From brain fog and joint pain to lung damage and nausea - scientists are racing to understand why the novel coronavirus can cause such a wide array of symptoms and organ damage to different people at different stages of their disease.
A group of researchers led by Dan Jacobson, a computational systems biologist at the Oak Ridge National Laboratory west of Knoxville, may have some of the answers.
"We're trying to understand what's going on in the human body that can lead to these dramatically different outcomes, and when things go wrong, what's responsible for this very curious set of symptoms," said Jacobson, who co-authored a recent study that suggests there may be a new pathway for COVID-19 inflammatory response.
Many scientists have suggested that a "cytokine storm" - a severe immune reaction - is what leads to the most life-threatening COVID-19 infections that result in pneumonia and acute respiratory distress syndrome. But Jacobson's team thinks another pathway could actually be to blame.
The researchers used a supercomputer to analyze genes from cells in the lung fluid of nine COVID-19 patients compared with 40 uninfected people as a baseline. They found that genes related to one of the body's systems that controls blood pressure - the bradykinin system - appear to be overly activated in the lung fluid cells of those with COVID-19.
"This is what we're calling the bradykinin storm," Jacobson said. The downstream effect leads to "leaky" blood vessels that cause fluid buildup in the lungs and an overproduction of hyaluronic acid, a gooey substance found in connective tissues, he said. This is "bad news," because hyaluronic acid turns into a "hydrogel" when it hits water.
"So now you're pouring fluid into your lungs, you're over producing this hyaluronic acid, and you're going to build up a big layer of this hydrogel in your alveoli [air sacs of the lungs]," he said. "It's like trying to breathe through Jell-O. The gases just can't penetrate that, which explains why we have such horrific mortality outcomes on people once they hit the ICU and are ventilated.
"At some stage, no matter how much oxygen you pump into the lungs, it's just bouncing off of this hydrogel. Patients literally can't get enough oxygen," Jacobson said.
A bradykinin storm may help explain other COVID-19 symptoms based on what's known about other diseases that produce excess bradykinin.
"Fluid leaking out of your blood vessels in your brain is going to cause all sorts of neurological symptoms - you're going to get these issues with cognition, brain fog, headaches - those are all completely consistent," he said.
"We know that people who are overly sensitive to ACE inhibitors. What happens? Well they develop a dry cough, and they lose their sense of smell. Also really similar for COVID-19."
An excess of bradykinin in muscles and joints will cause pain, and will cause cramps, diarrhea or nausea when in excess in the gastrointestinal tract.
"If we just keep going through all the systems, they are a very good match to this mechanism," he said. "This virus is very trophic, meaning you can infect lots of different types of tissues, but in different people, it's going to be hitting different tissues and different organ systems at different points in time. So in some people it will get to some tissues and not others."
Dr. Amy Justice is a clinical epidemiologist at the Yale School of Medicine and a VA scientific liaison who brought a medical perspective to the research team said the findings are "exciting."
"The most important insights are those that help us find means of preventing infection and preserving life for those who are infected. [Jacobson's] model offers insight for both," Justice said in an email.
"The main question I had was why we don't see more classic symptoms of angioedema in patients with COVID-19 (facial swelling etc). Nevertheless, I think there are important insights here," she said.
The good news, Jacobson said, is that there are already approved medicines that target the mechanisms his group identified, meaning they can start applying the research to see if it yields results without having to develop new drugs.
"We have these testable mechanisms. Then what are the right combinations of therapeutics? What's the right timing for them? The joy of science is every question you answer, you raise 10 more," he said.
If these drugs can help stop the disease progression in patients, Jacobson said it may help prevent the more severe COVID-19 infections and give the immune system time to combat the coronavirus so that patients can recover.
"We're pushing hard to get larger clinical trials going on these and other drugs and in combinations of them, because this is a complex mechanism. And we want to hit different parts of it at the same time," Jacobson said. "There's a lot more to do, but it's encouraging."
Contact Elizabeth Fite at firstname.lastname@example.org or follow her on Twitter @ecfite.