healthcare worker in protective gear checks critically ill patient

Scientists Believe Bradykinin (Huh?) Is Causing Trouble In COVID-19 Patients

Shortness of breath. Loss of smell and taste. Sore throat. Fatigue. Muscle aches. Diarrhea.

The list of COVID-19 symptoms goes on and on, with severity ranging from minor annoyances to life-threatening.

Since the beginning of the pandemic, these symptoms of COVID-19 have stumped scientists and medical professionals across the globe. Researchers have been thrust into a search for answers, with the stakes higher — and the timeline tighter — than ever before.

As the pandemic has unfolded, discoveries about the mysterious nature of the virus have sprung up in laboratories around the world.

One of the latest of these discoveries was born in the Oak Ridge National Lab in Tennessee. The Summit supercomputer in this lab analyzed over 40,000 genes from 17,000 genetic samples. Despite being the second fastest computer in the world, it took more than a week to complete.

Researchers analyzed the results from Summit and developed a model that could explain how COVID-19 impacts the body: the bradykinin storm hypothesis.

What Is Bradykinin?

Let’s back up for a moment and define some key terms needed to understand the bradykinin storm hypothesis.

Bradykinin

The renin-angiotensin system (RAS) is responsible for controlling many parts of the body’s circulatory system. This includes bradykinin, which is a chemical that helps regulate blood pressure.

It might seem like extra bradykinin wouldn’t be harmful and would further the body’s ability to control blood pressure — but that’s not the case. Bradykinin can also induce pain and cause blood vessels to expand and leak, which can then lead to swelling in the surrounding tissue.

ACE And ACE2

Angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme-2 (ACE2) are enzymes within the RAS, and are directly involved in regulating bradykinin.

The SARS-CoV-2 (the novel coronavirus) enters cells in the body through ACE2 receptors. This usually occurs in the nose, since the nose is home to an abundance of these receptors.

The Bradykinin Storm Hypothesis

The recent study found that the SARS-CoV-2 virus tweaks the RAS. It decreases ACE levels while increasing ACE2 ones. This causes bradykinin production into overdrive, creating a “bradykinin storm.”


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As bradykinin levels increase, blood vessels — the tubes that carry blood throughout the body — become leaky. When blood vessels leak during a bradykinin storm, the lungs can fill with fluid. Also, immune cells can make their way into the lungs and cause inflammation. With fluid and inflammation in the lungs, breathing becomes difficult — and that could be one explanation of why cough and difficulty breathing are effects of COVID-19.

Bradykinin Might Be Why Ventilators Aren’t Helping Everyone With COVID-19

Ventilators are machines that are like external lungs. They breathe for someone who can’t breathe on their own and reduce the amount of energy their body uses on breathing, allowing that energy to be redirected toward fighting an illness.

At the beginning of the COVID-19 pandemic, when it became clear that severe difficulty breathing was a potentially deadly side effect of the virus, ventilators were in hot demand. Hospitals across the country feared that they would not have enough of these machines.

As it turned out, the ventilator shortage wasn’t as devastating as originally thought — not because hospitals suddenly had enough of them, but because providers learned that ventilators were not helping as much as anticipated. Ventilators were still life-savers for some patients, but were not too effective in others. In fact, some researchers have argued that ventilators can actually do more harm than good in patients with COVID-19.

This begs the question: If ventilators are supposed to help people breathe, why aren’t they working as well as expected?

One potential reason is the combination of the bradykinin storm and hyaluronic acid.

Bradykinin Storm + Excess Hyaluronic Acid (HA) = Disaster

Hyaluronic acid (HA) is a substance produced naturally by your body and found in many areas, including your skin, eyes, and synovial fluid in the joints. It can absorb 1,000 times its own weight in liquid. HA is often used in addressing cosmetic concerns, from lifting cheeks to rejuvenating earlobes. It’s also frequently used in lotions and soaps.

Similar to bradykinin, HA is helpful in the right doses. In addition to its skin and cosmetic benefits, it’s also involved with wound healing. However, too much HA can wreak havoc on the body.

HA levels can increase when someone has COVID-19. As HA in the lungs combines with fluid leaking in from the bradykinin storm, the two substances form a hydrogel that is very difficult to breathe through. Regardless of how much oxygen gets pumped into the body via a ventilator, it can’t make it through the hydrogel in the lungs. A patient can suffocate even while hooked up to a ventilator.

The Bradykinin Storm Hypothesis May Explain COVID-19’s Unique Symptoms

The bradykinin storm hypothesis doesn’t just explain the breathing problems that come with COVID-19 and why ventilators aren’t as successful as expected — it also may shed light on why some of the other symptoms occur.

For example, a bradykinin storm could be behind some of the heart damage seen in 1 in 5 patients who are hospitalized with COVID-19. While some of the damage may be due to the virus infecting the heart directly, it could also be due to the fact that the renin-angiotensin system (RAS) controls certain cardiac functions and a bradykinin storm could cause arrhythmias or low blood pressure — the heart problems seen in COVID-19 patients.

A bradykinin storm could also be why some COVID-19 patients experience neurological effects, like dizziness, delirium, or seizures. Excess bradykinin can break down the blood-brain barrier (the filter between the brain and the rest of the circulatory system). If this happens, harmful cells could make their way into the brain, where they could cause inflammation, brain damage, and the neurological effects associated with COVID-19.

Additionally, too much bradykinin could explain other symptoms, such as fatigue, diarrhea, headaches, and decreased cognitive function. These symptoms are common in other conditions involving high levels of bradykinin, so it would be reasonable to hypothesize that these symptoms in COVID-19 patients may be the result of excess bradykinin.

Some researchers have even theorized that a bradykinin storm could be the culprit behind the more “bizarre” effects, from bruised toes to thyroid disease.

What Does All Of This Mean?

The bradykinin storm hypothesis might mean a lot — but it could also mean nothing at all.

Any time we learn more about how a disease works, the more information we have at our disposal for finding a vaccine or a cure.

For instance, there are already medications approved by the FDA for treatment of other conditions that involve overproduction of bradykinin. These drugs may be able to fight off potentially fatal bradykinin storms in patients with COVID-19. (Of course, the drugs still need to be tested in clinical trials — but it’s a good starting point). In fact, the researchers who developed the bradykinin storm hypothesis identified more than 10 of these possible treatments.

There are also medications that can reduce HA levels and stop hydrogel from forming in the lungs, as well as supplements for vitamin D — a vitamin that is involved with a healthy RAS and could possibly thwart bradykinin storms.

However, while the bradykinin storm hypothesis may be the key to unlocking the mystery of COVID-19 and finding a cure, it is far from being the definitive answer. There have been other promising theories circulating since the beginning of the pandemic, so the bradykinin storm hypothesis is not the first possible explanation.

Still, there is reason to celebrate. With each new promising theory like the bradykinin storm hypothesis, we inch closer toward a return to normal — from attending concerts to going out without masks to hugging our loved ones.

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