COVID Transmissions for 9-16-2020

Is bradykinin the explanation for COVID-19?

Sep 16, 2020

Good morning! It has been 303 days since the first documented human case of COVID-19.

Short headlines section today, in favor of an in-depth piece about the bradykinin hypothesis.

As usual, bolded terms are linked to the running newsletter glossary.

Keep the newsletter growing by sharing it! I love talking about science and explaining important concepts in human health, but I rely on all of you to grow the audience for this:

Share COVID Transmissions

Now, let’s talk COVID.

Bill Gates critiques US COVID-19 response

Bill Gates was responsible for the organization that made me decide to become a virologist. He has long advocated for better public health responses to disease, and for better pandemic preparedness. Recently, he did an interview with STAT where he excoriated the US response to the pandemic, which he called “shocking.” I find it hard to disagree.

Please see details here: https://www.statnews.com/2020/09/14/bill-gates-slams-mismanaged-u-s-response-to-covid-19-pandemic/

What am I doing to cope with the pandemic? This:

Watching

Last night, a local channel called Heroes and Icons played its usual Star Trek bloc. There was an episode of Voyager on about the crew being stuck in a featureless expanse where stars are not visible and everyone feels isolated. It was…a little cathartic, to be honest.

Is “bradykinin” at the center of COVID-19’s mechanism of disease?

Recently, an article in the publication Elemental on medium.com discussed what they called a “theory” of COVID-19 disease mechanisms surrounding a storm of a substance called “bradykinin.” I think this article made enough of a splash that it needs to be addressed here.

First things first, I want to say that I believe that this article misuses the word “theory.” A theory is an established scientific framework based on a combination of logic and evidence, with robust testing and confirmation. To create a theory, one must first develop a hypothesis, then explain a prediction that would be consistent with that hypothesis and no other viable explanations, and then create an experimental condition that would confirm that prediction and finally perform the experiment and analyze whether the results match your prediction.

I do not believe that this process—the scientific method, of course—has been satisfied in the case of the bradykinin hypothesis, but we will get to that.

First, let’s talk about bradykinin. Bradykinin is a small protein that has inflammatory activity that causes effects on the circulatory system at large. Bradykinin dilates arteries and constricts veins, and can modulate blood pressure. It is not a protein that I am very familiar with, though I do know that it is involved with the function of the blood pressure drugs known as ACE inhibitors, and helps to facilitate their effects. This is interesting, of course, because ACE2 is the entry receptor for SARS-CoV-2.

Bradykinin can cause angioedema, a tissue swelling that can also be caused by histamine through allergic reactions. Angioedema can be life-threatening. Bradykinin is also thought to cause the common ACE inhibitor adverse effect of dry cough.

You can begin to see why, perhaps, this could be a protein that is involved with COVID-19. However, I would like to point out several things. First, I have not heard widespread reports of angioedema as a characteristic symptom of COVID-19, though that would not necessarily happen if bradykinin were overproduced in the lungs. Second, there are a lot of inflammatory molecules that are produced in response to virus infection that could explain the mechanisms of COVID-19 disease. Bradykinin is, to me, another suspect to place on this list, but given the complex ballet of molecules involved in the pathogenesis of any disease, I do not think that it will emerge as the sole mechanism behind COVID-19.

However, the new hypothesis suggests that bradykinin is central to the pathogenesis of COVID-19, and I’d like to give that hypothesis the attention and treatment that it deserves.

Our story begins with a group of researchers in China who collected “broncho-alveolar lavage” (BAL) fluid from patients with COVID-19. BAL fluid is basically a wash of lung fluid, so they were collecting a whole bunch of stuff from inside the lung.

These researchers published a lot of information on what molecules were found within their samples, so much so that other researchers were able to analyze the data. This is a triumph of modern biology right here—international data from the beginning of the pandemic were shared globally and allowed for a really interesting analysis.

Specifically, the data were analyzed using supercomputers at Oak Ridge National Laboratory, and a network of gene expression changes was discovered. You can read the paper here: https://elifesciences.org/articles/59177

“Gene expression” is the word that we use in biological research to describe the amount of mRNA that is made from a given gene. It is a rough estimate of the amount of that gene’s final product that is being made—but it is only a rough estimate. Gene expression changes do not always translate to actual changes in the levels of those genes. In this case, the gene expression changes generated the bradykinin hypothesis.

The initial observation that generated this hypothesis was a change in the expression level of ACE2 during infection with SARS-CoV-2. Alongside the increase in ACE2 expression, expression of ACE, which is related to ACE2, went down. One result of this is that bradykinin levels go up, according to the expression analysis performed here. This would begin to have effects on the circulatory system and potentially cause inflammation, as per our understanding of bradykinin. It would also cause vascular leaking, a well-documented effect of bradykinin overproduction.

At the same time, the researchers detected increases in levels of machinery involved in synthesis of something called hyaluronic acid. Hyaluronic acid is really interesting for a lot of reasons—it can have major positive impacts on age-related joint decay, for example. Partly this is because it can form a viscous gel, which can be cushioning.

Let’s summarize what the data have shown us so far. We know that levels of bradykinin expression go up, and that there are effects on expression of ACE2 and ACE. We know that the expression of machinery that produces hyaluronic acid also increases. We do not have distinct evidence that bradykinins are actually overproduced, and we do not know that hyaluronic acid is overproduced. We also have to rely on the idea that the samples from China were representative, and that the supercomputer network analysis was based on solid assumptions of how these gene expression networks interact with each other.

So, this is where the explanation provided turns into a hypothesis. The authors of the study propose that an increase in levels of bradykinin would cause inflammation and induce vascular leakage, as well as coagulopathy—this is possible, but not confirmed. The authors also propose overproduction of hyaluronic acid could cause leakage of a viscous fluid into the lungs that would interfere with the ability to breathe. Together, they propose that these two effects could give rise to all of the documented signs and symptoms of COVID-19. To which I have to say, “Sure! That sounds possible!”

Unfortunately, none of this is actually confirmed by the computer modeling that was done in this paper. There is no evidence presented that hyaluronic acid is a major component of the mucus that is found in the lungs of COVID-19 patients. There is no direct evidence of elevated bradykinin. There is very little direct evidence at all.

There is also reasonable evidence that other pathways are involved in the pathogenesis of COVID-19. For example, it has been demonstrated in numerous studies that corticosteroids, modulators of inflammation and immune responses, are able to reduce the likelihood of death from COVID-19. This is what I would expect if the immune response is central to the pathogenesis of COVID-19, but the pathways involved are separate from the ones in this mechanism of disease.

I would also expect that patients on ACE inhibitors would experience more severe COVID-19 if this were true, due to elevation in bradykinin levels from administration of these drugs. To the best of my knowledge this is not the case. In fact, I have heard it suggested that ACE inhibitors may actually interfere with the disease in some way, though I have not seen good evidence of this.

This does not mean that the hypothesis is wrong. This just means that I want more evidence before I am willing to call it a theory. Even then, theories can be wrong. They can be incomplete, imperfect, and inadequate. I expect that if we do discover a direct role for bradykinin and hyaluronic acid in COVID-19, it will be part of a bigger picture of disease mechanisms that combine to create the pathologies that we see in the clinic in this disease. It is important, therefore, that this continue to be explored and tested as scientists and physicians further probe the pathogenesis of COVID-19.

Join the conversation, and what you say will impact what I talk about in the next issue.

Also, let me know any other thoughts you might have about the newsletter. I’d like to make sure you’re getting what you want out of this.

Viral Transmissions

Discussion about this post