- Tennessee researchers used a supercomputer to analyze lung fluids from coronovirus patients.
- They found that patients with severe cases can produce too much bradykinin, a chemical that regulates blood pressure.
- This may set a chain reaction that leads to a bizarre range of symptoms of COVID-19 – including cardiac, gastrointestinal, and neurological problems.
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Imagine trying to drive a car with a leaky engine. Now imagine that there are no brakes, either. Eventually, you are about to run out of fuel or an accident. Some travelers may escape – others do not.
According to a study by researchers at Oak Ridge National Laboratory in Tennessee, the human body can tolerate a similar experience in response to a coronovirus infection. The lab’s supercomputers – one of which is the second fastest in the world – analyzed lung fluid samples from nine coronovirus patients with severe cases in Wuhan, China.
The computer detected large differences in the way certain genes were expressed relative to these patients’ way of healthy living.
Based on those abnormalities, researchers came up with a new theory: patients with severe COVID-19 are known as “bradykinin storms”.
Bradykinin is a chemical that regulates blood pressure. Researchers found that some people with coronavirus can produce it in excessive amounts. This storm includes major systems – including respiratory, gastrointestinal, and neurological pathways – closed balance.
The theory aligns with researchers’ increasing view of coronaviruses as vascular disease rather than respiratory. Research has shown that COVID-19 can give rise to blood clots, constricted capillaries and inflamed blood vessels – which is why some patients may experience heart damage or stroke.
“We were really scratching our heads for a while, how is this wide pervasive symptom of the various different systems of the disease?” The leading researcher of supercomputer studies, Drs. Daniel Jacobson told Business Insider. “As we looked at the effects of bradykinin, our model was that the virus can affect many different types of tissues, many organs.”
Too much bradykinin can send spiraling out of control
Scientists already know that the coronavirus binds to cell receptors called ACE2. How the virus penetrates the upper respiratory tract of the body, then infects organs such as the lungs, heart, kidneys or intestines.
But the supercomputer found that there was a 200-fold increase in the expression of ACE2 in coronovirus patients relative to a healthy person. This suggests that the virus is actively affecting our bodies to make them easier to infiltrate. At the same time, they found that computer, coronovirus patients also had an eightfold decrease in expression of ACE, a protein that normally works with ACE2 to keep blood pressure under control.
“This system that is usually very carefully balanced – COVID-19 really makes it out of whack,” Jacobson said.
This imbalance leads researchers to see whether over-production of bradykinin, which swings to prevent blood pressure from getting too high. In severe cases, the cycle goes into overdrive: the body cannot stop producing bradykinin. This is what researchers have called a “Bradykinin storm”.
An excess of the chemical widens the gaps in the blood vessels, causing fluid to leak out. That fluid, in turn, begins to fill the alveoli: small air sacs in the lungs – so patients have trouble breathing.
Supercomputers also found that coronovirus patients could produce a highly absorbent substance called hyaluronic acid. When the acid is mixed with fluid in the lungs, patients may feel as if they are trying to breathe a “balloon filled with Jell-O”, Jacobson said.
“There may be a tipping point where there is enough buildup of this hyaluronic acid, then suddenly they have respiratory distress,” he said. “This explains why some people feel fine and then they crash and suddenly need to be hospitalized or worse.”
An explanation for the wide range of COVID-19 symptoms
The bradykinin theory provides a surprisingly cohesive explanation for how COVID-19 infection can result in a broad spectrum of symptoms. Although there are definite symptoms of the disease – fever, dry cough, and shortness of breath – patients have reported a range of heart, gastrointestinal, and neurological problems.
“Everywhere we go in the body and see the symptoms being reported, they map really well to what you’d expect to see from Bradykinin,” Jacobson said.
A Bradykin storm may cause fluid leakage from blood vessels in the brain, which would explain the neurological symptoms such as dizziness, headaches, fainting, and confusion experienced by some patients. It can also trigger inflammation, pain, and inflammation in the body – resulting in muscle soreness and body ache, which are now considered common COVID-19 symptoms. It can also give rise to purple, swollen toes.
What’s more, Jacobson said, loss of taste or smell is a classic response to decreased levels of ACE receptors. Lower levels of ACE have also been linked to dry cough and fatigue.
In addition, the increased production of hyaluronic acid may explain why some asymptomatic patients have abnormal lung scans, Jacobson said.
“The damage is probably happening to those who feel fine,” he said.
Implications for future treatment
Scientists still need to conduct more clinical studies to find out whether bradykinin storms are driving COVID-19 symptoms. But Jacobson’s team is not the first to suggest the theory.
In May, Michigan researchers speculated that a bradykinin reaction may cause fatal respiratory complications in some COVID V 19 patients. A study published a month ago also proposed that the body’s bradykinin response was to blame the blood vessels observed in the lungs of COVID-19 patients.
The researchers behind that work suggested that a drug called icabitant, which blocks the body’s signal to produce bradykinin, may help treat infected patients. A follow-up study showed that four out of four patients receiving the medication did not require oxygen support after 10 to 35 hours. The drug also had no serious adverse effects. But the study was too small for any significant conclusions.
Meanwhile, Jacobson’s study found evidence that vitamin D could prevent a bradykinin storm from developing in the first place. Studies have already shown that vitamin D may help reduce the severity of COVID-19 infection.
Their study also supports the idea that corticosteroids may improve survival rates for COVID-19 patients. Bradykinin receptors activate an enzyme called phospholipase A2, which is inhibited by steroids. The World Health Organization last week issued a “strong recommendation” for the use of steroids among critically ill patients.
A competition hypothesis: cytokine storm
Previously, some scientists suggested that people’s severe reactions to coronovirus may have a different internal “storm” behind them: a cytokine storm. That release of chemical signals, when it goes into overdrive, can direct the body to attack its cells. This reaction was also seen in patients who died of H1N1, SARS, MERS and 1918 Spanish flu.
Jacobson stated that the cytokine response may produce some COVID-19 symptoms, but it is probably not as “stormy” as the researchers once thought.
“That hypothesis is losing a little traction,” he said. “We’re not saying they’re not linked. I think they are doing it. It just doesn’t look like a full-blown cytokine storm that is supported for data.”
So far, the medical community has approached the bradykinin theory with cautious optimism.
Medicinal chemist Derek Lowe wrote in Science magazine, “To be honest, I am concerned that this proposal is almost too neat.” Hardly you find anything that falls into this well. ”
Still, he said, the findings are “very praiseworthy.”
Jacobson said his team hopes to conduct more follow-up studies to test this theory, including studies of long-standing coronovirus patients who have been ill for several months.
“My team has had some long races, so it’s really near and dear to our hearts, and we’re seeing it playing in real time,” he said.
The Bradykinin theory can also play there: Jacobson’s team feels that once this storm strikes, it can continue until the body figures out how to reset it. But it is still unclear whether any of the available treatments will make the difference for long-term patients.
“It’s part of the joy of science,” Jacobson said. “For each answer you have, it raises 10 more questions.”