By Tracy Cabrera
WE’VE all heard about the so-called cytokine storm that some experts say fuel most of Covid-19 deaths. But how about the new hypothesis on bradykinin storm?
A cykotine storm is when there is an overreaction of the body’s immune system in response to influenza or Covid-19. Scientists believe that cytokines are evidence of an immune response called a cytokine storm, where the body starts to attack its own cells and tissues rather than just fighting off the virus.
Cytokine storms are known to happen in autoimmune diseases like juvenile athritis. They also occur during certain kinds of cancer treatment, and can be triggered by infections, like the flu. One study of patients who died of H1N1 influenza, for example, found that 81 percent had features of a cytokine storm.
On the other hand, the bradykinin theory was outlined last and it connects many of the disparate symptoms of Covid-19, from the loss of sense of smell and taste, to gel-like substance forming in the lungs and abnormal coagulation.
It posits that the severe acute respiratory syndrome-coronavirus-2 or 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.
One of the great mysteries of the new coronavirus is why it causes only mild disease in most people, but turns fatal for others. In many cases, it seems the worst damage may be driven by a deranged immune response to the infection, rather than the virus itself.
In many of the sickest patients with Covid-19, their blood is teeming with high levels of immune system proteins called cytokines and this triggers the storm which is often fatal to Covid-19 patients.
Meanwhile, the Covid-19 bradykinin storm hypothesis is gaining a foothold among the medical community, offering new avenues for treatment using already-approved drugs. By detailed analysis of more than 40,000 genes, 17,000 genetic and 2.5 billion genetic combination samples linked to Covid-19, researchers from Oak Ridge National Laboratory in Tennessee, have come up with a theory as to how SARS-CoV-2 affects the human host.
In the previous weeks, questions have been raised about whether cytokine storm is indeed a culprit in severe Covid-19, but the Oak Ridge researchers have now made an intriguing and much-discussed case for the new mechanism called 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.
Piecing together the hypothesis was a ‘eureka moment’, said the study’s lead author, Daniel Jacobson, PhD.
Jacobson and co-authors used a supercomputer to compare gene expression in lung cells from nine infected and 40 uninfected individuals.
They found that 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 disclosed. “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 down regulated genes responsible for degrading it.
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.”
“That explains why ventilation has been so difficult. 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,” Jacobson noted.
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.