COVID-19 Pathophys Discussion: Does HCQ/Avigan Actually Work?
I'm getting tired of all the circular arguments here regarding COVID-19 mostly by people with no medical background so I'm trying spur on a discussion behind the mechanism by which the virus infects cells and how it operates utilizing primary sources. We know the President has been touting HCQ therapy for a minute now, but the only literature I can find that promotes this therapy outside of anecdotal evidence and suspect blogs is from here:
Chinese caveats apply, but the gist of the study states that in conjunction to the already known mechanism of entry into cells via ACE2r respiratory epithelium, novel coronavirus may bind to membrane porphyrins leading to inhibition of heme metabolism w/ regards to RBCs. Drugs like HCQ and Avigan may reduce that binding all while preventing lysosomal release of proteases leading to decreased viral load.
My first problem with this is that it's a model that just seems to be trying to explain a correlation with regards to acute phase reactants (ESR, ferritin) and decreasing Hgb in a small select group of patients. From what I know there does not seem to be any significant drop in Hgb in pts as a whole and labs would easily pick up massive degradation of RBCs. On top of that, I don't see how the virus would even infect RBCs considering they lack all the essential organelles needed for proper replication. Coronavirus isn't a protozoa like Malaria, thus how would HCQ's lysosomal effects even be relevant in this case?
UPenn is currently conducting a trial to see if this makes sense. I will be curious to see if this angle has actual merit.
Circulation has recently published an article on how ACE2r's downstream effects might be the actual culprit in these cases:
https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.120.047049
ACE2r converts Angiotensin I and II into Angiotensin 1,7 and 1,9 both of which are cardio-protective factors. Proteases like ADAM17 are upregulated when ACE2r is KO'd leading to expansion of pro-inflammatory markers such as TNF, IL4 and IFN. These things also lead to further coagulation issues (as reported from ICUs around the globe), vascular permeability problems (pulmonary edema, PNA) and myocardial issues (uncontrolled hypertension and MI).
We know pts with cardiac hx have higher expression of ACE2r and are thus at most risk and have the highest mortality associated with COVID-19. I'm more inclined to believe this angle rather than the hemoglobin one.
The curious case here is whether we continue drugs like ACEi/ARBs in these pts. Would depriving pts of substrates that can be converted into protective Angiotensin 1,7 and 1,9 be worthwhile? Or is that promoting a more harmful cascade in allowing for RAAS to function unmitigated?
NEJM has another good article regarding this:
https://www.nejm.org/doi/full/10.1056/NEJMsr2005760?query=featured_home
Thoughts?
Sorry but UofM has very little experience right now taking care of these patients. Last I checked beaumont has treated roughly 15-20 times the patients and has 1060+ admitted whereas UofM has 100. All high and nightly UofM hospital is relatively small and tends to exaggerate their experience because of their name. Proud alum and all but being a MD at nearby hospital, UofM doesn't impress me much on these issues
IDK about the entirety of your comment since I'm still new to the field, but can confirm that Detroit area hospitals are using the Plaquenil (hydroxychloroquine)/Azithromycin combo in many patients, especially in ICU setting.
Also don't drink fish bowl cleaner!
Speaking of the 70s, many a U of M college student took drug cocktails that were untested.
Yes.
Can't speak to the mechanism, but my understanding was that the hype surrounding HCQ therapy was mostly due to this paper:
https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v2
However, this study has been severely criticized, notably for its tiny sample size, and for other research design weirdness (e.g., one of the treatment arms seems to vanish from the discussion of results). The serious epi people I follow on twitter don't seem to think it has much credence. Their attitude seems to be "There's no credible evidence right now. It's worth investigating, but irresponsible to promote it."
Do you share this view?
Is "their attitude" a direct quote or your interpretation of what a "Serious epi" person posts on twitter?
I think my post made it pretty clear that this wasn't a direct quote.
I think Carl T. Bergstrom, Marc Lipsitch, Ellie Murray, and Matt Fox all commented on this paper, and their comments were all in this ball park (could be mistaken about 1 or 2 of those names). Would be pretty easy for you to find if you cared enough.
What's wrong with staying positive and not ignoring any options. We should have told everyone to wear masks Feb 1 ... RIGHT... THEN the important people in the trenches would never have PPE.
There are people everywhere with so much knowledge sitting on years of toilet paper that havent lifted a finger to help anyone because they are speaking from their bunkers. Cowards.
The only answer was to shut everything down in Feb. But then you would be racist. Crying wolf for 4yrs hurt the response to this problem.
It's great to be in the media and play arm chair QB with a virus.
Sick, irresponsible "people".
Que?!
Trump publicly peddling an unproven and potentially dangerous cocktail of drugs is not "not ignoring all options." It's planting a dangerous and irresponsible seed in people's heads.
Why do Republicans only point to Trump attempting to stop travel from China like that would've stopped everything? That's literally the only thing he attempted to do regardless of that there are numerous other countries that had COVID-19 cases. If anything, Trump trying to shutdown travel from China shows that he knew about the virus and did nothing to prepare the country for it
It wasn't a shutdown of travel from China. It was a shutdown of mostly Chinese nationals from China. Over 400,000 of all nationalities (including Chinese, and including lots of people from Wuhan) came in the weeks immediately before, and 40,000 mostly Americans and other authorized travelers who had been in China flew in after the "travel ban."
https://www.nytimes.com/2020/04/04/us/coronavirus-china-travel-restrictions.html
Toothpaste was outta the tube even at that point is what I'm saying. This wasn't a problem fixable with immigration policy at that point, it was a community spread problem already.
It was never a problem that was fixable with travel bans. It's also not a problem that's fixable by tanking our economy, but we sure seem to be trying do so so anyway.
You can't stop a virus; you can only hope to contain it. The only people have have actually had any success with social distancing are the Chinese, and that's only (a) if you believe their numbers, and (b) because they enforced it with guns. (And, even then, if a full and total lockdown worked, it never would have spread beyond Wuhan in the first place).
A disease with a relatively lengthy incubation period, a minor effect on most carriers, and the ability to spread asymptomatically, is impossible to stop. By the time we knew it was a problem, it was too late to do anything except try to deal with the aftermath.
And, please don't get me started on the masks. You're not going to stop a virus from entering your body with a cloth mask. That's like trying to stop the rain by hiding behind a chain-link fence.
The only thing that a cloth mask is potentially good for is to reduce (not prevent!) transmission by a sick individual to others.
GERDAMN ERCERNERMY!!!!
We've put ten million people out of work so far, just in the US, with more coming, and there's no reason to believe that it's accomplished anything.
We'll never know, because we can't go back and create a control group -- and you had better believe that whatever the figures end up being, the people who are busy panicking this country will never be held accountable: if they're bad, "we didn't act in time," and if they're not as bad, "see? Social distancing worked."
Meanwhile, people are scared to go anywhere, do anything, or buy anything, and we have only started to see the consequences. In some cases, the economic damage we're doing will take years to overcome.
All of this might have been a reasonable price to pay, but we never made that choice; the choice was made for us and imposed upon us. It's easy for someone to sit in the governor's mansion and decree that people shouldn't go to work for a month. It's a little tougher to live it.
"...there's no reason to believe that it's accomplished anything."
I understand your frustration with the lack of empirical rigorousness which allows parties to not only "juke the stats" but also make non-verifiable, agenda-driven interpretations. I recall that you're a statistician (or you have a good background in stats at the minimum). As a fellow statistician, I can relate.
But even in the absence of a control group, you should see the logic in social distancing which is fundamentally based on observed phenomenon in the hard sciences (i.e. molecular interactions from biophysics or biochemistry).
Ultimately, your post boils down to the following: "is the government-mandated approach designed to minimize loss of life in the absence of a cure actually worth it given the ever-increasing economic costs?" (Notice I said economic costs and not financial costs; the two are often conflated but are actually not the same thing. Economic cost accounts for opportunity cost.)
That's a cost-benefit analysis question no one but God (or an all-knowing cosmic entity if you prefer) can answer because it has many elements: For instance:
- How many deaths are/were/will be averted?
- Moreover, what is the value (or price) of life?
- Will the deaths averted contribute dividends in the future? If so, how much?
etc.
Yes, your calculation is the exact one that we've glossed over, because nobody likes the implications of putting an economic value on human life. The thing is, nobody's measuring the health costs of the additional stress being caused either. It's entirely possible that more years of life are being lost to the economic disaster than are being saved by ventilators. It's just that the costs will be diffuse -- a higher incidence of heart disease and stroke in fifteen years, for example.
As for the obvious value of social distancing -- I just don't think it's realistic. Yes, if you put zero value on personal liberty, you could wrap everyone in a plastic bubble. Barring that, you're always going to have people who will disobey the rules, and the virus still spreads. So, in a vacuum, sure, the fewer people with whom you interact on a given day, the less likely anybody is to get sick that day -- no question.
But, the social distancing agenda is just to slow things down: nobody's saying that it's actually going to prevent one single illness, just that it might slow the rate down to a manageable number, and thereby hopefully prevent deaths. But I look at NYC, and I look at California, and I look at Italy, and none of those situations look manageable to me.
So, if we don't prevent the virus from overwhelming the health care system, what have we really accomplished?
So it seems like wearing masks is a no-brainer good idea then? Cool, glad you agree
Here is a link discussing the French doctor's latest study on the use of chloroquine+ for COVID-19. Doctor Raoult's testing methodology leaves a lot to be desired, as does the doctor's publication history.
You seem to be fairly knowledgeable and may know more about this than me (I'm just a dumb heart surgeon). There was an internet rumor supported by weak science flying around 2-3 weeks ago that use of ACE inhibitors and ARBs may increase the risk of COVID-19 by upregulating the expression of ACE2 receptors and making it easier for the virus to bind. European and US heart failure societies have recommended continuing ACE-I/ARB therapy based on the absence of data showing negative effects. These recommendations are about 3 weeks old.
The NEJM article you linked came out about a week ago and notes that there are conflicting data regarding whether and which of these medications upregulate ACE2. It goes on to recommend that anti-hypertensive meds should be continued, as stopping them may lead to worse heart failure. Heart failure is a huge risk factor for mortality with COVID-19 infection.
As a personal anecdote, which should not be confused with science or medical advice, I stopped taking my ACE-inhibitor and started a Calcium Channel Blocker in response to the ACE2 theory. The CCB isn't as effective and I switched back to my ACE-I after reading the NEJM article.
I’m not sure how I feel about my heart surgeon referring to themselves as mgofoam with a beer for an avatar.
That's exactly the kind of heart surgeon you should want
The biology is a bit beyond my reach, unfortunately. That said, from what I’ve read and listened to there has been a lot of literature on this that give positive indications of effectiveness and show promise (both recent for C19, and older for Coronavirus like SARS and MERS), just no controlled clinical trials - so probably not something a public official should be promoting. So I think saying there isn’t any supporting science or research outside of suspect blogs and anecdotes might be going too far. Here are some examples going back to 2004:
https://link.springer.com/article/10.1186/1743-422X-2-69
https://pubmed.ncbi.nlm.nih.gov/15351731/
https://www.nature.com/articles/s41422-020-0282-0
on another note, I was listening to a podcast and the expert they had on was more optimistic about Remdesivire (sp?) than Cloroquine. Hopefully something pops in the trials that WHO is coordinating this month. We could all use some good news on this.
Yea the drug you mention at the end I saw has been utilized twice (at least) and thus far has been a successful remedy. Both patients were at points of pretty bad sickness and the drug turned their prognosis around. This drug I think is the RNA-Dependent RNA Polymerase interferer and disrupts replication of the virus.
Oh, yeah, the chloroquine question. Chloroquine is not being used for it's antibiotic properties, as it is for Malaria. My understanding is that it changes the pH of the cell membrane, making it harder for the virus to either enter or exit the cell. I don't recall which.
Mostly the former but potentially both.
Idk what these big words mean, but I'm determined to make this a political discussion!
I think I can’t wrap my head around your first sentence and your last.
I'm getting tired of all the circular arguments here regarding COVID-19 mostly by people with no medical background so I'm trying spur on a discussion behind the mechanism by which the virus infects cells and how it operates utilizing primary sources.
and...
Thoughts?
You realize posting a few sentences on some research does not make this board any more qualified to have valuable opinions, right?
The board has a bunch of highly qualified individuals who can give their thoughts on the matter. Those are the people I wanna engage with. The responses here already have quite a few intriguing posts that are way more informative than whatever else we’ve been jabbering about the past couple of weeks.
But it’s still insanely unreliable vs a forum dedicated for people who do this for a living. If your opinion on the matter has changed one bit from this discussion then that just shows the danger of message boards to shape public opinion, not the benefits of these forums.
Pretty sure that no other sports blog in the world has this kind of content. The MGoBlog Difference.
The MGoBlog difference: Fire Fauci!
WE MUST EXIT THE BLACK PIT OF NEGATIVE EXPECTATIONS!
I wonder why the Actemra work isn't getting more pub.
Price will also be a consideration with these drugs. Plaquenil runs about $20-40 for 60 tablets. Actemra is about $600 for the 4mL and an obscene $1600 or so if you're going to be paying full price.
If Actemra does end up being a superior enough treatment to be a first line treatment, there is going to be a need for someone or some entity to pony up and pay for it. But that's above my pay grade.
Or make the pharmaceutical company sell it at cost.
I've had just about enough of subsidizing the cost of prescription medications for the entire planet.
Simple answer, I will wait until blind control studies identify verifiable treatment outside of what is referred to as sympathetic treatment anecdotal evidence.
The ChemRivX paper is highly speculative mostly because they haven't backed it up with even basic in vitro binding assays showing the surface glycoprotein or various ORF products actually bind as the models might suggest. There is so much going on with destruction of the type II pneumocytes and various insults that lead to hypoxia well before you would even start worrying about the supply of Hb waning that I'm skeptical this is a major mechanism of pathology. But I'm not a pathologist, just a lowly immunologist (formerly).
As you mentioned, from the virus' perspective, why the hell would you want to bind Hb? What do you get out of it? If anything it would be slowing spread of virions to the next target cell.
As far as HCQ, the putative mechanism (from what I've read) is the pneumocyte's endosomal pH is being lowered and the lower pH reduces endocytosis after virus binds ACE-2. Here's a general schematic:
Inhibition of viral infection with the increase pH by chloroquine analogs ((Al‐Bari 2015). Steps: 1. Endosome formation; 2. Fusion; 3. posttranslational modification; 4. uncoating virus and CQ, chloroquine.
By neutrality of acidic pH in endosomes, chloroquine analogs inhibit these viral entry and replication processes into the cytoplasm of susceptible cells and thereby abrogate their infections (Chiang et al. 1996; Savarino et al. 2003). Furthermore, the dysfunction of various enzymes e.g. glycosylating enzymes, glycosyltransferases caused by increased acidic pH and/or structural changes in the Golgi apparatus with hydroxychloroquine or by specific interaction with chloroquine, have been shown to suppress not only glycosylation of SARS‐ coronaviruses (Vincent et al. 2005; Savarino et al. 2006)...
From: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461643/
That Savarino 2006 paper is from a Lancet journal and worth a look. Full text is on Google Scholar (LINK).
Also, some recent news on this topic in MI is that Whitmer softened her original stance on this a bit: https://www.metrotimes.com/news-hits/archives/2020/03/31/gov-whitmer-reverses-course-on-coronavirus-drugs-is-now-asking-feds-for-hydroxychloroquine-and-chloroquine
and I’m sure I will regret posting this as soon as I read the replies, but thought it was at least noteworthy. I’m hoping that maybe she was given some info from ongoing trials the public isn’t privy to yet on effectiveness.
This article mis-reports right leaning statements as facts.
https://www.michigan.gov/lara/0,4601,7-154-89505-523363--,00.html
I’m not sure what mis-reporting you’re alleging in this specific article. I’m not like “standing by the article” or anything like that. I’m just curious if I’m missing something. The article never states that Whitmer ‘banned’ the drugs (the focus of your fact check link). A major focus of they article is how that initial view was the result of a miscommunication:
”But apparently, Michigan's "ban" on the drugs to treat coronavirus patients was all just a matter of miscommunication.”
Was that your issue or was it something else?
The very first paragraph of the article.
Gov. Gretchen Whitmer drew fire from some on the right after the Michigan Department of Licensing and Regulatory Affairs (LARA) sent a letter last week threatening "administrative action" against doctors who prescribed two experimental drugs that could potentially help coronavirus patients.
Did you read the other two links I had from the State of Michigan?
To support your statements, all that really matters is that it was certainly interpretted as a ban. The issue the medical community had with Governer Whitmer was the language used in the initial letter issued on March 24th:
The first half of the first sentence in the second paragraph of the letter came across as a threat to physicians that use of Hyrdoxychloroquine of Chloroquine on COVID-19 patients prior to proof of efficacy with respect to COVID-19 could cost them their medical license.
The best way to really understand what happened is to read the actual letter vs. relying on the media's spin.
Yes, that was in the statement. The ban was on sympathetic treatment due to a shortage that could impact those that are in actual need. Hence the request for more, and to be part of a trial.
Also in the article: Conservatives, including Charlie Kirk and Rudy Giuliani, accused Whitmer of risking lives to oppose President Donald Trump.
Ok, I guess I thought you had an issue with something the article actually stated, but it sounds like you have an issue with the article reporting what some conservatives’ opinions were. I think technically it is a fact that “Conservatives, including Charlie Kirk and Rudy Giuliani, accused Whitmer of risking lives to oppose President Donald Trump. “ not a fact that those people were correct, but that those people did accused her of it. Or are you saying that those conservatives didn’t actually accuse her of that?
Notice the article didn't source the State of Michigan's official statement? Did not source medical studies showing alleged positive results. Did not give an explanation on what the ban entailed and why. Did not cite specifics on why Charlie Kirk and Rudy Giuliani were making their claim. Did not cite justification for their claim. Did not cite what the evidence gives on either side of the position at hand.
The entire article reads as an opinion piece.
That is my issue. The article is garbage.
Ha. Ok, I don’t really disagree but you should have said that in your first post.
You shouldn't have been doing your best to stand behind an article you claimed you weren't standing behind.
Wow. I never said and never thought it was exemplary journalism. You claimed “article mis-reports right leaning statements as facts”. I was trying to figure out which facts the article states actually weren’t facts. Then without comment you went on to quote portions of the article that explicitly mentioned whose opinions or statements were being presented. It was confusing. I’m sorry I linked a sub-par article that presented other people’s opinions as other people’s opinions and didn’t link to official statements from the gov.
I don't think it's a bad thing at all to have it as an option for the physicians. It's just that we won't know for a few months if it works, for who and at what stage of disease, dosages, etc. The real complaint is that it should be a doctor, not politicians, making those calls one way or the other.
It's not like it's being chosen over better options. The real downside is that it's already causing major disruptions for lupus and RA patients who have been prescribed and can't get refilled. That is grossly unfair to them given that it is a proven tx for those diseases.
Second issue is that if people who have gotten ahold of a stockpile of Plaquenil outside of a hospital setting might start using gobs of it prophylactically, and longer-term use has some serious potential side effects if not managed by a physician. That is all setting aside Darwinism at work with fish tank cleaners and such.