 50% of patients in the control group were admitted to the ICU, and two died in the end. But only 2% of patients receiving calcifediol required ICU admission, and none died.

This trial supports prior evidence that low vitamin D3 status increases the risk of Covid-19 positive diagnosis, greater severity, and mortality. Further, mechanistically speaking, there is no reason why vitamin D3 could not be helpful. Vitamin D3 regulates the RAS and immune system, both of which are critical determinants of how one responds to Covid-19.

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Decoding the microbial angle to health and the microbial world.