In February 2020 the nature of the 2019-nCoV outbreak is still slowly coming into focus but it appears to be acting more like bad pandemic influenza (efficient spread, overall lower mortality) than like SARS (less efficient spread, overall higher mortality). Dr. Anthony Fauci of the US National Institute of Allergy and Infectious Diseases (NIAID) discusses the latest developments with JAMA Editor Howard Bauchner.
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Howard Bauchner: Hello and welcome to this livestream event. This is Howard Bauchner, Editor-in-Chief of JAMA, and I'm here with Tony Fauci, the director of National Institute of Allergy and Infectious Diseases and we're obviously, once again, going to talk about the novel coronavirus epidemic, now pandemic that's occurred in China and now is sadly moving around the world. Welcome, Tony.
Tony Fauci: Good to be with you, Howard.
HB: I want to thank you for joining us, I know you're busy, you've been on a lot of different broadcasts, you know, this one is really focused for physicians and other clinicians, so I -- I really appreciate that you've taken the time. Before we start, I just wanted to mention to the people who are watching this, it's streaming on YouTube and Facebook, it will be live as a podcast sometime early tomorrow morning. JAMA has currently published three pieces, the first, which was in fact, by Tony with his two co-authors Hilary Marston and Catharine Paules was “Coronavirus Infections, More than Just a Common Cold,” that was accompanied by another viewpoint by Larry Gaston and his two co-authors, Rebecca Katz and Alexandra Phelan entitled, “The Novel Coronavirus Originating in Wuan China, Challenges for Global Health Governance.” We put up another viewpoint early yesterday by Carlos Del Rio and Preeti Milani entitled, 2019 Novel Coronavirus, Important Information for Clinicians.
What I want to alert the listeners and people who are watching is we are putting up two very important papers tomorrow morning [February 7]. The first is a long research report entitled “Clinical Characteristics of 138 Hospitalized Patients with 2019 Novel Coronavirus-Infected Pneumonia in Wuhan China.” We think it's the largest case series to date and has some really important information in it, I would just comment, we held that publication for a day or two because there were one or two critical facts that we really, really wanted to make sure were correct. But just to highlight two of the findings, the first is, of these 138 patients, 36 ended up in the intensive care unit, and so there's quite a bit of details about the complications of these 36 patients. And the other, which is using a preliminary definition was that almost 40% of this sample of 138 hospitalized patients were infected by individuals who had come to the hospital and were infected.
Now this is a presumed figure, but it's quite high, and I think it will be of interest to all of the readers. So, Tony, you and I correspondent yesterday a bit, why don't we start the big picture, and then walk through it, and then I know I have some other specific questions. So, as of this morning, about 28,000 infected individuals worldwide, over 500 deaths, where do we stand with respect to China?
Tony Fauci: Well -- you know, China has the overwhelming bulk of the infections and the issue here, Howard, that I think is really important is that the cases that we're getting the numbers every day in almost real time are the numbers that you just gave as of last night. If you do the math on that, as we've done every day, it's remarkable that the fatality rate -- the case fatality rate has stayed at 2%. The issue is on conversations with our scientific colleagues and public health colleagues in China, it's very clear that the people who are getting caught in that umbrella of reporting are the people who present themselves to a hospital, about 25%, as you mentioned, of these individuals have serious enough disease to put them in the intensive care unit. However, there's another whole cohort that is either asymptomatic or minimally symptomatic that are going to make that denominator much, much larger than it is.
And the reason I think this is important is because this is acting if the case fatality rate goes down to a really, really bad flu season type fatality, the fatality in a normal flu season is about .1%. When you get into the pandemics of 1957, 1968, it goes up to, you know, 0.8 to 1, 1.2. When you get to the 1918 pandemic, the famous Spanish flu that killed 50 to 100 million, people you go up to as much as 2%. So, if this goes down to the, 1, or .8, .9, 1, 1.1, it's acting more like a really bad flu season or a pandemic flu that we've experienced. The reason I say this is that it's acting less like SARS, which has much less efficiency in transmissibility, but a death rate of 9 to 12%, similar to MERS, which is not efficiently adapted to humans, it doesn't spread as well, but has a fatality of about 36%.
So, I think that we can say we don't know everything about this virus, but it's evolving in a way that looks like it's adapting itself to infecting much better. But we're going to start seeing a diminution in the overall death rate.
HB: Yeah, you and I chatted about this briefly before that we weren't quite sure what the denominator was, we were very good about counting the numerator, but the denominator was much more difficult. Tony, what's popped up in a number of viewpoints that's come across my desk, some of the literature is this -- RO. Could you explain this R thing that people have been writing a lot about?
TF: Yeah. You know, the R-aught is a population based determination that helps you to decide, is the outbreak taking off, leveling off, or diminishing? So, the R-aught is the number of people that a single infected person will infect. So, if I'm infected, and I infect you, Howard, but you -- I don't infect anybody else, the R-aught is 1. If I'm infected and I infect two people, the R-aught is 2. If I infect less than one, and -- and you say, well, how can be -- infect less than one person, it's a population based. If a number of people, the average is that they infect less than 1, then the -- the outbreak is in decline. If one person infects one person, it's steady.
As it goes above one, it goes up. So, th the R-aught for this one is supposedly and -- and -- and there's a lot of caveats with R-aughts, but it's supposedly somewhere -- you know, around 2, 2 1/2, 3 -- you know, depending upon how you model it, which means that it is a virus that is quite good at transmitting from one person to another.
HB: So, that -- that's why, when we went over the case fatality rate, it become so critically important because if -- if you have an R-aught of 2, 3, 4, 5, and the case fatality rate is very high, then -- then the world is going to struggle. If the case fatality rate is lower, even if the rates of infection are high, then I -- I think we may be able to deal with it, is that -- is that an accurate interpretation, Tony?
TF: That's precisely correct, Howard, that's precisely correct. And -- you know, the -- the -- the dictum that it was never 100%, but it holds true historically that when infections, particularly respiratory infections, the more efficiency they gain in spreading, the less case fatality rate they have. There are some notable exceptions here and that's when you really get a catastrophe, the way we had in 1918 with the famous Spanish flu, that had a fatality rate that was much higher than seasonal flu. Seasonal flu is .1%, seasonal flu fatality rate. When you go up to 2, and you have a widespread where -- you know, 40% of the population of the world gets infected, then you really got a problem, and that's what happens rarely in that incidence of -- of 1918.
Now remember, the 2009 pandemic, the H1N1 swine flu, that spread very, very well, but the fatality rate was quite low, and that's the reason why it wasn't a -- it wasn't dubbed as a particularly serious pandemic, even though it spread very rapidly.
HB: Now, Tony, we talked a little bit about China, we'll return, so I'm curious about your -- your sense of the quarantine that's not just in China but now with other countries. Where are we -- where are we at in the United States? A number of cases travel in and out from China, where are we in -- where are we in the United States?
TF: Okay, we have now 12 confirmed cases in the United States, 9 of them of are direct travel cases from Wuhan City in China. The 2 other cases are spouses of 2 of the travel related cases for a total of 12. Now you bring up the point, Howard. about travel restrictions -- you know, in general, historically -- and I've been one that has even spoken about this that travel restrictions, in general, don't do much to stop the entry of infection when there is a broad global pandemic because you can't restrict travel for the whole world. What it does do when you have travel restriction from a particular country a particular region, at best, it delays such that you hope that it delays the outbreak in your country long enough so that the country that is the epicenter, in this case China, controls it to the point that you put a lid on the outbreak.
Once you get a broad global pandemic, it's folly to do any travel restrictions because you can't cut yourself off from the rest of the world. But the rationale of the Chinese and putting the restrictions in their own country is to prevent the spread within their country. And the rationale for temporary travel restrictions is to try and keep that number of travel related cases as low as possible because right now, what you have is the 12 cases and the 9 of which were travel, were appropriately, and accurately, and correctly, and successfully identified, isolated, and the contacts were traced. If you have a very, very large number of those travel related cases, it becomes logistically very difficult to do that. A figure that I did not appreciate at all, until I got involved in it, is that prior to this outbreak, there were 22,000 people a day would come from China to the United States.
Even though that has cut down considerably, if you want to screen in a way that is -- you know, accurate and have an impact people who are coming in, it would overwhelm the system. And it was to that reason that the health officials felt they couldn't really even give the beginning of a guarantee that that kind of screening would be effective. So, it was felt that, at least on a temporary basis, let's shut off the faucet for a while to see where this is going, that was the rationale for the travel restriction. But in general, travel restrictions don't stop outbreaks, they merely delay it getting into a particular region.
HB: Well, it certainly takes any country, the U.S., any country in Europe, or other countries in Asia a few days to -- to gear up to be able to begin the screen and then quarantine, so from that perspective, I can understand it. Tony, let -- let's go through some of the more common details that always come up, for example -- you know, one of the issues that came up over the last couple days was so-called asymptomatic transmission, incubation period, and do we know anything more about antivirals. But let's start with asymptomatic transmission. Presumably someone is coming into the country, you take their temperature, do they have a fever, but what about everyone else who doesn't have a fever?
TF: Sure. That's a very important point and there has been some confusion about that. Let's just quickly start off with the incubation period. You know, classically in coronaviruses and with this virus, it was felt that the incubation period was anywhere from 2 days to 14 days. Right now, speaking to our Chinese colleagues, the incubation period is probably between 5 and 6, maybe closer to 5 days. So, the question is, is there a symptomatic infection? And can an asymptomatic person transmitted infection? As you mentioned appropriately, if there is a symptomatic transmission to any degree, it makes any sort of screening process difficult and problematic. So, we were hearing reports, Howard, from Chinese colleagues that there is clearly asymptomatic infection and they are seeing clear evidence of some asymptomatic transmission, it's not the driver of the outbreak, but they feel confident that it's happened, these are only anecdotal reports.
The New England Journal of Medicine, last week or so, came out with a report of a Chinese woman from Shanghai who went on a business trip to Germany, had business type casual contact with a German person at a time when she claims that she was -- well, she didn't claim, the paper claimed that she was without symptoms. She then went back, and on the plane going back to China, she developed symptoms, and when she got there, the diagnosis was made. So, the conclusion was that this was the first documented case of a person who in the asymptomatic state transmitted it. It became pretty well discussed because it would have been the first -- you know, published report of something that has some policy implications. Then it found out that when they really questioned this woman carefully, she really was not completely asymptomatic, she had some back pain, some fatigue, and she was taking an anti-inflammatory, or a painkiller, I think it was almost like an acetaminophen derivative.
So, all of a sudden, the conclusion coming from that case was now in question in the paper, at least for the time being, is flawed until maybe they find out that she actually really was asymptomatic, that created a problem. So, I figured I might as well just grab the bull by the horns. So, I made a call to a person who I know very well who is a highly respected scientist and public health official in China, and I said, it's important for us to get the answer to two important questions, A is this asymptomatic infection? Absolutely, yes. B, can an asymptomatic person transmit it? Absolutely, we've seen it, it's not the predominant road by any means, it's not driving the outbreak, but it occurs. So, we're left with a situation where we don't know what the impact of this is, it's likely minimal impact on the kinetics of the outbreak.
But what kind of an impact would it have on testing? And the reason we want to go over there as part of the WHO group is to do things like finding out the people who are asymptomatic, do they -- when do they get carriage a virus in the nasal passages? Is that virus transmissible virus? Is it replication competent? Or is it just PCR identifiable? These are very critical things, so this comes under the realm, Howard, of information we don't know that we need to know.
HB: You know, it's interesting, Tony, in the case series, which, as I said, we've held on to for a day to really clarify the facts that we're putting up tomorrow, I'll just read the most common signs and symptoms from these 138 individuals; fever, 99%; fatigue, 69%; dry cough, 59%; anorexia, 39; myalgia, 34. But then they get into less common ones and so it really becomes hard to know if someone is truly asymptomatic; diarrhea, 10%; nausea, 10%; dizziness, 9%; headache and vomiting, 6 and 3%, so I think defining asymptomatic becomes difficult. Tony, one of the questions that's come through, is transmission only through respiratory droplets?
TF: Well, again, I cannot say that definitively, Howard, because we haven't done the studies to prove or disprove that. I mean assuming -- assuming, this is a disease that involves the lungs that involves coughing in which you have virus in the respiratory tree in the upper airway, it's almost certain that it's respiratory borne. The question is, is it only respiratory borne? And we don't know that. I don't know that right now. I think we're assuming, and I think it's a reasonable assumption, we don't want to go way off the wall on this. I mean to me, it's -- it's -- it would act like any other coronavirus that's respiratory borne. There have been some reports about virus in the stool in people, you mentioned diarrhea that is isolated from the stool, but we better be careful that -- is that live virus? Or is that just remnants of virus that you're picking up by PCR?
A virus in the stool is an RNA virus would not survive very well, so I think what you're going to probably hear about is some reports about virus in the stool, and what role that have in the spread of infection? I think the answer is, we don't know, and we need to find out because that has important implications.
HB: Now in the report that we're putting up tomorrow, virtually every person got antibacterial, as well as many got antivirals, particularly those in the ICU, but there's no -- it -- they couldn't -- they weren't clear about the benefit of -- of either. In -- In the case series, we're putting up the mortality rate was 4.3%, but obviously, this included many individuals who were quite ill, they were in the intensive care unit. Tony, anything emerge -- emerging yet other than symptomatic treatment?
TF: No, there are -- there are clinical protocols being developed for antivirals that we already have available, such as remdesivir, which you remember was used as one of the therapies in the forearm trial of Ebola infection, it was not -- did not prove to be effective. But it has invitro antiviral activity. In addition, a anti-HIV drug, Kaletra, which is a combination of two drugs, ritonavir and Lopinavir, and those two drugs -- you know, are protein -- being protease inhibitors and this protease in this particular virus. Again, there are going to be clinical protocols to see if we can figure out. The Chinese are doing it now. If we go over there, and when we go over there, we'd like to help out and be involved in that. So, there are -- you -- you're absolutely correct. There are known direct proven any right -- antivirals at all that we know are proven, but there are some with some hint, which are being pursued, both in a compassionate use basis, as well as on a clinical trials, which are being developed.
Howard, one thing I do want to bring up that I was struck by in your very graciously showing me the preprint of the paper that's going to be coming out is that when you talk about the stories from the 1918 pandemic where someone would wake up in the morning feel, pretty well, go to work, fall down in the street, and then be dead in about 24 hours, that's the great frightening thing about the 1918 pandemic. Obviously, not everybody went through that, but that's something that keeps getting repeated in the historical type of discussions of that outbreak. The thing that was really interesting I thought in the paper, if you look at the duration of time from onset of symptoms to hospitalization, I believe it was 5 days.
TF: From the -- from the hospitalization to the ICU was 7 days.
TF: And from onset of symptoms to I think was intubation was 8 days. What that's telling you is that this virus is really acting different, this virus, when it gets in you, it adapts itself so that you can wind up days later getting really serious disease. So, I think -- you know, JAMA being a journal that clinicians throughout the world read, I think that's a heads-up if somebody comes in and has moderate to minimal symptoms stay heads-up for some deterioration over the next few days. Didn't you get that out of that?
HB: Yeah. No, I -- yeah, no. And this was for the -- the 36 of the 138 who ended up in the ICU, the median time from first symptoms to dyspnea was 5 days; to hospital admission, 7 days; and to ARDS was 8 days. So, I think -- you know, you're just raising the point that just because you're well on day 1 or 2 doesn't mean you'll be well on day 4, 5, or 6.
TF: Yeah, I was definitely struck by that.
HB: Tony, cases out -- so firstly, most -- most people who are hospitalized, seriously ill, presenting with pneumonia, that's the first. And then the second, the case is outside of China seem -- those individuals seem less ill. Can you comment on both the pneumonia issue, what percent are presenting with pneumonia, and the spectrum of illness outside of China?
TF: Yeah, I mean that's a good point. I'm getting -- you know, as you might imagine, I get thousands of emails from people who -- who have theories about things. But one thing is -- is starting to be noticed and -- and it -- it isn't -- it hasn't been done in a regimented, scientific, organized way, but it appears that the -- the travel related cases that are outside of China that then transmit to other people, it appears that somehow or other, it -- not a lot of them are catastrophic infection, but I think the N is too small, Howard. So, I would be very reluctant to make any -- even guess or discussion that disease in Wuhan is much more serious than disease, either in other parts of China, or outside of China where you have infection.
People are talking about that and I think it's something we just need to watch really closely. I cannot imagine why that would be the case, but -- you know, you get surprised when you -- when you follow brand new diseases, so going to keep an eye out on that.
HB: Right. I mean the other issues that most of the case series, the one we're publishing, the -- a couple that have already been published, it's really -- it's behaving, in many regards, like -- like flu in the sense that it's -- it's the -- the elderly with comorbid conditions that we'll record that tomorrow that are really -- seem to be most susceptible to needing ICU services or ultimately to dying.
TF: Right. You know, this virus doesn't seem to be an equal opportunity attacker. I think striking we'll see is the paucity of children who come up with -- with infection or even serious disease. The mean -- the average age I think was something like 56, was it in the paper, Howard? It was something like --
HB: Yes, yeah.
HB: Now just to let our listeners know again, I'll service as our own preprint, and -- and that -- that goes to the issue about children, I the listeners probably know that I am a pediatrician and -- and that always comes up when -- when we have these epidemic, pandemics, how are children going to do? Jody Zylke, who's our research letter editor, deputy editor, also a pediatrician just finished a -- a -- a back and forth, and -- and will be editing a -- a research letter, which is a -- a very small case series about infants with the disease, all have done well, we're hoping that that will come out over the weekend. And then we have another paper coming out tomorrow, which, again, another research letter about a small number of children. But it has been striking so far, Tony, that in most of the literature, there has been very little about children.
TF: Right. Right. That is true.
HB: Yeah. So, the -- the two reports that we'll come out with will be amongst the first. Any -- any concerns about maternal fetal transmission? I mean many, many women around the world are obviously pregnant. Any information about that? How -- how -- or is there -- is there an analogy with flu that would be helpful, or MERS, or -- or SARS that would be helpful about maternal fetal transmission?
TF: Well, there was a newspaper report, I mean here we are, my goodness, newspaper reports, of a woman who had the coronavirus who gave birth, and 30 hours later, the baby came up with symptoms and was diagnosed with the disease, so it brings up the question of vertical transmission. The problem with that, Howard, and -- and even going back to the second part of your question of, do we have any insight from influenza? The problem with making those kinds of determinations is the postnatal close contact between a mother and a baby in a viral infection that has an incubation period of as low as two and sometimes one day. I mean the Chinese are saying that it could be as low as one day, they say it's anywhere between two and five, with an average of five.
It really becomes impossible to say that it was vertical versus the mother gave it to the baby right at birth and the baby developed symptoms 30 hours later because it has a low incubation period. You know, I-- I don't think you're going to get definitive proof, unless you really do some very serious studies on a number of individuals, I don't think you could make on the basis of an N equals one or two, any determination of that.
HB: Tony, just one or two more questions, I know we've been on for almost 30, 35 minutes, but it's -- you're such an extraordinary resource, I -- again, I can't thank you enough. One of the questions that's come through social media, interestingly enough, and I -- I find this one interesting is blood supply. You know, you -- you lived that -- you lived through that with HIV, this is very, very different, but I'm -- I'm just curious, how quickly does -- do -- do can you sort through whether or not you have to worry about this visa a vis blood supply, blood transfusions?
TF: Yeah, I mean that's something in work that the FDA obviously is -- is all over working on that right now. The way you go through is you find out if, in fact, you get someone who is infected, you followed them, and you find out the degree of viremic, I mean are -- are these people viremic, or do they just have virus in the long end of the nasal passage? That is going to be absolutely critical and that's the reason why the FDA is very interested in that. And no determinations right now, you know, the better part of valor. You know, it's also going to be how often -- it's unlikely that someone with coronavirus is going to decide they want to -- you know, when they're sick, donate blood. But then you get to what you were saying, what about asymptomatic infection? So, all of the questions come up, Howard, and -- and -- and they're -- they're self-cascading questions. A, is it viremic? How long do they shed virus? When you're infected and asymptomatic, are you also viremic or not? Who is and who was not viremic? And how long are they viremic?
All of those things are open questions that absolutely need to be settled before you make any determination about any impact on the blood supply.
HB: So, last two questions, one is going backwards, and one is going forward for -- so let's go backwards. Any more information about where it came from?
TF: No, I mean obviously, if you look at the history of these viruses, we have SARS, which we know, after much experimenting, and epidemiological, molecular epidemiology, it went from a bat, to a civet cat, to a human. MERS went from a bat, to a camel, to a human. If you look at the phylogenetic trees of the coronaviruses, there are only four of the coronaviruses that account for 10 to 30% of the common cold. But clustered around those phylogenetic branches are a whole bunch of bat viruses. If you do the sequencing, you can make an assumption that a bat was involved one way or another, either primarily or giving it to an intermediate host. So, that's the likely issue. Having said that, there's all kinds of conspiracy theories, as you know, going around on the internet with social media about deliberate or accidental release, etcetera, etcetera.
I think the answers to all of those will come when you get a whole bunch of sequences and you trace the evolution of this. Because if you look at the red flag markers of mutations as a virus evolves from the bat group all the way into human, you can get a pretty good idea of how it evolved and what happened as it got into humans.
HB: So, the -- the last question, then I'll have some final comments. So, the Harry Potter sorting hat, sort of feel like I should make you put it on, Tony, I know people want to know. What's the next two, three, four weeks going to look like, both in China and around the world?
TF: Yeah. You know, if I knew that I'd feel a lot more I feel a lot comfortable than I feel right now, Howard. I can see that the virus and the pattern of disease continues to accelerate. You know, it goes up by a couple of thousands sometimes cases per day. I think in the next few weeks to a month, we're going to find out, is it turning the corner and coming down, which would be really very encouraging news. Or is it continuing to go skyrocketing? I can tell you that, if it acts like a coronavirus, whether by its natural dynamics, it turns around over the next month or so, that would be great. Even if it doesn't by natural dynamics, when you start getting into the spring weather of April, May, and June, it almost certainly would turn around.
But I would like to see it turn around by its own natural kinetics as opposed to, the warm weather is here so it's not spreading very well. And then when we get next winter, it comes right back. So, I think the next two to four weeks are going to be absolutely critical to see what direction this is going.
HB: This is Howard Bauchner, Editor-in-Chief of JAMA. I've been speaking with Tony Fauci. Tony, again, on behalf of our listeners, JAMA, the U.S. people around the world, thank you. I do want to emphasize that we have a coronavirus educational center. We've put up a number of opinion pieces, we'll be putting up two very, very important research papers tomorrow, and then a couple over the weekend. I'm sure we'll pepper some of the research papers with more opinion pieces. We've made these free to the world, many are being translated into simple Chinese. And I would be remiss not to thank everyone who I work with the JAMA. Tony knows his viewpoint came in and went up in three days, we are really trying to process these papers quickly, we realize it's a public health emergency. On the other hand, for us, it's critically important to make sure that what we put up is accurate and true, so occasionally we have held up a paper or two for a day or so. But we're working literally around the clock to try to get out papers quickly and to make them freely available to the world.
Tony, maybe again in two or three weeks, we'll chat. But again, thank you so very, very much for taking the time.
TF: My pleasure, Howard, it's always good to be with you, and I look forward to continuing this as we move on.
HB: Get some sleep and please stay healthy.
TF: Thank you very much, take care.
HB: Bye, Tony.
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