The Peter Attia Drive - #102 - Michael Osterholm, Ph.D.: COVID-19—Lessons learned, challenges ahead, and reasons for optimism and concern

Episode Date: March 31, 2020

In this episode, Michael Osterholm, Director of the Center for Infectious Disease Research and Policy at the University of Minnesota and author of Deadliest Enemy: Our War Against Killer Germs, provides an overview on the COVID-19 pandemic in regards to what has happened to date, what we’ve learned about how the disease spreads, and his optimism and pessimism about what potentially lies ahead. Michael gives his take on the true case fatality rate, why it differs around the world, and which underlying conditions, such as obesity, impact risk of severe illness and death. We also discuss the outlook regarding vaccines, repurposed drugs/antivirals for treatment, and Michael’s growing concern about supply chain limitations with respect to drugs, vaccines, n95 masks, and testing kits. We discuss: Recapping the brief history of COVID-19 and what potentially lies ahead [2:15]; Some positive news about immunity and reinfection [10:45]; Case fatality rate—The challenge in finding the true rate, difference by country, and the impact of age, underlying conditions, and obesity [13:00]; What has to be true for less than 100,000 Americans to die from COVID-19? [24:30]; How do we best protect healthcare workers? [29:45]; Concerns about testing capability—Reagent shortfall and a supply chain problem [39:30]; Vaccines and antivirals—The outlook, timing, and challenges [47:45]; Long term health of survivors of COVID-19 [56:45]; The impact of comorbidities—Diabetes, obesity, and immunosuppressed patients [59:30]; Understanding R0 and how the disease spreads [1:01:30]; The challenge of forecasting with so many unknown [1:08:00]; What explains the difference in cases and fatalities in different parts of the world? [1:14:30]; Repurposed drugs/antivirals being considered for treatment options—any optimism? [1:16:45]; A parting message from Michael about what lies ahead [1:18:30]; and More. Learn more: https://peterattiamd.com/ Show notes page for this episode: https://peterattiamd.com/michaelosterholm Subscribe to receive exclusive subscriber-only content: https://peterattiamd.com/subscribe/ Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter/ Connect with Peter on Facebook | Twitter | Instagram.

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Now, without further delay, here's today's episode. Welcome back to another special episode of The Drive focusing on COVID-19. My guest today is Dr. Michael Osterholm. You may have seen Michael on the Joe Rogan podcast a few weeks ago. I saw him then and was immediately impressed. Reached out to him and asked if he'd like to come on our show, which he graciously agreed to. Michael is the director of the Center for Infectious Disease Research and Policy at the University of Minnesota. He's also the author of a book that in many ways foreshadowed this. The book is called Deadliest Enemy, Our War Against Deadly Germs. And in that book in particular, he foreshadows

a lot of what we're going through today. Mike and I in this discussion talk about everything from our best understanding of what's happening in the United States with respect to the spread and the slowing of the virus, what he's optimistic about, what he's pessimistic about, what he thinks the end state looks like, and what you'd have to believe is true if that is to be altered. We also get into the weeds a little bit on some technical things around supply chain limitations with respect to drugs, with respect to masks, with respect to vaccines. There are a number of things we discuss. And again, I think just for the purpose of simplicity, rather than get into a laundry list of everything we talk about, I think if you've got this far, you're probably interested

in hearing it. So without further delay, please enjoy my conversation with Dr. Michael Osterholm. Mike, thank you so much for making time to sit down with us for some time today. And again, I want to thank you because I just know that you are constantly being bombarded by requests and there's sort of a challenge you have to deal with, which is on the one hand, you want to be able to do your job, but on the other hand, it's somewhat important for people like you doing your job to be able to communicate with the rest of us what you're seeing and more importantly, what the implications are and what can be done about it. Well, thank you very much, Peter. It's very the implications are and what can be done about it.

Well, thank you very much, Peter. It's very good to be with you. And I think that it's venues like yours that serve a very important role in getting information out today. Far too much of what we deal with is in soundbites. It's in three-minute segments. And I think that's really hard to convey the complexities and the overall short-term, long-term view of what's happening here. So I'm really pleased to be with you. Thank you. Well, yeah, you're in the right spot. We're not fans of soundbites here, so we'll get right to it and we'll get deep. So let's start with kind of the 30,000-foot view, which is when we sit here today recording this on March 30th, it feels like an eternity ago that you were on Joe Rogan's podcast doing what I thought was just an excellent job of giving Joe and Joe's audience an overview of

what we knew at the time, what we didn't know at the time, what the concerns were. What do you feel more optimistic about relative to that time, which has probably been three weeks? What do you feel less optimistic about? Well, first of all, I think that it's important to understand, as Lewis Carroll once said, if you don't know where you're going, any road will get you there. And I think that one of the things that I've been very concerned about is we don't really know where we're going. And that's not because the virus hasn't given us lots of clues. Just very briefly, to take a step back, just to remind everybody where we've been, we've been following this situation very closely since the end of December last year.

I have been very actively involved. I was involved with the SARS investigation in 2003, very involved with MERS on the Arabian Peninsula, and have obviously done a lot of work in influenza pandemic preparedness and planning. And so when this first happened and we saw these cases in Wuhan, it was really to us, oh my, here comes another SARS or MERS-like experience, which actually, in retrospect, those were the easy ones because patients were not becoming highly infectious till the fifth or sixth day of illness. You could identify them quickly, get them into appropriate isolation so you didn't infect others, and we could follow up on their context. But it became very clear to us by the second week of January, what was happening in Wuhan was not SARS and MERS. This was acting

much more like an influenza virus in terms of transmission dynamic. Lots have spread very quickly. And so on January 20th, we actually put a document out saying that this was going to be a worldwide pandemic, almost two months before the WHO did. We were convinced we would see spread. On February 3rd, we put out an additional document that said it would probably take until the end of February or early March before we would see cases around the world in any meaningful way because it just, the transmission of this virus was such that we had a sense even then probably had an incubation period of about five days from infection until the onset of symptoms. And that if it had an R0 or the number of people that you transmit on an average basis to of about 2 to 2.4. You go from

1 to 2 to 4 to 8 to 16 to 32. And knowing that the cases in China were largely about 80% were not seeking medical care, they were sick, but it wasn't sufficient. We said, you know, it'll probably be into February. Well, sure enough, it was. We also put out a document in mid-February saying that when it did start to show up, it would probably hit hotspots, metropolitan areas, because of number one, that's where most of the transportation communication of people from China to the rest of the world would be. Second of all, that's where the population density was high enough so that you would actually see this amplification. Sure enough, as you know now, that's exactly what we've seen. So having said that, it seems that we kind of know what's going on here. And I as you know now, that's exactly what we've seen. So having said

that, it seems that we kind of know what's going on here. And I'll say right now, we're done with that. I don't know where this virus is going to go next in terms of how long it'll be around. You can make assumptions of what we see with influenza. I think some of those are helpful, but I don't think that they're necessarily definitive. People talk about seasonality. I remind people all the time that we don't see that with the other two coronaviruses. SARS was not seasonality just because it ended in June. It was in a situation where we first understood we had a problem in February. It took us literally several months to figure out this infectivity period, get people isolated,

stop transmission, get palm civets out of the markets of the Guangdong province, and then it ended it. If you look at MERS, and I've been there standing outside of a hospital in Abu Dhabi when it was 110 degrees and transmission was going on just fine, thank you. It was not at all being halted by the weather. And because, of course, camels are not going to be put down as such, it just continues to transmit on the Arabian Peninsula year-round. And our primary means of dealing with it is just making sure that people don't transmit in the

hospital setting. So if you take that, but also take influenza, because this is where people come back on the seasonality piece. And they say, well, you know, it's probably going to be like influenza. We forget that while influenza transmits seasonally in the winter of each northern and southern hemispheres, it transmits year round in the tropics, never stops transmitting. You look at the last 10 influenza pandemics over the last 250 years, two started in the winter, three started in the spring, two started in the summer, and three started in the fall. the winter, three started in the spring, two started in the summer, and three started in the fall. And every one of them had their big peak six months after the original cases showed up. In 2009, with H1N1, it showed up in mid to late March, and we had a big peak mid-September to

mid-October in North America, and it was still warm. So I don't know what it's going to do going forward, but that's where when you ask me good news, bad news, I have every reason to believe that it won't stop transmitting in any meaningful way until we get 50 or 60 or 70 percent of the population infected. we are going to have to deal with those cases unless we can suppress them. And we can talk about what the implications that are. If we suppress them, meaning that we do what Wuhan did and the Chinese in Wuhan did of basically shutting down everything in the most draconian manner we've ever seen in modern quarantine history, that means we're going to shut down our country. We'll shut down the economy in any meaningful way. And not just about dollars and cents. Who's going to pick up the garbage? Who's going to basically be firing police? Who's going to do all the things that we count on? I'm pessimistic about the fact that we don't have

an easy way out. I like to say that right now we either suppress this and have this implication we talked about in hope that we can suppress it long enough until we get a vaccine, which I don't think will be any sooner than 18 months, or we let it go willy-nilly and we will bring down healthcare systems, many thousands to millions of people will die and our healthcare systems will collapse, or we try to thread the rope through the needle and hit the middle. How do we find a way to have those people who are at lowest risk of having serious disease problems who are at the highest risk of serious disease problems, who are at the highest risk of dying, be in our workforce, be more public, and handle the issues. So if we can do that, that's good news. If we can't, the rest of it's pretty bad news. Mike, the numbers you

just rattled off as sort of potential projections, is that worldwide or was that a domestic figure? That's in the United States. I mean, if you look at, you know, do the math and just a little over 300 million people, if you're talking about 60% of those infected, you're talking 170 to 175 million people. If you talk about 80% of those having relatively milder illness, now you're talking 20% that are going to have some illness that will likely require hospitalization. If you then take that down to even 1% or 2% of those who might die, you can just do the simple math and you realize we're talking about millions.

And that's what I don't think people understand yet is that this virus is going to keep going. It is very much like an influenza virus in that regard. It will go until it finds enough immune people that shut it down, meaning they don't let transmission continue. And that's what I don't think people are prepared to understand yet, is that they think that these waves are going to happen over the next two to three weeks and then we're done. Just remind people that right now in China, here we are, the end of March, this clearly was present in China in mid to late November. And we're still seeing transmission inside in China, even with these draconian measures to limit transmission.

There are people in the Wuhan area who've not been out of their house in 15 weeks, and yet we still see cases occurring. So this is going to happen here where it'll be months and months potentially of transmission. And I hate the thought of the fact that one of the primary ways that may limit that transmission is just enough people get infected and develop immunity. I might add one good news piece on the immunity piece. This is an important one. I think we can say with more certainty that there probably is durable immunity, at least for the short term. And what I mean by that is there was a study completed and published last week using macaque monkeys, and they infected a group of them with the virus. They all came down

with kind of the classic coronavirus-like illness. They then waited until they fully recovered. They re-challenged them a month later, and all of them were protected against un-re-challenged. None of them got infected again. And just to make sure I know what the re-challenge implied, were they PCR negative, IgG positive, IgM negative? Yes, they were. I can't say they're IgM negative. I'd have to go back and look at that. But they were definitely IgG positive and PCR negative.

Yep. And so we have evidence clearly. And they didn't just do PCR. They did culture too. So they actually were actually looking for the actual virus. In other words, they weren't just looking for surface protein. No, no, exactly. And so I think this study really gave us more hope that there really is durable immunity,

at least in the short term. I can't say it's going to be years and years. I know that if you have short-term immunity, oftentimes that bodes well for a long-term immunity picture. So that's actually an important positive step, that these are going to be people who will be, as I call it, kind of the human immunologic rods in the virus reaction. They will slow it down. And today, they could be the people that could be out there in the world, not worried about

getting infected, and also would not infect others. Yeah. I was having a discussion with one of the members of my team today and anyone who's ever worked with me knows I play this game called the what you have to believe game, which is sort of a way to probe the limits of what biology could tell us. We got a little deep in the weeds on this and I said, look, imagine for a moment two extreme scenarios. Scenario one is this particular coronavirus, SARS-CoV-2, is a total nothing burger. It's just another respiratory virus. It's getting a lot of attention right now, but the reality of it is when it all plays out and

everybody gets infected, it's going to have a mortality that's equal to or less than influenza, et cetera, et cetera. If that is true, how would you explain the current data through that paradigm? And we walk through it. But at the other end of the spectrum, I said, what if it's worse? What if it's the virus that could wipe our civilization off the map? Again, I don't think either of these extremes are correct, but it became a good illustration of what would have to be true. What do you have to believe if SARS-CoV-2 and COVID-19 will eradicate our species? Well, you'd have to believe the following. One, there is no long-term immunity. Two, each successive infection is worse than the previous one. And three, no effective treatments will be developed. If those three things are true, this would be the virus that eradicates our species. Fortunately, I don't believe any of

those are true. And you're making a very compelling case for at least the first of those not being true. And by the way, they would all have to be true for the scenario I just described. So I take that as some good news. I do want to ask, I mean, it literally just came out, I think 20 minutes ago. Did you happen to see that Lancet paper that came out going over the revised numbers in China in terms of case fatality? I have not seen that one. I have seen a similar one, but help me, maybe it is the same one I've seen. Well, so this one basically took the original case fatality rate of 1.38%, but followed it up and added a whole bunch of more people to the denominator that were previously in the unconfirmed bucket. So you took a bunch of people that were unconfirmed, you've now gone on to confirm them. And the case fatality rate now looks to be 0.66%. Again,

largely on the basis of not subtracting mortality, but adding denominators. Does that surprise you? And what do you think the CFR looks like if one could truly measure all the people that are in that category of having an infection, but not being either clinically significant enough to warrant attention or simply falling through the cracks due to socioeconomic factors, testing limitations, et cetera? Yeah. Let me take two pieces of information and go at that. First one is you're absolutely correct. It's a numerator denominator issue. Now, the challenge I think in adding to the denominator is that you can add quite a bit to that and drive the overall case fatality rate or CFR down. But what we're also missing is the number of people in the numerator. And our contacts in

Wuhan during that time period who were pretty reliable actually concluded in their assessment that probably six to eight people were dying every day outside a hospital that were not being counted, meaning that they were not being tested. And if you weren't tested, you weren't counted. And so think about this. If you have a case fatality rate of 1%, one over a hundred, and you suddenly add a hundred more people to that, you now have a case fatality rate of 0.5 per 100, okay, half of what it was. On the other hand, if you have that same 200, you added 100 more, doubled it, but you also add 10 more people who died who weren't counted, only 10. Now you're looking at 11 over 200, and you're now at 5% plus. So the numerator is actually more sensitive in terms of impacting the rate than is

the denominator. And so one of the challenges that we've had is what is that overall numerator and how many cases were missed? These have been well written up, these cases. So I don't know what it is, but let me tell you what I think is important now. We've known this, I think, from early on in China, that these comorbidities we talk about, these other underlying conditions play a very important role. We've known about that with influenza for years, that comorbidities can affect you in several ways. One, of course, is the occurrence of acute respiratory distress syndrome, or ARDS, and the cytokine storm picture. In some cases, there appears to be kind of a myocarditis-type picture that can occur. And of course, there's

always secondary bacterial pneumonias, but I'm not even going to count those in there because that, in a sense, is something we can often deal with with antibiotics. But what happened in China was, is if you look at the overall case fatality rate by age, we saw this exorbitant rate in those over age 65 who are male. Well, if you look closely in China, almost 70% of men over age 65 smoke and less than 2% of women over that same age group. So right there, you could have a impact on that situation because smoking has always been associated with a worse outcome with these kinds of viruses. And ironically, the other risk factors, essential hypertension was also seen as a risk factor for bad outcome. But beyond that, there

wasn't much else. Obesity, which has been highly associated with bad outcomes, is actually quite rare in the older population of China. It's primarily under age 30, where they are starting to see a real epidemic there. Well, okay, let's fast forward to the United States. We are now getting data out of New York. We're seeing an increased number of severe illnesses and deaths in people between the ages of 25 and 50. And almost to a T, the risk factor appears to be obesity. 45% of our population over age 50 is considered moderate to severely obese today. This, that one risk factor. On top of that, renal disease has been shown in the past to be associated with bad outcomes. 700,000 Americans are living alive today with end-stage renal disease.

And when you start adding up all these comorbidities that we uniquely have, in part because of lifestyle or because we happen to have a healthcare system that's able to keep us alive and with the right drugs and so forth. So we don't really know when you put this virus here, what it's going to do. A good example of that is the difference between Korea and Italy. Korea right now has actually just climbed over 1%. It had been below that. And part of that was a function is the big outbreak that they initially had, that they worked up extensively in the thousands of people was in this religious sect. The median age of that group was 43. So, you know, right there, you had a younger population that surely would have had a

lower case fatality rate. You go to Italy, and right now, about 80% of their cases are over age 80 with underlying health problems, and they have an 8% case fatality rate. So I think that one of the things we're going to find with case fatality is going to be really country by country dependent. It's going to matter where the virus is circulating and what age group, and it's going to matter in a large part as to what the underlying health conditions are. In China, there's almost nothing ever called a nursing home or long-term care facility. People are cared for in the home. In the United States, right now, we're sitting in a powder keg of long-term care facilities, for which for years, we've neglected them in terms of infection control. I can't tell you how many long-term

care facilities we have right here in Minnesota. They couldn't find one in a 95 in their house that they needed to, not one in 95. I think that we actually stand the risk over the course of the next several months of seeing it probably one of the highest case fatality rates in the world right here. That's the first point of what I would say. The second part though, you deal with this every day, every flu season, you are constantly confronted with this increased occurrence of illnesses, this increased occurrence of illnesses, et cetera. And even during the 2009 H1N1 situation, even in a bad H3N2 year in older people, nobody, nobody reports what's happening, what's happening now in places like New York and Detroit and Atlanta and Seattle.

And so I think that what's happening here actually matches up with the severity that we believe that it really is occurring. I've come to the point in my old age that when something walks like a duck, looks like a duck, and quacks like a duck, I think it's probably a duck. What would you put on the floor as the estimate for the CFR in a fully diluted sample? Do you think that there's a scenario under which the CFR is 0.1%? Again, fully diluted, meaning you actually know all the infected people, or do you think that that's really just a pipe dream and the best case scenario is closer to 0.4, 0.5? That's a pipe dream to me. And I think it's going to be in the 1 to 2.5 range. And I think that it's going to be heavily influenced by those who are over age 65,

70. And I think it's going to be influenced by the frequency of obesity in the younger age group in that regard. Mike, I've never wanted someone to be wrong more than I want you to be wrong, because if the CFR is 1% to 2% in the United States. And you're right about the spread of this virus. The implication of that is more Americans will die from this infection in the next 12 months than will die of all other causes combined. And I am absolutely on your side with this one. You will get no argument from me. I hope I'm wrong. I would welcome that opportunity to be wrong. I just look at what's happening right now. I look at indirect indicators. A good example right now, today, the New York Police Department reported out over 900 police officers in New York

are infected right now. 13% of the workforce is out. They just had their third death today in police officers. And when you start looking at that, and this is just getting started, when you start looking at that and compare that to a bad flu season, which you and I have to deal with far too often, with a vaccine on top of it, by the way, and we know what happens, look at this one. This one has that potential, I think, to be in the one to two. I don't think this at all is going to be like 1918 because that was so unique in how it took out 18 to 30-year-olds. This one's not doing that. This is going to clearly be associated with age and underlying health issues. But in some ways, we are a population that is highly vulnerable

because of all the other lifestyle and health conditions that occur in our group. So I think that that's where I'm very concerned about it and would agree with you 100% of what you just said. And I just say on a given week in New York City, in the past, 100 people die a day in New York. Right now, we're averaging close to 150 a day just dying from COVID-19. Think about that. If we're going to play that what if game a moment ago, what if this is something that is quote unquote only going to result in fewer than 100,000 lives lost in the United States, which again, still seems for most people struggling to understand what non-linearity means. We're a little over 2000 deaths today.

So even to propose that this could be capped at 100,000 seems very extreme. But I think you would agree that if only 100,000 Americans were to die before this thing was completely contained, you would consider that a victory. Absolutely. What has to be true for that to happen? What are the things that have to happen scientifically, policy-wise, in terms of personal behavior responsibility? What are the suite of things that must be true if that number is to stay below 100,000 in the next year? I think two things. One is we have to basically suppress transmission as much as we can, which I don't think is doable. And I say that because it would mean a Wuhan-like shutdown.

And I just don't think as a country we can sustain that. I think even, and I don't want to equate this in dollars and cents. I had an op-ed piece in the New York Times over the weekend in which I said, this is not a choice between saving lives and costing the economy. We have to look at, it's a combination of both. And we need people to carry on every day. I mean, I look at you. I don't want anything to happen to you for a lot of reasons, but one of them is you're a very key healthcare provider. You got to do your job. You can't shut down. We can't shut down. I

mean, when's the last time you saw anybody do remote work to pick up garbage? If you live in New York City, guess what? Elevator operators, maintenance people are really important because if you can't get up to the 40th floor, you shut down a part of the city that's really important. So I can go through a laundry list of whether it's foods, you know, people who provide our food, et cetera. So we've got to preserve that part of it. But at the same time, I worry that what's going to happen is an acceleration of deaths due to the failing of the healthcare system. Right now, keeping people alive on ventilators, having intensive care medicine does make a difference. Not for every case, but it makes a difference. But once you go off the edge of the cliff, where it's now no longer

do you have a ventilator available, you have to wait for someone to go off a vent and you have to make a choice to take them off. When you start running out of the critical supplies, one of the things that we've been working on in our center for the last year and a half one of the things that we've been working on in our center for the last year and a half has been looking at very acute critical drug shortages, meaning these are drugs that you need right now or in the next several hours or people die. What's on the crash cart, what's in the intensive care unit, what's in the ER. We came up with a list of 156 drugs, which we have vetted with all the major medical groups, the intensivists, et cetera. all the major medical groups, the intensivists, et cetera. Of these 156, all of them are generic,

all of them. Of those, almost 85% are made outside the United States. And of those, many were made in China. We are just beginning to feel the severe supply chain collision that's going to occur here in the next several weeks with increased number of cases of severe disease and these drugs that we need. Because in China, the supply chains, which were still thin, were filled just before this outbreak started. And there's about two to three months worth of supply in the chain, but there was nothing that came in the backside of it. So we're just about done. So if you add this on, Peter, this also then means now you got to deal with that situation on top of it. And if our healthcare system can't take care of these people, or we have acute shortages of what we need to provide the care we have been providing, then the case fatality rate is going to go way up.

It's going to go up. And that's, I think, a real challenge. the case fatality rate is going to go way up. It's going to go up. And that's, I think, a real challenge. So just to be clear, you're not saying that we're going to run out of, pick your favorite candidate drug that I want to eventually talk about with you, you know, remdesivir versus hydroxychloroquine, et cetera. You're saying epinephrine, norepinephrine, vasopressin, paralytics, the type of medicine we all take for granted that you need to run an ICU. But even take something as simple as antibiotics. When you're sitting in an ICU for three and a half weeks, the chance of developing a nosocomial infection as a result of being there-

It's pretty much guaranteed. It's almost guaranteed. So if you don't have the antibiotics anymore, guess what? 85% of all of our key antibiotics right now are made outside the United States. Ironically, you know, the two areas that have the most production capability, China and the Lombardi region of Italy. Can you imagine that? You couldn't make that up. You couldn't make it up, but you couldn't. And so, I mean, there's something we're looking at. So I think that, you know, the question is relative. If we had ideal intensive care availability, we could maintain the system.

We could take that kind of that spigot of cases and regulate them enough so that they didn't overflow the healthcare system. They just appeared. I like to say, if we have a hundred cases of the disease today and they all hit the healthcare system, that's one outcome. What if you have a hundred and they hit the healthcare system 10 a week for 10 weeks? That's one outcome. What if you have 100 and they hit the healthcare system 10 a week for 10 weeks? That's another outcome. If we could do that, if we could thread that needle with our rope, then we'd be okay. But I don't think we're going to be able to do that. Do you think we have a pretty good handle on what it's going to take to protect healthcare workers? Do we understand what amount of PPE is necessary first and foremost? And then secondly, of course, can we

meet that need? Can we meet the demand of that? Starting with the first question, do we actually know what it takes to protect doctors, nurses, respiratory therapists, and everybody who works in a hospital from the cafeteria to the parking garage? Yeah. I think we know. I don't think we talk about it very well. And we have people who are in denial about it. I've spent my career working on both coronaviruses and influenza. I can tell you we have absolute certainty today, no question about it, that influenza virus is in part transmitted by aerosols. These are the smaller particles, smaller than five nanometer particles. And people assume when we talk about airborne transmission, we're talking

about something that's many, many yards away. And they actually forget that aerosols are produced just where droplets are, right in that first six feet area. And so if you're that close, if you have a surgical mask on, you surely can do a lot to minimize the number of droplets you come in contact with. But that doesn't take into account the aerosol. Where there's droplets, there's aerosols. Where there's aerosols, there may not be droplets, but people have assumed it's droplets or then it's aerosols somewhere else. And so I think from a respiratory protection standpoint, one of the challenges we had in China with well close to 4,000 healthcare workers infected. Right now in Italy, there's well over 5,600 healthcare workers who have been infected. Now, some of them obviously got infected off the job, but many of them were on job. And respiratory protection was a key factor in each one.

sad that there are going to be many healthcare workers who are going to risk their lives to help with this who will not have N95 respirator, which they need to have, because we just don't have enough. We won't. And when I keep hearing about this additional production, the White House continues to talk about that. They never give you the numbers of what we estimate we'll need versus what's being produced. And it's so far short, it's not laughable because that would imply something funny. There's nothing funny about it. But the bottom line message is that we're going to have a lot of healthcare workers who are going to be exposed and infected with this virus because of that. What is the number, Mike? What would we need? I don't know. I think this is where, again, we have a PPE challenge here, particularly with N95s, that was even

much more severe than they had in China. Or to that extent, in Italy, they did several unique things, which I don't know if we'll do here. You may have heard, but in several of the really high volume wards in Milan, they had COVID-infected healthcare workers working. If they weren't that sick, they were working. They went in without masks, et cetera, because they didn't have them. And so I don't know what we'll do here, but I do believe we'll have a real challenge with

this. Now, some will say, well, and this is what I find very frustrating is we have to stick with the science. And what happened was CDC, to their credit, about two weeks ago issued new guidelines for the use of PPE, respiratory protection. But what they said was, if you don't have N95s, then use masks. But a number of administrators and some scientists have come forward and said, CDC changed their recommendation saying you don't have to use respirators anymore, you can use masks, meaning it's just droplet. That's not what they said. And so I think that today for a healthcare

worker, they just at least have to know what they're getting into. I think many of them will still go to work. I mean, the camaraderie, and you know what it's like to be in that kind of setting. These are some of the most amazing heroes in the world. We don't send our soldiers into war without some kind of protective equipment or without bullets in their guns. We send healthcare workers into this viral battle and we're going to be sending them in without bullets or without protective equipment. And that to me is really sad, but that's what it's going to have to take. That's going to be a big question as to what happens there. So really we have a problem on multiple fronts. We have a problem on the, on the supportive drug front. We have a problem on the treatment drug front, which I want to come

back to in a moment. We have a problem on the people who are going to administer care. We potentially have a problem on the number of ventilators and actual beds, et cetera. So is it a largely irrelevant academic exercise to understand which of those things becomes the first failure because it varies so much presumably by city hospital geography that it ought to be an all hands on deck for all of them? I mean, is there a model here where we pick the 10 cities that are either in the throes of hell or we know are about to be, and we start relocating healthcare workers to those areas if that's the thing that we believe is going to be the bottleneck first. Of course, that would only make sense if you could provide them with the necessary PPE. Otherwise, you're losing your soldiers in battle unnecessarily

without an appropriate risk to benefit trade-off. How do we think about this? I mean, I haven't spent a lot of time truly thinking about this at the full macro level of what the White House would hopefully be thinking about this, but I mean, what is the model? What can we learn from the successes and failures of any other pandemic? Well, first of all, let me just say you articulated it beautifully. You hit on every major piece. Let me just give some kind of relevant information that'll give you a sense. Right now, the largest manufacturer in the United States of N95s is 3M. They can produce 35 million N95s a month. They're trying to ramp that up to get maybe 5% to 7% more out of their machines, okay? You just don't build these machines overnight. So even when you hear other companies talk about how they're going to double or triple

whatever production it is, be very skeptical because these are machines that are really very, very sophisticated pieces of equipment. I mean, for example, with an N95, most people don't realize that piece of white in front of you is not paper. It's a matrix that was actually poured and dried. And it has a unique electrostatic charge on it, et cetera, so you can get air through but not virus. It's a very sophisticated thing. Well, they've produced $35 million a month. They've been doing it since late January. And we met with them and said, this is going to be a pandemic. There's one hospital in New York alone, just one, that used $2 million in 95s last month just one, that used 2 million N95s last

month in that month, 2 million in their institution. Now, you start to do the math where we have basically about 35 million of these in the strategic national stockpile. That's it. You start looking at the volume we'd need of 400 million or more of these N95s to get through the first couple of months. And you start looking at the shortfall. That's where I have a problem is just, let's just be honest, okay? I'm not trying to blame anybody. We're all to blame, everybody. Why are we so ill-prepared? But healthcare workers have to know. A statement I made earlier about one of the former defense secretaries said, when you go to war, you can't go to war with what you want. You have to go to war with what you have. And so to understand how do we best protect healthcare workers, I think this is a key.

And let me give you an example. If we can't protect them because we don't have N95s, what are the other things you can do? One is we should start forming wards, large wards, you can do. One is we should start forming wards, large wards, where basically we have 18 or 20 patients on one ward, and you never leave the contaminated zone. And at that point, rather than doffing, donning outside every room and having to throw that away, what do you do? Second of all, what can you do to reuse these? We're publishing an article this week on our website with 3M support, and I mean, not financial, but their intellectual support of what are the techniques we can actually use that will maintain the integrity of these N95s, but they can be reused so that we can decontaminate. We're working on that right now. Next is what can we do to get

infected healthcare workers back? If I had to ask right now for one gift we could give healthcare workers is serology. I'd like to test as many healthcare workers as I could for antibody and having the discussion we just had on the ability to know that somebody's likely protected, then I would know also that these are the people the safest to put back into harm's way. If we did a lot of things like that, I think we could really mitigate the risk for healthcare workers. But what we can't do is just administratively say, well, the CDC has made this recommendation, ignoring that there are things we must do and can do. And you and I both know that this is a numerator denominator world

we live in when it gets to rates, but it's a numerator world when that person that dies is your colleague, when that person is somebody who worked for you, when that person is somebody who day after day was there with you, bedside, holding hands, doing the kind of skilled work. That is so tough on these people. And so we also have to understand the mental health issues. And if we neglect that, I mean, I already know healthcare workers who literally go home and cry all the way home to work after they just finished another 14-hour shift. And I think that's another area that I've not heard anybody really talking about much, is this is just like battlefield trauma. We've got to start helping them right now. If we're going to maintain three or four or five

months worth of activity here, we can't count on these people to do this day in and day out with more help. Protect them first, support them second, and understand them and care about them third. And they all have to be part of the picture. Mike, I want to go back to something you said a second ago with respect to testing. Do we have a sense where we are now? I mean, it seems that we've done probably in the neighborhood of 800,000 tests in the United States in total. I don't know the breakdown of how many of those are PCR versus antibody, but does that sound about right to you? It does. Absolutely. Yes, it does. Yep. Okay. So tell me the status of PCR. Is Roche providing the majority of these tests?

PCR. Is Roche providing the majority of these tests? Yeah. I actually commented this also in my op-ed piece in the New York Times. Again, if there's an operative set of words in this whole entire experience, it's supply chains, supply chains, supply chains. Just like in real estate, it's location, location, location. We have changed our world. In 2003, when SARS occurred, China was not a big player in manufacturing the world. Supply chains weren't that critical to what happened in China. Well, it turns out today, supply chains are everything, including for testing. And I'll add the perfect storm here. One, the world basically is on fire. Everybody wants these reagents for whether it's PCR, whether it's antigen detection,

whether it's serology. Number two, guess where a lot of the reagents were being made? China. Number three, now we bring those two together and we're encouraging people to even do more testing. And you know what? Within a couple of weeks, we're going to actually see an implosion of testing. Right now in Minnesota, we are so limited in our public health lab to test. If we don't have more reagents in tomorrow, we're done. We can't test anymore. Commercial companies have been putting together great packages to sell for testing, but what they haven't given you is how deep is their inventory of resources for reagents, and they're not. It used to be we filled the reagent pool with a garden hose. Then we realized we needed a fire hose, and now we needed a damn water tunnel,

and we're not going to have it. So it's just at the time when we need more testing, we're actually going to, and I see these people get on talk shows and they sit there and say, oh, we'll just test our way out of this. They don't have a clue about a supply chain issue. And so I think this is a huge issue that you raise. And it's one that we're going to do less instead of more. And that seems counterintuitive, but it's what's going to happen. So based on that, the idea that we should hope for the best scenario where everybody gets PCR to detect and then antibody to follow. I mean, that's a pipe dream if we're going to be reagent

limited. Instead, it's going to be a bit of a pick your poison. And if you're lucky to get any test, if that's the setting, which it sounds like based on the reagent shortfall, we're going to get to that place. What other methods can be used? For example, could we rely on temperature changes? Can we rely on any other sort of biometric as a way to take patients who are suspected positive, but not yet confirmed and enact policy around that? This is where we're going to get creative. And this is ironically where things like 1918 are instructive. We're back to the future, you might say. First of all, we want to know when the virus is in our communities and when it's doing harm. And we have a system in this country called influenza-like illness surveillance or

syndromic surveillance. We have set up in a whole series of randomly chosen physicians' offices around the country. And we survey it every week to every several times a week during the flu season to give us an idea of, you know, if you have this constellation of signs and symptoms, it's probably highly suggestive of flu and this is what's going on. Well, it was very interesting. In New York City, flu had started to wind down by early February to mid-February and was actually coming down. All of a sudden, in the end of February, boom, up goes the number. And it goes and it goes and it goes, long before anybody was test positive. And guess what? It was COVID-19.

We see the same thing here in Minneapolis. We just saw that thing go up about two and a half weeks ago, and it started going up again. So I feel confident that we can monitor enough illness in the community this way and other means that we have that we can tell people it's time to put the pedal to the metal. Okay, it's happening. We got to shut it down the best we can. And so I think that's the kind of methods that public health is going to be reverting to. But you raise a good point. What can I do for any one patient? And I think the only thing we have going for us season-wise right now is if they are sick with an influenza-like illness, it's likely not influenza because we don't see it circulating right now. And we can test for that and we haven't

seen it. So I think you have to assume that they're a COVID-infected patient and go with that. But it's going to create challenges. I mean, one of the things we're concerned about right now is in Minnesota, our priority is testing first sick individuals who are in the hospital. Are they really infected or not? The second thing is to test healthcare workers who are sick, whether they're in the hospital or not, because we want them to work or not. And the third thing is testing workers in long-term care. That's all we have the ability to test for right now, because we don't have any other reagents. And I said that we may run out tomorrow. So we're all going to be finding ourselves, I think, in different scenarios.

And as much as we hear this good news about the new point-of-care test coming out from Abbott and things like that, we welcome all the tests. Just make sure you have reagents to go with them. And that's where the challenge is. Yeah. So your fear is that this Abbott test could be technically a wonderful test, but it might only be able to do a million tests in total before the supply chain falls apart. Exactly. You nailed it. That's exactly it. And we have been talking to the companies at some length. And remember, when Abbott says a million, they could tell me 10 million. It's over what time period? But it's

over a whole world too. And that's the problem we have right now. You could not buy a Roche PCR machine right now anywhere in the world. The Chinese went and bought them all up 14 weeks ago. You can't buy one in the United States. As soon as they saw what was happening, they bought every machine they could. And so we're in a global market for these tests too. And it's not just the US. And that's another reason why this is such a unique event is because it is a global house on fire where everybody wants reagent water and the truck can only deliver so much. Yeah. I mean, gee, I hate saying such stupid glib things, but I really feel like we're playing chess, not checkers.

I say this all the time. I say, we got to stop playing this. I play checkers with my 10-year-old grandson, which I'm lucky if I beat him in one move down the board. Yeah. Yeah. It just seems like I may have missaid it, but I think you know what I meant. No, I know.

You were right. You said it right. Yeah. We're playing checkers. We're playing one move ahead and the speed with which this is moving again, to borrow from Wayne Gretzky, right? We have to go where the puck is going, not where the puck is. And it seems like every time, every step we take is going towards where the puck is. But in the case of a viral pandemic, the puck moves faster than it moves in any other game. And you're really on your heels when you're just going where the puck is,

as opposed to anticipating where it's going. And that's another really important point is, you know, we plan for catastrophes, but we typically plan for a hurricane or an earthquake or a tsunami, one region, and then we get into recovery right away. Not that it's not devastating, but FEMA can't be in all 50 states at once and do the magnificent job that we're seeing in New York. And frankly, many of us fear that you don't want to be on the tail end of this outbreak where you are one of the latter cities to break, because by that time, a lot of the resources are going to be used. And even those that aren't going to be used up

where they can be moved, like if additional ventilators, if you can move them from place to place, it's still going to be a challenge because you will have used so many of the critical things like drugs and so forth. And so where you place yourself in this outbreak right now,

as bad as New York is, they have the benefit of, or at least now, like Seattle, they got more resources than most other places will likely get. Mike, I've spoken to many people about the situation around vaccines, including a number of people sort of off the record who work in biotech companies. I've spoken with at least three CEOs of biotech companies off the record. Without exception, no one has been able to give me a scenario under which a vaccine is available inside of 12 months. Can you explain from your point of view why you think that that's likely

and why you're saying, look, we're not going to have a vaccine until 2021? I always come back and clarify, I could make a vaccine tonight for this. I could, even with my simplistic knowledge of this issue. But the question is, would it be safe and effective? And that's what's key. So I think from an effectiveness standpoint, I do think we can probably find something that will be effective even if temporarily, meaning it's not permanent long-term protection, but something that might require boosters. We don't really know that yet. The whole T-cell, B-cell combination of immunity with coronavirus is still a question. I'm more optimistic about that. Where I think is going to hold us up a lot is safety. In the 2003 SARS vaccine work, there was some real challenges that developed

with the animals with something called antibody-dependent enhancement, ADE, where if you made just a little bit of antibody, that was bad because then when you got infected with the real thing, you had this antibody-dependent enhancement that was a shock-like picture and was a real challenge. And that's exactly what happened to the dengue vaccine in the Philippines that got pulled two years ago, was that that vaccine had an ADE component to it that nobody had appreciated. And because we have a history with this vaccine with ADE, I think that no regulatory agency, at least in North America or EU, is going to license that without

substantial safety data. And if that occurs at, let's just say even one per 10 to one per 100,000 population, think how many people you have to study before you can actually know, is there an increased risk or not? And if this was a really common side effect, three or four or 5% got it, that would be a much easier situation to study. So I think that there will surely be pressure to get it evaluated and licensed and made as soon as possible. But right now, I think the ADE thing is one that's going to hang over its head and regulators are going to make certain that we have enough data to at least begin to address it. What's the technical reason for that, Mike? Because that's not something that we see with influenza, for example. No, we don't. In fact, it's more of a

flavivirus type issue and the coronaviruses we've seen it where basically this whole immune system set up. I mean, in a sense, it's somewhat like dengue hemorrhagic fever where you've been infected with one strain and then you have the second strain infection that has enough cross-protection but not sufficient to fully protect you. And so it really is an immunologic phenomena. This is part of why hep C vaccination has never really been successful as well. Isn't hep C also a flavivirus? Yeah. I think that's also, but it's exactly one of the reasons why it's been a problem. So I think that's going to be a challenge. But let me just say there's one other challenge

that I think people haven't thought about yet. And that is, again, the supply chain thing where we just assume anybody can do anything because we got something. Vaccines take manufacturing capacity. Right now, there is no big manufacturing capacity sitting out there empty, waiting for some unknown virus to attack us and then cause for a need for a major vaccine program. And so right now, the only players, there's one single one player in this entire effort that even has the capacity to manufacture these in any meaningful way. manufacture this in any meaningful way. All the other ones are smaller startup companies that are bringing some good science to the table, but they all are likely acquisition type issues where if they got the product, they get bought by a big company and move on. And relatively speaking, the big companies have not gotten involved. And I think that we have to also look at how do you make enough of this vaccine for millions and

millions and millions of people? And how long would that take? I remind people that Ebola vaccine, which was heavily funded by the defense industry in both the United States and Canada because of the concern about a bioweapon use. And so therefore, when it came into the, quote unquote, Ebola battlefield in 2015, a lot of work had been done on it already. And it still took almost four years to get that thing licensed with the data that it had and the ability to provide manufacturing dynamics, et cetera. So I think if we do everything we possibly can here and we can show it's effective, a relative sense of safety, being able to find the manufacturing capacity. We're still talking 18 months, I think, at the earliest. And that's not because people aren't going to be working 26 hours a day. It's just,

that's what it takes. Yeah. I mean, I think another just point to make that and drive it home is just looking at Shingrix. When we came out with a much improved vaccine for shingles, I don't know if you recall, but you couldn't get that vaccine for your patients over 50. I'm one of the high risk people. I'm an old guy. I know that. Yeah. We had a really hard time getting that vaccine for our patients. It took, many of them needed to wait six months to get it. And obviously it's a fraction of the demand. So it's just worth sort of contemplating that. And I think the other thing that, you know, I want to go from this vaccine discussion into the sort of the antivirals, you know, I read a really interesting statistic the other day that I actually, I guess I knew it was not

great. I didn't know it was this bad, but it looked at sort of antiviral drug development from about 1963 until present or thereabouts. It was a couple of years old, a little over, oh, I don't know. I want to say in the neighborhood of 5,000 antiviral inhibitors were proposed in the scientific literature, but only 90 of these, nine zero were approved for final use over about a 55 to 60 year period. And by the way, of those 90, about 40 were for HIV. So again, not minimizing. Yeah, yeah. So if you took HIV out of this, we're talking about maybe 50 drugs developed with any efficacy and safety to warrant approval in a 55, 60 year period of time. What does that tell you? Well, I'll tell you what it tells me is I hearken back to when I was in medical school and I went to NIH to spend some time there

and I was in an immunology lab. And I just remember a lecture one day that left such an impression on me, which was, and this was immunology through the lens of cancer. But the point was the T-cell biology is so robust. T-cells are so amazing at what they do that they save us from all these viruses that otherwise we'd be hosed from as evidenced by how few we have in terms of effective antiviral drugs. In other words, if not for the fact that we had a competent immune system that could fight off most viruses, we'd be doomed because our hit rate of developing drugs to stop viruses is actually pathetic compared to our ability to stop bacteria. No, you're absolutely right. The good fortune, I think, is we are today in a better place in part

because of the research that HIV led us into and gave us a better sense of how to do research. But I would absolutely agree with you. Anybody thinks this is a slam dunk, it's not. And I worry about the fact that we've already made judgments to a certain degree about what works and doesn't work. I happen to chair four different major work groups for WHO on what they call the R&D roadmaps for epidemic diseases, Ebola, Laos, and Nipah, and Zika. Early on, Ebola vaccine was moving along fine. We were overseeing that, but the therapeutics were still a question. And everybody had assumed ZMAP, a monoclonal antibody, was the drug. If you didn't use ZMAP, it was almost unethical. Finally, in this most recent outbreak in the DRC, a randomized control trial was set up,

and ZMAP didn't even finish in the top five drugs. And it was one of those ones where when you realize, wow, we've been using this for years with the assumption thereof. I hope that we have very effective drugs in this current regimen approach with the COVID-19 disease, but I don't know that we do. And I think as you so well know, we have two kinds of drugs. The quarkin, for example, are immunologic modulators, toll-like receptor modulators. Whereas if we have people dying from a myocarditis type picture, well, that's a whole different situation. We may actually cause problem using quark-quinton. So

I think that we just don't know yet. And I hope we have multiple fronts to deal with this, but the answers are far from there yet. They're just far from being there. I want to come back to the antiviral in a sec, but I want to pick up on a thread there, which is, this is now the second time you've mentioned it. Basically, we're so early in this and we're still back on our heels. I feel like a boxer who's been punched in the head so hard. I'm having a hard time thinking about counter-punching. All I'm thinking about doing is not getting hit again. We haven't really done the analysis on the survivors yet. We don't understand how much lingering myocarditis is out there. We don't understand how much lingering kidney disease is out there. We don't understand how much lingering lung disease remains in terms

of fibrosis or permanent destruction of a subset of the pneumocytes. Is there anything that you've learned from SARS and MERS about the survivors that we can take as a potential proxy for long-term view on the health of the survivors? I can't say from a clinical standpoint I know that. SARS was the one in and out. There surely were over 7,000 some survivors and how much subsequent morbidity that they had with that, I can't tell you. The one thing I can tell you, which I think is another observation, but hopefully a positive observation, is that having done all the work in the Middle East on the Arabian Peninsula, unlike with SARS, or once the palm civets were taken out of the market, humans weren't getting pinged anymore with the virus. They stopped it. With MERS, those camels keep transmitting and transmitting. And people who come from herds

where they're close to those animals, those are the same animals that infected them that they go back to. And it turns out that I'm not aware of anyone since 2012, almost eight years, who have been infected going back into a high, relatively high infection rate in their own animals have ever gotten reinfected. Again, the assumption that I think we have to be careful about, does that mean they're really protected or not? But we haven't seen that again. So that's probably the only takeaway I can come with, but it doesn't answer the very important question you're asking, what is that residual? What's it all about? And even understanding for certain what got us into this situation with underlying comorbidities. I mean, I'd like to understand more, why do certain

comorbidities actually predispose you to a bad outcome? What is it about that? Yeah, I was going to ask you, what do you think, for example, in, I mean, type 2 diabetes makes a bit more sense, but what about type 1 diabetes where there still seems to be an increased risk? And that's especially concerning for young people. Exactly. I don't know that. And of course, that's going to be overlaid with obesity. So then you're going to have both issues operating at the same time. How much of that is compromised lung capacity? How much of it is actually the diabetes? That's what's really unclear. What about immune compromise? What do we know about immune suppressed patients? We've actually tried to get more information from the Chinese on that. We've actually made

formal requests for that information. And all we get back is saying is that they didn't see any big increase in immune compromised people, whether they were surviving cancer patients who may have been predisposed to an immunocompromised condition, et cetera. No one has reported out of the Chinese data. I've not seen it out of the data from Italy other than to say, what do you mean by immunocompromised? You're over 80. What does that mean? But from a clinical standpoint, not someone who would actually, we'd classify as immunocompromised. I've seen nothing on HIV AIDS, for example. Nothing that suggests HIV status puts you at a higher risk at all. Yeah. Again, this is yet another point on the list of things that

differentiates this from influenza. If we're looking for ways to contrast this, again, it's hyperimmunity, immune paralysis versus not especially immunogenic to the same extent. I mean, there's just so many things that make this different that as more and more time goes on, the more and more I feel we do ourselves a disservice trying to compare these two. And it's understandable why we do, but it could potentially mislead us if we continue to use influenza. Yeah. And you raise a very good point about, I use influenza from a transmission model, but I don't think clinically you can. And one of the areas we ran into that was with kids. When you look at kids today, there is pretty compelling evidence now out

of studies that were done in China that the kids do get infected at the same rate that the adults do, but they just don't show clinical signs and symptoms, which is just the opposite with influenza. Kids become little viral reactors in school. They transmit to everybody, including their parents and their older sibs, and they're sick. And so there is an example of a difference right there, where what's happening with influenza in kids is not the same thing that's happening with COVID-19 in kids. Mike, have you given any thought to the notion that you alluded to at the outset that you estimated R0 was somewhere between 2 and 2.4. We tend to talk about R-naught as though it's a blended number between the symptomatic and the asymptomatic

spreaders. Is there any utility in trying to think of R-naught as separate and potentially assuming that the symptomatic people might have a higher R-naught, although that doesn't necessarily have to be the case? Again, you're asking a great epidemiologic question because we're having that debate right now in a sense. You know, I've always said R not really didn't apply to MERS and SARS because these super spreaders were so important. You could have five patients, six patients, 10 patients didn't transmit to anybody even when people let their guard down and didn't do good infection control. And then somebody could come in and wow. I was involved with helping the follow-up investigation at Samsung Medical Center in Seoul in 2015, when an individual came back from the Middle East to Seoul, and they actually were infected.

They went to Hospital A. Another patient was in Hospital A. That person infected that other patient, who then then upon discharge went over to hospital B, i.e. Samsung Medical Center and transmitted in one afternoon in an emergency room, 60 some people. I mean, that was dynamic. And just to be clear, this is a property of the host, not the virus because it's the same virus. Exactly. You're right. The same virus, same virus. Okay. And so to say that they are not inught on a situation like that is kind of like saying your head's in the freezer, your feet are in the oven, but on average, your temperature is just right. It doesn't make sense.

So I've always challenged the R-naught because I think that it was way, way, way out on the curve. In some cases, we saw lots of transmission. Well, I think with this disease, we have a hybrid. In fact, there's a great article in today's LA Times. I urge you to go look at it, highlighting a major event that happened at a choir in Seattle. I saw it. If I recall, 60 people in the choir showed up to practice. 45 have gone on to test positive. Two have died. One was 80, one was 83. Three are in

the hospital. So yes, there was something strange about that. So we had these events like that. And I think that we've had more of those than we care to realize. But on the other hand, we also have, I think, the regular transmission. What was really fascinating about the... Christian Drazen and his group in Munich have followed up on individuals there who were part of this early outbreak associated with somebody who'd flown from Wuhan, China to a car manufacturing location in Germany, was supposedly mildly ill, asymptomatic, transmitted, okay? Well, they followed up on

a group of these contacts and they said, okay, as soon as you get the first symptom, call us, which they did. And they have a series of patients that they literally have blood, urine, feces, throat swabs, nasal swabs, et cetera, in the earliest hours. And these people were just getting sick and they were getting progressively sick over time. But what they found with the virus in the throat was fascinating. This is on culture now, not just PCR. The virus level in the throats of these people were about a thousand times what they see with SARS at its highest level. And this was right at the very first moments that they were just showing clinical symptoms. And if you follow those cases, the virus level drops precipitously

over each day. Day four or five, it's really much lower. Now, clearly before that, and their hypothesis is that these virus levels may have been higher on day. Now, clearly before that, and their hypothesis is that these virus levels may have been higher on day minus one, day minus two, but they weren't coughing or they weren't sneezing. So you can say, well, they may not have been as infectious, but to see that kind of virus level, just breathing, creating the aerosols. And people want to understand an aerosol. I tell them there's two things to understand it by. Next time you're in your house and sunlight is peering through a window and you see all that dust floating there and you think, oh, my house is dusty. Those are aerosols. That's just from us talking. That's from us breathing.

That's what goes on in your house. The second thing is next time you're at a shopping center, hopefully they open up, and you are in a department store, you're three aisles, four aisles away from the perfume section, you can still smell it. It's an aerosol. So I think that breathing and just the talking would an aerosol. So I think that breathing and just the talking would put that out there. So I think that rather than call it asymptomatic, we kind of call this pre-symptomatic, meaning that they're going to get sick, but they may be infectious beforehand. And this is not a surprise. We see this with influenza all the time. Whether somebody is truly asymptomatic, never showing discernible signs or symptoms, I think

is a question that is, the data really come down harder and harder. In fact, I just reviewed a paper for a major journal from the group in China that found a sizable number of people who are asymptomatic, never had reported symptoms where they had more than just PCR data. They actually had culture data and they were pretty loaded too. So I think there is a role for these people. How much they're driving the outbreak, I don't know. But I think we can't ignore that they have to be there. And I do believe we have SARS-like super spreader events, just like the one we just talked about with the chorus. But there's a lot of it that's just efficient transmission. Did we learn anything about

what characteristics those super spreaders had that made them super spreaders such that we might be able to identify these people a priori and isolate them better? No, that is again a million dollar question. We haven't, even with all the years of looking at what happens with MERS. And part of the reason is with MERS, for example, it's not that the virus got less effective in spreading. We just got more effective in early detection and getting these people isolated. The first outbreaks, for example, in the Arabian Peninsula with MERS were largely in dialysis units where people who were in sick, they were in there for a while, and then classic hospital-associated infections occurred where they transmitted to others.

Once they figured that out, and as you alluded to a moment ago, R-naught is a relative term. It refers to in the natural state unaltered, this is who you transmit to. But if you have somebody that's just hotter than the devil, but you put them in an isolation room, they should transmit to nobody. Technically, their R-naught should drop to zero, even though if you had them out in the waiting room, their R0 might be 10. And so I think that's one of the issues with MERS. We can't even tell you for sure because we've just gotten a lot better at making sure they don't transmit. And had these occurred otherwise, like the one happened in Samsung Medical Center, I think we'd see more

of these. So I don't think we know yet, but it's a very important point that we do need to understand much better than we do now. How is anyone to be able to model this out given all of these unknowns? So on the one hand, I mean, I think we would all agree forecasting could be helpful because it would be great to know some order of susceptible areas in the country, if not globally. We've talked about it now on a couple of occasions here. We're going to have to allocate resources intelligently. We can't take an approach that says it's going to be all hands on deck simultaneously everywhere because one, we don't have the resources to do it. And two, it doesn't mirror what's going

to happen. So it would really be helpful to know that while New York is right now the epicenter of this in the United States, these five cities are next in line. And therefore we should at a national level be ramping them up such that at a local level, they're ready. But how do we do this? I mean, I think my fear is, and we've internally been working on models. We continue to work on models. We're collaborating with people, putting together models and they're beautiful and they're elegant, but ultimately they're wrong. I mean, they just have to be wrong because we don't know the simplest things that the models are very sensitive to such as are not. And I mean, that's by far the most important metric, which of course the problem is it's a single number

or a couple of numbers in a model that as you point out is anything but a single number. The average, the example that is often used, the average, you can drown in an average of three inches of water. So just as you can have your feet in a freezer and your head in an oven and still be on average at the right temperature, it's very complicated. And it's not just to say, we don't know what the distribution looks like. We don't know what the probability distribution looks like of these things. So as someone who has studied these things for such a long period of time, are you more or less optimistic that this exercise of projection and modeling is a fool's errand? Or what do you think we should

be doing here? Well, first of all, let me just say I'm not a modeler. I've had a lot of graduate hours of statistics classes. And I ascribe very much to the fact that all models are wrong. Some just provide helpful information. And I've always said that. I've always been, I mean, I had to live through the 2014-15 Ebola situation where WHO came out and modeled it and said, we're going to have 20,000 cases. And CDC said it could be as high as a million. And it scared the hell out of everybody. And we had to explain the next year why we didn't have a million cases. It was close to 20,000. And just that error by itself created a lot of controversy because it made it look like

we're trying to really hype this. I think here, the points you're raising are exactly the ones that we've been looking at carefully to say the variability around this feature is from zero to one. I mean, it's from infinity. And so that one factor is kind of like A plus B plus C plus miracle, and you get an answer. And the miracle part just can't be there, okay? And so I think that that is a challenge. On the other hand, I would say you can theoretically say, without knowing, if it works like this, this is what

will happen. If you were able to suppress it in 85 or 90% of the transmission events, you can have this happen. Or if you do this, you can have that happen. But it can't tell you that's what it's going to be. It can just tell you within the framework of what might it look like. I think you're exactly right. I have gone, my predictions, which I talked about earlier, and I surely don't mean to sit here and sound, well, look at me, but we were right on with this thing all along, right to this point, even to picking hotspots. And now we can't. I can't tell you for certain what it's going to do because it's beyond the scope of our experience. And we were just modeling the lot intellectually, not statistically, on the fluke transmission model

because it looked like that a lot. I think you're asking exactly the right question. What intelligence would give us the information so that we could plan, this is the next front. Two weeks from now, this is where we're going to need to be. This is how much we're going to need to have. And we just don't have it, which is one of the other real shortcomings of our ability to respond. Today, weather forecasters can tell you, you got 80% chance in this region right here of having tornadoes today. I can tell you, I can paint the whole United States, we have 100% chance of having a COVID-19 problem, but I can't tell you exactly much more than that right now.

Is there any evidence that this is a globally coordinated effort on intelligence now, or is everybody still kind of acting like the guy who just got punched in the nose, who's still stinging from the pain and trying to not get hit again to worry about the person sitting in the front row and whether they're drinking a Diet Coke or a Diet Pepsi? Many of us were incredibly disappointed, for lack of a better word, in the WHO in its response. There was a sense that China's going to contain it. The whole world can contain it. And I give great credit to China for what they did, but they didn't contain it.

They slowed it down. I surely give them that. But why did they close down all their movie theaters last week again? Why did they remove all the outside reporters to China two weeks ago? I think many of us think that they are in part experienced in some resurgence as they're opening up their economy again, and they don't want anybody to know it. And I know that's a strong statement, but I've talked to a number of people from Asia who would say they tell you the same thing. So when you look at what WHO did, I think they set us back a great deal because they made countries believe if just the few countries that were going to get this would just do the containment work, we could stop it. And we couldn't. Trying to stop this kind of transmission

is like trying to stop the wind. And so we held back on preparedness and gave people excuses not to do it. Now, again, we don't have global leadership in terms of how do we coordinate this? How do the low and middle income countries do with this versus the high income countries? Every country is fighting for the same tools, the same tests, the same N95s. And we don't have a way to globally allocate those in any kind of meaningful way. So the have and have-nots are going to fight it out, and the haves are going to get more, and the have-nots are not. The only thing that ironically we have going for us, which is in a sense a sad commentary, there are a lot less at-risk people living in low-income countries because they already died. And they're not able to be around 80 with long-term renal

disease. They died a long time ago. And that's a sad commentary, but in a sense may do better on case fatality rates overall than we do because they're not going to have that high risk. Yeah. When you, again, this is not a statement of low-income countries, but looking in Europe, again, when you consider Italy, Spain looking very similar, and then Germany looking different, do you think that the majority of that difference is explained by the underlying health of the population? Do you think more of it is just stochastic bad luck where in Italy and Spain, the regions that got hit first happened to have a greater center of older, more susceptible individuals. Do you think it is an artifact of testing? I mean, how do you explain,

what are your explanations for potentially those differences? Yeah, I think it's totally artificial. And I think as demographics, if you look at what happened in Italy, it started in the ski areas, but it quickly got into older populations. If you look at Germany, a lot of that was introduced back in Germany from the Italian ski areas, and it was in a younger crowd. If you look at where the illness is, I can tell you right now that it's starting to change, and it's starting to see more transmission in Germany in older populations. And when that happens, case fatality rates go up.

It's just like in Korea. When Korea had this predominant case mix of these younger individuals in this religious sect, case fatality rates were one thing. Now look at what's out for the next two to three years, I think there'll be a lot more similar kinds of pictures that will over time bear that out. That where the risk factors were for comorbidity associated severe disease, we're going to see higher case fatality rates. When you age adjust and when you adjust on risk factors, I don't think there's a lot of difference here that we're going to see around the world. Mike, I want to be sensitive to your time. And of course, I want to make sure that you'll agree to come back and talk with us in a week, two weeks, something like that. Because as you said, the rate at which this is changing, I mean, to talk again in two weeks would be like talking over two years outside of the timeframe of an epidemic. But the last question I want to ask you is, is there any of the sort of repurposed drugs that are currently being thrown around in non-RCT

manners that you have any optimism around? I mean, as you probably saw the study that was published out of France on Saturday, looking at hydrochloric, you know, I mean, again, I thought the study was impossible to interpret because without randomization, it looked promising, but you could argue that all those patients would have done just fine without the drug. I mean, without a control group, it's very difficult. At the same time, I don't want to be critical of that, that we have to do something in terms of studying this and using case control cohort, if that's the best we can do, so be it. But you gave a great example with Ebola, which said, look, you can be really deceived by these non-randomized trials. And when you

put them to the gold standard, they can fail miserably. If you're lucky, they just fail in futility, not harm. Based on that, how much of your energy are you spending looking at the different types of repurposed antivirals, everything from remdesivir to camostat to hydroxychloroquine? Are you looking at these closely enough to comment on your optimism or pessimism? I'm not because I'm not in that part of it. I'm doing much more in the epidemiology prevention side, but I think it's a critical question. I actually feel confident though that the systems are being set up to actually collect the data in a meaningful way so that we can have answers. And I think you nailed it. I mean, I actually read that same study you're talking about,

and I had the exact same conclusions you did. So I think we just have to, as Godspeed, do these as fast as possible, but we have to keep an open mind and let the data take us wherever it's going to and do them. So in that regard, hopefully I can come back in a couple of weeks and we can have more information. I do believe we're going to have much more information on therapies much sooner than vaccines. And that could be a really important response. So I know I said that was my last question.

I guess I want to give you one last thing to say. There's people that are going to be listening to this less than 24 hours after we've recorded it. So consider it as current as possible. What's the message you want to deliver to people listening to this who are afraid, who are not afraid? Just assume you're talking to a heterogeneous mix of people. What do you want to communicate to them as far as what steps they should be taking to protect themselves and the people they care about? Well, number one, we throw around a lot of numbers and we have to never forget these are all people. They're our loved ones. This is real. And more people are going to know somebody in the next couple of weeks that are

going to be seriously ill or die. The second thing is I would just say that we're going to get through this. We are going to get through it. The question is how do we do it? And that's where I think some of us are trying to get the kinds of approaches in place that have a better chance of getting us through than not. I appreciate it. You were wonderful. I would be happy to do this with you again. You're great at it. You're really good at it. I appreciate that, Mike. And we'll get back to you soon. Thank you so much. Bye for now. Bye. Thank you for listening to this week's episode of The Drive. If you're interested in diving deeper into any topics we discuss, we've created a membership program that allows us to bring you more in-depth

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