Vitamin D May Treat Covid-19, Suggests Bradykinin Hypothesis and New Clinical Results

Thomas Smith

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Beginning in April of this year, a team at Oak Ridge National Laboratory used the powerful Summit supercomputer to analyze Covid-19. Their results became the basis of the bradykinin hypothesis, a new theory of how Covid-19 impacts the body which I covered in Elemental earlier this month.

One of the most surprising and compelling elements of the bradykinin hypothesis relates to Vitamin D. As the team described in their landmark, peer-reviewed paper in the journal eLife, “Vitamin D deficiencies have recently been associated with severity of illness in COVID-19 patients.” Based on the vitamin’s theorized role in promoting potentially deadly bradykinin storms in Covid-19 patients, the researchers found that “Vitamin D supplementation when warranted” could be a potential treatment for the disease.

The bradykinin hypothesis and its predictions were supported by gene expression, autopsy, and clinical data, but need further testing in clinical and laboratory settings. In their paper, the researchers clearly state that “the testing of any…pharmaceutical interventions should be done in well-designed clinical trials.” Since the publication of their results, however, scientists have performed several such trials. One, performed in Spain, looked specifically at the role that Vitamin D plays in the disease.

Dr. Daniel Jacobson, the lead researcher on the team behind the bradykinin hypothesis, told me in an interview that the study “is a nice one showing efficacy in the clinic, but needs to be shown in much larger clinical trials.” Additionally, the ORNL team’s own research — not yet published — is testing whether “areas of the world with less UV light are having worse Covid-19 outcomes”, as Dr Jacobson described during an episode of the Science on Tap podcast on September 16. Because UV light contributes to production of Vitamin D in the human body, these findings also support the theory that Vitamin D plays a role in the disease.

If these clinical and real-world findings continue to be borne out, Vitamin D could emerge as one tool (among many others) for treating Covid-19 and its symptoms.

In their eLife paper, Jacobson and his team describe a detailed series of molecular pathways through which Covid-19 affects the body. They focus on pathways in the Renin Angiotension System (RAS) and the Kallikrein-Kinin System (KKS). The researchers conclude that Covid-19 makes dramatic changes to patterns of gene expression in the RAS and KKS, leading to a buildup of copious amounts of the chemical bradykinin, as well as other compounds. It is this massive buildup — dubbed a “bradykinin storm” that that researchers believe is responsible for many of Covid-19’s symptoms, from “Covid toes” to brain injury.

According to the researchers, Vitamin D is intimately involved in the RAS. As they describe in their eLife paper, the vitamin binds to a special receptor in the system, called the Vitamin D Receptor (VDR). When it does so, VDR acts like a molecular brake, preventing the transcription of a gene called REN. REN codes for the renin protein, which is one of the proteins responsible for creating peptides that — after several other steps in the RAS pathway — would resensitize the bradykinin receptor and thus exacerbate bradykinin storms.

By reducing the transcription of REN, Vitamin D and the VDR normally work together to keep bradykinin storms from forming, and to keep the RAS in balance. As the researchers found, however, Covid-19 messes with both Vitamin D and VDR in a variety of ways.

Firstly, the researchers found that “VDR is 2-fold down-regulated” in Covid-19 patients, versus healthy controls. That suggests that the virus is actively preventing the body from making VDR. Without VDR, there’s fewer places for Vitamin D to bind, and the vitamin can’t play its usual role in balancing the RAS.

But Covid-19 doesn’t stop there — it also attacks Vitamin D directly. The researchers found that two enzymes (CYP3A4 and CYP24A1) were up-regulated 200x and 400x, respectively, in Covid-19 patients. These enzymes are like Vitamin D assassins — they catabolize (or break down) the vitamin. When Covid-19 upregulates them, they do their job even more effectively, breaking down more of the body’s Vitamin D than normal, leaving less of the vitamin available to bind to VDR.

The end result, as Dr. Jacobson told me, is that “a drop in VDR and Vitamin D will lead to more expression of REN, which will accelerate the phenomena we describe in our model.” It’s a one-two punch with devastating results. Because of the virus’ actions, Vitamin D and VRD can’t perform their normal duty as a molecular “brake” in the RAS. Without their modulating effects, REN surges nearly 400x, touching off a cascade that ultimately leads to a bradykinin storm — and, the researchers believe, many of Covid-19’s deadly effects.

There are several ways medicine could intervene in this process in order to treat Covid-19. One would be to upregulate the production of VRD receptors, counteracting the virus’ efforts to downregulate its production. Another would be to disable the assassin enzymes CYP3A4 and CYP24A1, allowing more Vitamin D to survive in the body and bind with VDR. No readily available pharmaceutical does these things.

But there’s also a simpler option: increase the amount of Vitamin D in the body. By providing the body with more Vitamin D, one could increase the amount of the vitamin that reaches its target receptors — even if fewer of those receptors are present due to Covid-19’s effects, and even if some of the Vitamin D is destroyed by CYP3A4 and CYP24A1. It’s a bit like a tree trying to spread its seeds. If it releases enough seeds, some are bound to reach the ground, germinate, and grow — even if the soil is poor, and even if most seeds are destroyed along the way.

Despite these promising possibilities, the National Institutes of Health says that “there are insufficient data to recommend either for or against the use of vitamin D for the prevention or treatment of COVID-19.” The necessary data, though, is fast emerging.

In a study at the Reina Sofia University Hospital in Spain, researchers gave 76 hospitalized Covid-19 patients either Calcifediol (essentially a prescription form of Vitamin D), or a placebo. Of the 26 patients who received a placebo, 13 were admitted to the ICU, and 2 died. Among those treated with Calcifediol, only 1 was admitted to the ICU, and none died. In his Science on Tap presentation, Dr. Jacobson called these results “very encouraging.”

A study from Boston University — published on September 17 in the journal PLOS ONE — shared similar findings. The Boston University team, led by Dr. Michael F. Holick, looked at Vitamin D levels and Covid-19 outcomes in 191,000+ patients. They found that people with a Vitamin D deficiency were 54% more likely to test positive for Covid-19 than those with adequate levels of the vitamin. Holick said the results were “remarkable” and called for further study of Vitamin D’s effects.

The clinical findings of the Reina Sofia team, combined with the statistical findings of the Boston University team, are bolstered by follow-up studies at ORNL. Dr. Jacobson told me in an interview that his team is using the Summit supercomputer to analyze environmental effects on Covid-19 outcomes. He confirmed that the team “are looking at the spectral quality of the relevant UV bands to see if they are predictive at a population scale.” In short, they’re looking to see if areas with more sunlight (and thus more Vitamin D production in local populations) have less Covid-19 prevalence.

Clinical studies thus far have looked primarily at how Vitamin D might help patients who have been hospitalized with Covid-19 infection. But the studies also raise a compelling question: could taking a Vitamin D supplement (or simply spending more time in the sun) reduce an average person’s risk of contracting Covid-19?

Again, official organizations like the NIH still say that more evidence is needed before a recommendation can be made about Vitamin D’s effectiveness against Covid-19, or before supplementation could be recommended. But review studies have consistently shown that many Americans were Vitamin D deficient even before Covid-19 began. One study found that over 39% of the United States’ population is deficient in Vitamin D.

Alarmingly, the study also found that more than 82% of African-Americans were deficient in the vitamin, as well as 62% of Latinx individuals. These populations have been shown to be more susceptible to Covid-19 infection than others. A multitude of factors is likely responsible for these disparities. Higher levels of Vitamin D deficiency, however, may be one of those factors.

Given the prevalence of Vitamin D deficiency in the overall population, some prominent individuals are not waiting for official guidance before beginning to take the vitamin. Dr. Anthony Fauci, one of America’s top infectious disease experts, reportedly told Insider that he personally takes a Vitamin D supplement, saying “if you’re deficient in vitamin D, that does have an impact on your susceptibility to infection. I would not mind recommending, and I do it myself, taking vitamin D supplements.”

If you’re considering taking Vitamin D (or any new medication or supplement) yourself, stop immediately and talk to your physician first. Even relatively benign compounds like Vitamin D can be contraindicated with certain medications and medical conditions.

If you do decide to take Vitamin D — and your physician approves it — several experts and organizations provide guidance on the proper dose. The United Kingdom’s National Health Service says in a Coronavirus Update that “there have been some news reports about vitamin D reducing the risk of coronavirus. However, there is currently not enough evidence to support this.’ Despite this, the agency still says to “consider taking 10 micrograms of vitamin D a day to keep your bones and muscles healthy”, especially if “you’re indoors most of the day.”

Dr. Holick of Boston University recommends a higher dose, saying in a report in Boston 25 News that the proper dose is “Infants 400 to 1000 units a day, children 600 to 1000 units a day. And teenagers, in my opinion, should be treated like adults: 1500–2000 units a day…If you’re obese you need two to three times more.”

By “units”, Dr. Holick is likely referring to International Units (IU). One hundred IUs are equal to 2.5 micrograms, so Dr. Holick is likely recommending 10–25 micrograms per day for infants, 15–20 micrograms per day for children, and 30–50 micrograms per day for non-obese adults.

For his part, Dr. Jacobson said on Science on Tap that he is not a medical doctor, but cautioned that people “…need to be careful not to completely overdo Vitamin D. Really high doses like 60,000 units (over 30 times the normally recommended dose) can be toxic.” The Mayo Clinic echoes that caution, saying that “hypervitaminosis D is a rare but potentially serious condition that occurs when you have excessive amounts of vitamin D in your body”, and urging readers to “talk to your doctor before taking vitamin and mineral supplements.”

Despite encouraging new results from clinical studies, the bradykinin hypothesis remains a theory. If its predictions — including those about Vitamin D — continue to be borne out in well-designed clinical trials, however, those recommendations could prove extremely valuable in fighting Covid-19. Experts and leaders are already discussing the theory and urging further study.

In testimony to the House Science Space and Technology Committee, for example, Representative Bill Foster (D-Illinois) mentions the bradykinin storm hypothesis (and possibly my Elemental article), saying that the hypothesis “explains everything from Covid toe to the fact that the virus gets in through the blood brain barrier, to the fact that Vitamin D is a very promising therapeutic and prophylactic“ and that he believes “those [results] are being followed up in clinical trials.”

For now, the bradykinin hypothesis’ predictions about Vitamin D remain theoretical. As research teams like Dr. Jacobson’s continue their computational research on the compound — and as more scientists delve into its effects through well-designed trials in the clinic — though, Vitamin D may continue to emerge as a promising, relatively inexpensive, and readily available treatment for Covid-19.

This article originally appeared on Medium.com.

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Award-winning entrepreneur, and the co-founder and CEO of Gado Images. Thomas writes, speaks and consults about artificial intelligence, privacy, food, photography, tech, and the San Francisco Bay Area. As a professional photographer, Thomas' photographic work regularly appears in publications worldwide. Pitches/news tips: tom@gadoimages.com

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