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We’re getting close to a year of living with Covid-19, but work is still ongoing to understand the mechanisms behind some of its most devastating effects. A lot of attention has been given to Cytokine Storms in this realm, but with some conflicting evidence there, Bradykinin Storms are starting to share some of the spotlight.

Sources:

https://jamanetwork.com/journals/jama/article-abstract/2770484
https://european-biotechnology.com/up-to-date/latest-news/news/roches-il-6-receptor-blocker-fails-in-phase-iii.html
https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.202000967
https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-race-ethnicity.html
https://elemental.medium.com/a-supercomputer-analyzed-covid-19-and-an-interesting-new-theory-has-emerged-31cb8eba9d63
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2769237
https://clinicaltrials.gov/ct2/show/NCT04488081

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Since it's been all Covid all the time basically since March, many of you are probably familiar with the handful of Covid buzzwords. One of those buzzwords or I guess buzz phrases is Cytokine storm. There's been a lot of talk about this is relation to the severe inflammation known to occur in very ill Covid-19 patients. But lately a new phrase has been creeping in – Bradykinin storm – and that's the topic of this week's Healthcare Triage.

[Intro]

This video is supported in part by viewers like you. You, too, can support the show at https://www.patreon.com/healthcaretriage.

Mike Manning and a couple other viewers have been asking about the Bradykinin theory of Covid-19, so, we looked into it. As mentioned you may already be familiar with the term Cytokine storm.

Cytokines are small proteins secreted by some cells of the immune system. While they are important to a normal immune response, they can wreak havoc if the body releases too many at once, causing symptoms like high fever, severe inflammation, fatigue, and more.

Scientists call this a Cytokine storm and many pointed to it as a potential culprit behind severe Covid-19 reactions. However, recent research suggests that cytokines might not be elevated in Covid-19 patients, and a medication that blocks Cytokine release did not appear to reduce disease severity and mortality in ventilated Covid-19 patients.

So if not cytokines, what might be causing this massive inflammation of the respiratory system? Some researchers are convinced that the term we should be using is "Bradykinin storm".

We know that SARS-CoV-2 enters cells via ACE2 receptors on the cell surface and based on previous evidence researchers hypothesize the following chain of events once a cell is infected. A cascade of activity begins that includes the virus telling the cell to reduce ACE expression once it has entered. This reductions then increases levels of DABK in both the infected cells as well as their neighbors. ACE normally breaks down Bradykinin, and DABK is a metabolite of Bradykinin associated with inflammation.

Based on further evidence, they hypothesize that a positive feedback loop is then established, with cell injury and inflammation eliciting changes in Bradykinin levels and Bradykinin receptors – changes that lead to even greater levels of DABK- and Bradykinin-mediated inflammation.

Put simply: Infection with the virus may increase inflammation and tissue injury by increasing levels of DABK, and then that injury and inflammation up-regulate Bradykinin receptors and DABK, which leads to more inflammation, and the cycle continues.

In support of this hypothesized cascade of events these researchers also point out previous evidence suggesting that African Americans possess increased sensitivity to Bradykinin which could help explain higher mortality rates among this population. They also refer to studies of patients on ACE inhibitors reporting loss of taste and smell in some participants – a symptom that is also common to Covid-19.

There are many other potential contributing avenues that support the credibility of the Bradykinin hypothesis – we'll link to an article on this down below – and researchers point out that we may have an easy way to test it out. Icatibant is an FDA-approved medication for treating hereditary angioedema, and it's known to block DABK signaling through one of the Bradykinin receptors. It doeasn't block the receptor that DABK most strongly binds to, but researchers argue that it could disrupt the cycle enough to make a difference in patients with Covid-19-induced respiratory distress. Given that we don't have any FDA-approved medication for blocking the receptor most preferred by DABK, using what we do have is a good place to start.

And it looks like we've already taken a step in this direction. A study published on August found an association between Icatibant and improved oxygenation in patients with Covid-19, with a decrease in oxygen supplementation in 9 patients receiving the drug. This study looked at a very small number of patients and it was not a randomized controlled trial, so it's no guarantee. But it does suggest a reason to move forward with testing this hypothesis.

And it looks like others agree. At least one clinical trial that includes Icatibant – the I-SPY Covid trial – has been announced. No data are available yet, but we'll keep an eye out and let you know if anything exciting happens. Remember though, this is all preliminary we're still in the hypothesis testing phase not reporting definitive findings that should change clinical practice.

[Outro]
Hey, did you enjoy this episode? You might enjoy this previous episode on how Covid is not the flu. We'd also appreciate if you subscribed and liked the video down below and go on over to https://www.patreon.com/healthcaretriage where you can help support the show even through a global pandemic we'd especially  like to thank our research associates James Glasgow, Joe Sevits, Josh Gister and Michael Chinn and, of course, our Surgeon Admiral Sam.