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Coronavirus testing, mortality, vaccine development, containment vs mitigation, and more. JAMA Editor Howard Bauchner, MD, interviews US NIAID Director Anthony Fauci, MD, about the latest developments in SARS-CoV-2 science and global spread of infection.
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From the JAMA Network, this is Conversations with Dr Bauchner. Interviews featuring researchers and thinkers in health care about their publications in the latest issue of JAMA.
Howard Bauchner: Hello, and welcome to this livestream podcast. This is Howard Bauchner, Editor in Chief of JAMA, and I'm here with a remarkable individual, and I'll say more about that towards the end, Tony Fauci, who is director of the National Institute of Allergy and Infectious Diseases. Tony, thanks for spending some time this morning with me.
Anthony Fauci: Good to be with you Howard.
HB: Numerous requests for me to continue our conversations. Obviously, your first report, seminal, January 23rd, 2020, in JAMA titled Coronavirus Infections—More Than Just the Common Cold. Forty-three days have passed since then, and the world's a changed place. But before we get into some of the details, Tony, how many Presidents have you now advised?
AF: This is my sixth. I started off advising President Ronald Reagan in the very early years of the HIV/AIDS epidemic.
HB: So, Tony, before we get into some of the seminal questions that people have asked me to focus on, can you just clarify the language so that people really understand what we're talking about. COVID-19 and then SARS-CoV-2. Can you distinguish between those two?
AF: Yeah, it's very similar, Howard, to when we had that issue years ago with HIV/AIDS. HIV is the virus, AIDS is the clinical syndrome that the HIV virus can cause. SARS-CoV-2 or novel coronavirus is the virus, and COVID-19 is the disease. It stands for Coronavirus Disease 2019. One is the disease; the other is the virus.
HB: Thank you.
So, a lot about testing. I'm really not that interested in going over what we could have done. That's for the future to talk about, but I think there's been uncertainty this week about where we are on the ability to test in the U.S. and then equally as important, what will be the quality of those tests in terms of sensitivity and specificity. So, where are we with the capacity to test in the U.S.?
AF: Well, just to reflect back for a moment, Howard. There were clearly some missteps. Generally, when you have a new infection and a new disease like this, the CDC would jump on it to make a test quickly, rev it up, and give it to the public health departments in the various state and local authorities. That, in fact, had a misstep. because there were some issues technically with the test, which slowed things down. When it became clear that there would be a need for much more widespread testing, they revved it up themselves, but importantly, what happened was that they embraced and utilized private sector companies, the ones that do the standard diagnostic tests for other things that we as physicians use. And it became part of the routine.
We're not there yet, but soon, you know, and that's not something I control, Howard, so I hate to give listeners any guarantee of anything, but the goal over the next week to two is to rev it up that you could have at least a million plus tests available for deployment within the next week to two. Hopefully, that eventuates into a reality and not just a goal. Then after that, when you get online, some of the really good companies that know what they're doing when they're making a diagnostic test. Then I think the flow of those tests will be really smooth, but unfortunately, today we're not there yet.
HB: Sensitivity, specificity of tests like this, Tony?
AF: You know, they're good, Howard. They're standard PCR tests, and if you do a PCR test right, it's highly specific. Obviously, there are confirmation tests that you'd want to do if you just get one, because there can be contaminations with PCR. But they're very sensitive down to a few copies. Very much like some of the tests that we have for HIV, we can get down to really a few copies.
HB: So, from a clinical standpoint, if you have a test and it's positive or negative, you can make a clinical decision based upon that test?
AF: If it's positive, Howard, you absolutely can make a decision. If it's negative, you may be early on in the infection, and the viral load may be so low you don't get it. But that's more of a concentration issue than it is a problem with the test. So, a negative I feel comfortable with. A positive I'd be positive about.
HB: Okay. So, Tony, let's go to one of the other really complicated issues that's been debated over the last couple days, in part because of the language that people are using and what the WHO announced, which is the case fatality rate. Knowing we were going to talk this morning, I looked it up this morning with respect to Korea, because I think they've done widespread testing. They have a reasonably healthy healthcare system. My understanding from this morning's report from their CDC-like is 6088 cases, 35 deaths. Do you want to say anything about the case fatality rate?
AF: Yeah. Well, the case fatality rates, Howard, come from large studies not only from Korea but an even larger one from China and some information now from Italy. So, I'm glad you brought it up, because there's some understandable confusion. If you go onto one of the many sites that track global cases, such as Coronavirus Tracker, and you click, you see two numbers. The number of cases that have come to the attention of healthcare providers, as of this morning that's like 98,000. Then on the other side, they have the number of documented deaths. That's now about 3700, 3800. When you do that pure simple math, the deaths are the numerator, the cases are the denominator. That's where you get the report from WHO that it's somewhere between two and three percent case fatality rate.
However, when people do modeling, and you very well know Howard, and our listeners know, that a model is only as good as the assumptions that you put into the model. So, you have various assumptions that there are these many asymptomatic cases that never get counted. There are these many asymptomatic cases that never get counted, etc., and when you do that, you get a range of case fatality rates that's always less than the actual numerical one because it always factors in relative proportions of asymptomatic ones that you don't count. So, when you hear it's two to three, and then you hear well other people model it and it's somewhere between, you know, 0.8 and 1.5 or 1 or what have you, those are all assumptions based on varying degrees of what you would consider asymptomatic infection. That's where the confusion comes in.
HB: There's so much apprehension in the United States and around the world, around these numbers that people keep hearing. So, we'll return to that in a bit of time, but as I said, I'd look carefully at the larger series. I'm not quite sure that the China numbers are representative for the United States. But I think only time will tell.
AF: Well, that's true. You know, there was an article or an interview with one of the people, Bruce Aylward, who went to China as part of the WHO group as did my own deputy went, Cliff Lane, as well as someone from the CDC. And they were looking at what's going on there, and the Chinese don't feel that there are that many people who are so completely asymptomatic, they never get sick and they don't get counted. So they kind of think that that case fatality rate is closer to the one that's real, whereas others, when you get out of China, and you see a lot more cases that are mild or maybe asymptomatic, you always get a lower level than what you're seeing from the global report.
HB: Yeah, and it's been interesting in the China data, because we had the report from the CDC China that the case fatality rate within Wuhan versus outside of Wuhan are very, very different.
AF: Absolutely. Absolutely.
HB: So, Tony, three areas to focus on, advances in science in the last six weeks, then clinical issues, then public health issues. So, any major advances in the science of what we know about the organism?
AF: Well, with regard to the science, you know, they've done a lot of elegant basic work, doing the crystallographic and conformational structure of the spike protein, which I think is going to have downstream advantages of knowing how you can target blocking the interaction between the spike protein and the ACE2 receptor, particularly on the pulmonary cells in the lung. So, that's the typical basic science stuff, but the stuff that is of immediate interest and applicability is the issue with vaccines. You know, we have a bunch of vaccine candidates that are in various stages of development. The one that we're working with mostly that no way may it turn out to be the best one, but it's the one that seems to be furthest along is one that is an mRNA candidate that we're working on that we hope, I had mentioned to you and to others, that we had hoped that it would take from the time of the availability of the sequence to the time we got it into a phase one trial, would be about two to three months.
Well, I think it's going to be less than that. We're probably, four weeks or so away from going into a phase one trial. That always causes confusion because I think most of our listeners know this, but the general public should not know it and certainly do not, that getting a vaccine into a phase one trial doesn't mean you have a vaccine. It's going to take several months to see that it's safe, and then you go into a phase two, as you know, and you'll do that in an area where there's active infection. You'll ratchet up the numbers to anywhere from hundreds to thousands. That should take another six to eight months. So, you're really talking about a year to a year and a half before you even know something works. If you want to do what has been done in the past, which I don't think is a good idea, is to just get what you think is a vaccine and give it to people. That's dangerous. You know, in medicine, as we all know, the first mandate is to do no harm.
So, you got to make sure you have something that's safe and that works. So, we're not going to have a vaccine in the immediate future, which tells us we have to rely on the public health measures. Therapy is a different story. So, there are a couple of randomized control trials, a couple in China, and one that we're doing here in the United States that we're going to do in some of our evaluation units, because we have continuing number of increasing people who are infected, to test the drug such as remdesivir, using a standard of care vs standard of care plus remdesivir. Hopefully, in the next few months, if we have enough accrual, certainly the Chinese are well into a few hundred in their clinical trial, that when the DSMB looks at the data, we'll know whether it works or not. If it does, that would be wonderful. Then we could start distributing the drug. If it doesn't, then we'll obviously have to go to other avenues.
HB: Tony, returning to the vaccine, and then we can put that story to rest. I think people should also recognize just because we have a vaccine and we test it through phase one and phase two, it doesn't mean it's going to be effective.
AF: Oh, absolutely not. I mean that's the point, that's the point I made. I said it would take a year to a year and a half to find out if it even works.
HB: So, Tony, in the clinical trials that are ongoing, in a number of the case series that JAMA's received, and published in other journals, early on, many of the clinicians in China appropriately treated patients with antibacterials, antivirals, steroids. Are the clinical trials that are being conducted, are they cleaner? So, will there be a clear intervention group and a clear control group?
AF: You know, Howard, you bring up something that I have to say personally sometimes is painful for me because, having been through so many of these outbreaks, you could understand the desire of people when you have an intervention that either in vitro or in an animal model shows some degree of optimism. You immediately, when you have a desperate public health situation, you want to just give it to people. I understand that. The only trouble with that is that you almost never find out if it really works, and at the end of the day, if you've given a lot of stuff to people, and then you don't know what works, well it may have satisfied your humanitarian instincts of giving something to someone when there's no proven therapy, but you've in some respects done a disservice, and that's the reason why we lean heavily towards and recommend strongly that when you have these interventions, you do it in an ethically sound, randomized control trial to find out quickly and definitively whether something works or not.
HB: Yeah, we received a number of case series that were suggesting that this treatment or that treatment worked, and we had a number of people evaluate them, and their conclusion was just because they had done so many different treatments, it was not possible to conclude what had worked and not worked. And that's meant not to criticize the clinicians who cared for these patients, but it's more, then how do we present that information to the clinical community and the public so that there's faith that what we're presenting is accurate.
AF: Yeah, it's a good point, Howard, and just one other thing that, again, I'm sure our listeners are very well aware of, when you're dealing with a disease that has a certain percentage of spontaneous recovery, then just giving somebody something and saying they got better in many respects is meaningless, if it's not controlled. If you have a disease that's 100 percent fatal, you don't need a control. If they live, that's it. But a disease in which people spontaneously recover, that's a different story.
HB: Tony anything new on the various groups, high-risk groups that people are always interested in. So, the elderly was quickly defined. Then children were quickly defined at not being high risk. Then obviously people are always concerned about women who are pregnant. So, can you say anything about any of the new epidemiology about the various risk groups that people are always conscious about?
AF: Yeah, we know less about the pregnancy group than we do in influenza because we obviously haven't studied it enough. But the thing that's very clear, and there's some recent unpublished stuff from Korea and Italy in which, if you look at the mortality according to age and then according to underlying comorbidities, it's so clear, Howard, that the overwhelming weight of serious disease and mortality is in those individuals who are elderly as well as comorbidity- heart disease, chronic lung disease, diabetes, obesity, respiratory difficulties with asthma, etc. Every once in a while when you read the reports carefully, some individual case reports, some as part of series, you will see that there will be outliers. There will be, as we've seen in influenza, an occasional person who is young and healthy who winds up getting COVID-19, seriously ill and dies. But if you look at the weight of the data, the risk group is very, very clear, the ones that I just mentioned.
You mentioned it, and it's really interesting. I still don't totally understand it, is the lack of detectable infections in children as well as the lack of any degree serious disease. I mean, you know, in the report that came out, one of the several reports, there wasn't even a single identified case of a person less than 15 years old, which seems almost unbelievable. They have to be getting infected, Howard. Why they're not developing clinical disease is really interesting. This is something we really need to study because it certainly will tell us something about what a correlate of immune protection is.
HB: I'd like to focus a bit on the United States now. So, what's crossed my desk in the last few days, quite frequently now, is this notion of mitigation strategies versus quarantine. Obviously, the events in the state of Washington in the nursing home have focused now on quarantine, but could you tell our listeners the difference between what a quarantine strategy would be versus what a mitigation strategy would be?
AF: Okay. Well, let me add another word in there that might help us in the discussion, Howard. It's containment versus mitigation.
AF: So, I mean containment can be containment from without to within, as well as containment within. So, you do travel restrictions from China. That was very, very helpful in blunting the degree to which we seeded people from Wuhan and other parts of China coming into the country and giving us cases. We have some of them, a few, but relatively few. Blocking that is containment. Doing contact tracing: if you have someone and quickly get their contacts, that's part of containment. When you have mitigation, and I'll get to quarantine in a moment, mitigation says we're not trying to prevent it to come from without in, nor are we trying predominantly to contain it from within. We're trying to mitigate and say, we have a problem: How do we mitigate it? How do we prevent further infection without necessarily doing the contact tracing.
And that's where you get social distancing. So, mitigation can be almost synonymous with social distancing. Namely, staying away from crowded places, closing schools, closing and interfering with events in which you put people in a very, very large space that are crowded. Teleworking. That's the kind of mitigation to some degree that's going on in the Seattle area.
Quarantine is an old-fashioned word that means you take someone who is suspected of being infected and you keep them in a closed space until a certain period of time elapses beyond the incubation period. That's different than isolating someone who is infected to prevent them from infecting someone else. So, I mean I know that when you throw all those terms out to people they sort of get a headache.
AF: There's containment, mitigation, quarantine, isolation. But they do have subtle differences among them.
HB: So we've had some medical meetings cancelled. Others are likely to be cancelled. Many, the academic medical centers as well as hospitals are now restricting travel of their faculty, I think in part because they don't want them traveling to certain areas and then bringing back a disease to their institution. So, I'm beginning to see some commitment to mitigation. Now, I don't think there's been massive school closings like in Japan. Do you see mitigation as a part of what we'll roll out next week in the U.S. or the following week? Do you see it as something that is likely to become important, or more important than it is now?
AF: What I'm seeing and what I think we'll see, Howard, is not an official country-wide mitigation. I think the public will essentially make their own decision. People will be doing things like decreasing travel by doing the kinds of things that you mentioned- cancelling conferences, encouraging people to not work in the workplace if they could do it at home. They're going to be doing that anyway, so I don't think it's going to be like a public health mandate, but people are going to start hunkering down a bit. Because you see them doing it spontaneously anyway.
HB: Tony, the data about the elderly with comorbid conditions is clear. It's emerged from virtually every country. Obviously, the events in the state of Washington and nursing home are concerning. How do we protect the elderly, Tony?
AF: Well, you know, Howard, that is a great question. To me right now, we have this area in Seattle where they are doing official type of mitigation. You know, I spoke to Governor Inslee, who was just the other night, the other day before he made his decision to essentially initiate a mitigation strategy, which I thought was a really good idea. When you're talking about the elderly, even if you are not in an area where there is ongoing community spread, and you would do mitigation for everyone, whether they're elderly, immunocompromised, or young, I think right now common sense should prevail that if you have a person who is elderly- and many elderly people as the natural course of life are going to have some sort of underlying condition- sometimes a compelling one, sometimes a minor one.
The way we protect them, I believe, in general, is to don't take any unnecessary risks with them. So, if you have someone who is in their 70s, 80s, or beyond, and even if they're relatively healthy, do you really want to get on a plane and fly to wherever, unless you have to? I mean I think you have to treat the elderly and those with underlying conditions to try and protect them because they're vulnerable. And that's what we need to do. When you're talking about nursing homes, that is a very important issue. Seema Verma, who is the head of CMS I've been going on, you know, a lot of the meetings. She's now part of the Task Force, the President's Task Force that I'm on, is really making it a very important goal to get the nursing homes up to speed with regard to infection control capabilities, because they are so vulnerable. I mean you saw what happened in the Seattle area. That's not the last time that's going to happen.
HB: Tony, just a few more questions. I'm conscious of your remarkable work schedule. The southern hemisphere is beginning to see cases. Their resources are often substantially less than other parts of the world. It's an area in which WHO has been very active, obviously, around Ebola. Any sense of what may happen in Central and Latin America and Africa?
AF: You know, it's with trepidation that I think about that, Howard, because when you don't have the capability of doing the kind of public health measures and you have so many other confounding diseases going on, it's going to be a challenge. You know, and that's what the WHO keeps talking about on the weekly and sometimes twice-a-week conference calls that we have with them, where we bring in people from all over the world on a WHO-led conference call. That is the real topic of discussion of how we can get some resources. And it's going to be playing catch-up, as you know. You're not going to change the healthcare system in a country over a period of a couple of months. That's something that should have been done years and years ago, but to the best of our ability, help them out with resources to be able to respond.
HB: Tony, in our first podcast, you said something that I've remembered since, which is, we compared early coronavirus information to flu. It's been a difficult flu season in the U.S. You went through some of the past flu epidemics that we've had in the U.S., and you made a comment that flu tends to wane when we move into the spring and summer months, and there's varying reasons why. It's very interesting. It doesn't happen all the time, but it happens most years. Do you think there's enough signs of Coronavirus known now with the Ro other information to know if that will be the case with Coronavirus, or is it one of the great unknowns?
AF: Unfortunately, Howard, it's one of the great unknowns. I certainly hope that happens. The precedent with flu is every year it happens, it goes down and almost goes under the radar screen when you get to the end of March, the beginning of April, and then into the late spring, early summer. You see that with other respiratory-borne viruses. One of the things, we didn't see too much of that with SARS back in the day in 2002, 2003. I am hoping that as we get into the warmer weather we will see a decline that would give us a chance to get our preparedness much more up to speed. But, it's a big unknown, Howard. We don't know what's going to happen as we get into the warmer weather.
HB: Tony, so for reasons that are uncertain to me, there's this pall on the country, a sense of anxiety, which I can only recall as a young child with the polio outbreaks in the '50s, certainly around HIV/AIDS within the gay community, I think, the same trepidation, massive trepidation occurred. But we've been through SARS and MERS, Ebola, but I sense that it's different in the country this time. Do you have a sense of that, and if so, why do you think that's the case?
AF: You know, I'm not sure. It's amazing how much attention is being concentrated on this. You know, I think it is much more of what we talk about how the unknown is so scary, and it's still the unknown. And the unknown is punctuated by facts that tend to confuse people. Like you see pictures of so many people in hospitals on respirators, and then you get data that says, well, you know, 80 percent of the people don't even need medical intervention. They tend to spontaneously recover. It confuses people, and confusion leads to more anxiety, I think. You know, that's just one of the issues that I think make it different, Howard.
HB: You know, I was going through the numbers. The U.S. healthcare system has just remarkable capacity. I know people have been very concerned about the various numbers that have been projected, how many ICU beds we have, will we really be able to contain the spread of the virus. What's your sense of the capacity within the U.S. to care for what is likely to be an increasing number of people who are infected?
AF: Well, I think the capacity, if we don't have a massive outbreak that would require a lot of intensive care, that we'd be able to meet that. If, and it's a big if, don't want to scare anybody, but if we get into a situation where we do have a significant distribution throughout the country of people requiring specific type of intensive care, that could be a problem. I mean a real bad outbreak will stress any healthcare system, no matter how good it is. The hope is A, that it doesn't occur naturally, and B, that we can do some intervention that'll prevent it from getting that bad.
HB: One last question, and then a closing comment from me. Tony, you've been at this for six weeks. What's your daily schedule like?
AF: Well, it's untenable, Howard. It just is. I mean I did my medical training back in the day when you were an intern, you were on every other night and every other weekend, and you rarely got any sleep. I think this may be worse than that. It's very, very intense. The spotlight is always on you. You have to read everything, analyze it, come up with judgment calls, and there's not enough hours in the day to be able to do it. So, you just suck it up and do it, but it wears you down.
HB: I was talking to someone last night, my nephew actually, Josh Bauchner, and he's studying the history of science, and he said- what's Tony really like? And I said, he's exactly what you see when you see him in person or see him on the screen. He's extraordinarily wise. He has decades of experience. He's calming, and he has a remarkable ability to present information so that people can understand it and don't feel like he's being pedantic in any way. And you know I love your Brooklyn accent that comes out periodically. Tony, on behalf of a grateful clinical community, patients in the United States and around the world, and many, many other people, thank you for just your remarkable service and once again taking time to talk with me today. Thanks Tony.
AF: Happy to do it, Howard. It's always good to be with you.
HB: Be well, be safe, and try to get some sleep.
AF: Thanks a lot. Take care.
HB: See you, Tony.
AF: Bye, bye.
HB: This is Howard Bauchner, Editor in Chief of JAMA. Thanks so much for listening. For more podcasts, visit us at jamanetworkaudio.com. You can subscribe to our podcasts on Stitcher and Apple Podcasts.
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