Yves here. This author no doubt chose easy-for-laypeople-to-understand examples to make his point about sloppy coronavirus studies. I’m sure our savvy readers can offer far more sophisticated advice on how to read medical studies, but it’s always useful to keep a few things in mind (and you’d be surprised to see how many studies fall short on these very basic tests):
How big was the sample population? I’ve been told by MDs who review medical research that they regard anything less than a sample of 100 (with a similar sized control) as not reliable. Smaller samples can be flukey. With coronavirus, there are presumably a lot of controls via the large population of the already sick; it would be nice to see a study take some trouble in creating its control out of available cases.
Is there bias in the sample? Age, ethnicity, gender, lack or presence of other conditions….
Are the authors careful in stating findings? Correlation is not causation!
Also watch what is being tested. For instance, the author discusses a preliminary hydroxychloroquine study. More studies are underway. But most appear to be evaluating the efficacy of hydroxychloroquine against coronavirus all by itself, when most of the experiments in the field I have read about are of either hydroxychloroquine + azithromycin or hydrochloroquinine + azithromycin + zinc sulfate. HIV is treated with a drug cocktail and that is where we may wind up with coronavirus. So a negative on hydroxychloroquine as the sole remedy does not establish it isn’t useful in combination with other drugs.
By Irving Steinberg, Dean for Faculty, USC School of Pharmacy; Associate Professor of Clinical Pharmacy & Pediatrics, School of Pharmacy & Keck School of Medicine of USC; Director, Division of Pediatric Pharmacotherapy, Dept of Pediatrics, LAC+USC Medical Center, University of Southern California. Originally published at The Conversation
It has been barely a few weeks since the coronavirus was declared a pandemic. The pace at which the SARS-CoV-2 virus has spread across the globe is jolting, but equally impressive is the speed at which scientists and clinicians have been fighting back.
I am a pharmacotherapy specialist and have consulted on infectious disease treatments for decades. I am both exhilarated and worried as I watch the unprecedented pace and implementation of medical research currently being done. Speed is, of course, important when a crisis such as COVID-19 is at hand. But speed – in research, the interpretation and the implementation of science – is a risky endeavor.
The faster science is published and implemented, the greater the chances it is unsound. Mix in the panic and stress of the current pandemic and it becomes harder to make sure the right information is communicated and adopted correctly. Finally, governing bodies such as the World Health Organization, politicians and the media act as sources of trustworthy messaging and policy making. Each step – research, interpretation, policy – has safeguards in place to make sure the right information is acquired, interpreted and implemented. But pace and panic are testing these safety measures like never before.
Unprecedented Pace
The process of taking an idea from theory through testing and eventually toward implementation has been refined in modern times to make sure medical studies and publications are truthful and accurate.
Once research is completed, investigators analyze their results and write a manuscript. They then submit it to a journal, where it is reviewed by experts in that field who assess whether the methods, analysis and conclusions are sound. If the paper is accepted, it is then further edited and published in a journal.
From there, groups like the WHO, medical societies and government agencies evaluate this and other evidence-based information to decide whether to establish new recommendations or change previous ones. It normally takes from several months to more than a year to go from submission to publication. But the rush to publish during this pandemic has shortened the time from submission to online publication to one to two weeks in numerous cases.
There has also been a huge increase in preprint publication – publishing studies online before they are adequately peer-reviewed – and these are a good example of the risk that comes with the rapid release of data.
On March 17, French investigators posted a prepublication clinical paper online touting the successful use of hydroxychloroquine in COVID-19 patients. Despite the media and government attention, the study was described by director of the National Institute of Allergy and Infectious Diseases Anthony Fauci as “anecdotal” due to the poor study design.
On April 3, the International Society of Antimicrobial Chemotherapy, the sponsoring organization of the very journal posting this prepublished article, agreed and stated “….the article does not meet the Society’s expected standard,” and “Although ISAC recognises it is important to help the scientific community by publishing new data fast, this cannot be at the cost of reducing scientific scrutiny and best practices.” The debate over the usefulness of hydroxychloroquine will likely continue until well-designed trials are completed.
The deliberate steps of scientific investigation, followed by editorial scrutiny, are guardrails. When these are disrupted there is a real risk that policy organizations may make consequential mistakes in spite of good intent.
When Pace Meets with Panic
Nothing better illustrates how trusted institutions can make misinformed recommendations than the recent fiasco over ibuprofen.
The most common early symptom of COVID-19 is fever, and ibuprofen is one of the most widely used drugs in the world to treat fever. In a letter published in The Lancet Respiratory Medicine, European researchers raised concerns that ibuprofen use could worsen COVID-19 symptoms. The idea is that since ibuprofen increases the quantity of ACE2 in human cells – the protein that the coronavirus uses to enter lung cells – the virus could infect lung cells more easily if a person was on ibuprofen. This was not a study nor did it present sufficient experimental evidence; it was simply a theoretical concern based on a mechanism.
Three days after the letter was published, the French health minister tweeted a message urging people to avoid ibuprofen for coronavirus associated fever based on four “cited” cases of people getting sicker after taking ibuprofen. These cases were never published in a journal. The French Health Ministry followed this with a broad ban on treating COVID-19 fever with nonsteroidal anti-inflammatory drugs like ibuprofen. The WHO tweeted an essentially similar warning. The media followed with more case anecdotes, dubiously relating worsening early symptoms with ibuprofen use and referring to the letter as a “study,” adding to the confusion and fear.
The Lancet letter also hypothesized that two other drugs commonly used to treat hypertension and diabetes – ACE-inhibitors (ACE-I) and angiotensin receptor blockers (ARBs) – could be problematic in people with COVID-19. However, the mechanism they put forward was incompletely described and neglected that a protein these drugs promote can be helpful in reducing inflammation and tissue damage in the lungs and heart.
The Response
This letter to The Lancet slipped past the safeguards in research and institutional and media interpretation, but one of science’s oldest pastimes – definitively calling out the errors of others – reestablished patience and perspective.
Clinicians and scientists pushed back swiftly, supporting the use of ibuprofen in COVID-19 patients. The support was outlined in a published literature review. In response, the WHO quickly reversed its position on ibuprofen.
There was a similar rapid response to the statements about ARBs. Within days, three prominent cardiology groups, including the American Heart Association, released a joint statement urging practitioners not to discontinue ACE-I and ARBs in their patients.
The risk-benefit ratio is always a clinical factor for the use of any drug in any patient. But the risk must be more than theory for the use of a drug to be discontinued or any major policy change to be implemented.
Some Perspective
As the coronavirus rampages across the U.S., it is incredibly important to know whether commonly used drugs like ibuprofen or ARBs are risky, neutral or of therapeutic potential. There are ways to find out quickly. Researchers can look for correlations between the use of ibuprofen or ARBs and more severe infections or deaths, for example. And standard clinical trials can, should and are being done. There are several studies currently underway testing the effect and risk of ARBs for COVID-19 patients. But until the science is finished, it is foolish and potentially dangerous to flee from tested clinically important drugs.
Scientists and policymakers must take quick steps and avoid missteps. Proper scientific method and conduct of studies, carefully reviewed publications and cogent post-release interpretations are necessary safeguards that ensure the best and safest medicines are prescribed and provided. The pressure and desperation of the moment are forcing researchers and policymakers to be innovative and act quickly, but what is done should stay within the guiding concepts of medical research.
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I think the author also comes at his perspective from that of a pharmacotherapy researcher, which emphasizes the scientific basis of claims. Medicine, in my view, is better described as a scientifically informed art than a science.
When presented with a novel case MDs are going to do their best to extrapolate from known data (hence the Ibuprofen concern, for example) and take their best guess as to what might work or be problematic. In the end, what matters to the Physician is that the treatment is effective, while causing as few side effects or unintended harms as possible. (I’m sure many commenter have heard a Doctor say that the mechanism for a particular drug is unclear for a certain condition.)
This means that untested but plausible theories, small anecdotes or small uncontrolled studies reported by colleagues probably get more valued under circumstances such as the present as they provide new ideas or possibilities of helping the patients, or at least avoiding unnecessary harm, that cannot wait for a retrospective analysis or a controlled study to finish.
>as a scientifically informed art than a science
Seriously.
There are lies, damned lies and statistics. Medical “science” tends, in the long run to hew pretty closely to the third and they should get credit for that. Except they use the word science, that bothers me a bit. Are statistics actually a branch of “science”? It’s far above my pay grade but they should at least have been careful with the moniker.
For instance – “when most of the experiments in the field I have read about are of either hydroxychloroquine + azithromycin or hydrochloroquinine + azithromycin + zinc sulfate.”
Well that’s interesting. Where did they get the idea to try these combinations without testing the constituent parts? Did they have actual models where X couldn’t do what it wanted to because it was blocked by Y so adding Z opened up that door?
This should not be taken as an argument against testing lots of things and figuring out how they work once you narrow it down to what’s effective! It’s just why we can’t rush things like we want to.
Statistics, as a branch of mathematics, is a set of absolute rules. The problem is that the tools of statistics can be misused or abused, mostly, I think, through reliance on bad data (whether such reliance is unknowing or intentional). In the end, inputting bad data results in false conclusions in the sense that such conclusions are not necessarily in accord with reality. However, these conclusions are “accurate” in the sense that they are derived from and consistent with the bad data. (The long and short of it is the old “garbage in, garbage out” mantra always holds.)
In partial answer to your second point, the theoretical possibility of using chloroquine/hydroxychloroquine for treatment for coronaviruses has been known for years. In researching the matter a few weeks ago, I discovered articles dating as far back as 2004 that have results suggesting that _chloroquine _could be_ a treatment for SARS-CoV (the SARS causing coronavirus). The full text of the 2004 article is here: https://www.sciencedirect.com/science/article/pii/S0006291X0401839X?via%3Dihub
In turn, the authors of the 2004 article apparently drew inspiration (as indicated by citation) from a previous 2003 discussion in _The Lancet Infectious Diseases_ generally analyzing chloroquine’s antiviral effects and potential mechanisms, as well as specifically speculating that the medication may be viable for treatment of SARS (https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(03)00806-5/fulltext).
It’s important, I think, to note that _The Lancet_ article is labelled a “Personal View.” It is not a scientific study, but a theoretical analysis for to guide future research and potentially even medical treatment in the absence of better data.
I haven’t had a chance to determine what inspired Azithromycin to be used in combination but that’s something I am planning to research.
My understanding as a lay person is that both HCQ and Azith, coupled with the zinc, put zinc into cells where it interferes with virus replication
That is why it makes sense as a package.
Statistics are a bedrock in science to decide whether something is (very likely) real or just wishful thinking. You may imagine how central that is to science. If you can’t, it is very central. How scientists talk very clearly reflects this. You will almost never hear a scientist speak with 100% certainty about anything, even things he or she is more certain about than any other truths in their life, especially to other scientists. There is in fact a whole nuance there In language coming from a scientist about how sure they are about what they are talking about, that most people do not use. The lay public usually interprets this as Scientists not knowing what they are talking about, because it doesn’t come across with the same level of conviction as say the preacher on Sunday morning or Perry Mason, Which are closer to the more common way of speaking in black and white terms about things that you know not that all much about.
Medicine is fully capable of using the same tools. To the extent that they do and publish controlled experiments in the literature, they are doing science. Drugs get approved this way. Procedures too, I’m sure. There is a whole cadre of MD/PhDs who specifically do this work, but you don’t need a Ph.D. to do it. Scientists are not exclusive in the way MD.s are. Mostly they just want to see your data and see if they agree with your conclusions. Got a good head on your shoulders, know what you are talking about and aren’t making unsubstantiated claims? You’ll fit right in.
The daily practice of medicine as a GP is a lot less like science. There is a sample size of 1. It would be unethical to run negative controls with uniformed patients seeking treatment. These sorts of restrictions make treating patients difficult to quantify with statistics. Though, you can do some stuff. Alas, knowing little about medical practice as I do, I’ll stop there. I may find myself in the hands of a Physician unable to breathe sooner or later and I’d like her to know what a swell guy she is.
As for which tools to use, there is a tool kit of various drugs that are known to produce effects. How those effects are produced is usually pretty well understood. It usually comes down to the drug blocking some enzyme or another in the body so that it doesn’t work anymore. It’s function disrupted, the downstream effects of whatever it usually did in the body get turned off, and the materials it was consuming start to pile up, which may have its own effects. So, you turn one knob to shit off one pathway, and maybe another knob to cancel out some other effect, and maybe in some combination it will work pretty well, at least until your liver or kidneys get sick of processing all these drugs. Keep in mind that you are effectively throwing a wrench into a pile of gears. You need to make sure it is the right wrench I the right quantity and placed in the right set of gear. Otherwise the clock stops. Clock stoppage is not a good thing when we are metaphorically talking about a human life. It is best to seek the help of an expert practitioner in such things and not self medicate.
My thesis advisor was fond of a theory that zinc disrupts binding of viral proteins to neuraminic acids. At the time, he was mostly talking about influenza and Sialic acid. He would tell us to take zinc gluconate when we didn’t feel well. The process is integral to how it infects cells. It appears that coronavirus also recognizes neuraminic acids.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554059/
I should mention that since he wasn’t a MD, I routinely ignored his advice on this point.
I also thought it interesting to note that the Links today included one concerning a NIH study of hydroxychloroquine that is expected to complete in July 2021 (!)–which I understand is not too far off from when a vaccine is expected to be fully approved, if a vaccine is even possible. That being the case, it seems like anecdotes, uncontrolled studies, etc., as well as personal judgment and experience, are what Physicians are going to have to rely upon for quite some time.
Its nice to have an organized structure to do research in. However, when you have something like this explode in less time it than it normally takes to write a grant application, the doctors are often working off of gut feelings based on their knowledge and expertise. A case in point is a doctor trying clot-busting drugs on cases where patients are being starved of oxygen when they shouldn’t be based on conventional thinking: https://www.latimes.com/science/story/2020-04-11/doctor-treating-coronavirus-patients-gambles-on-clot-busting-drug
Wards full of dying patients with no standard playbook means a lot of off-the-cuff experimentation that then needs to be followed up with real statistical analysis. I am sure this doctor would love to have a statistician work real-time on the data his work generates, but he is not about to wait for complex double-blind studies to be completed, peer-reviewed, and published.
Ibuprofen is an example. They have two alternatives (acetominophen and aspirin) to lower fever and address pain that are very well known and understood that do not have the problematic pathway they suspect might be an issue. I am sure these doctors are staring at enough challenges that they don’t want to introduce another potential one. I am sure the data will get generated and reviewed on all of these, but when you have 24-hours to figure it out on a novel disease, you don’t grab the thing that could theoretically potentially make it worse.
There seem to be enough different, often weird, presentations of this disease, potentially triggering latent infections among other things, that the front-line workers need to be operating creatively on extreme cases while other people clean up the stats behind them. A system that can’t even deliver protective garments or basic testing to the front line is in no position to whine about the science.
I am not a doctor, but I am an engineer who has had to stand in the field and make decisions in minutes or hours without the benefit of the normal 2-6 month investigation and analysis process. You quickly resolve what information you have that you can rely on and try to simplify the problem to its bare essence to focus on the important things. There is never a shortage of Monday Morning Quarterbacks afterwards unless it is something executives just want swept under a carpet.
Yes, I have been reading a lot lately and I agree with much of what is said. Notwithstanding, Science, as the rest of our activities is facing an unprecedented challenge so we have to be somehow balanced with our critics. On the clinical side we have been playing, sometimes in the most useless way, with the existing pharmacopoeia. There are things to like and to dislike. First there is much low-quality research (this has been in place for long, so not new) and if you are watching the scientific literature, though it is much better than media reporting, you find also much hysteria mixed with good research. I even notice that the political realm might be influencing what is researched and what not. For instance the enormous failure of Chinese science in its (almost inexistent) effort to determine the true origin of the disease is for me one of the most evident red flags. On the bright side we have more transparency and most publications are now open online, at least those that cover Covid-19 and this is really great.
Just spitballing here Ignacio (sorry, can’t help myself) – If (just if) the new coronavirus does have HIV-like segments in its RNA and that could cause the “second wave” due to lowered immunity, would it be possible to treat coronavirus with other attenuated bacteria (not just BCG) that usually attack the upper respiratory system? I’m thinking strep throat, etc. Bacteria to the rescue?
The second wave is expected to occur because the vast majority of people haven’t had the virus yet. We had some people get sick, went on a big lockdown so no more would get sick and the virus is on hold. But it is really on hold. It isn’t done with us yet and won’t be until 50-85% have had the disease or a competent vaccination to instill immunity, depending on Ro. Even then, typical corona virus immunity only lasts a few months and you can get it again. So, this might be with us for a while.
I hope nobody is finding evidence of coronavirus HIV hybrids. I’m not a virologist, but they are quite different viruses that attack different cell types. I rather think it would be as unlikely as a horse and eagle mating to make a gryphon. But viruses do find a way. They can be nucleic acid garbage collectors.
This is why it is likely to have a second, and third, and fourth wave of infections.If 10 million people get infected, then you still only have 3% of the population that has been infected. That is barely a blip on what it would take to slow transmission in a normal environment. Without fast testing and immediate quarantining of people exposed, we would be back to where we are today within weeks of opening things up.
Science has been very much crapified over the last 20 years that I’ve been in it. It’s sad to watch because it’s not even generational. I see older scientists, whom I have great amount of respect for, submitting garbage for publication because that’s how the game is played these days. It’s not just scientists, the journals are trying to ride the hype as well and editors are going with flash over substance.
Yes, sadly. Number of publications is rewarded more than new research that takes a long time to complete and often results in fewer fewer interim publications. It’s not unusual to see older scientists ‘repackage’ bits of their earlier publications as new articles for publication to keep their publication numbers high. I think that has a negative effect on continuing longterm projects with no immediate rewards, but which might result in important breakthroughs.
Recycling is a time honored tradition going back since forever. Publish a poster at a conference, then a communication, then the full paper. Some time later you can review your own work and maybe others in a series of review articles. I don’t really see this as a problem. Each of these stages serve a purpose. The poster gets your student some exposure and public speaking. The communication gets your foot in the door for academic credit. The paper is what we wanted in the first place. The review articles are helpful for those new to the field to play catch up, and help to focus the reader on the best work. We should expect the science to be sound at each step, of course.
In this way, I don’t see the early publication of fragmentary results as a problem — for scientists. They deal with unfinished stories all the time and can be quite helpful in their own work and certainly will look at it critically. They need the freedom to do that kind of thing. The problems happen when the lay public seize on these things without much critical thinking And start acting on it before the story is clear.
“….World Health Organization, politicians and the media act as sources of trustworthy messaging and policy making. ….” (?)
Two giant red flags on HCQ. (1) It’s off patent, cheap and ubiquitous (no fortunes to be made). (2) Liberal Nemesis, the Evil “Mr T” has been proposing it. “If he’s for it, then we’re agin it!”
The tonic water in your supermarket has quinine in it. Originally, quinine (and tonic) came from the ground up bark of the cinchona tree (the fever tree). HCQ is pure, synthetic quinine. The fever tree bark has many other alkaloids, as well as the quinine.
I can understand the fear of “deadly” HCQ amongst the prohibitionists folk, but for anyone else, who has ever enjoyed a gin and tonic, Fear Not.
Quinine and hydroxychloroquine are quite different molecules With different chemical structures, and should not be confused with one another.
https://pubchem.ncbi.nlm.nih.gov/compound/hydroxychloroquine
https://pubchem.ncbi.nlm.nih.gov/compound/Quinine
The Good News:
In a Mar 28 video, N.Y. country doctor Vladimir Zelenko who devised the drug formula that he says has prevented 98% of his at 375+ high risk patients from having to go to the hospital, spoke of the virus having created a “wartime” situation where normal procedures must be supplanted by “what works and saves lives.”
The video is an hour long, but enormousy interesting because it allows you to make an objective evaluation of the Dr’s competence and credibility. Judge for yourself : https://www.youtube.com/watch?time_continue=2360&v=Z7SDemHGl8U&feature=emb_logo
Zelenko’s 3 drug protocol for early “preemptive” treatment of vulnerable patients (over 60, and/or, with co-morbitity risks) is:
HydroxyChloroquin- 200mg 2xday for 5 days,
Zinc Sulfate- 220mg 1xday for 5 days, and
Azithromycin (not Z-pak) 500 mg. 1xday for 5 days.
He makes it crystal clear that the HC IS NOT EFFECTIVE WITHOUT THE ZINC SULFATE. and that the HQ merely creates a pathway for the Zinc to enter the cell to destroy the virus before it advances from the upper respiratory system, down into the lungs.
A followup Apr./8 video, again features Dr. Zelenko starting at the 8:08 mark at: https://www.youtube.com/watch?time_continue=1237&v=EuLg_ltVfFc&feature=emb_logo
IMO, his language and logic are entirely persuasive. He relates that he was contacted by the head of the US FDA, and alerted to hearing from the NIH. He mentions he and his colleagues working on formal presentation of his findings, and that India, Ukraine, and Broward County Fla.,(w an over-60 population of one million), have all contacted him, and are investigating or about to implement his protocol.
(From Thursday’s news, a Dutch GP also using the Zelenko protocol w great success: https://www.sott.net/article/432141-Dutch-GP-Cures-Coronavirus-Patients-But-The-Dutch-Government-Isnt-Happy) stopped by Dutch gov.
(LA MD also successfully used Zelenko formula: https://www.zerohedge.com/health/while-left-continues-pan-trump-touted-treatment-another-doctor-reports-dramatic-impro)
~~~~
The Bad News:
Just as the Dutch Gov. has turned a blind eye to the findings of a local GP MD, because of ignorance, laziness, and pure political bias, it looks like the U.S. public is being substantially misinformed by the legacy media about the efficacy of a Hydroxychloroquin-Zinc sulfate-Azithromycin protocol as an effective “preemptive” treatment for Covid-19.
The stigma of casual endorsement by Trump (whom I personally revile) has unfortunately poisoned the well for objective evaluation and reporting, with heaven knows how much unnecessary death and suffering likely to result.
“Azithromycin (not Z-pak) 500 mg”
Do you know why he says not Z-pak?
Yes, this makes no sense. Azithromycin is as I am sure you know the generic name for Z-Pak. Unless there’s some weird dosing size limits with a Z-Pak. The only time I took it, I recall it was for 5 days.
Yves, the dosage in the Z-pak starts with a double dose on the first day, then level for the remaining 4 days:
“Zithromax is most familiar to the public as the “Z-Pak,” a convenient five-day pill regimen with a dose of 500 mg (2 tablets of 250 mg) the first day and 250 mg for the remaining four days. But, Zithromax comes in several dosages and forms, including oral tablets and liquids for oral use, injections and intravenous drips.”
I think the idea is to get a large initial blood serum level and then maintain that for the 5 days.
Suffice it to say that his pursuasiveness and logical rhetoric is not how we determine efficacy…case series is one way to begin to understand that but methodologically most inferior
Yes. I listened closely to the interview and a few red flags went up for me, not doubting Dr. Zelenko’s sincere desire to add what he believes is good information.
But, when asked how many patients he’s treated: 500- 600.
ok. over what time period is this: “Since last Tues.” so less than 2 weeks. (?!)
ok. were all of these people in serious condition when you saw them: no, none of them required hospitalization. They came into my offices where my nurses assisted them with my telemedicine consult.(!?)
—
Certainly worth more investigation, but the first unanswered question, for me: Since only 10% of covid sufferers appear to need hospitalization, how do you know the treatment kept them out of the hospital vs they were all in the 90% that would not need to go to the hospital, even without that treatment?
second question: did the treatment cure, or simply do no harm. Correlation or causation?
I am more persuaded by reports out of Italy, where they threw everything against the wall. They found steroids, normally a front line of defense in respiratory cases, made things worse, and I recall hydration beyond a very limited level was a bad idea too. The reports were hydroxycholorquinine + azrithromycin did best of what they experimented with.
Zinc is generally a good idea, won’t hurt you, cheap, and supposedly impedes one of the pathways in.
Apparently, adding the azithromycin can lead to prolonged QT interval and/or other issues, in susceptible patients.
https://www.acc.org/latest-in-cardiology/articles/2020/03/27/14/00/ventricular-arrhythmia-risk-due-to-hydroxychloroquine-azithromycin-treatment-for-covid-19
https://www.dicardiology.com/article/aha-acc-hrs-caution-use-covid-19-therapies-hydroxychloroquine-and-azithromycin-cardiac
Besides HQ, AZM was used in Raoults’ team (small) study probably because macrolides had shown before very interesting immunomodulatory properties (reducing inflammatory response) as well as antiviral properties (preventing viral entry) against some respiratory virus like RSV and Influenza.
As long as patients show tolerance on the potential adverse effects of HQ and there are no contra-indications with existing treatments, this is for now the best treatment at hand. I wish I could find solid evidence of Zinc Sulphate as a helper here.
It is only anecdote, but I know a London GP who contracted COVID, treated it with hydroxychloroquine and azithromycrin and was 95% better within 36 hours. He is hoping the UK government will shortly allow treatment with that combination plus zinc.
My mom is now under HQ + Az treatment starting as soon as she was seen symptomatic (the bad news is that Covid-19 had progressed to lungs early and the good news is that it was localized, not extended. I am crossing fingers. She has been stable now for 5 days after initial shock.
Sorry to hear about your mum, Ignacio. As you say, fingers crossed that she has a quick recovery. Luckily she has a son well versed in this virus to help her through this.
Thank you Rev! After a few days Lolita Schwartzenegger is not in bad shape. It is amazing how strong are these old ladies!!! It is tough we cannot visit her but at least we can organize from time to time video-phonecalls.
This was my worst fear about Covid-19 and it came true, but yet i keep hope!
I only have good words for the HC (public) services she has received and also for the nursing home. They are battling this difficult times and behaving like excellent human beings. The military have been helping overwhelmed nursing homes to get clean and organized, so I extend to them my gratitude.
Best wishes to your mother, Ignacio, she sounds like a tough lady.
Greetings from Madrid, take care PK!
I will never miss an opportunity to recommend Ending Medical Reversals. It changed my mindset from “new experimental therapy? Sick people deserve to try anything that might work!” to “we can’t afford to let another unproven therapy be codified into accepted practice. Generations will suffer!” Yes we are on a new frontier of medicine, but that is why every covid19+ patient possible should be enrolled in a clinical trial testing one of these as-yet-unproven interventions.
this is such a hard thing for people to grasp and support. We all want “need” to have somethng to hang on to.
I find myself badly wanting HQ and Zithromax to work…but the universe doesnt work that way
Well while there’s some debate about the matter my understanding is that the risks of hydroxychloroquine are low or at least well known since it has been in use for many years. And if it helps then the benefits would be very large if it saves the patient’s life. Therefore this may be very poor example by the author’s own standards. And while it’s quite true that Trump shouldn’t be giving medical advice it’s also true that those who attack the drug just because Trump touted it are doing the same thing.
I’m not sure the Ibuprofen story really illustrates the point that the author is, presumably, trying to make. At least in France, the health authorities have been concerned for some time about the misuse and over-use of easily obtainable drugs like Ibuprofen and Paracetamol. This is part of a wider push to reduce the number and quantity of medicines that French people take – they are one of the most medicalized societies in the world. Over the last couple of years, for example, both drugs when combined with codeine have been withdrawn from sale in pharmacies and are only available on prescription. The 400mg dose of Ibuprofen has never been on sale. Earlier this year (before the virus panic started) both drugs were withdrawn from the floor of pharmacies: you now have to ask the pharmacist for them, and you get a little lecture about not using them lightly, or for too long. So the French authorities were understandably nervous about the possibility of people dosing themselves heavily with a drug which is known to have side effects. In the circumstances, it’s hard to argue that it was wrong to be cautious.
Yes – ibuprofen is a bad example and the author didn’t do justice to the French argument for not using it. That argument, as I understand it, is that ibuprofen is among a group of drugs that act to suppress the immune system and have been shown to extend hospitalizations / ICU and other bad outcomes for serious lung infections like pneumonia. Since Covid-19 infections sometimes end in pneumonia-like conditions, the French are standing by their recommendation to avoid it. Might be just a theory (with Covid,) but given the relatively rare need to reduce a fever and other options for doing so, the French recommendation seems appropriate.
let’s say compound X/drug course Y is a low cost, low-side-effect treatment with multiple, independent anecdotes touting its efficacy in the most severe cases
in a pandemic with no extant best practices (in my opinion) , it’s unethical to withhold that treatment.
but in a true double-blind clinical study that’s exactly what has happen
I don’t think it’s that straightforward. We’ve also got studies and reports, admittedly unsatisfactory in various ways, doubting CQ/HCQ’s efficacy. Is it ethical to give that treatment? Withhold it? Do double-blind studies? I’d enrol in a study where I might get the drug or might get a placebo in this case.
The author doesn’t mention the 1976 Swine Flu vaccination program rushed into place because of political demand. That public vaccination program was abruptly halted 10 weeks after it started when serious complications from the vaccine started appearing in numbers.
The LATimes recounted the debacle in 2009:
https://www.latimes.com/archives/la-xpm-2009-apr-27-sci-swine-history27-story.html
I’ve often speculated that debacle was part of what cost Ford re-election in 1976.
Just to add–if risk versus benefit should be the gold standard in medicine shouldn’t today’s Links story about ventilators be a far more compelling example? In NYC 80 percent of patients who are put on ventilators don’t survive and yet a shortage of ventilators has become the media mantra for demonstrating the failed preparations for this epidemic. The fact that doctors are putting too many people on ventilators out of a limited understanding of the disease exposes the reality that medicine is indeed an art, not a science at least when it comes to something so unfamiliar as novel coronavirus.
I’d say lets take the politics out of this altogether and accept that ad hoc solutions will always be necessary in an emergency.
Panic and bad journalism have elevated politics over science.
The April 5 reporting in the Financial Times of the work being done at the University of Padua comparing infection and death rates in Lombardy and the Veneto are a case in point. It appears that there is significant economic and political pressure in Lombardy to hospitalize 65 percent of diagnosed patients, while in the Veneto home treatment of all but the most dire 20 percent of cases is preferred. The preference has more to do with the politics of hospital funding and the rhetoric of elected officials than it does with science or medicine.
It now appears that hospitalization has been a major vector of the disease. The death rate in Lombardy has been 17 percent, while in Veneto it is just 5 percent, although Veneto has a high rate of confirmed cases thanks to early testing — nearly as many tests administered as in Lombardy although having only half the population. A key vector being studied by Padua U is that Lombardy has a smaller number of large private hospitals, while the Veneto has a dispersed network of small public clinics.
The Lombard model appears to be more like the American model (especially in New York) — driven by the economics of admitting patients for treatment rather than keeping them dispersed in the community.
Unfortunately, we will only fully understand the vector points of this virus in retrospect.
Exactly. In the real world medical decisions are driven by so many more factors than pure science with the wallet biopsy (in this country) being one of them.
And it should be pointed out that the heroic intervention model is a big driver of the lockdown and its economic consequences. We are “flattening the curve” in large part to allow limited hospitals and equipment to cope even if, in the case of ventilators, that may not always be the right decision. In a disease where the cure is your own immune system it’s hard to see why many more patients couldn’t be treated at home or special virus only locations with daily visits from doctors or nurse practioners. In many ways, for a disease like this, the medical response needed may not be much different from what it was in 1918.
Not an ER doctor but I think the take home finding here is not that ventilators are killing people, but rather the people going on them are pretty far gone already. While ventilators do cause their share of problems, are we saying here that people are getting out on them unnecessarily?? This I find hard to believe. I mean if you can no longer breathe on your own, even with supplemental oxygen, it rather seems like the choice is die now or likely die later. Given that choice, most would opt out of the die now. Between that and the shortages of devices, paralytics, etc. it seems quite improbable to me that they are over prescribed.
Established procedures that confer scientific rigour are inextricably linked to time. To be thorough and explore all variables, correlations, causal relationships etc, and interpret the findings in line with accepted scientific standards is a process that requires time. The panic laden environments that scientists are working in as a result of this pandemic are throwing up a very real conundrum akin to the “re-start the economy vs flatten the curve” debate for which there are no easy answers. It’s much like when crime investigators work on a high profile case where politicians, media and the public agitate for updates on a near constant basis. The normally methodical, patient approach to building a case away from the spotlight is jettisoned in favour of chasing down anything that smells like a lead in order to provide “promising” updates and calm the nerves of a clamouring public.
It feels like the same thing is happening here, medical scientists are working in a pressure cooker environment to reassure an increasingly panicked populace that they’re getting on top of this pandemic. Established processes for conducting credible scientific research will likely fall victim to this mad rush: I.e. at the first sign of a correlation extrapolations will likely be made and causations inferred with a “and hope for the best” attitude added to the mix.
Competing priorities and incompatible objectives are the order of the day during this pandemic and resolving these conundrums is as intractable a problem as containing the spread of the virus itself. I think scientists will attempt as far as possible to track established processes very closely while keeping the urgency of the situation top of mind, and this will result in the most promising early findings perhaps making the leap to e.g. WHO directives in a manner that wouldn’t be possible during normal times. A few backflips from authorities are also to be expected owing to the fluidity of the situation.
Everyone is in virgin territory, scientists included and as such the level of prudent experimentation we will witness is unprecedented in its scale. This may require a safe deviation from established norms as a small price to pay to wrestle this pandemic to the ground.
PS: A friend of mine went to see a Dr here in Johannesburg on Thursday and was told that doctors are seeing encouraging signs treating covid 19 patients with ARVs meant for HIV but that this will not be published as a recommended treatment option, at least not yet (sample size and all I guess)…
medical scientists are working … to reassure an increasingly panicked populace that they’re getting on top of this pandemic
My impression is that most scientists are genuinely trying to get on top of this, but not overstating their conclusions. On the contrary, their reports are full of words like may and potential, and many are far from reassuring. Of course others will be quick to pounce on ill-digested scraps offering ‘hope’ of a return to normal.
I think what we are seeing is the general public increasing their understating about what science is. There is a reason that science is conducted and appraised by other scientists. These scientists will interpret the findings of the study within the necessary caveats. Of course these caveats are not necessarily obvious to lay people, and if they are, the implications are not always clear.
What scientists are doing is putting their experience and ideas out there, in case it is useful. If subsequent studies do not support the ideas they are dropped, even if initially supported by interesting data. This is science, it is a living process.
Just because there are caveats with studies it doesn’t necessarily follow that they are of no use, or that they are flawed. Somehow the author needs to understand this.
The ibuprofen story is a case in point. It’s reasonable to have a discussion in a medical journal as to whether it’s a safe treatment for Covid-19. As you can see there is a good reason to state the hypothesis that it may be harmful. There are also good reasons to state the alternative hypothesis, that it’s not harmful. Such a discussion may lead to a study and then to data, and in the end it might be something or nothing. This is science, the normal scientific process, with no flaws.
“the media followed”…”referring to the letter as a “study'””
*Thesaurus Syndrome* …this very common device-too often frequenting media publications- conflates as equal/identical/interchangeable words which in certain cases may be substituted without significant interference with understanding.
Unfortunately, (accidentally???) the result is commonly a product full of ambiguity; with meaning determined by the recipients familiarity with the most frequent context in which they have experienced the words.
Example: Crash, collision, accident, mishap, incident. All used interchangeably, none identical in meaning.
Non-specificity in media is a huge player in the dumbing-down of peoples. At least here in U.S.A.
Bug?…or feature???
+1
A new Vico?
Doesn’t it also make sense to study the exceptions? Like studying the one person in the family who did not get Covid-19? Or the one neighborhood that avoided getting it, but for none of the obvious reasons like protecting themselves by quarantine, masks, etc. There are people who just get a slight case of it. Shouldn’t those people also be studied to see how they fare over the years? Which ones do better? Natural immunity seems to be a non-subject. When it might well be the best subject. We’ve got very impressive tools these days for studying the immune system and the genome.
Yes but medicine rarely works that way
I think some countries are at least identifying many who just get a slight case. Over the years, I’d expect some follow up, thought that may not be the highest priority right now.
Incredibly high noise to signal ratio here. It is high in the best of times. I would say less than 1 in 100 papers right now have anything to add. Not that they are wrong but just that you could not possibly know if they were wrong
I listen to the NC commentariat and to citizen journalists. I research and then I craft (or often, change) my own response to the Coronavirus.
We are not debating “numbers of angels able to congregate on a pin head.” If I personally make a bad call (re the virus), then it’s people that I love who could suffer (as well as my own sorry ass). Thank God for the few remaining comment sections on the internet!
Great post, and I’ll add a few thoughts. First, and to my mind the chief problem, is the current political economy fosters the production of bad science (leaving aside debates about what science is and isn’t). I’m sure most everyone in the commentariat is familiar with the “publish or perish” mantra in academia. Of course, academics are in a creative profession and thus produce research as part of their job, but the university is basically full on corporatized now. With that comes an increased focus on branding, productivity metrics, outcome data, etc., that among other things puts the heat on academics to focus on # of publications and to territorially mark their contributions to a subfield. Early career academic without many novel ideas? Well, better come up with some fast. The university, which we have increasingly privatized and stripped of funding, isn’t going to pay you and your grad students so you’ll need grant money. To obtain this grant money, you’ll be “competing” against others in your field for the same pool of funds. Often these grants require you to state how your study/line of work is novel, interesting, pushes things forward, etc. Oh, and have fun in front of that tenure committee that will likely evaluate your work along similar lines. And that’s just the people who are in TT jobs. There’s even more pressure for grad students, post-docs, and adjuncts to get papers out into the world. Again, some of this has probably always existed but it’s exacerbated by the neoliberalization of the university.
Enter into the equation the fact that statistics are not necessarily easy for most. Many of the fields that require the use of statistics are populated with people at all levels who, however lovely and well-meaning, may not be great with numbers. But their high-pressure job requires them to use these methods regardless. You do see some instances of outright data fraud as a result of the pressure, but I think much more of the junk out in the ether is the result of poor training in math and statistics.
This is the background that work is being done in. By the time you take all this into account – the immense pressure to stay afloat and how much work you can imagine that entails – another part of the job description is peer review. I can only guess how many articles are reviewed late at night with a pair of tired eyes and a glass of booze.
The last thing I’ll add is, in addition to Yves solid list of things to keep in mind, check the results section. See what values they report, and more importantly, what they don’t report. Lots of researchers, including many doing biomedical work, operate under the Null Hypothesis Significance Testing (NHST) framework – way too much to go into how problematic that has been for science, but if you’re interested dig around Andrew Gelman’s blog. Personally, if I read a study that only reports p-values, I’m much more skeptical. Again, problems aside, if you’re going to use NHST the kicker isn’t just a significant p but the effect size of that finding. A “significant effect” could be entirely meaningless if the magnitude is negligible. For example, a researcher studying the effect of some test drug on mice, with a condition and control group, could find that there was a significant difference between the two groups, say at the .0001 level. Sounds impressive, right? But the key question is how much different? There are a variety of effect size metrics, each appropriate in different situations, that attempt to express that difference. If the effect size is tiny, can you really say the drug is all that useful? The Wikipedia article on effect sizes is a good place to start if you’re unfamiliar.
https://medium.com/@jamesheathers/the-grim-test-a-method-for-evaluating-published-research-9a4e5f05e870
Simple way of checking some numbers in a paper.
I saw a quote today from a paper where 12.5% of 20 patients showed X result. However 12.4% of 20 = 2.5. Were they reporting on the right half or left half of the patient?
Come on let’s be clear, this is not news, but part of any standard undergrad training.
Now we have a new treatment using TPa, which is primarily used to break up strokes.
Quite frankly, this re purposing of drugs fails more often than it is successful.
Guidelines used in China –
https://www.chinalawtranslate.com/en/coronavirus-treatment-plan-7/?utm_source=share&utm_medium=ios_app&utm_name=iossmf
For a better understanding of the contradictions in the media, I collected a hoard of interesting literature (PubMed) about the Adenovirus. For some reason no-one (CDC, Dr. Fauci ) is talking about it. . .
Imho, there is a reason why some therapies work and others don’t. I believe a mutated Adenovirus is co-circulating. The 2 common strains are HAdV-4 and HAdV-7. Both have a higher morbidity rate than Covid-19.
Military barracks, summer camps, and long-term care facilities are most vulnerable. In 1980, the FDA approved an “live” Adenovirus vaccine for use on military personnel, (not allowed for civilians because of SV-40 contamination) and was discontinued in 1994. By 1999, supplies were exhausted and Adenovirus returned to military installations.
Emergent BioSolutions Inc. (Gaithersburg, Md.-based giant) is now developing an updated Adenovirus 4/7 vaccine for military personnel under a contract with the DOD, which prior to re-introduction of the vaccine were responsible for several sick days per trainee.
Emergent BioSolutions Inc. is now (coincidentally) working on a Covid-19 nanovax.
Locations of severe outbreaks in the past have been in Care homes and Military Bases in Italy, Guam, Philippines, Germany, China, Pennsylvania, New York, Washington State, and Oregon.
Also explains symptoms that are not commonly Covid-19, like severe ‘pink eye’ (conjunctivitis), diarrhea and extreme confusion. Chest x-rays are very similar and can be mistaken for Coronavirus (ground glass opacity). And for some strange reason, the CDC does not require reporting of Adrenovirus deaths or outbreaks. . .People basically die of suffocation. . and organ failure. Young people . .
The other interesting bit I ran into was that flu vaccinations have been known to impair antigen response to Adreno.
A peak positive rate for Adrenovirus infection occurred in African American soldiers March–April 2014. The mean age of the patients was 21.7 years. Among the 69 patients with HAdV infection, 40.6% were new recruits and 75.4% were hospitalized
I have no medical training (barely finished high school), so salt shaker appropriate.. Hoping someone with Bio background and curious mind might take notice.. .