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COVID-19: Bradykinin hypothesis supports vitamin D’s vital role

- so make sure to get enough of the nutrient during the winter period

COVID-19: Bradykinin hypothesis supports vitamin D’s vital role COVID-19 is highly unpredictable and be either totally harmless or life-threatening. Scientists from Oak Ridge National Laboratory in Tennessee recently made a comprehensive genetic analysis that reveals a new hypothesis – the bradykinin hypothesis – which shows why COVID-19 attacks the way it does, why symptoms vary, and why some groups of people are more vulnerable than others. The hypothesis also underpins the importance of getting enough vitamin D to prevent or possibly treat the disease. Vitamin D deficiency in the winter period is quite common and that may pave the road for new rounds of COVID-19 and an increased risk of complications.

Scientists from Oak Ridge National Laboratory in Tennessee recently made a comprehensive genetic analysis using a super computer that compared data from more than 40,000 genes taken from 17,000 samples. The process involved over 2.5 billion genetic combinations and lasted more than a week. When the researchers analyzed the results, they came up with the bradykinin hypothesis that can possibly explain COVID-19’s unusual behavior. But what actually happens during a COVID-19 infection and why is it so important to get enough vitamin D?

  • Virus has no metabolism and must therefore enter living cells in order to replicate
  • Its ability to attack different cells depends on the cell receptors
  • Different types of virus attach to different types of cell receptors
  • That is why virus infections can cause many different symptoms

How COVID-19 gains access to cells and behaves like a burglar

COVID-19 apparently gains access to the host cells by attaching itself to the ACE2 receptors. ACE2 (angiotensin-converting enzyme) is located in the membranes of cells in the airways, arteries, heart, intestines, and kidneys
According to Thomas Smith, who has written an article about the new hypothesis and published it in Medium, a COVID-19 infection typically starts when virus invades cells in the nasal mucosa via the ACE2 receptors. If the immune defense works optimally it should not be a problem to combat the virus before it succeeds in replicating. However, if this is not the case, COVID-19 spreads from the nasal mucosa to other cells with ACE2 receptors that can be found in the airways, the arteries, the heart, the intestines, and the kidneys. This explains some of the symptoms that are seen when these organs are infected.
According to the new data from the super computer, unusual things may happen in the body as soon as COVID-19 gains foothold. COVID-19 does not only attack cells with many ACE2 receptors, it is actually able to take over the body’s own system, thereby upregulating ACE2 receptors in e.g. the lung tissue, where the number of receptors is normally not that high. This is what makes the airways so vulnerable and it is also why the entire process can easily become derailed.
COVID-19 is often compared to a burglar that enters a house through an open window. Once the burglar is inside, he searches the house and opens all the locked doors and windows so his conspirators can join the party.

Bradykinin storm is responsible for life-threatening reactions

Not only is COVID-19 able to upregulate ACE2 receptors in the body, it can also downregulate the body’s ability to metabolize bradykinin. This sets the stage for a bradykinin storm. Bradykinin is a chemical compound that normally helps enlarge or dilate blood vessels to help lower the blood pressure. Bradykinin also promotes inflammation.
Bradykinin is controlled by the renin-angiotensin system (RAS) that has a key role in controlling various functions in the kidneys and the cardiovascular system.
It is important that the bradykinin levels are tightly controlled. The scientists behind the new hypothesis say that a bradykinin storm may lead to many of the life-threatening complications that are seen with COVID-19. Bradykinin storm is even more dangerous than cytokine storm, which is also part of the disease development. The new hypothesis also suggests that COVID-19 becomes much more of a cardiovascular disease than a respiratory disease once the bradykinin storm breaks loose.

How COVID-19 attacks the lungs

COVID-19 attacks the lungs in different ways. To begin with, it enters the cells via the ACE2 receptors. Secondly, bradykinin storm may cause a buildup of fluid and hyperinflammation. Thirdly, COVID-19 seems to increase the production of hyaluronic acid in the lungs. Hyaluronic acid has the ability to absorb 1,000 times more fluid than its own weight, which turns the pulmonary fluid into a thick gel that makes it virtually impossible to breathe. It is already known that COVID-19 leads to acute respiratory distress syndrome (ARDS) that destroys epithelial cells in the airways and causes hypoxia (lack of oxygen).

How COVID-19 attacks the heart and brain

The heart has many ACE2 receptors, which means COVID-19 can attack the heart directly. Bradykinin storm may even lead to arrhythmia (heart rhythm disturbances) and low blood pressure. High bradykinin levels may cause leakages in the cerebral blood vessels and cause the protective blood-brain barrier to break down, thereby allowing harmful toxins to reach the brain. All these things may result in inflammation, brain damage, and various neurological symptoms.

Why women are less exposed

Women have lower COVID-19 mortality than men. According to the new hypothesis, this is because women compared with men have twice the amount of certain proteins that control the renin-angiotensin system and, subsequently, the bradykinin system
Besides, men compared with women tend to be affected harder or even die of infectious diseases, including influenza and tuberculosis.

COVID19 mimics ACE inhibitors

According to Thomas Smith, elevated bradykinin levels may also account for the other COVID-19 symptoms that are very similar to the side effects seen in patients that use ACE inhibitors. These are medical drugs that are used to treat hypertension and they also increase bradykinin levels. One of the known wide effects of using ACE inhibitors is loss of taste and smell, which also happens to be one of the early signs of a COVID-19 infection and also a sign of zinc deficiency. This problem must be addressed immediately.
ACE inhibitors can also increase levels of potassium and cause fatigue and dry cough, both of which are symptoms that are observed in COVID-19 patients. COVID-19 patients who already take ACE inhibitors against elevated blood pressure may be even more vulnerable to their infection because of the drugs they take.

Different therapies

If the theory about bradykinin making COVID-19 life-threatening is true, we already have a number of medical drugs that have the potential to prevent bradykinin storm, either by lowering levels of bradykinin or by blocking the receptors. The scientists have addressed this topic in an article in eLife.
However, many of these drugs may have serious side effects, which is why the researchers also point to vitamin D with reference to the latest scientific data and decades of research.
Most cells in the body have vitamin D receptors (VDR), and the vitamin helps regulate a number of genes and countless biochemical processes. Therefore, lack of vitamin D may have serious consequences that include the immune defense and may increase one’s vulnerability to virus infections. It actually makes sense to use vitamin D for prevention and treatment, simply because it is an essential nutrient. Also, it is inexpensive and has no side effects, provided you use the right doses.

  • According to calculations, around one billion people worldwide have minor to moderate vitamin D deficiency
  • Most people feel completely fine even though they lack vitamin D. But the immune system is very sensitive to deficiencies

Vitamin D strengthens the immune system and regulates bradykinin storm

Vitamin D activates both the innate and the adaptive immune defense. The adaptive immune system is able to specialize and form immunity. There are particularly many white blood cells in the airways, especially the macrophages that need vitamin D to attack germs. Vitamin D also boosts some antibiotic peptides in the lungs. When the immune system’s special troops, the so-called T cells, are exposed to virus and bacteria they signal for more vitamin D to help them divide and form a complete T cell army that can direct a swift attack against the enemy.
Vitamin D also helps the immune defense by preventing it from overreacting with undesirable inflammation that can harm healthy tissue. The bradykinin hypothesis also claims that vitamin D is involved in the RAS system (renin-angiotensin) and regulates levels of bradykinin.

Lack of vitamin D increases the risk of infections and complications

Our modern lifestyle is partly to blame for the global vitamin D deficiency. Dark-skinned people, old people, overweight individuals, nursing home residents, diabetics, and people with chronic diseases are also at risk of a vitamin D deficiency.
Low vitamin D status weakens the immune system and increases the risk of virus gaining foothold and spreading. It also increases the risk of a derailed immune system with cytokine storm and hyperinflammation. Bradykinin storm, however, poses the greatest threat, according to the new hypothesis.
A number of studies suggest that lack of vitamin D increases the risk of contracting COVID-19 and also steps up the severity of the disease
There is a higher COVID infection rate at northern latitudes where there is limited sunshine and/or blood levels of vitamin D are low. Patients with low levels of vitamin D are twice as likely to get life-threatening complications from a COVID-19 infection than people with adequate levels, according to a study from Northwestern University in the United States. Here, scientists gathered data from patients in 10 different countries.
A study that is published in JAMA shows that twice as many testing positive for COVID-19 lack vitamin D, compared with those that test negative.

  • When we synthesize vitamin D from sunlight it is in the form of cholecalciferol. This form of vitamin D is also available in supplements.
  • In the liver, cholecalciferol is converted with help from enzymes into calcifediol or 25-hydroxyvitamin D3, which is the active form that is measured in the blood.

Vitamin D supplements can save lives

Spanish scientists recently conducted a randomized pilot study of 76 hospitalized COVID-19 patients that were given either standard treatment or standard therapy coupled with supplements of vitamin D3 (calcifediol). This is the active form of the nutrient and works faster.
The patients in the vitamin D group got 532 micrograms of calcifediol on the first day, followed by 266 micrograms on the third and seventh day. After that, they continued getting 266 micrograms once a week until they were discharged, put in intensive care, or died. Only two percent of the patients in the vitamin D group required intensive care, while 50 percent of patients that did not get vitamin D ended up in the intensive care unit. No deaths were recorded in the vitamin D group, and every patient in the group was discharged without any complications. The study is published online in the Journal of Steroid Biochemistry and Molecular Biology. Earlier randomized studies show that vitamin D supplements are particularly effective for protecting against respiratory infections. However, you can only expect to see an effect if the patient is already vitamin D-deficient and if the dose is sufficiently high to increase vitamin D in the blood to an optimal level.

Call for action: Optimize your vitamin D status before it is too late

Lack of vitamin D is a common problem. Over the years, many scientists and experts have argued for the importance of optimizing vitamin D levels, especially during the winter period where infections like colds and influenza are far more common. The same goes for COVID-19 where the whole world can expect to see the infection rates go up. The official guidelines for vitamin D do not appear to be able to optimize blood levels of the nutrient, which should ideally lie around 50 nmol/L and preferably 60-100 nmol/L. In order to reach this level, people living at northern latitudes needs high-dosed vitamin D supplements from October to May. If they do not get enough sun during the summer, they should take a vitamin D supplement all year round. The actual need for vitamin D depends on genes, age, skin type, BMI, and chronic diseases like diabetes. According to EFSA (the European Food Safety Authority), the safe upper intake level for vitamin D is 100 micrograms per day. According to the Spanish pilot study and other studies, one can easily take larger doses if you don’t do it every day. Vitamin D is lipid-soluble so you get the best utilization of the nutrient by taking a supplement with vitamin D in oil in gelatin capsules.

  • Vitamin D is important for the immune system, it is anti-inflammatory and regulates the RAS system that is important for the bradykinin levels
  • In countries with less sunshine and where people have lower blood levels of vitamin D (25-hydroxyvitamin D), the COVID-19 mortality is higher
  • The following people are at risk of lacking vitamin D: People living at northern latitudes, dark-skinned people, older people, nursing home residents, overweight individuals, diabetics, cardiovascular patients, kidney patients, and people with other chronic diseases
  • People with low vitamin D levels in their blood are more likely to test positive for COVID-19 compared with people that have adequate levels of the nutrient
  • The less vitamin D you have in your blood, the more serious a COVID-19 infection may become
  • Earlier studies show that low blood levels of vitamin D increase the risk of respiratory infections and comorbidities
  • A vitamin D supplement can lower the risk of respiratory infections, especially in people who are already deficient and if the supplement is able to optimize their levels of vitamin D.
  • Vitamin D supplements help protect against COVID-19 and comorbidities


Thomas Smith. A Supercomputer Analyzed Covid-19 – and Interesting New Theory Has Emerged. Medium. September 1, 2020

Michael R Garvin et al. A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm.
eLife Jul 7, 2020

Yan Chun Li. Vitamin D regulation of the renin-angiotensin system. J Cell Biochem 2003

JoAnn E. Manson. Commentary. Eliminating vitamin D deficiency during the COVID-19 pandemic. A call to action. Metabolism Clinical and Experimental. July 23, 2020

Northwestern University. Vitamin D levels appear to play role in COVID-19 mortality rates. Science Daily. May 2020

Ali Daneshkhah et al. The Possible Role of Vitamin D in Supressing Cytokine Storm and Associated Mortality in COVID-19 Patients. medRxiv April 30, 2020

Eamon Laird, Rose Anne Kenny. Vitamin D deficiency in Ireland – implications for COVID 19. Results from the Irish Longitudinal Study on Ageing (TILDA) April 2020

Marta Entrenas Castillo et al. Effect of calciferol 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. The Journal of Steroid Biochemistry and Molecular Biology. October 2020

Shin Jie Yong. The First Trial to Support Vitamin D Therapy For Covid-19. Microbial Instincts. Sep4, 2020

Joseph Mercola. Bradykinin Hypothesis Explains COVID-19 Complexities. 14.sep.2020

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