Expert Excerpts: COVID


James Meigs – Wuhan Lab Leaks

James Meigs Transcript

I think that understanding the origin of the COVID-19 pandemic is one of the most important public health questions, certainly of our lifetime. And unfortunately the way the global health establishment, many leading scientists, the news media, and government agencies in the U S approached this question was very problematic, and actually disturbing to some degree.

So I want to go back to the very early days of the pandemic and just make sure people have the right perspective, because we tend to edit our memories of how these things went down.

So in January and February, the idea that the COVID-19 might have leaked from one of the labs in Wuhan, China, was not considered a really bizarre or extreme idea. It was floated, actually, in China. A number of scientists thought this is something we should look at. A leading virologist named Christian Anderson actually emailed Anthony Fauci saying, looking at the genome of the virus, saying some of the features potentially look engineered. Which would refer back to the idea that in some types of virus research, there’s some manipulation of the genome for various reasons. And it may not, it’s not necessarily to make it into a bio weapon or something like that. It’s a legitimate aspect, or controversial, but generally accepted aspect of research to do this kind of manipulation.

Well, if this virus really came out of a lab and had been manipulated, that was a real bombshell. Almost overnight people started pushing back against that idea, including the virologist who’d sent that email to Anthony Fauci. Peter Daszak, the head of a group called the EcoHealth Alliance, which is a group that distributes a government grant money through its organization to scientists around the world, a leading figure in this world, he organized a letter to be published in the Lancet, the British medical journal with 27 top public health experts and virologists. And they didn’t just say that they thought that that lab leak theory was unlikely, that an origin in the natural world was more likely, but they said it was a conspiracy theory to suggest that COVID-19 does not have a natural origin.

A lot of scientists looked at that and said, “Well, that’s not a very scientific statement. Really, we don’t have the evidence to know one way or the other.” But nonetheless, that was the version of this theory that took hold among a lot of scientists, and then even more strongly among the news media.

In late January, Senator Tom Cotton gave a talk in which he mentioned the possibility of a lab leak, it’s something that should be looked into. And that almost immediately caused this kind of antibody response in the media and in our political circles to condemn the idea of even looking into the lab leak, as if it was some kind of crazy, out there, Trumpy and conspiracy theory. The Washington Post called and said he was quote, “Fanning the empires of, excuse me, fanning the embers of a conspiracy theory that has already been debunked by experts.” And Slate called it “Good old fashioned racism was what explained this thinking.”

Very premature to say that this thing had been debunked. It had been questioned, there had been pushback from some scientists, but it certainly not been debunked. There was also some similar reaction from world health organizations, especially the WHO which, in the early days of the pandemic was, again and again, seemed dangerously deferential to the accounts of this, that China wanted to promote. It described the spread of these ideas as quote, “An info-demic.”

So it was widely assumed that this was all a reaction to Trump. But actually if you go back and you look at Trump’s statements regarding China in January and February, they were actually quite positive. Again and again, he said, well, I just got off the phone with Xi, they’re doing a great job. They’re working hard on this. It was only later that the Trump administration really began to politicize and go overboard on lot of these statements, as it did on so many different issues.

We later learned that Peter Daszak, who had organized the letter to the Lancet, that because he’s involved in distributing all these grants, he had a long history of funneling grant money to the Wuhan Institute of Virology. Nothing wrong with that, but it certainly put him in a compromised position, in terms of conflict of interest, to be poo-pooing the idea that the virus might’ve come from that from that institute.

What we see in the reaction to the reaction is a more positive story, where some independent scientists began to explore this outside of the mainstream channels of their fields, typically. Some reporters start kept working on this, and plugging away. And typically not, this wasn’t the New York Times or the Washington Post, typically. It was, Vanity Fair, did a really impressive big story. You wouldn’t think of a mostly entertainment magazine doing it, but they did an excellent story by a writer named Katherine Eban. Novelist Nicholson Baker looked into it in New York magazine.

And I think, most telling, in early 2021, Nicholas Wade, former New York Times Science writer, who’d been kind of pushed out for being sort of a crusty, not necessarily politically correct, force on the paper, he published a long, self published a long piece on Medium. A couple of weeks later Donald G. McNeil, another, the New York Times former top reporter on COVID, who had also been pushed out sort of for political reasons, wrote a piece called, How I Learned to Stop Worrying and Love the Lab Leaks Theory, again, self published.

So the key point here is that there was, for well-intended political reasons perhaps, but political nonetheless, there was a really premature effort to prevent the discussion. To stigmatize the discussion of what should have been something that was certainly within the realm of things that we would want to explore as possible sources of the COVID-19 pandemic.

And the fact that it took the mostly outsiders and people working slightly out of the mainstream, tells us that we have a culture, in science, in the media, in politics, that is not as open as it should be. And is too quick to try to close doors on information that might be perceived as helping the wrong side, or providing ammunition to the wrong side. And you still see people defending this reluctance to address the lab leak theory in that way. So my basic takeaway from this is we need to really fight for diversity and an open dialogue in our media, in the scientific establishment, certainly in our global institutions. Over the last few months, we’ve seen this discussion open back up, the Biden administration has demanded a more thorough investigation and more cooperation from China, which will not be forthcoming, but at least they are acknowledging that this is an important issue to look at.

Now, you’ll notice I haven’t answered the question, “Did the virus come from the Wuhan Lab?” I’m afraid we may never know. I am not a virologist myself, so I can’t say, “Oh, it’s 70% likely or 80% likely,” but certainly, in the months since this has come out, evidence in favor of a natural origin has not materialized. Whereas, provocative findings that suggest the strong possibility of a lab leak origin keep coming out. None of this is proof, but it certainly shows a direction that we should be investigating.


Nobel Prize Winner Angus Deaton — Death & Despair


Dr. Ari Ciment — COVID on Treatments, Steroids, Monoclonal Antibodies, and Lung Damage

Dr. Ari Ciment Transcript:

Larry Bernstein:
We’re going to go onto our next speaker who is Dr. Ari Ciment. You just heard from him very briefly a second ago. He is a pulmonologist and COVID expert. Ari, go ahead.

Dr. Ari Ciment:
In my six minutes, I want to touch base on three topics. One is monoclonal antibodies, which I’m very excited about. Number two, just talk about COVID lung problems in general, as you asked. And number three, why the disease lingers and what’s the story with the long hauler syndrome. So, we’re going to do all that in six minutes.

Monoclonal antibody, the two companies that you might’ve heard of are Eli Lilly, the Bamlanivimab and Regeneron, which is casirivimab and imdevimab. Both of those together, make what they call a cocktail. So, what’s the difference between polyclonal, monoclonal cocktail. You hear all these terms. Also hyper-immune globulin. We don’t have time to go through everything. But two weeks after you beat COVID infection, you have the antibodies to the spike protein in your blood. The spike protein is that protein of the virus that enables the virus to get into your cell. So, two weeks after you would beat COVID, you have the antibodies. If you donate your plasma, plasma is about 45% of your blood. It’s like a diluted soup full of many antibodies, meaning you’ve had antibodies versus rhinovirus, the common cold, CMV, other viruses. But there’s also several different types of antibodies versus that-… but there’s also several different types of antibodies versus that spiked protein of the virus. That’s polyclonal. There’s a whole variety of antibodies that bind to multiple epitopes or antigens of that spiked protein. Monoclonal means that it’s actually directed to one epitope. They genetically engineer it. Regeneron is a company that did it, Eli Lilly, and it’s a more concentrated soup. Think about that plasma full of just monoclonal antibodies. It can be much stronger.

Both companies looked at patients who were newly infected within three days, and basically it lowers the viral load, and more importantly, it prevents perhaps the cytokine storm, which really causes the problem later on. Right now, we have an emergency use authorization. It’s not FDA approved officially because the production, it was the lagging behind. Whereas, I was sending my patients here in Miami that had Regeneron trial, I was sending 19-year-olds, 25-year-olds, 30-year-olds.

It was a safe drug. However, the EUA only applies to the people who are at most risk. Who is that? If you’re less than 55, you have to have a BMI greater than 35. That means you’ve got to be six foot tall, 260 pounds. You’ve got to be very heavy, or chronic kidney disease, diabetes, immunosuppressed. If you’re 55 to 65, you have to have chronic lung disease or cardiovascular disease or hypertension.

Now, anybody over 65 should be getting this therapy. All your listeners today, if anybody is over 65 and they have acute COVID, they need to go get this monoclonal antibody infusion within three days. That’s what’s going to be the best bang for their buck. The BLAZE-1 trial, which was the Bamlanivimab, basically showed that 97% of those high-risk patients did not have problems. That’s where that basically comes from. That’s monoclonal antibodies.

But what about COVID lung problems? How do you see it? Why do you see it? Alveolus is where the gas exchange occurs in the lung. The alveolus is important, and it interfaces with the capillary in the pulmonary, in your lungs. And if you have a problem with the alveolus, it gets flooded with fluid. That’s the main issue with COVID. If you look at the autopsy studies, not only is there ARDS, which is fluid filled alveolus impairing that gas exchange, but there’s also micro thrombosis.

What we’re finding is not only treating with steroids later on in the disease, but perhaps anticoagulation as well seems to be beneficial. Treatment in general includes antivirals early, like Remdesivir, or even things like you heard of Plaquenil or Zithromax, Ivermectin. If you take it early, it might have an effect on the virus. But later on in the disease, steroids and IL-6 inhibitors, you might’ve heard of Tocilizumab and anticoagulation, that is really the key leader on a disease.

What about fewer deaths, higher hospitalization? 4,000 people dying a day is not fewer deaths, but the percentage mortality has been decreasing. Early on in the pandemic, we saw here and they saw everywhere, 30% mortality. But now, we’re seeing mortality is about 10%. People seem to be living. Why is that? Because we are focusing the strategies as we see them later on in the disease to steroids, early anticoagulation, these IL-6 inhibitors, and of course, avoiding intubation.

And the last topic you asked me to touch upon is the long hauler syndrome. We’re now seeing patients who’ve survived COVID but now have other problems. What is the long hauler syndrome? There’s a variety of symptoms related to this. The article that really stimulated this buzz about long hauler syndrome was out of Italy in August. Actually, in JAMA it was published that 40% or 50% of patients had fatigue out of 143 COVID survivors, and about 40% had dyspnea.

Just published last week in Journal Lancet was a six-month follow-up from China. In Wuhan, a lot of the patients were in Wuhan, 1,733 patients, , 63% of them had lingering fatigue, a quarter of them had sleep problems, and a quarter of them had anxiety and depression. What is the etiology for the long hauler syndrome? It’s partly psychosomatic, partly physical. It probably will be a little bit like fibromyalgia perhaps. Nobody knows.

Those patients who’ve had severe lung disease, who had documented pulmonary fibrosis, are obviously going to have shortness of breath, they’re going to have pulmonary function test findings consistent with pulmonary fibrosis, and there’s also an element of myocarditis perhaps in probably a smaller amount of patients, but inflammation of the heart as well. That’s my take on those three topics.

Dr. Ari Ciment QA Transcript

Larry Bernstein:
Awesome. All right, let’s start with the monoclonals. My audience has a substantial number of 50-year-olds, and I’m not sure our 50-year-olds are taller than six feet or weigh more than 260, but you say that the monoclonal antibodies is the gold. That’s what we so desperately want. How do we get them if we follow these EUA guidelines? First of all, I know that the government thought that these Monoclonal antibodies were originally in tight supply. Is it, and if not, what can we do to get this? And will it make a big difference even for us 50-year-olds in terms of preventing a cytokine storm, or will prevent hospitalization or make the disease much less problematic?

Dr. Ari Ciment:
Right, that’s a great question. Yeah, the EUA is primarily because the highest risk patients will have problems. If you look into Johns Hopkins, they actually have an online risk calculator. You could plug in your age, your comorbidities. They will tell you the risk of having a problem. Even these patients that are high risk, there’s still a good 80% chance that you’re not going to have a problem, but there’s a 20% chance you will have a problem. I’m a big fan of using it whenever you can.

Dr. Ari Ciment:
You shouldn’t look for reasons not to get the medicine, you should look for reasons to get the medicine. If you’re a 50-year-old, but you were told you had hypertension once, I would say that’s hypertension. You were really told you in hypertension. You can’t lie, but if you had diabetes, there is a tighter supply.
But as you pointed out, the supply is coming up. Initially, we might’ve had a rigorous EUA. Now, it’s probably maybe a time to loosen up a little bit. And I would be a fan of loosening that requirement, especially because it’s very safe. But yeah, we can’t lie. But if you have those risk factors, you should find a reason to get the drug. That makes sense?

Larry Bernstein:
Yeah, you mentioned that it has best results within three days of… Is that symptoms, because I see how time works. You get symptom, and then in the next day or two, you go run out to see if you get tested. And then, some of these tests take two or three days to come back to you. And now, we’re on day four. Have we already blown our window?

Dr. Ari Ciment:

Larry Bernstein:
How much worse is it on day four than day three? Could still get it in day eight. How do we think about the efficacy depending on day pass for symptom?

Dr. Ari Ciment:
That’s a great question too. That was within three days of getting the test done. Patients typically had symptoms a couple of days before. I would say if you’re within the first seven to 12 days, you’re still before the cytokine storm, it’s very variable in people. I would say that there’s probably a clear benefit. When I say within three days, it’s within three days of the test being positive, you want to be able to get it. And there’s no reason for somebody to wait two days for a PCR test if you’re really a high-risk person. You pay extra money to get that PCR test fast.

Larry Bernstein:
Just changing subjects within, in one of your papers, you quote a Dr. Martin Landray from Oxford. And he said that COVID is really two phases. There’s a phase where the virus dominates and an immunological phase when the immune system causes trouble. How do you think about these two different phases?

We talked about this first phase with the monoclonal, which is the virus phase. But when we switch out of the virus phase into the, I’ll call it that storm phase or the immune system phase, how do we change medication? How do you think about the risks? And maybe you can describe what it’s like when you first see that patient who comes in at day 10, who’s going through the storm and what you’re going to do to make them healthy.

Dr. Ari Ciment:
Right, when you see the patient, typically in the first phase, when we first started out in March, we were seeing all the patients, we thought this was their acute virus, but it really wasn’t. It was day seven to day 12 of their disease, which was really the cytokine storm. When we were treating with these drugs, like Kaletra, these HIV medicines, high dose Plaquenil and Zithromax, all across the nation, nobody was seeing any results because we were treating the wrong phase of the disease.

Now, when we see the patients, yeah, we might use the convalescent plasma, which might have some anti-inflammatory mechanism as well, but really the hallmark is steroids, is trying to break down some of the inflammation, which unfortunately, it doesn’t work all the time, but it does work a good portion of the time, as well as these IL-6 inhibitors, which are other anti-inflammatories, like Tocilizumab.

When you see the patient, it’s quite clear that they’re not in acute virus phase already because they’ve had their symptoms already for the last seven to 10 days, and they are coming with more pulmonary infiltrates, that we already know, this is the cytokine storm. We could also follow the inflammatory markers, like CRP and sed rates, those sort of markers that tell us that this is more of the storm than it is the acute virus.

Larry Bernstein:
I don’t think the audience is that familiar with these inflammatory variables. I’ll start it out and then maybe, Ari, if you could fill it in. When you’re in the hospital, every morning, you take a blood test. And in that blood test, they check for certain inflammatory variables. And maybe, Ari, if you could explain which variables do you look at, why and how they show inflammation, and then once you see those variables, how do you vary the steroid or Remdesivir response to deal with those inflammatory variables, and then check to see what’s working and what’s not to make your next judgment call?

Dr. Ari Ciment:
Right, I personally am not a huge fan of the inflammatory variables, but we do test them. CRPs, C-reactive protein, I spoke about ESR, but we don’t really check the sed rate with this disease. We check ferritin levels and D-dimer on a daily basis. That actually might be of benefit because, remember, I had mentioned about the micro thrombosis. If we see a D-dimerizing, we might say, “You know what, it’s not a good idea just to have them on prophylactic anticoagulation. We might need to step it up to intermediate anticoagulation.”

But this ferritin and CRP helps us understand, perhaps, should we increase our steroids? Should we not just give six milligrams a day? Should we give it twice a day? It helps us understand if it’s getting out of control, despite our therapy, if we need potentially to think about stepping up our game and moving them to the ICU for heightened coverage. And also some alternative therapy, some places use plasma exchange if the ferritin levels are going very high to try to eliminate some of the cytokine storm and very high dose steroids too for such a condition.

The most important element of the cytokine storm is really looking at the patient and seeing the oxygenation, has it come down, has the x-ray really gotten worse? That will be more important than any inflammatory marker that you could see.

Larry Bernstein:
Got it. All right, next question relates to when should I go to the ER? We had discussions with Dr. Levitan in a previous episode of What Happens Next about what oxygen levels are dangerous and how to monitor it, and then when to make the move to get admitted to the hospital. And could you talk a little bit about that and maybe make it age related as well? Imagine we have a 25, a 55 and a 75-year-old person, young, middle-aged and elderly. And everyone now has their oximeter, they just drop from 96 to 93. Go to the ER or not? 91, 89, 85. Tell me how we should be communicating with our physician. If we don’t have a physician, when should we make a run for the ER?

Dr. Ari Ciment:
Okay, great question. It’s changed over time. Initially, we would say even a 25-year-old with hypoxemia, “Oh, you’ve got to run to the emergency room.” More and more doctors, such as myself, have treated hundreds of patients with COVID. But most of my patients are actually outpatients. If a patient who’s 25, let’s say, or even middle-aged without risk factors, and they desaturate on day eight of their disease after I gave them, let’s say, Ivermectin and I gave them Bamlanivimab perhaps, if they qualified, or just let’s say, Ivermectin and Z-Pak. I treated something as an outpatient.

And then, day eight, they have hypoxemia to 94%. If they’re young without risk factors, I might put them on steroids and avoid the hospital, and closely monitor them and text them at night, “What’s your saturation?” But if a patient is with high risk factors, 65, and they start seeing their oxygen levels drop to 91%, that’s a warning sign. You don’t want to wait, do you want to admit, because there are other therapies you could only get in the hospitals, such as Remdesivir, convalescent plasma. As of now, you can’t get that at outpatient.

That’s what I would do. I can tell you, most patients respond very well to outpatient Decadron, but it has to be treated with a physician who’s used to treating this and somebody who understands that you need very close follow-up.
Larry Bernstein:
There’s been a lot of positive articles in the medical journals about this steroid, dexamethasone, and it seems like that’s a central part of care now. Can you tell us a little bit about that steroid, why it works, and why it’s at the core of current treatment?

Dr. Ari Ciment:
Yeah, it’s based on that recovery trial, which I don’t have the data in front of me, but basically, if you were requiring oxygen in that trial in England, then there was an actual mortality benefit if you were given Decadron over placebo. It was one of the very first positive trials. It obviously got a lot of press. Interestingly enough, I’m not even sure if it’s FDA approved for COVID.

I think the only FDA approved COVID drug is Remdesivir. You can double check that. But Decadron is the most widely used steroid, but we’re also using Medrol dose pack. A lot of people are using just Solu-Medrol, we’re finding to be very effective. I don’t think it really matters the type of steroid per se. Dexamethasone seems to me to be the best one, but the other ones haven’t had a positive randomized trial. But in the metanalysis, they’re showing benefit as well. I don’t know if it’s just with Decadron.

But bottom line, this is an anti-inflammatory and it decreases the inflammation, which will blunt the cytokine response, which is actually at the core of breaking that barrier. The capillary alveoli barrier is really broken because of that inflammatory milieu you that the steroids block.

Larry Bernstein:
And that’s the key part. It’s stopping the storm in that way. Is that what you’re saying?

Dr. Ari Ciment:
Yeah, there’s a storm there and it gets to a point where it’s irreversible, but if you start it early enough, you could really stop the expulsion of proteins where they’re not supposed to be. They’re not supposed to be in that airway, that alveolus. It needs to be clean. And that steroid is able to block that expulsion of protein into that airway.

Larry Bernstein:
And so, if a 50-year-old comes down with COVID and he calls his internist and says, “I’ve got COVID,” currently, what they’d tell you is, “How about some Tylenol and take lots of fluids and rest.” Should we ask the internist, “How do I get that monoclonal antibodies? Do you recommend some of these steroids? Should I go for the Remdesivir? What do you recommend?” And so, what would you recommend to that 50-year-old?

Dr. Ari Ciment:
Well, a 50 year old, I would recommend looking at that history, believe it or not, still tons of the primary care doctors that I work… Not here, in other places, have not even heard of the monoclonal antibodies. You really need to talk with a pulmonologist, a local pulmonologist, to make sure that you’re really being offered whatever you could be offered. And Remdesivir has some good data. And if you need to be admitted, remember, you can’t get that yet as an outpatient. So, you would consider being admitted early.

Any therapy given early is going to be more efficacious than later on. On one hand, if you’re mildly ill and you feel like you’re okay, and your saturation is a little low and it’s day eight, yes, your primary might call in a little steroid trial, but he could easily call in for you to be admitted and be formerly treated and evaluated in the emergency room. Most emergency rooms are very good at doing a little walk test to see if you desaturate below 91, 92%. Then, you qualify for admission and they will do advanced therapies.

Larry Bernstein:
Okay, let’s talk about vaccines. Ari, you mentioned to me in the past that you recently got vaccinated. Do you have a vaccine preference, did you experience any side effects, and have you talked to your staff? Are the other hospital workers you’re working with getting vaccinated or is there just very little buy-in from the nurses who you work with?

Dr. Ari Ciment:
I think, overall, and that’s speaking about Mount Sinai specifically because I’m not going to talk about our hospital, but overall, speaking to doctors in general, there is definitely buy-in to get vaccinated. I don’t have a definite preference between Pfizer versus Moderna. I think they’re both excellent. And the good news is Fauci’s just announced that J & J and AstraZeneca will probably be available within a couple of weeks. So, you’ll have more vaccines to look forward to.

I can tell you that the younger you are, the more likely you are going to have symptoms. For instance, I have my second shot and I’m 46 years old, and I could not get out of bed for a day and I had pain in my arm. But I actually took that as a blessing. Hopefully, that means I had an immunologic response. There are going to be side effects. As long as you’re okay with the side effects, that’s good. A lot of the nurses in other places I know have not taken it because they’re young and a lot of them are of childbearing age and they want to make sure that the vaccine is safe before they do it.
I am a believer in vaccines because they studied thousands of patients in the trials and it has been demonstrably safe. I think the faster we get it, the faster we get to some sort of herd immunity. Especially healthcare workers, I believe should be taking vaccines.

Larry Bernstein:
You recommend that COVID patients use Listerine afterwards to reduce transmission. I don’t think many people have talked about the role of Listerine or use of a neti pot to reduce transmission. Could you just spend a second on that topic?

Dr. Ari Ciment:
Yeah, it’s great because it’s an easy thing and it could really save people. There are actually articles about it. You can look in the Journal of Medical Virology. They talk about using mouthwash as different from gargles. That’s actually a study on Listerine. I think the author’s name is Rena Cass and Craig Meyers. You can Google it, but it’s a fascinating, easy thing that anybody can do, is do a Listerine mouthwash, gargle for 30 seconds, two or three times a day, because Corona virus lives in the back of the throat. They replicate in the back of your oral pharynx.

So, it makes sense that if you could try to decrease at least maybe some of the viral load, that could decrease the transmission. Anybody who is positive, I always recommend to their family members to decrease the household transmission, to take Listerine. A more controversial topic is actually iodine rinses, which I personally do myself, but there’s also articles on iodine rinse. It’s by Samantha Frank. You could look in it, from JAMA head and neck surgery. They looked at iodine rinses and the rapid inactivation of SARS.

It’s not been a randomized double blind study, but it decreases the viral load. I’ve been doing that for eight months. I do iodine rinses personally, but it’s based on literature showing that it has in-vitro killing of the virus.

Larry Bernstein:
Perfect. Ari, Thank you.

Dr. Ari Ciment:
Thank you.


Dr. Andrew Racine — Treating COVID

Dr. Andrew Racine Transcript

Larry Bernstein:
Dr. Andrew Racine. He is professor of clinical pediatrics at the Albert Einstein College of Medicine. He’ll be discussing COVID and the patient doctor relationship.

Dr. Andrew Racine:
Thank you, Larry. I’m going to speak about three elements of the current COVID-19 situation. First, the inherent uncertainty in the practice of clinical medicine. Second, how medicine confronts this uncertainty. And then third, what those efforts have taught us during this pandemic.

The practice of medicine is an exercise in decision-making in the face of uncertainty, just like investment strategies for financial managers. Unlike investors, however, where astute practitioners may profitably exploit information asymmetries, the information asymmetries facing physicians universally diminish the efficiency of clinical decision-making, and invariably provoke anxiety in the process. Physicians come to clinical encounters with knowledge about the epidemiology and the pathophysiology of various ailments, information that is usually unavailable to the patient. Conversely, patients possess intimate understanding of their own condition, the duration of their symptoms, the effect on their functioning and their appetite for risk regarding potential interventions.

To reach the optimal clinical decision, the parties attempt to bridge these asymmetries through iterative exchanges of information, until they arrive at a mutually agreeable plan. Novelty, from any source, makes this process more challenging. What we’re witnessing now, in real time, is how this plays out in the context of a never-before seen infection that has disseminated globally in a matter of months. Because COVID-19 is a brand-new disease, there’s heightened uncertainty regarding clinical decision-making about it.

How has the medical profession addressed this? Principally in four ways. One, the application of standard scientific laboratory techniques that have been able to rapidly sequence the viral genome and understand its replication dynamics. Two, large-scale, controlled experiments involving thousands of patients that have shown us, for example, that the two new MRNA vaccines prevent COVID-19 infection in about 95% of recipients. Three, public health observations and the effectiveness of non-pharmacologic interventions, such as mask wearing and social distancing. And four, our oldest approach, that of clinical practice itself.

Iterating changes in treatment protocols over time, literally practicing medicine, has decreased mortality rates among hospitalized patients at Montefiore to the point where they are now at about a third of what they were in the spring. Which brings me to my third point. What have we learned? Well, we’ve learned that the COVID-19 infection is caused by an RNA virus that is really a very simple construct. It consists of a core RNA molecule of about 30,000 base pairs, which is just a set of genetic instructions about how to replicate a copy of the instructions, and make an envelope to contain and transport it. That envelope is merely a shell of fat, festooned with a variety of proteins, including the spike protein, which functions as a kind of key specifically designed to fit into a lock known as the ACE two receptor, sitting on the surface of epithelial cells in a variety of human tissues, most notably those in the respiratory tract.

When the spike protein key attaches to the ACE receptor lock, it opens a hole in the cell membrane, ushering the virus into the cell. Now the virus is in an environment where it’s RNA instructions can be read by the cell’s own machinery, to make more viruses.

With this knowledge in hand, all known treatment strategies for COVID-19 are designed to do one of three things. Prevent the virus from reaching its target, interfere with the cellular machinery that helps the virus replicate, or moderate the body’s own immune response to the infection. Non-pharmacologic interventions, mask wearing, social distancing, hand hygiene, when practiced consistently, limit transmission of the virus even among non- symptomatic carriers who are quite capable of unknowingly spreading the infection. These measures are cheap, readily available to all, and effective.

Monoclonal antibodies and convalescent plasma both work off of a similar principle. They target a specific part of the spike protein known as the receptor binding domain that sits at the tip of the spike protein key, where it inserts into the Ace Two receptor lock. If an antibody can get between the key and the lock, it can prevent attachment and prevent viral entry into the cell. But this only works well at a point early enough in the infection, before most virus particles can gain entry into the host cells. Nor is it particularly useful to those who are destined to limit the infection on their own.

We’ve also learned to design vaccines which, much like the virus itself, recruit the body’s own cells into making, in the case of vaccines, only the critical spike protein. So, the body’s immune system can recognize it and be prepared with antibodies and primed T-cells should the actual virus appear.

And, we’ve learned that the virus changes over time. The initial Wuhan strain mutated fairly early, with a modification to the spike protein that rendered the virus more transmissible, and rapidly became the dominant strain throughout the world. More recently, three new variants, one from the UK, one from South Africa, and one from Brazil have recently been identified in the U.S. Both MRNA vaccines, as well as the Johnson and Johnson vaccine, protect against severe disease or hospitalization from any of these new strains. This is probably because they all produce a robust neutralizing antibody response and a very strong T-cell response that appear to protect against severe disease even with these new mutations.

Finally, MRNA vaccine technology makes it much easier to tweak the vaccine design in order to meet the challenge of any newly emerging variants as they get identified. In the end, what we’ve learned in particular is that uncertainty and information asymmetries, much like the virus itself, can provoke in the scientific and public health communities a robust, defensive response that results in substantial resilience over time.

Dr. Andrew Racine QA Transcript

Larry Bernstein:
Let me start out with a basic question. You’ve become aware that you have COVID, your test is positive. You call your internist and you inform him that you tested positive, and that you’re not feeling well. You detail your condition. If you could describe a little bit about what the role of the physician is to gather information, to create an action plan. What is it the physician needs to know to advise you? And what should you be telling your physician in case he doesn’t ask the right questions?

Dr. Andrew Racine:
That’s a terrific question Larry, and I’m particularly gratified to be able to follow John and set up some discussions. Because this may get, and I’d be interested in his comments on this, this may get at the issue of probabilistic thinking versus uncertainty with respect to any given individual patient. What the physician does is he or she attempts to bring to bear what they know about the epidemiology of this condition, and about the pathophysiology of it. And to illicit certain kinds of information clues from the specific patient that is in their office, about what those risk factors might be. So, you go back to essentially the basic history and physical examination that we do, which is what kinds of previous conditions have you experienced in your life in terms of things that we know puts you at increased risk for bad outcomes with this infection? What medications might you be taking or allergies that you’ve had? What other kinds of infections have you been subject to in the past? And essentially, what kinds of behaviors are you involved in that may also influence the likelihood of you experiencing a bad outcome?

What’s your age? Where do you live and what kind of work do you do? These kinds of things also help try to give the physician some idea of, let’s say among other things, the volume of virus to which this person may or may not have been exposed. And putting all of that together in a fairly intuitive model, then the physician will come up with certain kinds of recommendations. Knowing that the vast majority of people who get this infection, particularly if they are less than 65 years of age, actually do quite fine on their own without any intervention at all. They may get sick, mildly sick, over the period of a few days, but they don’t get severely ill. Once you get beyond 65 years of age, and certainly 75 and 80 years of age, then the probabilities change quite dramatically, and then you have to really be thinking about the kinds of interventions.
So, what the physician might say, depending upon what they’ve heard, is stay home, take Tylenol, stay away from people, keep a mask on, drink plenty of fluids, get some rest, and let’s check back in in a day or so. And that’s an important thing. Because the best predictor of how someone is going to do with this infection is how they are currently doing with the infection. And to the extent that their status changes, that’s a signal to the person who’s responsible for their care, that perhaps the response now needs to change. So follow up in these kinds of instances is extremely important. Because for some of the interventions, like we mentioned, monoclonal antibodies are a good example, there is a window during which a trigger needs to be pulled. Because if you don’t do it beyond a certain point, it’s no longer effective.

As we were talking about, once you get to the point where someone has a huge amount of virus already in their cells, there’s no point in giving them antibodies to try and impede that from happening, it’s already happened. And now you’re left with trying to either interfere with viral replication, through the use of something like Remdesivir or other antivirals, or trying to dampen down the inevitable immune response of the body using steroids.
And that’s why different interventions for this infection take place, at different points in time, in any given individual’s experience with the disease.

Larry Bernstein:
One of the things you mentioned was your appetite for risk. Let’s imagine you’re under the age of 65, say you’re in your mid-50s. You come down with COVID and you’ve got a bad case, but you know you have somewhere between three to five days to make this decision on the monoclonal antibodies. If you don’t have pre-existing conditions, somehow the medical system is opposed to you getting these monoclonal antibodies. I don’t know if there’s a true sense of scarcity or at one-time, a false sense that there wasn’t enough of the monoclonal antibodies around. But let’s imagine that you were very risk averse, you just don’t want to die or be hospitalized. Should you encourage your physician to get the monoclonal antibodies? And if your physician is resistant, what other options do you have? What happens if your risk tolerance is different than your physician’s? You talk about this like we’re a team, but sometimes the team members are not on the same page.

Dr. Andrew Racine:
Well, this actually gets to the issue of professionalism in the practice of medicine. The physician-patient relationship is a principal agent relationship. And the physician, if he or she is acting according to the precepts of what medicine is supposed to be like, should be acting as an agent for that principle. Regardless, actually, for example, of issues of scarcity or not. The idea that physicians are to take into account social goods goes out the window once you cross the threshold of the examiner, because there you are obliged in a sense, professionally obliged, to be an advocate for the person sitting across from you, and to do whatever you can to maximize that person’s outcomes.

As you point out, that will change depending upon the information you receive from the patient, about their own tolerance for risk and uncertainty. And there are certain people, for example, and let’s get away from COVID for a moment, let’s use something else that some people in the audience may be some somewhat familiar with. People who have an elevated number in their prostate specific antigen. This is a a signal, if you will, of potential problems with prostate cancer. And there’s been a lot of talk about what’s the most efficacious approach to that. Some people will advocate what’s called watchful waiting. So the PSA goes up a little bit. You sit, you wait, and you see what it means. Other people say, “No, no, no, I want a biopsy and I want one right now.” Or other people will do something in between, they’ll wait and then we’ll get a biopsy.

There is no right answer for any of this. It really depends on what the patient feels comfortable with, and what the physician knows about the likely outcomes. And that may change. That may change over time, which gets back to this issue of how it is that the physician-patient
relationship is managed. Because the astute clinician understands that people will change their minds about things, and there’s nothing wrong with that. That kind of inconsistency is fine.

I’m going to give you one other thing, because this is something that actually may also speak directly to what John was talking about before. We know through a series of neurologic studies, quite frankly, that decisions that are made under conditions of risk are made using a different part of our brain than the prefrontal cortex, that’s responsible for calculations.

There’s a very famous experiment that’s been done, some people on the phone might know about it. And I’ll play it with you for a moment. So, I have a jar that has 90 balls in it. 30 of them are blue. 60 of them are either red or yellow, I don’t tell you what that ratio is. And I propose to you the following. I put my hand in the jar and I pull out a blue ball, you get $100. Or, I put my hand in the jar and I pull out a yellow ball, and you get $100. Which bet do you want? The vast majority of people, if you ask them one question, will say, “I want the first bet. I know there are 30 blue balls there. I don’t know how many yellow balls there are, I want the first bet.”

You say, “Fine, let me give you another example. I put my hand in the jar and I pull out either a blue or red ball. You get $100. Or, I put my hand in the jar and I pull out either red or yellow ball, you get $100. Which bet do you want?” Most people will choose the second, because they know there are 60 red and yellow balls. But think about that for a second, because what they’ve said in their first bet is they believe that there are less than 30 yellow balls in the jar because they prefer betting on the blue ball draw. But if there were less than 30 yellow balls in the jar, by definition there have to be more than 30 red balls, because yellow and red together make 60. And yet in the second bet, when they’re asked about that, they prefer the red and yellow
bet as opposed to the blue and red bet, which would be more consistent with their first bet. So, they do this inconsistently. Why is that?

The reason is that if you actually hook these people up to a functional MRI machine, you find that the area of their brain that lights up when they’re being asked to make these decisions is not the area of their brain that makes calculations. It’s much deeper structures. The amygdala, the hippocampus. Very primitive areas of the brain that are responsible for fight and flight reflexes. When we are asked to make decisions on the basis of uncertainty or risk in that way, and I will leave it to John to distinguish these two, we don’t ordinarily use our brains to calculate that.

And this gets back to what I was saying before. So how do we overcome that? The way we overcome that is we do structured experiments that essentially re-impose the prefrontal cortex part of our brain. Re-impose the activity of that part of our brains to bring to bear on the decision making. We do experiments with people, we do observational experiments, we do experiments in the lab, all of which are designed to get us away from our amygdalas and our hippocampus.

Having said all of that, once you get into the exam room and you’re having a conversation between a physician and a patient, you’re left with decisions that oftentimes are not based on calculations on probabilities, but are based on fear, anxiety, the things that people normally confront when they feel vulnerable. And that has to be taken into consideration. What the physician can do is they can bring to bear the probabilistic information that’s available, but that may not be the governing thing that makes the decision at the end of the day, and that has to be respected.

Larry Bernstein:
Andy, I had some abdominal pain 15 years ago, and I went to my doctor and he ordered a CAT scan, and they were checking to see if I had appendicitis. It happened to be that Renee Yap was the radiologist on call, and she had gone to my high school and had been a friend of mine in college. She took me into the back room to look at my CAT scan results. And the first thing she said to me is, “My God, do you not eat any vegetables at all?” And then the second thing she said was, “It looks like your appendix is inflamed, but I don’t know. I don’t think we need to do anything.” I said, “Thank God,” and I went home.

The next Monday afternoon, she called me and she said that every Monday morning in the radiology department at Northwestern University, they have a conference to discuss interesting cases. She said, “Larry, I put your appendix up on the wall, and I asked for a vote whether or not it should be removed. And at the end of the vote, it was five to five. Five said it should stay in,
and five radiologists said it needs to go.” I said, “Good God, what should I do?” She said, “It’s a push. Anything you want. Half the radiologists would agree with you, whatever decision you want.”

How should a patient analyze that information when they hear something like that?

Dr. Andrew Racine:
Yeah. Look, it’s interesting the way you bring that up, because oftentimes the way that gets resolved in the context of the doctor patient relationship is the doctor presents what they know, the probabilities, et cetera, et cetera. And then, and this happens to all of us who practice medicine, it’s happened to me a bunch of times, the patient says, “Well, if this were you,” and in my case, because I’m a pediatrician, “If this were your child, what would you do?” It’s a curious question, quite frankly. The implication is somehow that the advice that I would give a patient is different than what I myself would think would be the best thing. Which is not the case. But what it does is it speaks to what patients are looking for in this relationship. They’re looking for reassurance that they are making the right decision.

And again, this gets back to some of the things that John was talking about. Whether or not your appendix was taken out, no one at the time the decisions was being made, could predict with any certainty as to what would or would not happen. Again, this gets back to what I was talking about before though. Because clinical medicine, in that sense, is forgiving, so long as you don’t lose sight of the ball, so long as you don’t take your eye off what’s happening. Anybody could look at you and say, “Okay, right now at this moment, on Thursday at two o’clock in the afternoon, we could go either way. Let’s check back at eight o’clock tonight. See how you’re feeling, see what your appetite’s like, see if you have any fever, see if your abdominal pain has changed.

These are the things that make the decisions more accurate over time. Because, quite frankly, pathophysiology is not rocket science. The body does what it does in predictable ways. And if you’ve seen enough patients over enough encounters, you begin to anticipate those things. So while it seems somewhat arbitrary maybe, and mysterious, from the patient standpoint, from the provider standpoint, as long as you know you have access to that person over a timeframe that you can monitor, you can feel more confident over time that you’re not going to make a wrong decision, if you will, or miss something with regard to the clinical evaluation and the condition you’re confronting.

Now, does it happen that you’re thinking that it’s X and it turns out to be Y, because Y is one of the things you hadn’t considered? Yes, that does happen. Sometimes you bring in other people, other sets of eyes, particularly when things don’t go according to the way you might predict. But a lot of it really has to do with continuing to accrue information. It’s like basic probability theory. You make a decision on the basis of your priors, and then you add more elements of information over time, and that changes your decision about what the probable nature of something that’s going to happen is. You just have to continue to do that though.

Larry Bernstein:
Andy, thank you so much.


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