Research Misinfo/Disinfo: Off-Label COVID-19 Therapy Has No Proof
[Check the byline, thanks! /~Rayne]
Funny enough, this COVID-19 post originally came about because of one of my family members.
They sent me a link to an op-ed from the Detroit News — the more conservative of the two major Detroit-based papers in this state — in which the author took Michigan’s Gov. Gretchen Whitmer to task because the state’s Department of Licensing and Regulatory Affairs clamped down on off-label prescriptions of an antimalarial drug.
“Any thoughts on the mandate against hydroxychloroquine?” they asked along with the link.
“Oh no,” I replied, “the author is going to regret writing that op-ed.”
They really had no idea what they were writing about. But then Trump doesn’t either.
~ ~ ~
We’re desperate. Trump and his minions don’t want to admit it, carrying on with Trump’s daily self-fluffing at the podium in front of his narcissistic supply, I mean, select White House press pool as if everything is under control.
We the public know it’s not. On Wednesday March 25, actor and activist George Takei pointed out a person died of COVID-19 in New York City every six minutes the previous day. The numbers have only grown worse.
We are that measurably desperate.
We’re grabbing at any kind of research, peer-reviewed and not, to find a way to shut down this fire hose of death because the other realistic alternative is at least 18 months of alternating levels of social distancing until a vaccine for COVID-19 has made it through multiple trials.
In a previous post I did homework and laid out some of the off-label approaches which have been taken in other equally desperate countries — like the antiviral remdesivir and the rheumatoid arthritis medication tocilizumab. These are in studies and haven’t been approved for use against COVID-19. We can only hope that other countries’ desperate, compassionate use of drugs off-label will add to the body of knowledge we have about effective treatments between now and the vaccine to come.
Our desperation makes us sloppy. We forget that what looks too good to be true often is just that.
Like the combined drug cocktail hydroxychloroquine and azithromycin.
~ ~ ~
Back on March 13 while writing about drug therapies in research, I wrote:
A number of existing drugs have been revisited for repurposing against COVID-19 instead of their original intended purpose. Antiviral remdesivir and antimalarial chloroquine are among them.
Chinese researchers posted a paper about in vitro results, not peer reviewed (at least I didn’t see that it was).
There’s a paper about chloroquine alone; in vitro studies suggest it may work against COVID-19. Chinese researchers have a number of in vivo studies in progress, but no data has been released.
Chloroquine by itself as an effective therapy would be a miracle in that it’s an old drug now off patent and available as a generic, super cheap to produce. Can’t imagine Big Pharma would like this. But we won’t even face this conflict if we don’t get data from in vivo studies.
Data. We needed data from peer-reviewed in vivo studies before any pronouncement could be made about the antimalarial medication as a therapy for COVID-19.
Published March 2 in Science Direct, a commentary by researchers at Aix Marseille University said essentially the same thing after examining an announcement by Chinese researchers that chloroquine phosphate was better than a control in treating SARS-CoV-2 (COVID-19) pneumonia — an announcement which had no supporting data:
In conclusion, the option of using chloroquine in the treatment of SARS-CoV-2 should be examined with attention in light of the recent promising announcements, but also of the potential detrimental effect of the drug observed in previous attempts to treat acute viral diseases. We urge Chinese scientists to report the interim trial results currently running in China as soon as they are available. This should be preferentially done in a peer-reviewed publication with detailed information to allow the international scientific community to analyse the results, to confirm in prospective trials the efficacy of the proposed treatment and to guide future clinical practice.
These researchers are literally begging the Chinese researchers to provide data as soon as possible, after noting that while hydroxychloroquine’s precursor chloroquine appeared effective as an antiviral in vitro against different viruses, it has shown no benefit in animal models. (They also noted in a study of its efficacy against chikungunya virus, chloroquine actual “enhanced” viral replication in animal models. Not good.)
A study was published around the March 24 but reports said it was unfavorable for the antimalarial. (I haven’t been able to get my hands on the study; the link from each news source citing it has failed.) The size of the group studied was very small — only 30 patients with a control group of 15.
And yet sandwiched in time between the first Chinese study and this most recent one was another one submitted for publication on March 17:
Gautret et al. (2020) Hydroxychloroquine and azithromycin as a treatment of
COVID‐19: results of an open‐label non‐randomized clinical trial. International Journal of
Antimicrobial Agents – In Press 17 March 2020 – DOI : 10.1016/j.ijantimicag.2020.105949
The researchers from Aix Marseille University made no mention of this study though it must have been underway in their own backyard, so to speak.
No one noticed this — the dog that didn’t bark.
Meanwhile, on March 19, Trump talked about hydroxychloroquine from the podium during a briefing before a White House press pool. He not only mentioned it in glowing terms but he tweeted about it. Mike Pence also promoted the antimalarial two days later.
On March 24 an Arizona man died and his wife was hospitalized after taking hydroxychloroquine’s precursor, chloroquine — used to maintain their fish tank — having heard Trump talk about it so positively. The couple poisoned themselves; Trump scored two casualties with his misinformation.
~ ~ ~
A critical threat to U.S. health security is its monoculture — specifically, its complete investment in English excluding other languages. Back when we worried about Zika virus posing a threat to Americans traveling to South America and when Zika arrived in Florida, we were combing through research from other countries. The Chinese fortunately published much of their work in both Mandarin and English, but Brazil had a considerable amount in Portuguese. Their work was ignored in favor of less credible work which appeared in English.
This same dynamic is at work with regard to potential drug therapies — hydroxychloroquine in particular.
The study Gautret et al. (2020) was published in French and English, you’ll note. Many people picked up on it because it was so accessible.
What wasn’t picked up readily was the problems with an affiliated researcher. Many reported problems have been documented online where the world can read them, in of all places, Wikipedia.
But that’s Wikipedia France — a different address than we use in the U.S., published in French.
Use Google Translate and read the section on COVID-19. The translation isn’t entirely smooth but it does well enough for the average English speaker to figure out Raoult is a character.
He also has a history of sexual harassment and possible abuse according to a number of accusers, also documented in this Wikipedia entry.
(I’ve scraped that entry and translated it out of concerns it might change over time. You can read the portion of the French Wikipedia entry on Raoult and COVID-19 at this link. You can compare it against the Wikipedia page’s editing history though you’ll need to reverse translate it.)
It could be said in the MeToo age that many accused abusers are competent at their professions and are simply jerks when it comes to managing their attitude toward co-workers. But in Raoult’s case the accusations are smoke and where there’s smoke there’s an ethical fire.
It seems Raoult’s research has had a problem with data which looks artificial in at least two other studies, noted during peer review.
He’d previously been banned from publishing in microbiology journals.
Complaints about a hostile work environment in his lab do not offer reassurance about the credibility of his work. Were subordinates pressured for results?
It also seems odd this one study from France has been relied on so heavily by others, when the underlying drug is manufactured by a French manufacturer (though not the only company which does).
None of this passes the smell test.
Gautret et al. also didn’t pass the sniff test with the journal in which it was published though it did not retract the study:
The April 3, 2020, notice, from the International Journal of Antimicrobial Agents, states that the March 20 article, “Hydroxychloroquine and azithromycin as a treatment of Covid-19: results of an open-label non-randomized clinical trial”
does not meet the [International Society of Antimicrobial Chemotherapy’s] expected standard, especially relating to the lack of better explanations of the inclusion criteria and the triage of patients to ensure patient safety.
The notice, which is from the ISAC and not the journal itself, is a bit ambiguous. The society says it “shares the concerns” about the paper, but it doesn’t appear to be taking additional action.
It’s unclear what took the journal nearly a month to make this statement of doubt. Because it hasn’t been retracted references are still made to Gautret et al. (2020).
~ ~ ~
Studies to date on hydroxychloroquine or its precursor chloroquine have been small or flawed; the merits of these antimalarials were thin to begin with.
Zumla, A., Chan, J., Azhar, E. et al. Coronaviruses — drug discovery and therapeutic options. Nat Rev Drug Discov 15, 327–347 (2016).
Published: 12 February 2016
An excerpt from this review of drug therapies notes chloroquine had limited promise against SARS-CoV-1:
…Chloroquine is an anti-malarial drug that sequesters protons into lysosomes to increase the intracellular pH. It has broad-spectrum antiviral activities against numerous CoVs (SARS-CoV, MERS-CoV, HCoV-229E and HCoV-OC43) and other RNA viruses in vitro 123, 210, 211, 212, 213, 214. However, it did not substantially reduce viral replication in SARS-CoV-infected mice, possibly because the cell surface pathway was not simultaneously blocked. …
This study of antiviral remdesivir with antimalarial chloroquine was in vitro, not in vivo:
Wang, M., Cao, R., Zhang, L. et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 30, 269–271 (2020).
Published: 04 February 2020
Remdesivir may act alone as antiviral. Conclusion is that these two drugs “should be assessed in human patients suffering from the novel coronavirus disease.” The drugs were assessed but not employed as a protocol.
This next study is again in vitro, not in vivo:
Liu, J., Cao, R., Xu, M. et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov 6, 16 (2020).
Published: 18 March 2020
Its conclusion calls for more testing, while implying hydroxychloroquine’s use would be better as an anti-inflammatory during cytokine storm though this study didn’t examine its anti-inflammatory effects:
…HCQ is a safe and successful anti-inflammatory agent that has been used extensively in autoimmune diseases and can significantly decrease the production of cytokines and, in particular, pro-inflammatory factors. … In combination with its anti-inflammatory function, we predict that the drug has a good potential to combat the disease. This possibility awaits confirmation by clinical trials. We need to point out, although HCQ is less toxic than CQ, prolonged and overdose usage can still cause poisoning. And the relatively low SI of HCQ requires careful designing and conducting of clinical trials to achieve efficient and safe control of the SARS-CoV-2 infection.
Hydroxychloroquine is toxic and it needs carefully designed clinical trials — this prediction of its “good potential” is happy talk until there’s data to prove its effectiveness for its intended purpose.
A pre-proof study about the two-drug hydroxychloroquine and azithromycin cocktail published on March 30 is small but makes a more declarative statement right in its title:
Molina JM, Delaugerre C, Goff JL, Mela-Lima B, Ponscarme D,
Goldwirt L, de Castro N, No Evidence of Rapid Antiviral Clearance or Clinical Benefit with the
Combination of Hydroxychloroquine and Azithromycin in Patients with Severe COVID-19
Infection, Medecine et Maladies Infectieuses (2020),
In summary, despite a reported antiviral activity of chloroquine against COVID-19 in vitro, we found no evidence of a strong antiviral activity or clinical benefit of the combination of hydroxychloroquine and azithromycin for the treatment of our hospitalized patients with severe COVID-19. Ongoing randomized clinical trials with hydroxychloroquine should provide a definitive answer regarding the alleged efficacy of this combination and will assess its safety.
This study was in vivo, using the same dosing regimen reported by Gautret et
al. study on a cohort of patients similar to the same study. The results were unsatisfactory:
At the time of treatment initiation, 10/11 had fever and received nasal oxygen therapy. Within 5 days, one patient died, two were transferred to the ICU. In one patient, hydroxychloroquine and azithromycin were discontinued after 4 days because of a prolongation of the QT interval from 405 ms before treatment to 460 and 470 ms under the combination. Mean through blood concentration of hydroxychloroquine was 678 ng/mL (range: 381-891) at days 3-7 after treatment initiation.
Nor had the virus been cleared 5-6 days after treatment began in 8 of 10 surviving patients. The study’s authors made a point to compare their findings against the Gautret et al. study:
These virologic results stand in contrast with those reported by Gautret et al. and cast doubts about the strong antiviral efficacy of this combination. Furthermore, in their report Gautret et al also reported one death and three transfers to the ICU among the 26 patients who received hydroxychloroquine, also underlining the poor clinical outcome with this combination.
Hydroxychloroquine doesn’t work against SARS-CoV-19 even when paired with the antibiotic azithromycin, but a larger, randomized clinical trial with appropriate controls is still necessary to beat it through the heads of people pushing this therapy.
~ ~ ~
But out of desperation, hospitals have been using hydroxychloroquine anyhow, only to discover it doesn’t work against COVID-19 — it may even make patients sick.
That last French study above squelched further use of hydroxychloroquine at the St. Louis Hospital in Paris.
Hospitals in Sweden stopped using it after negative effects (open link in Chrome and use Google Translate to read in English) including impaired vision.
On Sunday, Dr. Sanjum S. Sethi, Vascular Medicine and Interventional Cardiology Columbia University Irving Medical Center, shared that ALL patients treated in the ICU for COVID-19 have received hydroxychloroquine:
6) Every single ICU patient (barring QTc issues) got hydroxychloroquine and it doesn’t seem to have helped. Maybe it helps for prophylaxis or in mild disease, but doesn’t appear to do anything once in ICU. It is NOT a pancea and should not be given indiscriminately. (7/10)
— Sanjum S. Sethi MD, MPH (@sanjum) April 12, 2020
Dr. Sethi doesn’t say how many patients have been treated with the drug so far — there could be as many as 1,000 patients in ICU at one time based on a newsletter by Surgeon-in-Chief Craig R. Smith, MD for NYP/CUIMC — but it didn’t work for severe-to-critical patients in ICU.
Which means the Chinese researchers’ suggestion that hydroxychloroquine’s anti-inflammatory qualities may help with cytokine storms didn’t pan out.
~ ~ ~
Meanwhile, Trump continues to tout hydroxychloroquine, as does his best buddy in Brazil, Jair Bolsonaro.
Brazil, like other tropical countries has ongoing incidence of malaria. It’s endemic along the Amazon River and treated with chloroquine or hydroxychloroquine. The drug has also been used prophylatically.
And yet Brazil is experiencing a growth in COVID-19 cases even along the Amazon River, suggesting hydroxychloroquine or its precursor are not effective in the early stages of the disease, failing to fend off infection and contagious pre-symptomatic progression to mild, severe, and critical cases.
Further assessment is difficult because like Trump, Bolsonaro has undermined reporting and efforts to limit contagion.
Brazil’s Minister of Health Luiz Henrique Mandetta nearly lost his job late last week when he refused to authorize a protocol prescribing hydroxychloroquine for COVID-19 patients. A few doctors continued to press him on this after he survived a heated cabinet meeting in which this pharmaceutical was discussed.
Two days later a small study was published; chloroquine as therapy for COVID-19 patients had been halted early after more than 25% of the subjects died:
Borba M, Almeida Val F, Sousa Sampaio Vanderson, CloroCovid-19 Team, et al. Chloroquine diphosphate in two different dosages as adjunctive therapy of hospitalized patients with severe respiratory syndrome in the context of coronavirus (SARS-CoV-2) infection: Preliminary safety results of a randomized, double-blinded, phase IIb clinical trial (CloroCovid-19 Study)
Published: April 11, 2020
medRxiv 2020.04.07.20056424; doi: https://doi.org/10.1101/2020.04.07.20056424
~ ~ ~
The bottom line is that we are still without an effective pharmaceutical antiviral therapy, no matter what Trump says.
What he’s said from the podium has only encouraged risk-taking pushing past the limits of ethics guiding the practice of medicine and human experimentation. The Texas City nursing home administration who has dispensed hydroxychloroquine without advanced informed consent is a perfect example of ethics collapsing under Trump’s equally unethical practice of medicine and pharmaceutical lobbying from the presidential podium.
Though we know more now than we did at the beginning of March about hydrochloroquine as a tool for treating COVID-19 — and we know that no study to date has suggested the drug will be effective for a majority of COVID-19 patients — we still do not know why Trump is so invested in this generic medication.
Who told Trump this drug was an effective treatment for COVID-19?
Has someone continued to reinforce this fallacy though Dr. Fauci has yet to reverse his own professional opinion about hydroxychloroquine?
Who likewise sold Bolsonaro on this drug? It likely wasn’t Fox News though the network may have irresponsibly reinforced Trump’s lobbying for hydroxychloroquine.
Why are talking heads on Fox News still promoting this drug with impunity — like Laura Ingraham who is not a medical professional?
laura ingraham, who advised trump personally days ago, calls for firing the cdc director for dismissing hydroxychloroquine on cnn pic.twitter.com/e6RryGkQti
— John Whitehouse (@existentialfish) April 10, 2020
Why are other right-leaning pundits continuing to press for this drug though they do not have medical background, and while other experts continue to express doubts about hydroxychloroquine?
None of this makes sense; we lack information. As I said before, we need data from peer-reviewed in vivo studies before any pronouncement can be made about the antimalarial medication as a therapy for COVID-19.
And we need to know more about Trump’s reasons for promoting this drug while ignoring the risks hydroxychloroquine poses.
I started writing this damned post on March 27. There’s been a metric shit ton of research and news to read about this goddamned drug mostly because Trump won’t shut the fuck up about it.
That may be the one thing this is intended to do, a page from Steve Bannon’s playbook: bury them in bullshit. That’s what this is, all bullshit.
Thanks for the post.
My mother-in law in Michigan just passed away due to COVID-19.
To make matters worse, while Mom lay dying, members of the family started spouting this Chloroquine nonsense. I hold Trump fully responsible for her death and for the cloud of misinformation and incompetence that led to it.
For all who have been affected —not to mention our own safety—we must defeat Trump.
I am so sorry for your family’s loss.
Hydroxychloroquine or chloroquine works best as means to upset and divide people, I think we can agree.
Join Rayne. This thing is not some amorphous thing, it affects real people, including here. Condolences.
Joining Rayne and bmaz in offering condolences. I can’t imagine how difficult it all had to be for you and your family.
Thanks for the support and condolences, everyone. We’re hanging in there as well as can be expected.
RacerX, deeply sorry for your loss.
You have my condolences.
(To the mods, I am the same Troutwaxer, but my email has changed.)
“This study was in vitro, using the same dosing regimen reported by Gautret et
I could be just brain-fried, but shouldn’t this say “in vivo”? They were looking a patient cohorts, weren’t they?
You’re right, that’s what I meant. Thanks, will correct ASAP. Poor patients, I turned them into Petri dishes…
Another treatment being studied is nitric oxide (not to be confused with nitrous oxide, otherwise known as laughing gas.) There are clinical trials going on now, some on the government’s clinical trial website.
“Miller School pulmonologist treats COVID-19 patient with nitric oxide therapy” – April 2, 2020
“A medical specialist with the University of Miami Health System and the Miller School of Medicine has initiated a new therapy for the first time in a patient with the novel coronavirus diagnosis. The treatment has the potential to delay the need for a ventilator.”
“Roger Alvarez, assistant professor of pulmonology, began treating his patient on March 26 using the INOpulse inhaled nitric oxide system (iNO). “INOpulse has the potential to be used as a viable treatment option for COVID-19, based on previous studies that demonstrate the benefits of iNO in oxygenation and immune response,” said Alvarez, who, in addition to his clinical practice, conducts basic, clinical, and translational research in pulmonary hypertension. He has done extensive research on using nitric oxide treatment for pulmonary conditions.”
You had me there for a second, was looking forward to the nitrous treatment.
LOL (teehheehee) But if it’s any consolation, nitric oxide is related to a tiny blue pill…
Believe it or not, this has been around for quite a while. I’ve never seen it used in non-intubated patients, though. There was a period a while back where nitric oxide was thought to be connected to just about everything in the body, so it’s been pretty well-studied, and it has an extremely short half-life, so the inhaled form is out of the body fairly quickly (in minutes, if not seconds, and I think it’s closer to seconds) if there’s a problem.
The idea here makes sense from a scientific standpoint, and the intervention point (before intubation) is a good one, as doctors are finding that once they intubate COVID-19 patients, they tend to require mechanical ventilation for something like 10-20 days, and they’re extremely difficult to manage. This is something that would probably be given to patients who are already on oxygen, so you’d be giving this to patients who are already pretty sick.
(And as Savage Librarian notes, it is indeed related to the little blue pill, which is sometimes used on newborns with pulmonary issues like the ones this guy studies. It leads to the inevitable question of “Why is the baby taking Viagra?”, which doctors LOVE asking the residents and med students.)
Thanks, Frank. And, as you suggest, being on a ventilator creates problems in and of itself. I think doctors don’t always explain the risks involved and the various consequences that occur.
“Doctors think ventilators might harm some COVID-19 patients” – Raw Story
I have a long personal history with inhaled nitric oxide dating back to my days in training. I was part of the large trial of nitric in ARDS which demonstrated no benefit in ARDS. It was a very disappointing moment. At bedside I would watch the oxygen levels rise and I was sure nitric oxide was part of the answer. But it wasn’t. It was a hard lesson in the importance of good clinical trials. It is easy to give a therapy and believe it to be of benefit. The rise in oxygen levels did not translate into a survival benefit. It should have been the end of nitric oxide for ARDS but for reasons I do not understand it has persisted.
We now have one patient with COVID 19 now on nitric oxide, one of my partners started it out of desperation. It did not raise the oxygen levels significantly. She was teetering on the edge until I turned prone her a second time, which worked better than I have any logical explanation for. The second COVID patient this has happened with proning.
I once posted here that I thought COVID caused garden variety ARDS. That was about as wrong as wrong gets. It is fascinating, spooky and terrifying. So maybe nitric will work.
By the way, nitric oxide can be blended into nasal canulas or any oxygen delivery device. The we do this mainly for post-op thoracic surgery patients. It brings down pulmonary artery pressures nicely.
Interesting. Covid-19 is anything but garden variety ARDS. Clue #1 is the utter lack of neutrophilic infiltrates in autopsy studies in most patients. It is predominantly a lymphocytic infiltrate.
In fact, I question whether ARDS is cause or consequence of needing ventilation. I’m working on another comment, but suffice to say my reading and discussion with colleagues is pointing to the inciting insult being high viral loads and massive destruction of type II pneumocytes leading to innate immune dysfunction and high Ang II levels (due to lack of ACE2). This results in a microangiopathic thrombotic state in pulmonary capillaries, and possibly high pulmonary pressures contributing to a heart failure picture. If true, NO might be of significant benefit here.
Couple of points, the Berlin definition of ARDS had no pathologic findings as part of the definition. This make sense as ARDS is not a disease but a physiologic syndrome. Second, there is no question that ventilation can cause and/or exacerbate ARDS. We do what we can to mitigate using “lung protective strategies.” This leads to my final point, good lung protective strategies for mechanical ventilation require a Ferrari of a ventilator, not some hastily engineered vent. Too much emphasis on numbers of vents, not quality.
As far as the microangiopathic findings in ARDS, can be part of “garden variety” ARDS as well. Back in the day when everyone with ARDS had a right heart catheter in place the numbers were almost always abnormal. But we shall see.
What’s your thought on early proning? From my days as an intern in the ICU, I remember that proning was kind of a last ditch effort, but I’ve seen some anecdotal reports saying that it seems to work particularly well for COVID patients, even earlier than you might think.
Just spitballing, if the initial insult is this high pressure pulmonary state from Ang II excess (where it behaves more like HAPE, as some have suggested), perhaps proning works because the superior lobes are less affected early on, being more anterior and having less blood flow when the patient is lying supine? Thus, proning allows for better V/Q matching early in the course of the disease?
Not a critical care doc… (I know you are) but just wanted to see what you think.
According to Gattinoni, prone early and prone often. It tends not to be a good rescue method. In New York the doc are proning people while on high flow nasal canula. The explanation for why proning works is very complex. Much of it is do to reduced pleural pressure, improved lung morphology, and reduction in shunt. V/Q is a part as well. As a fellow I gave a talk and it was quite an effort. Really takes a good 30 min and slides to explain fully.
Also read the latest from Gattinoni from ESICM, I think he is correct. He is one of the greats.
Not to intrude on the professional space (and thanks for all the info!) but, anecdotally, some have suggested that sleeping on our stomachs (or even sides) is preferable these days, rather than on our backs. Tough habit to break, though. But maybe even some time trying to do this is better than none?
Dr. Robert Gallo world-renowned virologist, who was a leading figure in HIV research, is stating that he believes the oral polio vaccine may be a source of enabling the human body to postpone Covid19 progression. He feels it could provide 6-8 weeks, or possibly longer, of neutralizing of the advancement of the virus in patients thus allowing the body time to develop it’s immune response. He says if he was a betting man he would bet this is a very strong candidate to have some success. The video is on the PBS website presented by Christine Amanpour.
Here’s that interview:
Can an Oral Polio Vaccine Help Stop the Coronavirus?
Dr. Robert Gallo, who helped identify HIV in the 1980’s, is leading an initiative to use the oral polio vaccine for short-term coronavirus treatment. He believes it could provide a couple of months of immunity, buying time for anyone infected to develop the antibodies to fight it. It still awaits FDA approval, but Dr. Gallo believes there is cause for hope — as he explains to Walter Isaacson.
04.13.2020 [Amanpour/ Isaacson/Gallo]
[VIDEO] [TRANSCRIPT] [DR. ROBERT GALLO, DIRECTOR, INSTITUTE OF HUMAN VIROLOGY, UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE]
Here’s some info on a study that was pre-released recently – the authors claimed benefit, even though they have to do some statistical yoga and look sideways in order to get there:
And a twitter thread from someone much smarter than me laying out the details:
Thanks for that. Might have been one of the studies I was having difficulty snagging from a Chinese journal.
Very unimpressive data.
I’ve been seeing reports that people who recover from the virus may have problems with lungs, heart, and kidneys, and even neurological problems. This is a *very* nasty virus.
Yup. I’m wondering if it has an effect in early pregnancy, which could end up being bad. The virus is so new that we haven’t even seen those patients yet, so we’ve got that on the horizon.
It would depend a lot on *when* during pregnancy – so all newborns should be monitored more closely than usual for a year at least.
And there’s this: the virus is most contagious in the three or four days *before* symptoms appear.
Just saw a report of a health care worker who was described as “heavily pregnant” who died of COVID-19. They took the baby by C-section, haven’t seen if it survived. The problem, of course is whether the fetus was getting enough oxygen if the mother was suffering from hypoxia and cardiomyopathy.
EDIT: when I track that report down I will share a link here.
I saw it earlier also, many links, Mary Agyeiwaa Agyapong, 28
11:55 AM · Apr 15, 2020
Jesus. Sounds like they’re using military personnel and vets as guinea pigs.
“The CIA has privately advised its workforce that taking an anti-malarial drug touted by President Trump and some of his supporters as a promising treatment for the novel coronavirus has potentially dangerous side effects, including sudden death….A CIA website for employees with questions about the coronavirus addressed the topic on March 27, noting there had been media reports suggesting the drug “has activity against the COVID-19 virus.”
The study being stopped in Brazil should be enough to stop the Chloroquinone (CQ) / Hydroxychloroquine (HCQ) nonsense here, since it has been proven to be unsafe even under medical supervision. That of course assumes that Hannity / Ingraham / DJT will allow such an outcome, but the FDA when it was still apolitical would have banned the usage.
That combined with the journal withdrawal of its endorsement (in all but name) for the idea means there is no reason to keep doing this. Earlier we saw some excellent posts by the EW team and commenters on how COVID does its dirty work, and there are options that should succeed out there. However, it appears none of them are monetized by the Trump Org or Kushner Industries and so must be banned.
It might be time for a legal opinion as well, since we have John Burris in Alameda County urging the local DA to file criminal charges against the Gateway nursing home for demanding that staff continue to work without protection and with symptoms, and at least one patient died of COVID-19 when he was in for something completely unrelated or for that matter a co-morbidity. It seems the people who own this home have five others all averaging something like 30 violations of the code. Gateway is the place where an intense cluster (something like 60-70 exposures) occurred, and it was still taking in admissions.
Given how much Faux News and the administration’s various voices from DJT on down had been touting HCQ and CQ as the cure-all du jour, without any of the warnings that were already known about these particular drugs, where and how does the liability for essentially practicing medicine without a license start? Faux News was apparently worried about this possibility last week, but I would think an explainer would help us here.
Lastly, to the GOP (of course) US House member that said some deaths were necessary because the economy needed to be reopened now: You first.
My proposed bumper sticker for this election: Trump/Death 2020
Whaat ?? Mike Pence has been replaced on the ticket ?? (Always thought Trump should’ve chosen death over Pence back in 2016)
Didn’t SNL have Bannon as Death?
Yep – forgot about that! Played by Bill Murray.
For the first three years it was hard to tell the difference.
Back around 1990 I visited Mozambique where a friend was working on a research project. I had to take Plaquil (hydroxychloroquine) once every 2 weeks for a few times before leaving for Mozambique and then a few times after returning. That was the standard anti-malaria prophylaxis. That shit was awful. It made me so sick. The doctor warned me that it was rough medicine but it was at that time the only thing you could do to protect against malaria which was endemic in Mozambique.
It must wreak havoc with already weakened Covid-19 ravaged bodies.
We had the same thing in Southeast Asia, two hours later and it was a mandatory trip to the can.
While on CVN-70, we visited Mombasa, Kenya, and went through the prophylaxis regime. The Navy was serious enough about it that UCMJ prosecution for malingering awaited anyone that did not take their pills and came down with malaria after the port visit.
Malaria itself is pretty nasty, in that apparently it comes back again later since the parasite is not always fully killed off. I had a bro in college that had been through four rounds after his tour up western Africa in the early 80’s which was apparently rather unusual.
Yeah I understand you can get a relapse, sometimes years later. We had UCMJ enforced mandatory pill taking also but it worked for the majority of us. It also beat being packed in ice and alcohol to keep your temperature down. A friend who had it told me he got to 106 and hence the treatment.
My brothers ship had liberty in Hong Kong in 69 70 or so and the whole ship at different times got the flu. He told me one minute you were feeling fine and another you couldn’t make it to your bunk. Because of the way it spread, ships are basically incubators, they were still able to function. But the navy knows of incidents like that and it’s stored somewhere in memory and then we have incidents like the TR. Its kinda crazy but each generation has to find out the hard way, like now.
They’re still trying to figure out how it got there – the crew who died didn’t get symptoms until three weeks after the last port call. They think maybe via COD.
The character, Robicheaux in the James Lee Burke books suffers from malaria, and he frequently describes the symptoms therein – they seem to be consistent with the literature, and his character has high fevers, sweating and hallucinations/visions in many of the novels, sometimes as a central plot device. I mean, I realize it’s fiction, but his writing about it seems pretty real …
Canadian Forces used Mefloquine on a African mission 3 decades back and it did not end well. ( same old, take it or else). After the death of a boy at the hands of the unit, it was disbanded in total disgrace.
Inquest pointed the side affects of the anti malaria drug.
Veterans Affairs Minister Kent Hehr must be starting to recognize the can of worms that landed on this desk this fall.
To be fair, this particular bucket of problems didn’t start with Hehr, or with his government. It dates back to 1992, when 900 Canadian Airborne soldiers were given an experimental anti-malarial drug called mefloquine (sold under the brand name Lariam) under a flawed clinical trial run by the Department of National Defence and Health Canada.
More than twenty years later, some of those soldiers say they are still suffering from neuropsychiatric side effects from the drug, including uncontrollable anger, anxiety, hyper-aggression, paranoia, hallucinations and suicidal thoughts. Recent research shows the drug can cause permanent brain damage.
The veterans want an outreach program, more research into better treatment and acknowledgment by the government that the drug was improperly prescribed to those soldiers serving in Somalia given that it had not been licensed for use in Canada (the conclusion of a 1999 auditor general’s report).
Is it time to re-open the Somalia probe?
By Sheila Pratt. Published on Dec 5, 2016 8:58pm
Thanks Rayne for the post.
When I hear the occupant of the WH pushing a drug, what comes to mind, a president profiting off this pandemic.
I know I’m not the first to say this, but the press is doing an absolutely horrible job of framing the president’s response to the pandemic. Stating it as his “failure to act quickly or effectively” is totally misleading. He DID act quickly and effectively, but in the wrong direction. He acted decisively and early, in doing everything he could to completely dismantle our nation’s ability to be prepared and respond effectively to a global pandemic, despite being told often, by multiple agencies and advisors within his own administration, that we were unprepared. The timeline put together by the folks at just security will make you heartsick. ALL of this was preventable.
All the advance warning in the world, everyone telling him we were not prepared for a pandemic, and Trump didn’t just ignore it, he went the opposite direction, actively defunding the agencies that were meant to protect us. He fired the global pandemic preparedness team! He cut budgets for the health agencies. It makes me wonder about psychiatrist Dr. Bandy Lee’s statements, that most are missing how incredibly sick this man is, she says he is not just trying to cover his failures, he is actively trying to kill as many Americans as possible. When you look at this timeline, it starts to look like that might actually be possible, as horrible as it sounds…
Just one example of how quickly he acted to create the greatest harm to the greatest number of people:
May 7, 2018 – the National Security Council warns that pandemic flu is the top health security concern and that the country is not prepared for it.
May 8, 2018 – The WH disbands the global health security team.
The pattern of behavior is clear – every time he was warned of the danger of pandemic, he either a) took no action, or b) took action designed to harm the greatest number of people possible. It boggles the mind. This is a sick, evil man.
At Tuesday’s presser, Trump said Obama failed badly during the 2009 H1N1 pandemic because we had 17,000 deaths in the US, and not one reporter stated the obvious, that on that day we were at 25,000 deaths, under Trump’s watch, and that by his own logic, his failure is far worse than Obama’s. They are simply not up for this.
From the justsecurity timeline:
Either Trump *is* the Manchurian Candidate or he is simply a tool of the Mnuchin faction, i.e. big money, or both.
“The Mnuchin Faction”…I like that!
FWIW, and I hope I’m not wasting anyone’s time, but I found this Chinese study of March 3, 2020 that might have come out a little later?
Seems to (and I have no medical training) have found no beneficial effect re hydroxychloroquine …
You know my feelings on chloroquine derivatives, might work for SARS-CoV-1, doubt it works on SARS-CoV-2 due to the presence of the furin (RRAR) cleavage site in Spike. CQ and HCQ really won’t prevent efficient spread of the infection due to this cleavage site, which essentially “cocks” the Spike protein into a ready to infect position, and is probably the reason why the virus spreads so quickly and leads to such high viral loads. It can bypass the need to use the lysosome, where CQ and HCQ have their effects.
WARNING: INFORMED SPECULATION FOLLOWS
My personal (and professional) belief right now is that COVID-19 is not really a disease of the lung or a pneumonia per se, but rather a disease of innate immune dysregulation leading to high viral loads and out of control innate responses. Some people are able to clear the virus before the viral loads get too high and especially before the lung type II pneumocytes are damaged. Others are not, and that leads to the second phase of the disease, which some people call a “cytokine storm”, but I think is really dysregulated innate immune response set off by high viral particle levels and free spike protein levels. What I think may be happening, and there is some autopsy data to back this up (see this paper and this paper), is that with destruction of the type II pneumocytes by SARS-CoV-2 you get locally high levels of Ang II, the vasoconstrictive hormone that regulates blood pressure. This leads to vasoconstriction in the pulmonary arterioles and capillary beds, which leads to increased pulmonary vascular pressures, and increased shear stresses in the capillaries.
The increased pressures in the capillary beds cause leakiness of the alveolar capillaries similar to what happens in high altitude pulmonary edema (which has some overlap clinically with early phases of the lung involvement in COVID-19), and leads to impaired gas exchange and hypoxemia (low oxygen), which causes further vasoconstriction of the vasculature and more shear stress.
At the same time this is happening, the viral replication and spike protein production gone amok has now attracted the attention of the early neutralizing IgM antibodies and the innate pathogen receptors (known as lectins) that then activate something known as the complement pathway (a blood-borne innate immune system to destroy pathogens that doesn’t rely on the adaptive immune cells. It is an ancient system, and is especially important in blood-borne bacterial infections). This is designed to kill the virus (or usually bacteria), but what it ends up doing instead is causing more damage to uninfected bystander cells, like the cells lining the air sacs or the capillaries of the lung. Such damage, with the increased shear stresses in the capillaries will lead to activation of a protein known as von Willebrand’s Factor, which is designed to recognize damaged blood vessels and initiate the clotting cascade to stop bleeding, especially in high flow areas, like big vessels. Unfortunately here, abnormally narrowed small vessels will mimic that state, and you will get lots of micro clots in the pulmonary capillaries, which will impair blood flow and gas exchange through the alveoli thereby worsening hypoxemia, and also put a whole lotta strain on the heart as it will increase the already high pressures in the pulmonary circulation even higher. Indeed in one of the autopsy reports, they saw several cases of severe right heart failure, which can occur suddenly because the right heart is usually used to operating in a low pressure environment, and sudden increases can be catastrophic, and eventually lead to left sided heart failure and death (not to mention also kidney failure too).
So that’s all speculative, but it does kind of fit with the clinical data that’s starting to come out. This is NOT just garden variety ARDS. People are NOT dying of secondary bacterial infection like is commonly seen with severe influenza cases, so we should stop treating it like it’s a severe influenza epidemic. I question if it’s really a “cytokine storm” as we typically define it, or is it really more of an innate immune response gone haywire that we should focus on stopping. There are antibodies to complement protein C5 that are used in something called atypical hemolytic uremic syndrome that has some overlap with the pathology we’re seeing here. Perhaps that would be a useful avenue to explore.
And finally, I wonder if the reason people with hypertension are so at risk is because their ACE inhibitors or angiotensin receptor blockers are being discontinued at the first sign of sepsis from the “cytokine storm” due to low blood pressure? That could be catastrophic as it would potentiate the high levels of Ang II that are already there, as ACE2 is the body’s only natural check on Ang II level, and if you discontinue a drug that either blocks the production of or the effect of Ang II on the body when it lacks the ability to degrade excess Ang II, you could see how that could be VERY VERY bad.
I know this is really technical, and I apologize, but for the MDs in the group, would love to hear your comments.
Non-MD here — I know you’ve been busy, but I have been wondering if some of the dysregulated coagulation you’d mentioned before might have a genetic origin for a specific demographic of patients. Now even more curious about this after your mention of von Willebrand’s factor.
See my question here: https://www.emptywheel.net/2020/04/05/research-misinfo-disinfo-its-a-scam/#comment-837207
So, really interesting question Rayne regarding B-thalessemia. I hadn’t even thought of that. Initially, my thought was, no, probably not, but it turns out I was totally wrong! That’s a review on patients with B-thal intermediata and B-thal major. They actually do have increased coagulation states for a variety of reasons (a lot of it has to do with damaged red blood cells and activated platelets from spleen dysfunction)!
To translate into English, these are folks who are either entirely missing the beta chain of hemoglobin A (and thus have to rely on the minor forms of hemoglobin in our genome, like fetal hemoglobing), which would be B-thal major, or for B-thal intermediata, they have significantly reduced amounts of beta chain in their HbA molecules. Both types of patients have anemia to one degree or another; the B-thal major will also be transfusion dependent and also will have a shorter life span due to iron overload from all those transfusions over the years. B-thal major patients will require removal of their spleen at an early age because the spleen will become enlarged and non-functional from having eaten up all the malformed red blood cells with defective hemoglobins in them. B-thal intermediata may not *require* splenectomy, but do have functionally deficient spleens also for the same reason, from being clogged up with eaten up poorly formed RBC’s.
So, there’s multiple reasons to believe B-thal patients might be at higher risk with COVID-19: 1) Coagulation issues as noted above, 2) reduced O2 carrying capacity from anemia (which these patients all have to different degrees, 3) increased pulmonary artery pressures due to increased blood viscosity (this is also mentioned in the review I linked to), and 4) spleen dysfunction/aspenia (this is conjecture on my part, as it is interesting that fatal cases of COVID all have necrotic spleens, makes me think the spleen is important in the proper clearance of the virus, but just a WAG).
Note that the American Society of Hematology right now says there’s no evidence for thalassemia patients to be at higher risk, and they cite a cohort study done in Northern Italy that says they actually had milder cases than the rest of the population, but then also noted that they were much more vigilant about social distancing, so there’s that.
Also, I should mention that the review cited above only applies to B thal-intermediata and B-thal major, not B-thal minor, or thal trait, which is the heterozygous condition. Those folks may have minor anemia, but do not require transfusions. I don’t think they have any coagulation defects either, so I doubt they necessarily would be affected any worse than the general population when it comes to COVID. But it’s certainly possible that thal trait in combination with other genetic predispositions in those areas of the world (e.g. Factor V Leiden, a known hypercoaguable state which has a similar geographic distribution as B thal) could explain some of the severity wrt Italy and Iran.
Thanks for taking a look at my question. I haven’t see demographics from NY on patients admitted and COVID-19 deaths. I have a feeling we will see more than expected numbers of people whose ethnic heritage means they may be β-thalassemias heterozygotes, and these will be the patients who had the most damage to kidney and liver in addition to lungs and heart. If my hunch is right, we’ll also see more sequelae in the same group even if they weren’t admitted as COVID-19 patients. Would certainly explain above and beyond structural racism why we see persons of color with a higher percentage of poor outcomes.
EDIT: I need to look at the Chinese study wrt occurrence of ACE2 receptors throughout the body. Highest concentrations are in the lungs and ileum, but I don’t recall if spleen was another organ with ACE2 concentration, just not as high as lungs+ileum. Wonder if this is another genetically determined issue as well — could β-thalassemias heterozygotes have more ACE2 receptors in spleen, allowing virus to damage spleen preventing it from clearing virus? I’ll come back and add another Edit to this comment once I look into this.
EDIT-2: Frustrating. I don’t think anybody has looked at spleens wrt SARS-CoV-2 yet.
This one says low ACE2 in spleen while focusing on SARS’ attack points:
This one ignored spleen [**but keep this one in mind wrt ACE2 and ileum**]:
This one doesn’t look at spleen but might help validate your position on secretory cells:
Confirms I Hamming et al. (2004) re distribution of ACE2 — low in spleen:
Review of SARS-focused studies but look at the material on spleen in this! (ctrl-f for ‘spleen’) See also the remarks about genetics and pathogenesis — SARS disproportionately affected a specific haplotype.:
We still need so much more information. Hosts’ and donors’ genetics may play an important role if antibodies in plasma are more widely used once testing has become available on a broad basis.
The ACE2 receptor story is very confusing. I have seen multiple reports saying it’s present on ciliated epithelial cells in bronchi and in type I pneumocytes, yet others which say it’s only present on type II pneumocytes. And same story for the epithelium of the nasopharynx and the nasal cavity, some say it’s widespread, while others say it’s just in the neurosecretory cells. The consensus is that in the lung, it’s only on the type II pneumocytes which are secretory cells that make surfactant. However, there have been electron micrographs that show ciliated bronchial cells with viral inclusions and budding of virions, so they were somehow infected, even if they don’t express ACE2.
Personally, my money is on secretory cells only. They are the ones that would have furin and other enzymes that would allow for the cleavage events for viral entry. The other confounding factor, don’t forget, is there’s this idea of horizontal infection, whereby an infected cell can fuse with a neighboring cell that lacks ACE2 and infect it because it expresses high amounts of cleaved spike protein on its basolateral cell membrane. I think that’s a big way that the virus spreads and leads to the high viral loads.
And then there’s the gut, which supposedly has lots of ACE2, yet only a few patients ever develop GI symptoms, so go figure with that. Perhaps that’s because the pancreas secretes a butt load of trypsin which will fully cleave the spike protein to its fusion conformation before it is able to engage with an ACE2 on a cell membrane? Basically it’s like firing the gun before you aim it. Might also explain why RNA is able to be detected from the stool, but no one has been able to obtain infectious virus.
“And then there’s the gut, which supposedly has lots of ACE2, yet only a few patients ever develop GI symptoms, so go figure with that.”
I still think there’s different immune system signaling going on depending on gut biome which may explain why some patients have only mild symptoms if any and some fair worse. If gut biome is damaged and patient has been off their regular diet due to illness, gut-brain signaling may change during the progression of the illness. I wouldn’t be surprised if this is why some patients appear to improve and then take a turn for the worse — but we need more postmortem studies to know if this is the case. I’ve yet to see that anybody’s checking stool for live virus postmortem — only in patients who are believed to be recovering.
Still picking away at the dysregulated coagulation and possible genetic link to a certain patient demographic experiencing poor outcomes. This piece mentions loss of anticoagulant protein C and protein S post-splenectomy:
Also left more re: ACE2 in my previous comment. Link: https://www.emptywheel.net/2020/04/15/research-misinfo-disinfo-offlabel-covid-19-no-proof/#comment-838428
I don’t have anything worthwhile to add about your hypothesis of lung circulatory congestion, but I wonder if perfluorocarbon liquid breathing might help to reduce the viral load before all that damage can occur. Of course, liquid breathing does not yet exist for humans (as far as I know) but work has been progressing on liquid ventilators to induce rapid hypothermia (see https://pubmed.ncbi.nlm.nih.gov/26110489/ for example, where they are used on rabbits). Flushing the lungs with liquid would seem like a very efficient way to clean out excess viral particles as well as water from edema. Again, I don’t know how close these liquid ventilators are to being used in humans, nor if perfluorocarbon flushing would have any beneficial effect; it was just a thought triggered by your post.