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Bradykinin and the Coronavirus

There’s a new paper that a lot of people are talking about recently that presents a rather large unifying hypothesis about the effects of the coronavirus (and suggests some new modes of treatment as well). This is the “bradykinin hypothesis”, and before digging into it, it might be worth a paragraph to talk about what bradykinin is.

It’s a 9-amino-acid peptide, and it’s got a ton of biological activity. Bradykinin lowers blood pressure by dilating blood vessels, but it causes contraction of the smooth muscle in the lungs and in the gut. It’s a diuretic in the kidney, and in the nervous system it’s involved in the sensation of pain. Bradykinin receptors (there are two types) can signal to attract neutrophils (giving it a role in allergy and inflammation), and its pathways have also shown up in the functioning of several types of cancer cells. So there’s a lot going on! People taking angiotensin-converting-enzyme (ACE) inhibitors are getting bradykinin effects as well, because ACE is one of the enzymes involved in processing the larger precursor peptide down to bradykinin itself (as it does for angiotensin and its precusor). In fact, the dry cough that’s a side effect of some ACE inhibitors may well be a bradykinin-mediated effect, via hypersensitivity of nerves in the upper airway. And the bradykinin B2 receptor forms an actual protein complex with angiotensin-converting enzyme itself, although all the functions behind this haven’t been worked out.

That ACE part of the story is where this new paper comes in. The multicenter team behind it re-examined the composition of lung fluid collected from coronavirus patients, and found that the disease lowered the amount of ACE and increased the amount of ACE2 (readers will recall that the latter is the surface protein that the coronavirus uses as a cellular entry point). ACE2, in fact, appears to increase by 200-fold (it’s normally not found in high levels in lung tissue). Angiotensin II itself goes up by more than 30-fold, and renin (another enzyme involved upstream in the formation of angiotensin) and the two angiotensin receptors all go up several hundredfold.

These imbalances cause bradykinin levels to increase – in fact, most of the proteins involved in bradykinin production and signaling are undetectable in such lung fluid under normal conditions, but go up sharply during coronavirus infection, while enzymes that are involved in bradykinin degradation go down. In the lung tissue, this new imbalance causes pain, dilated blood vessels, and increased vascular permeability. The bradykinin system also has complex links to blood coagulation, which could tie in with some of the observed coronavirus pathology in that area as well.

At the same time, another set of proteins seems to be similarly deranged: the ones involved with hyaluronic acid (also known as hyaluronan). That’s a large carbohydrate polymer that’s found throughout extracellular fluids – in the joints, for example – and its involved with all sorts of wound repair, cell migration, and tissue surface effects. As with bradykinin, the enzymes involved in its production are all ramped up rather steeply in the coronavirus patient samples, and the ones involved in its degradation are all down. HA can be rather thick and slippery, and the authors believe that having it produced in excess in the lungs during coronavirus infection is a major factor in making things worse. In fact, its overproduction has already been associated (pre-pandemic) with respiratory distress, low oxygen levels, and even with some of the radiological findings (“ground-glass” opacities) that are also associated with coronavirus infection. The HA system has been tied in some work to the renin-angiotensin system, although that’s also a complex story, since there are many states of hyaluronic acid polymer and various proteins and receptors that respond to their presence. As this new paper notes, though, HA has already been implicated as a player in coronavirus pathology.

So the authors are proposing a “bradykinin storm” model, where increased bradykinin levels tie into all sort of coronavirus pathologies. The model fits many of these well, and also suggests other clinically observed features such as low potassium (hypokalemia) and low Vitamin D. It’s a very appealing theory, but it’s also important to remember that a lot of very appealing theories in this business turn out not to be true. Or not completely true. Or not true in the ways that were originally thought. The way to find out is through clinical testing. To be honest, I’m worried that this proposal is almost too neat and form-fitting; rarely do you get something that falls together this well. It’s also quite possible that you could come up with a reasonable set of literature references and previous reports that cast many of these connections into doubt – the medical literature is large, and you can find support for a lot of things if you’re putting together a brief for the prosecution. But overall, I find this work pretty plausible.

To that point, a very good feature of this work is that it immediately suggests several interventions with FDA-approved drugs. Not all of these are actionable (for example, androgenic steroids decrease bradykinin production, but do a hell of a lot of other things besides!) But icatibant (brand name Firazyr) is an antagonist of bradykinin B2 receptors, and ecallantide (brand name Kalbitor) is an inhibitor of kallikrein, a key enzyme in bradykinin production. Both of those would seem to be directly targeting the proposed mechanisms. Hymecromone is a small molecule that’s known to inhibit the synthesis of hyaluronic acid. And thymosin beta-4 is a protein that could tie into the connection between bradykinin activity and coagulopathies; a version of this protein has been in human trials as Timbetasin. As mentioned above, vitamin D supplementation might also be beneficial – its receptor has connections with vascular permeability and with the renin/angiotensin system, and its deficiency has already been noted as a rsk factor in the current pandemic. I agree with the authors that controlled trials of all of these therapies would seem very worthwhile – hymecromone is a particular standout from what I can see, being generic and inexpensive, and if it can directly improve lung function in severe coronavirus patients, that would be a real accomplishment. Its weak point is that it has caused diarrhea as a side effect with even further potassium lowering, so you might want to give that with potassium supplementation (?) I am most definitely not a clinician, though, so I’ll leave my suggestions out of it.

69 comments on “Bradykinin and the Coronavirus”

  1. Tourettes of Chemistry says:

    Great to see you have picked this up for wider broadcast.

    A bit more resolution in the pathology appears therein independent of the ‘Mind of Man’ motivators that have been dominating some of the chatter at this site.

    The virus has no agenda – it is surviving in the best way it knows. Lots of people were not prepared for that kind of challenge.

  2. David Eugene Young says:

    Now, this will happen. Some one in the world will prescribe one of these Bradykinin inhibitors to their next 70 patients with a cough. All 70 will stay at home and that physician will brag that he or she has found the cure for Covid! And then you won’t hear the end of it.

    1. Eric Lucas says:

      Or, alternatively, responsible clinicians will begin properly controlled Phase 3 trials (safety has already been demonstrated during trials of the same drugs for other uses), and medical science will control the message, not some quack in France who hasn’t a clue about Responsible medical Research, or even basic elementary statistics.

  3. knapp says:

    The Oak Ridge supercomputer biology team is going with the bradykinin hypothesis after decoding more of the cov-2 chemical complex.

    1. Akin Arnie says:

      They did most of this running the second fastest computer for a week.

  4. Patrick says:


    The vitamin D deficiency paper link seems to be busted.

    Thanks for a very interesting post…

    1. Nick says:

      agreed the link is down. however searching for the link revealed a possible alternate try this one

    2. Riah says:

      I must say the Oakridge findings didn’t make sense to me and I have been scratching my head: How can there be both high ACE2 and high Angiotensin II when ACE2 quickly breaks down Angiotensin II to Angiotensin 1-7. It only makes sense when you consider that something being upregulated or finding lots of RNA for its coding does not mean there is lots of it in the body – because it can be just as quickly broken down by something else that is also upregulated. (sorry, terribly explained) . I agree that much caution is therefore needed in interpreting these findings.

      The other puzzle is that ACE2 being upregulated in serious cases doesnt actually fit with a protective role for vitamin D as vitamin D also upregulates ACE2! But we know there is now overwhelming evidence for vitamin D, including the Spanish double blind RCT mentioned elswhere here. Anyone have any ideas/answers on how ro reconcile these?

      1. Riah says:

        I have tried to answer my own question – yet to get through moderation and appear on here.

        This is a ps. to that:
        Derek, re your “because ACE is one of the enzymes involved in processing the larger precursor peptide down to bradykinin itself (as it does for angiotensin and its precusor)” , shouldnt this say ACE in an enzyme that breaks down bradykinin to the inactivated form bradykinin 1-5? or did you mean ACE2?

  5. Bryan says:

    One major caveat of the eLife paper is that the COVID-19 samples and the control samples they compared them to were from two different populations (COVID-19: patients with severe disease from Wuhan, China, control: people recruited for a 2018 GSK study on obesity and asthma) and samples were processed by two different teams. This makes it difficult to interpret differences they observe between the two populations as they could be due to underlying differences between the populations unrelated to COVID-19 or technical differences in samples collection/preparation. Usually, one would like to see validation of the differences in an independent cohort where samples could be processed in parallel, but no such validation was done for the study. I agree with Derek that the data and underlying model they propose make sense and warrant further investigation, but it’s also important to acknowledge the limitations of their study design.

    1. Ed says:

      In addition, it is important to keep in mind that they only measured RNA and not protein levels. You would think these would correlate, but very often they do not. So saying that, for example, ACE2 or Angiotensin II go up x-fold is misleading since most readers will assume this means protein and that has not been shown in this work.

      1. That is what I have been thinking since I saw this on HackerNews – why this roundabout way of measuring genes influencing some chemical complex production and no direct measurements of the substances involved? I’ve got some answers that it is just easier – you have standardized genetic kits with amplification etc – but nothing similar for the other substances. I wish there was more here about direct detection possibility.

        1. John Cooper says:

          Because measuring RNA levels for many genes is easier and costs less than measuring levels of proteins or peptides.

          1. theg9 says:

            Is the above commenter correct in saying that there is often no correlation between RNA and protein levels? I would hope that accuracy is valued over speed of the experiment in these situations.

    2. Rasmi says:

      That is a major caveat which can not be ignored. Gene expression data is easily confounded due to differences in methods, ethnicity, phenotype etc.

  6. Ron says:

    If this theory turns out to be correct (I understand that much more investigation is necessary), what would that mean for people who are on ACE inhibitors? Would it put them at higher risk of severe symptoms? Lower risk? Could the “dry cough” symptom of the ACE inhibitor signal a more likelihood of severe symptoms? Would the lack of theses symptoms signal a lower risk? Not look for answers with certainty. Just discussion from this group full of people who have incredible knowledge.

    1. Bryan says:

      Researchers have been studying the issue, and while the evidence has been somewhat mixed, it seems like people on long term therapy with ACE inhibitors or angiotensin receptor blockers are not at higher risk of poor outcomes. See this WHO document for more details:

  7. Karl Pfleger says:

    Finally the vitamin D elephant in the room gets mention not just in the comments. The vitamin D writing has been on the wall for some time. See Benskin’s excellent (peer reviewed, to-be-published) review of literature through mid-June:

    Evidence for vitamin D being a game-changer for the pandemic since mid-June is increasingly compelling with the latest being the small RCT out of Spain that showed an incredible effect size: Hospitalized patients given calcifediol were significantly less likely to progress to needing ICU admission vs controls (1/50 treated vs 13/26 controls; multivariate OR=0.03 correcting for confounders) and less likely to die (0 treated vs 2/26 controls). Small n but even the upper bound of 95% CI was 0.25. Compare this with the WHO recommending steroids based on effect size of ~1/3 fewer deaths.

    1-page summary of vitamin D & COVID-19 facts including pre-pandemic facts such as D deficiency prevalence and most compelling studies showing causality here:

    That should satisfy the above commenter who noted that Derek’s link about D deficiency is broken. Derek ended agreeing that RCTs of some of the existing drugs in the bradykinin area are a good idea and called out hymecromone but with caveats about some potential risks. Vitamin D is much safer than hymecromone or steroids. So safe in fact that further RCTs are probably unethical as it would be wrong to withhold it from controls with a disease as bad as COVID-19.

    1. Marko says:

      If anybody is waiting for the US-based scientific community to provide compelling RCT evidence on the benefits of Vit D in Covid-19 , be prepared for a long wait. There’s no money in it , so it probably won’t happen at all , but if it does it will be long past the time when it will do anyone any good for this pandemic. There are dozens of RCTs pending , almost all in foreign countries , and most are either still recruiting or not even recruiting yet.

      If you’re dark-skinned or don’t get outside much , just start taking 1000 IU/day as a new lifelong habit. It’s a few cents a day , and there’s no downside. The next time you see your doc for any reason , demand a blood test for Vit D status if you’ve never had one done. Then you can adjust your supplement intake if necessary.

      Save yourself. Our healthcare system is only designed to save you once you become a profit center.

      1. Karl Pfleger says:

        @Marko There is no need to demand a test from your doctor. There are now many direct-to-consumer blood test websites that will let you order a wide variety of tests for yourself. Eg, the vitamin D test is currently $35 from (no affiliation, except as happy customer). You get a lab order form and take it to any LabCorp and get results in a few days by email.

        There are also home finger-prick tests but they are more expensive. I’m told their accuracy is well characterized and good by one researcher in the field, but haven’t seen publications on it.

        1. Marko says:

          I agree , that’s a good option , particularly for those who have no regular interaction with the health care system. I’ve used the direct-to-consumer tests myself in the past and wouldn’t hesitate to do so again.

          1. Riah says:

            I have been taking 8,000 IU daily with K2 and magnesium – 1,000 IU is probably not enough to get serum levels above 40 ng/ml for most of us over autumn/winter/spring . Fauci takes 6,000 IU apparently.
            But as mentioned in my other message I am now confused as I cannot reconcile my understanding with the Oakridge theories

        2. TallDave says:

          also a longtime LE customer

          find their mag overly promotional and the products often overpriced but they do emphasize research and their mix is quite convenient

          will have to try the D test, thanks for recommending, been wanting to check that more often

      2. Marko states, ” just start taking 1000 IU/day as a new lifelong habit,” and this may not be adequate. See the paper supported by numerous others, “the big vitamin d mistake” – A mistake was made in the original calculations for a MDR. I’m a survivor of neuroinvasive West Nile Virus with a remarkable recovery by prescription dose Vitamin D prescribed by a young astute neurologist. She likes to maintain a blood level between 80-100 mmol/L. I currently take 10K units daily with testing 4x year. One MUST also supplement with vitamin K to prevent calcification in the soft tissue.

        1. Marko says:

          Yes , I’m sure you’re right that more would be better. It’s clear that the MDR is way out of whack. I also suspect that the typical so-called “normal range” is not really the range needed for optimal health. Routine screening of Vit. D status should be available to everyone , then supplement regimes could be individualized as indicated , using updated target levels.

        2. Marko says:

          BTW , Fauci himself takes Vit. D supplements , and recommends them for those who are “deficient”. He doesn’t explain how people without health care are supposed to know that , nor why vit. D status testing is far from routine even among those who do have good access to health care. ~Min 32:00 in this video :

          If Fauci is supposed to be one of our best scientists/public health officials , we’re in deep doodoo.

          1. BC says:

            I think there’s a blanket public health recommendation for everyone in the UK to take Vit. D.

    2. Lynnepi says:

      I’m not convinced that is a real study. Or at least, as written suggests that it was not competently designed and conducted. Some comments to illustrate my concerns:
      1. A pilot study is meant to assist in the design of a larger trial, not provide substantial evidence of safety and efficacy. It would provide information on safety and efficacy inadequate to inform clinical practice. True, “pilot trial” is a commonly misused term.
      2. The authors report they conducted an “open-label, double-masked” clinical trial. That’s certainly an odd combination and they should inform us who was blinded and who knew which patients received active treatment.
      3. The authors state they calculated a sample size to show a difference of 5% ICU admission rate in the calcifediol group compared to a 10% ICU admission rate in the “no calcifediol” treatment group (so it sounds like the patients were not blinded). This supposed analysis showed that they needed 75 patients. This is laughably way off. The actual estimated sample size would be 868 patients. They also assumed an attrition rate of 12%, which is somewhat puzzling considering that this means they expected to lose track of patients while they were still in the hospital??
      4. They enrolled “76 consecutive” patients. 76 patients were “assessed for eligibility” and no one met exclusion criteria? Also, every single patient gave informed consent to participating in the study. Unheard of.
      5. Although they estimated that 10% of patients not receiving calcifediol would be admitted to the ICU, 50% were admitted. A control group not having expected outcomes generally makes it very difficult to interpret the study results, although this could be due to the small number of patients in the study.
      The article is woefully lacking in details necessary to assess the quality of evidence and comes across more as a document generated by an artificial intelligence application that was fed catchphrases.

      1. Marko says:

        Don’t worry. Surgisphere is preparing a study , soon to appear in Lancet , in which they examine the patient records of 942,000 Covid-19 admissions and find that not only is Vit. D supplementation or treatment not beneficial , it is , in fact , deadly in some cases.

        The ultimate result of this study will be that all pending RCTs involving Vit. D will be suspended , and the threat that this cheap , readily-available substance poses to Big Pharma profits will be eliminated.

        Hope you find this good news , but my guess is you were already aware of it.

  8. steve says:

    I think you’re missing several elements. I saw a webinar by one of the groups doing this with rather spectacular results. The idea is that it’s specifically the B2 receptor that is responsible for the florid pneumonia in some patients (two involved to explain here but your readers may want to see the literature on this receptor subtype). The group reported that treatment with icatibant allowed some patients who would otherwise be intubated to leave the hospital in a day or two. The issue with icatibant is that it has a short half life so they are looking for longer-lived inhibitors but the results were impressive.

    1. steve says:

      “too involved”

  9. Dr. Seymour Tushi says:

    After 47 years off the air, the Brady Bunch have finally taken their revenge.

    1. Thomas says:

      I have encountered “bradykinin is a kind of quinine, you see”. (Quinine is spelled in Dutch as kinine). Luckily only once.

  10. Another One says:

    Non-biologist/medical person here. A quick google search shows me that there are bradykinin knockout mice. Does bradykinin function similarly enough in mice that these could potentially be used to test this mechanism? Or are there other complicating factors I’m not aware of?

    1. Christophe L Verlinde says:

      Are you sure you were reading info about bradykinin knockout (KO) mice?
      As far as I know researchers have made KOs of bradykinin receptors (B2, B1)
      but not of bradykinin. Bradykinin is one of the 6 proteins/peptides encoded
      by the kininogen-1 precursor gene.

    2. cassandra says:

      In theory bradykinin in Covid 19 is elevated not knocked out.

  11. RM says:

    Good work on bradykinin. But my guess is that at the speed we are going, a cure or vaccine will appear only after Covid-19 has killed 90% of the people it would have killed anyway.

  12. ILikeMike says:

    Derek, since you mentioned Vitamin D, there was a report of a small, pilot clinical trial in Spain that seemingly had impressive results. That said, I make no representation about the merits of the trial protocols or results. I am, however, curious to learn what others think of it. Thank you for your posts!

    1. Karl Pfleger says:

      I think the pilot vitamin D RCT from Spain is a big deal. (I also linked it, in an early comment above.) Many others agree that it’s a big deal. Eg, search Twitter for calcifediol.

      1. Marko says:

        Many on twitter ARE interested. Just not among the blue-check crowd. They know where their bread is buttered.

      2. Lane Simonian says:

        The following studies are way around the edges, but they point to Vitamin D3 as a potential way to restore the balance lost as a result of oxidative stress, excessive inflammation, and nitric oxide depletion in COVID 19.,in%20the%20development%20of%20atherosclerosis.

        1. John Aspray says:

          Well done. I’m so pissed off that people keep going on about Vit. D. It has to be D3 to be effective during the dark months of the year. Beetroot is also necessary for the phosphorous it supplies, and D3 regulates this. They mentioned Potassium, Bananas for that, and a bit of Zinc is always beneficial, tomatoes !
          Let food be thy medicine.

          1. Riah says:

            Hey, you’ll be glad to know zinc inhibits bradykinin formation. Thats because kallikrein, the protease enzyme that is required to convert the kininogen precursors of bradykinin into bradykinin is inhibited by zinc!

            So vitamin D3 , (which also reduces BK by at least 2 mechanisms – I will answer my own previous question about this),and magnesium which is required to convert D3 to its active form, K2 to keep the increased calcium D3 causes to be absorbed from the gut, out of arteries and pull it into bones, plus now zinc to prevent BK formation should together keep us safe! People are generally far more likely to be deficient in D3, magnesium (stress, excercise and metabolism of carbohydrates deplete magnesium significantly), and k2 which is why supplementation is often ncessary. We may have enough zinc if we eat well (red meat and shellfish are rich sources).

        2. Terry Harnden says:

          Can anyone explain a mustard plaster delaying a further shortness if breath attack by four months.

      3. TallDave says:

        yep glad this is finally getting attention

        the May results should have rung a bell, those correlations were crazy

  13. bt5 says:

    Derek, The bradykinin hypothesis is really interesting and ties into an interesting early paper which mentions both hyaluronic acid synthesis and Niacin:

  14. Alan says:

    This paper shows there might be issues with measuring the amount of ACE2 (link in name)

    Interferons and viruses induce a novel primate-specific isoform dACE2 and not the SARS-CoV-2 receptor ACE2

    1. Riah says:

      Thanks! This is so interesting. I will look that up

      1. Riah says:

        Alan – this is GOLD! A BIG thank you!

  15. SALEH says:

    Great Derick,
    All types of research efforts to better understand pathological pathways are open doors for potential treatments.
    Maybe those available products can sufficiently mitigate the cytokine storm to a level that can improve clinical picture for the benefit of patients.
    Dont know if Colchicine have a role here ? maybe you can tell us.

  16. Diana Garcia del Barco says:

    In this post some elements are missing:
    -ACE2 (and not ACE) hydrolyzes the most active metabolite of bradykinna, DABK (J Renal Inj Prev. 2020; 9 (2): e19.)
    -ACE2 depletion due to the internalization of the SARS-CoV-2 + ACE2 complex, leads to an increase in DABK, which through its congnate receptor, BKB1R, leads the cascade of inflammatory events in the lung (FASEB J, 34 , 7265-7269.). A decreased activity of ACE2 impairs the inactivation of DABK and therefore, enhances its signaling through BKB1R. The consequential events are fluid extravasation and leukocyte recruitment to the lung
    But all this overlaps with the increase in Angiotensin II, which is also due to the depletion of ACE2 (Am J Physiol Lung Cell Mol Physiol. 2018;314:L17-l31.). The contribution of bradykinin and its most active metabolite (desArg973) in the pathogenesis of COVID-19 is a consequence of ACE2 depletion. However, the inflammatory effect of Angiotensin II, which also increases as a consequence of ACE2 depletion, is much more pathogenic than that of bradykinin and its more active metabolite, [desArg973] *

    1. Riah says:

      Thanks for this. This is my understanding too so I am puzzled that Oakridge are saying that pathology is inccreased in Covid infection because the virus upregulates ACE2.
      This review says vitamin D prevents Ang II’s inflammatory action by upregulating ACE2.

      Which is right?

      1. Marko says:

        The reported effects of Vit. D on ACE2 are indeed conflicted and confusing , however , I don’t think it should cloud thinking about the beneficial effects that have been demonstrated in every way except by the insisted-upon , gold-standard , slam-dunk RCT that we all know will never be completed because there’s no money in it.

        Vit. D is a hormone , analogous to testosterone or any other. It has pleiotropic effects , and the balance of beneficial activity regarding COVID-19 seems to be involved with immune modulation that prevents the severe outcomes associated with cytokine storm-type immune dysregulation. The fact that it may , to some degree , increase viral entry by upregulating ACE2 could well be immaterial to its overall effect. After all , over 99% of people clear COV2 and survive. The idea is to to chip away at that 1% who don’t. If a significant fraction of those people who die are due to a simple Vit D deficiency , it’s a travesty , and a condemnation of our profit-driven health care system.

        Fauci , and now Trump , have adopted Vit. D. When will they advise the great unwashed to do the same ? Since most of the people who’ve been dying of COVID-19 are not essential – or may even be counter-productive – to the profit-making , I suspect never.

    2. Riah says:

      Thanks Diana, I think your comment “ACE2 (and not ACE) hydrolyzes the most active metabolite of bradykinin, DABK” is really critical here. Do you have any idea how much more active DABK is than BK?? That would be great to know. If it is much more active (similar to the order of active D3 which is 1000 x as active as the circulating form) that would mean upregulation of (properly functioning) ACE2 by vitamin D will be very important in preventing a potential BK storm.

      The high number of ACE2 genes expressed found in the Oakridge study may all represent the iso form mentioned by Alan above and/or internalised ACE2 and/or represent RNA not transcribed/converted to actual ACE2 at all. That would explain the high BK and high Ang II they are seeing. ie. the ACE2 is not actually doing its job.

      Vitamin D also downregulates renin production which in turn also reduces BK receptor and Ang II formation. So Vitamin D reduces BK by 2 separate means.

      Does that all sound like possible explanations which reconcile the things that don’t fit? If so, this would really confirm a huge role for vitamin D – for which other biological evidence re effect on T-cells is also incredibly strong, see:

      Would be really greatful for feedback.

  17. Fernando Bazan says:

    I would also check out Frank Van der Veerdonk’s (& colleagues at Radboud UMC) April 27th paper that’s out in eLife:

    Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome.

    This came out before the July 7th Jacobsen eLife paper (check out The Scientist’s rendering of the story:–67876)

  18. Toby Gibson says:

    This is my first post here but I have to say that I’m struggling that anyone is taking bradykinin seriously. The amount of ACE2 in the lungs is negligible. Anyone can go to the human protein atlas to see for themselves the tissues where ACE2 is strongly expressed.

    And read the following publications

    And compare and contrast these 2020 publications to the 2004 publication which shows abundant ACE2 in lungs

    And then go to this Nottingham COVID Research Group website to see that ACE2 does NOT get up-regulated in severely ill patients

    To recap, ACE2 is not responsible for severe COVID-19 lung disease. It cannot be because there is not enough of it to sustain a serious infection in that organ.

    Whereas Neuropilin-1, which is abundant in the lungs, has been shown to be a SARS-CoV-2 receptor

    We ( and others (PMID:32130973) think that integrins will join Neuropilin-1 as receptors in the lungs. The best evidence so far to be made publicly available for the role of integrins as SARS-CoV-2 receptors can be found on the Nottingham website linked above.

  19. RAD says:

    The Bradykinin discussion confuses me. We know SARS-CoV-2 attaches to cells that express ACE2 receptors so, logically, these cells will be damaged or destroyed by either the virus or the immune system. We also know that ACE2 and ACE work in tandem to regulate the renin–angiotensin system (RAS). It is perfectly reasonable that the selective damage/destruction of ACE2 cells will lead to an imbalance in the RAS system, including possible Bradykinin storms.

    Isn’t the fundamental question still the ACE2 tissue tropism (which cell tissues are infected and when) and the recovery/dysfunction of the damaged tissue?

  20. Egan Peltan says:

    Hey Derek,

    Thank you for covering this! Your coverage of the pandemic has been spectacular so far.

    I’m working with a group based out of Stanford trying to get a repurposing study of Hymecromone off the ground ( Please feel free to reach out if you have any questions. We’re currently seeking support for the trial which has been hard to come by as the idea doesn’t fall neatly into the anti-viral/anti-inflammatory/vaccine trichotomy.

    Always happy to discuss more!

  21. Robin E. Schlinger says:

    Reading of this Vitamin D and COVID-19 trial might interest Marko and others: That the company that owns icatibant is a collaborator interested me enough to buy stock in Takeda Pharmaceuticals, which I did this week.

    1. Marko says:

      Yes , that’s good to see. I hope they can get it enrolled and underway in a timely fashion. I’d rather they were using calcifediol rather than D3 in the newly-infected patients , as was done in the Spanish study , so as to avoid the delay due to liver conversion. Using D3 in the uninfected contacts of the index patients is OK , I think , since there will presumably be days or weeks that elapse between the time they start on the supplements and the time they become infected ( if ever ).

      I hope they do a baseline Vit D determination on all enrollees. The results from the Spanish study may have been so dramatic because it was done in a region known to have high levels of Vit D deficiency.

      1. Madge Hirsch says:

        There is a problem with giving fixed doses ( especially of cholecalciferol) because of the wide variation in metabolisation between individuals. It would be better to aim for getting patients to a high level of vit D say 60ng/l and dosing according to baseline. Calcifediol works faster and also gets round any liver disfunction in metabolisation. I am prescribed this on a daily basis in drops ( I live in France ) and 3 drops a day ( 600iu) keeps my levels between 60 ng and 80 ng/l ( variation probably due to amount of sunbathing I do. I could not stay within the normal range on 3000 iu of cholecalciferol.

        1. Marko says:

          Interesting. Thanks.

    2. TallDave says:

      thanks! will follow closely

      now have studies showing a 20:1 correlation between mortality and D levels, and 25:1 (50% to 2%) ICU rate with calcifediol supplementation

      of course at least some of those correlations has to be random variance (they’re absurdly large), but even a small fraction of that result outperforms most every treatment currently available, hope we see more being done in this vein soon

      1. Madge Hirsch says:

        There is no dosh to be made from vit D as Marko has pointed out. There have been various studies showing correlations between low vit D and poorer outcomes for Covid for several months now. The news is not getting into the mainstream media. Given the safety of vitD no governments are advising their populations that in waiting for a vaccine they should be taking doses much bigger than the current RDAs. Fauci is taking 6000iu a day – 10 times the RDA. So why isn’t he pushing this for the rest of the population instead of Remdesivir? See my first sentence.

        1. Dafydd says:

          The NHS in the UK is offering free vitamin D to high risk groups such as the elderly

  22. Robin E. Schlinger says:

    Madge, check out this Nikki Hancocks article of 4/23/20 that I just found after reading the 9/17/20 comment made by “BC”:

  23. Synaptosomal studies showed that bradykinin increased sodium-dependent, high-affinity uptake of choline and the conversion of [3H]choline to [3H]acetylcholine.

    I think the horseshoe bat picked up a toxic viral particle from a golden orb spider (which it may eat) and the ultimate result was a a7nAChR deficiency.

    The body is trying hard to restore acetylcholine. IMO.

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