Scrutable

I don't know enough to judge the validity of this, just enough to be sh.t scared. What do you all think?


https://elemental.medium.com/a-supercom ... cb8eba9d63

Interesting, the hypothesis does seem to tie together many of the seemingly unconnected features of a severe Covid-19 infection. Everything from Vitamin D apparently offering protection, to reported neurological and vascular symptoms.

That said, I'm not in a position to judge whether its correct.

Very interesting.

And good news, which is what we're in short supply of in 2020.

That is interesting - the writeup makes it seem quite a compelling hypothesis. I look forward to the inevitable "It's a bit more complicated than that" responses in a few days.

I'm not sure that the bradykinin hypothesis makes covid any more sh.t-scary than it already is. Indeed, knowing which systems to target treatments towards should be helpful, and the article suggests several candidate drugs already exist and have regulatory approval. To me, this sounds, tentatively, like potential good news.

As an irrelevant aside, the article's headline "A supercomputer analysed covid etc" really annoyed me - it makes it sound like some kind of w.nky "machine-learning" exercise, when in fact what happened was a bunch of biomedical scientists analysed transcriptomes from covid patients using a (super)computer. The fact that a big computer was involved in the analysis isn't really that surprising in 2020 - even I've used them on occasion for bird stuff - so f.ck knows why the author thought that was the thing to lead with.

It certainly is an interesting idea that can account for many features of the disease - but...

This review (https://pubmed.ncbi.nlm.nih.gov/24925394/) of "Bradykinin-mediated diseases" in 2014 asserts that...

"Diseases which have been demonstrated to be caused by increased plasma levels of bradykinin all have angioedema as the common major clinical manifestation."

Pronounced angioedema - including ACE Inhibitor-Related Angioedema - produces some pretty obvious dramatic visible signs. If the major effects of COVID-19 are related bradykinin-mediated increases in vascular permeability - why would the external visible signs be so subtle? How would it only tend to cause angioedema in places you can't readily observe (e.g. the lungs).

Google "ACE Inhibitor-Related Angioedema" - it is anything but subtle!!

I won't pretend to know anything about the specific pathways involved, but they do touch on that:

However, the BAL fluid expression data indicate that the Bradykinin Storm is instead caused by upregulation of ACE2 and reduced degradation of BK by ACE. Based on this data-driven model, an individual’s symptomatology is likely directly related to the specific tissue distribution of viral infection around the body (Figure 4) and should be viewed in the context of an overactive bradykinin response. The majority of circulating BK is degraded in the lungs by ACE and therefore heterogeneous symptoms of COVID-19 could also be the result of systemic effects of increased levels of circulating bradykinin and the eight-fold reduction of ACE in the lung microvasculature that would normally degrade it.

If I'm understanding correctly, they're proposing that the ACE2 gene, which inhibits ACE, does so in a tissue-specific way (but potentially leading to a systemic buildup of bradykinin), whereas I'd guess that ACE-inhibitor drugs circulating in the blood have a wider systemic effect on ACE from the get-go?

Naively, it makes sense to me that if the virus is first affecting respiratory systems, and then the intestines and heart, that the earliest/most severe symptoms might be concentrated there rather than in, say, facial skin. But (in case I didn't make that clear) I haven't got a clue really

It should be straightforward to test for bradykinin build up (ELISA tests are available, as are more selective LC/MS/MS methods).

It’s testable which is good. Hopefully it’ll be quite quick to rule it in or out?

Bit of a fail by the sub-editor (a bot?), which turned this

In this sense, Covid-19 is like a burglar who slips in your unlocked second-floor window and starts to ransack your house. Once inside, though, they don’t just take your stuff — they also throw open all your doors and windows so their accomplices can rush in and help pillage more efficiently.

into this large-font highlight

Covid-19 is like a burglar who slips in your unlocked second-floor window and starts to ransack your house.

thus missing the point entirely. (I think we can all imagine why a virus is like a regular burglar.)