COVID-19 Storms: Bradykinin In, Cytokine Out?

In the last week, questions have been raised about whether cytokine storm is indeed a culprit in severe COVID-19, while a paper from a government lab has made an intriguing and much-discussed case for a new mechanism, bradykinin storm.

While the concepts are not necessarily mutually exclusive, scientists trying to understand how COVID-19 wreaks its damage on the human body have been buzzing about the new possibilities.

The bradykinin theory was outlined in a July research paper published in eLife, but it was recently featured in a widely read article published on Medium's science website, Elemental.

The theory connects many of the disparate symptoms of COVID-19, from a loss of sense of smell and taste, to a gel-like substance forming in the lungs, and abnormal coagulation. It posits that SARS-CoV-2 disrupts both the renin-angiotensin system (RAS) and the kinin-kallikrein pathways, sending bradykinin -- a peptide that dilates blood vessels and makes them leaky -- out of whack. The process impedes the transfer of oxygen from the lung to the blood and subsequently to all other tissues, a common abnormality in COVID-19 patients.

Piecing together the hypothesis was a "eureka moment," said the study's lead author, Daniel Jacobson, PhD, of Oak Ridge National Laboratory in Tennessee.

Jacobson and co-authors used a supercomputer to compare gene expression in lung cells from nine infected and 40 uninfected individuals.

They found the COVID-19 cases had extremely high levels (increased nearly 200-fold) of angiotensin-converting enzyme 2 (ACE2), the surface protein used by the coronavirus to enter the cell.

When the virus interacts with ACE2, it triggers an abnormal response in the bradykinin pathway, Jacobson said. At the same time, levels of angiotensin-converting enzyme, which is involved in the breakdown of bradykinin, were lower in COVID-19 patients than in controls.

"This is the perfect storm, where all the things that could go wrong will lead the system to really go out of control," Jacobson told MedPage Today. "When that happens, you're going to get hyper-permeable blood vessel fluid pouring out of these infected areas and into the lungs."

Compared with controls, patients with COVID-19 also had upregulated genes responsible for synthesizing hyaluronic acid -- a polymer that can absorb more than 1,000 times its weight in water -- and downregulated genes responsible for degrading it, Jacobson said.

In effect, the bradykinin dysregulation will cause blood vessels to leak, and the hyaluronic acid dysregulation will pour massive quantities of a gel-like substance into the alveoli. This aligns with autopsy reports that detail the lungs of patients with COVID-19 feeling "like a water balloon that is filled with Jell-O," Jacobson said.

"That explains why ventilation has been so difficult," he noted. "At some point when you have enough of this hyaluronic acid in your lungs, with all the water you've captured, it kind of doesn't matter how much oxygen you're pumping into the lungs -- it can't get through to do gas exchange in the capillaries and alveoli."

Excess bradykinin can also shift important electrolyte levels, like potassium, which in turn can cause angioedema, sudden cardiac death, diarrhea, and reduced cognitive function, Jacobson and co-authors noted. ACE inhibition has also been linked with a loss of taste or smell.

The bradykinin storm is not mutually exclusive from the cytokine storm described in severe COVID-19 in the early stages of the pandemic. While cytokines are involved in the virus's attack, Jacobson said they did not see the same out-of-control, cascading effect represented by the cytokine storm hypothesis.

That's consistent with a growing sense of doubt cast upon the "unproven dogma" of the cytokine storm, as Italian anesthesiologist Maurizio Cecconi, MD, called it on Twitter.

Cecconi cited a recent JAMA research letter that found critically ill patients with COVID-19 and acute respiratory distress syndrome actually had lower circulating cytokine levels than patients with bacterial sepsis or other critical conditions.

In contrast, one promising exploratory study published in JAMA Network Open found icatibant, an antagonist against bradykinin receptors, improved oxygenation in early-stage COVID-19 patients, Jacobson said.

"[The cytokine storm] was really based on other diseases, and the more we learn about COVID, the more we learn how different it is from most things we've encountered in so many ways," he added.

However, it's also possible, or even likely, that both types of responses are occurring simultaneously in COVID-19 infection, commented Allen Kaplan, MD, of the Medical University of South Carolina.

Kaplan, who has done fundamental research on bradykinin for the past several decades, said the literature on bradykinin and COVID-19 is "very exciting" and worth pursuing.

"This article mainly just measured protein levels but when you see numbers like that, you can intuit, 'Gee, if it's that high, what is it doing?'" Kaplan said of the Oak Ridge paper. "They haven't taken it to the next step to show what it's doing; we are inferring based on the protein levels they have measured."

Another study released in preprint in April also postulated that bradykinin receptors were playing a major role in the body's response to the virus. However, neither actually measured bradykinin levels in the body.

Measuring bradykinin itself is challenging because it is formed and degraded during the process of drawing blood, said Nancy J. Brown, MD, of Yale University, who also studies bradykinin.

Still, the findings are "really intriguing," and could also explain some aspects of the abnormal coagulation associated with COVID-19 patients, Brown said. In animal studies, bradykinin has been shown to boost levels of tissue plasminogen activator (tPA), a protein involved in the breakdown of blood clots, she explained.

"This may be a culprit," Brown told MedPage Today. "The way to know that for sure is to do studies looking at bradykinin receptor blockers or drugs that prevent the formation of bradykinin."

There are drugs on the market that target this mechanism -- for hereditary angioedema, a condition marked by bradykinin overactivation -- and at least two U.S. trials are currently underway. One trial is looking at icatibant (Firazyr) in critically ill COVID-19 patients, and another is testing lanadelumab (Takhzyro), a monoclonal antibody that targets kallikrein, in patients hospitalized with COVID-19 and pneumonia.

Jacobson said targeting this mechanism would likely require multiple treatments. "If you're in a boat with a lot of holes, there is not one huge cork that's going to fill all the holes. You want to cork each of them individually," he said. "With different points of intervention, we are thinking we will probably have better outcomes, but that is what we want to get tested in a clinical trial setting."

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