- Researchers in Tennessee used a supercomputer to analyze lung fluid from patients with coronavirus.
- They found that patients with severe cases can produce too much bradykinin, a chemical that regulates blood pressure.
- This could set off a chain reaction that leads to the bizarre range of COVID-19 symptoms – including heart, gastrointestinal and neurological issues.
- Visit the Business Insider homepage for more stories.
Imagine trying to drive a car with a leaking engine. Now imagine that there are no brakes either. Eventually, you will run out of fuel or crash. Some passengers might survive, some might not.
The human body could undergo a similar experience in response to a coronavirus infection, according to a study by researchers at Oak Ridge National Laboratory in Tennessee. The lab’s supercomputers – one of which is the second fastest in the world – analyzed lung fluid samples from nine coronavirus patients with severe cases in Wuhan, China.
Computers have detected major differences in the way these patients express certain genes compared to the way healthy people do.
Based on these abnormalities, the researchers proposed a new theory: Patients with severe COVID-19 may experience what is known as a “bradykinin storm”.
Bradykinin is a chemical that regulates blood pressure. Researchers have found that some people with the coronavirus can produce it in extreme excess. This storm imbalances major systems – including the respiratory, gastrointestinal and neurological tract.
The theory aligns with researchers’ growing view of the coronavirus as a vascular disease instead of a respiratory disease. Research has shown that COVID-19 can lead to blood clots, leaky capillaries and inflamed blood vessels – which is why some patients may suffer heart damage or stroke.
“We were really scratching our heads for a while, how does this disease have this hell of a set of symptoms on so many different organ systems? Dr Daniel Jacobson, the lead researcher behind the supercomputer study, told Business Insider. “By looking at the effects of bradykinin, our model was that this virus can affect many different types of tissue, many different organs.
Too much bradykinin can send the body out of control
Scientists already know that the coronavirus binds to cell receptors called ACE2. This is how the virus finds its way into the upper respiratory tract of the body and then infects organs such as the lungs, heart, kidneys or intestines.
But the supercomputers found that coronavirus patients had a 200-fold increase in ACE2 expression compared to a healthy person. This suggests that the virus is actively influencing our bodies to make them even easier to infiltrate. At the same time, according to the computers, coronavirus patients also exhibited an eight-fold decrease in the expression of ACE, a protein that normally works with ACE2 to control blood pressure.
“This system which is normally very carefully balanced – COVID-19 is really throwing it out of control,” Jacobson said.
This imbalance, the researchers believe, is what leads to the overproduction of bradykinin, which breaks down to keep blood pressure from getting too high. In severe cases, the cycle seems to overdrive: the body cannot stop producing bradykinin. This is what researchers call a “bradykinin storm”.
An excess of the chemical widens the spaces in the blood vessels, allowing fluid to escape. This fluid, in turn, begins to fill the alveoli: tiny air sacs in the lungs – hence the difficulty in breathing.
Supercomputers have also found that coronavirus patients can overproduce a highly absorbent substance called hyaluronic acid. When acid mixes with fluid in the lungs, patients may feel like they are trying to breathe through “a balloon filled with Jell-O,” Jacobson said.
“There may be a tipping point where enough of this hyaluronic acid builds up, and then all of a sudden they have respiratory distress,” he added. “This explains why some people seem to be doing well and then they break down and suddenly need hospitalization or worse. “
An explanation of the wide range of symptoms of COVID-19
The Bradykinin Theory offers a surprisingly consistent explanation for why COVID-19 infections can cause a wide range of symptoms. Although the disease has certain characteristics – 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 look at the reported symptoms, they match up pretty well with what you would expect to see from bradykinin,” Jacobson said.
A bradykinin storm could cause fluid to leak from the blood vessels in the brain, which would explain the neurological symptoms such as dizziness, headache, fog and confusion experienced by some patients. It can also trigger swelling, pain and inflammation in the body – which can lead to muscle pain and stiffness, now known to be common symptoms of COVID-19. It could even lead to purple and swollen toes.
Plus, said Jacobson, loss of taste or smell is a classic response to decreased levels of ACE receptors. Lower ACE levels have also been linked to a dry cough and fatigue.
Also, the increased production of hyaluronic acid may explain why some asymptomatic patients have abnormal lung scans, Jacobson added.
“People who otherwise feel good are probably doing damage,” he said.
Implications for future treatments
Scientists still need to do more clinical studies to find out whether bradykinin storms are causing symptoms of COVID-19. But Jacobson’s team is not the first to suggest the theory.
In May, researchers in Michigan speculated that a response to bradykinin could lead to life-threatening respiratory complications in some patients with COVID-19. A study published the previous month also suggested that the body’s response to bradykinin was to blame for leaking blood vessels in the lungs of COVID-19 patients.
The researchers behind the work suggested that a drug called icatibant, which blocks the body’s signal to produce bradykinin, could help treat infected patients. A follow-up study showed that four of the nine patients who received the drug no longer needed oxygen support after 10 to 35 hours. The drug also had no serious side effects. But the study was too small to reach any meaningful conclusions.
Jacobson’s study, meanwhile, 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 infections.
His study also supports the idea that corticosteroids may improve survival rates in patients with COVID-19. Bradykinin receptors activate an enzyme called phospholipase A2, which is inhibited by steroids. The World Health Organization issued a “strong recommendation” for the use of steroids in critically ill patients last week.
A competing hypothesis: the cytokine storm
Previously, some scientists had suggested that a different internal “storm” could be the source of people’s severe reactions to the coronavirus: a cytokine storm. This release of chemical signals, when it goes into overdrive, can instruct the body to attack its own cells. This response has also been observed in patients who died from H1N1, SARS, MERS, and the 1918 Spanish flu.
Jacobson said a cytokine response could produce some symptoms of COVID-19, but it’s probably not as “stormy” as researchers once thought.
“This assumption loses some force,” he said. “We’re not saying they’re unrelated. I think they are. The full-blown cytokine storm just doesn’t appear to be fully supported by the data. “
So far, the medical community has approached the theory of bradykinin with cautious optimism.
“To be honest, I’m afraid this proposal is almost too neat and tight,” Derek Lowe, a medicinal chemist, wrote in Science Magazine. “You rarely get something that goes together so well. ”
Still, he added, the results are “quite plausible”.
Jacobson said his team hoped to do more follow-up studies to test the theory, including studies involving long-haul coronavirus patients who have been ill for several months.
“I have a couple of long haul hauls on my team, so it’s really close to our hearts, and we see it happening in real time,” he said.
The bradykinin theory could also play in there: Jacobson’s team believe that once this storm takes off, it could continue until the body finds a way to reset it. But it’s still unclear whether the available treatments would make a difference for long-haul patients.
“It’s part of the joy of science,” said Jacobson. “For every answer you have, that brings up 10 more questions. “