TWiV 660 In case of emergency finish the trial

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 6 September 2020

Vincent Racaniello: This Week in Virology, the podcast about viruses, the kind that make you sick. [music]

VR: From MicrobeTV, this is TWiV, This Week In Virology, Episode 660, recorded on September 4th, 2020. I’m Vincent Racaniello, and you’re listening to the podcast all about viruses. Joining me today from New York State, Daniel Griffin.

Daniel Griffin: Hello, everyone. Nice to see you again.

VR: Hello again, Daniel. A week later, I just looked at the–

DG: You look good. You look like you’re surviving the pandemic.

VR: I’m back in my office. I kind of like it here. [chuckling] There are a lot of people around now on the floor.

DG: You look more professional for those people who are doing this on YouTube. I mentioned you’ve got the collared shirt. You’re still not shaven, but you never did shave, so you’ve got– [chuckles]

VR: Yes. I’m working on having a nice little look here and you got the background, you’ve got the books, you know what to do too. Daniel, I just looked at the New York State figures. September 7th, eight deaths, 710 new cases, 698 cases per day over the last week. It’s an increase of 8% from two weeks earlier. I guess things are rising.

DG: Yes, it’s interesting. I’m going to say you can trust those numbers. The nice thing is that I was like– I feel like I’m Ronald Reagan, trust but with verification. [chuckles] I’ll trust the numbers as well as I have a secondary source telling me because I always get the feedback from ProHEALTH. ProHEALTH New York does, other than New York State, we do the majority of the testing in the tri-state area.

I always get the feedback. What are our percentages? And they’re staying under 1% positive but as you’re saying, we’re seeing a little bit of a creep. We’re starting to see outbreaks, Stony Brook had a little bit of an outbreak. We’re seeing the numbers rise in the younger folks in our area, just as we’re seeing them around the country and I’m a little worried. I was talking to, and I’ll bring this gentleman up again later because the reason I was talking to him was about something different, but his daughter went out to University of Ohio or Ohio State, one of those.

I said in the old days when you went to college you used to get a diploma. Now what do you get when you go to college? COVID.


DG: What’s happening is these kids are getting sick at the college campuses. If you’re a teenager in your early 20s, you don’t feel well and you get the COVID, what do you want to do?

VR: Get tested?

DG: Shelter in your dorm, of course, so you don’t spread it? No, you want to go home and have mom take care of you. Now we’ve got all these kids flying home from all these little outbreaks. We’re expecting some presence to come from all these colleges, all the kids who went off to schools and are now coming home sick with the virus.

VR: Yesterday, we spoke with Christian Drosten in Germany and he said they’re very much fewer older people being infected because they’ve learned to stay home and keep out of trouble. [chuckles] That’s good.

DG: You’re right, actually. I’ll make sure I get to– I’ll get to that. But let me start off, I know we’ve got a lot of busy clinicians and they always want the bullet points. I’m going to give you the verbal bullet points. Kiki with her synopsis where she does that write-up, that’s actually kind of nice. For people who want their bullet point write up can go to Kiki’s TWIV synopsis, but let me start off.

This is a quotation that Ben LaBrot, the founder of Floating Doctors actually suggested. It’s from Ray Bradbury’s book, Something Wicked This Way Comes. “A stranger shot in the street, you hardly move to help. But if half an hour before, you spend just 10 minutes with the fellow and knew a little bit about him and his family, you might just jump in front of this killer and try to stop it.”

I’m going to try to get us to all start working together again here. I feel like there’s way too much conflict going on here, but also I appreciate everyone reaching out and helping us with the Floating Doctors fundraiser because these are people down in Panama that a lot of people don’t know. Ben thought of this when I talked about it in one of my earlier episodes, how a lot of these people in Panama I know personally. It’s really very hard to know that they’re starving, that they’re having issues with access to medical care.

I’ll do my plug right up front, go to and help us raise money for Floating Doctors.

Also, here in the U.S., let’s try to get along. I’ve added a new section to my weekly update and this is called ‘Good News.’ There’s plenty of bad news out there. I was so tempted to start throwing more of this in, even just today as I came across stuff. I’m not going to mention that they shut down some of the college sports because a third of the elite athletes had heart inflammation, I’m just not going to mention that, we’re going to ‘Good News.’I think many of us are a bit grumpy as this drags on, not just you, Vincent. I’m going to add this first part because there is some good news, but I just want to couch this, it’s good news relative to how bad things could be.

One, not that many children have died in the U.S. We just got numbers that came out for the pandemic. So far, in the U.S., up until the 27th of August, and although we’ve seen a significant increase in the number of children in the U.S. that are testing positive for SARS-CoV-2, the virus that causes COVID-19, the deaths and hospitalizations in those 18 or under remains low.

Even though we have over 6 million cases, and even though we’re approaching 200,000 deaths, you never want to put the word ‘only.’ I’m just going to put the word only, but I’m going to say there are 101 deaths in children 18 and under. That is fortunately much smaller than the 200,000 or so that have died in the U.S. Every one of these deaths is a tragedy, but good news relative to how tragic this could have been if this virus acted differently and targeted young people.

I’ll go back to what you brought up, Vincent. Not only are we seeing less deaths per age group, so if you’re at a particular age, you’re less likely to die, that was the article by Jeffrey Harris, I’m going to refer to it a bit, but it is true that younger individuals are at lower risk of dying. Older individuals are doing a better job. I think they’re aware of the risk relative to them. I also think across the board we’re doing a much better job in the U.S. of protecting some of our vulnerable populations, the nursing homes, limiting visitation, testing, frequent testing, actually.

Next bit of good news, I’m going to say the case fatality rate, this ties in, has dropped in the U.S. I just want to take a moment and reflect on why this might be the case. I appreciate everyone, I get a lot of communication, a lot of emails, and I really appreciate that because I think that communicating during the pandemic is critical so that I hear other people’s ideas. It gives me the ability to think about my ideas in that context. Not a time to silo up. It’s a time for people to talk and communicate and share their thoughts and experiences.

I was emailing this week with Jeffrey Harris, he’s another MD, PhD. About 1% of us MDs also have our PhD., and he’s a professor of economics at MIT. I don’t know if it’s affectionately called MIT, but that’s what my oldest daughter calls it. We were emailing a little bit about a phenomenon that the people probably know about from other disciplines, the whole concept of learning by doing.

He actually wrote an interesting article that specifically focused on this issue in COVID entitled, “Declining COVID-19 Case Mortality: Learning by Doing.” I think that this article may resonate with a lot of people. This is not just medicine, but when you do something for a while, there’s a lot of little things that you start getting that early on you just get wrong once you’re developing a certain experience. I think non-medical people can think this makes sense there as well.

I’ve been mentioning a few times that one of my colleagues at the hospital developed COVID-19 and her care was quite a bit different than I think some of the care that we were delivering back in March and April. One of the things that just Jeffrey and I were emailing back and forth about was that with her, here we were in that like week four, week five, her white blood cell count started to go up. Discuss with the team, this is right about when we start seeing infections. Let’s start the antibiotics now, and then let’s send off those blood cultures before the first dose. The next day, the blood cultures come back positive, but she’s already on antibiotics because we know what to expect.

As we know with a lot of things in medicine, that 24 hours of getting her on appropriate therapy because we anticipated this, that makes a difference. We’re getting enough sleep, in general, people and things are calmer. There actually are veterans with us in the trenches so when someone is seeing their first few cases, there’s those of us with experience who can walk through, “Okay, this is what we expect, etc.” Because it is amazing to see that for each specific age group, we’re seeing less people dying. And as we’ve talked about many times, not a lot of randomized control trials that we’re drawing on. Somehow, the care is getting better.

This translates to medicine where outcomes are consistently better for those that seem to do more in a particular area, be it surgeons, medical doctors, nurses. I think our physician listeners might find that there is some insight in, I’m going to attribute Jeff’s comments, but also I think our listeners in other fields. After you’ve been doing something for a while, as some people in the lab say, you develop good hands. The first week, I’m back in the lab. I just don’t expect anything to work. [chuckles] I plan a few experiments, then I think about the second week, the training wheels can come off and I’m back in the saddle.

Vaccine trials are really up and running and more are starting all around the world and here in the U.S. As a teaser, I like to give people a warning, next week, I’m going to talk a little more at a clinician-patient level about the different vaccines. I know TWiV, the science has started to come more into this. As these trials open, I think a lot of physicians and patients are going to have questions about, “Should I sign up? Should I be part of a trial? If I am, which trial should I sign up for?”

With all this Warp Speed stuff going on, you need volunteers in the trials. They want 30,000 people in each one of these trials. You’ve got to get those 30,000 people. You’ve got to get them in the trial in a rather quick way. Still in my good news, I’m going to say one of the things that we’ve been working on at UnitedHealth Group is something called Readiness Cohorts. I don’t know if our listeners are familiar with that? People sign up and basically say, “Hey, if there’s a trial, I would be interested.” Then, what we can do is look at certain areas of the country where we think there’s going to be a high enough burden of disease. Because you do it in New York right now, not a lot of people getting infected.

We can trigger the emails, the correspondence, to go out to these people in areas that we see as burgeoning hot spots. If you’re going to do 30,000 people, you want a certain percentage of those people to get exposed to the virus and the people with the vaccines to get less disease than people without. There’s really a lot of positive things going on, a lot of coordination here between different groups to make sure that those vaccine trials get filled quickly so we can get that information. Because you’ve got to get your vaccine trial up and running, you’ve got to get the volunteers in there, you’ve got to get them vaccinated, and then it takes time to look at exposures.

I’m going to move into transmission testing in schools. I’m going to try to be positive. Our listeners may remember that the U.S. Government has embraced the idea of using rapid antigen tests to reopen the economy and they’ve already committed close to $1 billion to purchase over 100 million of some of these rapid tests. The news that came out the last few days, which I thought was really positive, it was like, “What are they going to do with those tests?” I think Dickson thought they were going to burn them or something. [laughs] He’s not as positive as I am at the moment.

The plan was the majority of these are going to go to the governors of the different states to help support school re-openings and other critical tasks. I think people are listening, but I want to go back a little. We give Michael Mina and TWiV a lot of credit, but now I’m going to try to get hate mail from the coastal liberal elites here.


DG: I want to point out, Deborah Birx was actually pushing for rapid, limited resulting delay testing as early as April. Everything they do in Washington is wrong, but remember they’re the ones that actually rolled out the Abbott ID NOW for screening, really a let’s-get-back-to-work at the White House. They weren’t testing people with symptoms, they were just saying, “Everyone that walks in the door, let’s not have people with infection come in here.”

There was a little bit of bad press there I guess, and I do worry that we lost some time, but I was going back to actually some of her earlier articles in early April where she was saying, “Listen, we could do one million of these tests, we’ve done 80,000. What’s going on? Let’s start embracing rapid testing.” I feel like this is bipartisan where we all want testing without resulting delays.

The other thing I’ll talk about is we’ve been working with a lot of the schools, and I get emails, so thank you, Vincent, for connecting people with me so we can help with testing. I want to share a little bit, a few of the different approaches we’ve been using to get, I’ll call it get-around-the-bureaucracy. You get on the phone with the superintendent or you communicate with the superintendent, “Oh, our budgets, we already have everything in place. We started planning this. It’s all ready to go.” We ask, “What about testing?” They say, “Oh, we don’t have money,” or, “We don’t have plans for that.”

What we’ve done in several areas is we just go to the teachers’ associations. We go to the PTA, the parent-teachers association, and we basically say we are willing to set up no-cost-to-anyone access to testing. We’ll give you a phone number, we’ll give you a contact person. In a lot of schools, we’ve actually started firing this up. Don’t feel like your superintendent can block your access to testing.

They may not orchestrate it at a school level, they may not orchestrate it at a school district level, but parent-teachers associations, teachers’ associations, we’re always happy to reach out. Our person who’s in charge of our Let’s Get Back Testing Program and our Let’s Give Back Testing Program, Bonnie Simmons, people, feel free to contact her. Vincent, you’re welcome to put her contact stuff in the show notes We are excited to give access to testing in our area in the Tri-State with our Testinator Program. [laughs] Reach out to health groups in your area, call your doctors. Let’s try to get testing really out there.

VR: Daniel, what do you think about New York City’s plan to test in the public schools, selected students and faculty twice a month?

DG: That’s not enough. We’ve been reaching out, and actually several of the schools particularly in, I’ll say lower-income areas, and part of our Let’s Give Back program, a lot of the kids in one of the schools that I was working on, 80% of the attendees are below the poverty line. We talk about the lick-a-stick testing in homes, a lot of these kids, the home environment is not great.

What we’re trying to coordinate with them is more frequent testing at the end of the school day, and then what we’ll do is we’ll do it through these high throughput platforms. If we do get one of these positives, that need to be indeterminate, it needs to be dealt with. What we’ll do is when they come back, do a rapid testing to verify if that’s an issue. Every two weeks, it’s not enough. There’s different solutions that are going to work for different areas. There’s actually a lot of the New York City schools that we’re trying to jump in and help them as far as testing goes.

As mentioned, it isn’t always the school district that’s onboard, there’s various political reasons why they may or may not want to endorse or affiliate or whatever it’s called. We’re not trying to endorse or affiliate or anything. We’re just trying to get access to testing so that we’re not sending kids into an environment where they spread the virus. I say, and I try to be completely positive here, but now I’m going to step back and just– People want the truth.

I was talking to some clinicians today, sometimes the kids don’t get that sick, but sometimes the parents get that sick. We had a lot of mothers and fathers who died this spring in New York and now the kids are orphans, and that’s a tragedy for the children. If you don’t do the right thing by our kids and their parents get sick and die, you have not done the right thing by our kids. Really, come on, let’s make this happen.

Treatment and drug updates, there was an interesting pre-print out of Spain on convalescent plasma for COVID-19. Really what this was, they took a bunch of trials that were having trouble enrolling and they put it all together. The title was “Convalescent Plasma for COVID-19: A Multicenter Randomized Clinical Trial.” What they did is they brought a number of trials together because you had the trial with the 81 patients, and then it stopped too soon.

We’re trying to get more information on plasma. Maybe if you get it earlier, it’s a little bit better, but the jury is still out. Not only is the jury out, but I think we have better stuff coming. People are starting to refer to these monoclonal cocktails, monoclonal antibody, either cocktails or just specific as convalescent plasma on steroids, so it ties into our next topic. It’s all the stuff you want without the stuff you don’t want. They’re getting all those clotting factors out and they’re just giving you the antibodies that you’re after.

We’ll jump to steroids, with that being said. This was a study that was published in JAMA, “Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19.” Here, they took seven pooled randomized studies and they suggested really along the lines of saying, “A consistent approximately 30% reduction in mortality.”

When they say this 30% reduction, we’re talking about a consistent absolute 3% reduction in mortality. You go from a 25.7% mortality down to a 22.9%. Just keep this in context. We’re chipping away at the iceberg. Someone kicked the side of the Titanic, and there’s a little bit of a dent. This is not, “Take off your mask and go to those parties.”

VR: Why do you think monoclonals are going to be better? They’re going to be more potent, less of the other bad things like the clotting factors, so forth?

DG: Two things, I think. One is you’re not going to have the clotting factors. I don’t think we want the clotting factors. There’s also going to be a consistency in the level of the antibodies. Because they always try to take these studies and then do these subanalyses where you look at levels of neutralizing antibody in the convalescent plasma that was given. It does look like there’s a trend towards better outcomes if they have higher levels.

I’m also hoping that these trials are, and it looks like they will be, targeting earlier disease. In the little thing that I mentioned about the 81 patients, those patients were getting it in the first eight days on average, and we think this is mainly an antiviral. Some people think it has some immunomodulatory effects, I’m not sure about that. Maybe this is Niels Jerne anti-idiotype network effect. I think we’re mainly thinking of this as a, “Neutralize that virus,” approach.

VR: Is there any attempt to try prophylactic trials where you would give a healthcare or frontline worker a bolus of monoclonal and it would protect them for three months? That could be helpful, right?

DG: Yes. I don’t know if you remember, I’m sure you don’t. [chuckle] There was a conference at Columbia that a select group was allowed to attend, it was like the VIP people. We had just earlier that day met with Regeneron and offered specifically to do that trial and basically said in the same conversation, “We’re going to create a relationship with Regeneron to use urgent care centers to recruit early-stage people.” Also, we pitched the idea of, “Why don’t we take high-risk people, maybe people in the ERs, etc.,” and you’d be amazed, well, you wouldn’t be amazed. A lot of ER docs would love to have the opportunity to participate in that kind of a trial.

VR: Is that happening?

DG: It’s in the works, so hopefully it’s going to happen. Actually, that’s where I got where we’re looking at these monoclonal antibodies individually, cocktails. There’s also people looking at interferon therapies, antiviral specifically designed for SARS-CoV-2. Stay tuned, there’s going to be a lot more coming here. Previously, we just grabbed what was on the shelf and hoped it worked, but now we’ve got people actively working on specific therapies.

Vaccines, I’m just going to do some basics because I plan to give that physician-patient primer next week. I think there’s several audiences that listen to us; there’s the physicians, there’s the patients, and then there’s the hardcore scientists. Sometimes I wish there was a little more hardcore science because I want a like deeper discussion into the adenoviral vectors, and the messing with the e-genes, etc. I think, for a lot of people, they need a different level and that’s what I’m going to try to do.

Just to get people up to speed, there are some moving targets, but we have lots of vaccines, 36 vaccines are in clinical trials in humans. Over 90 are in preclinical trials, being tested in animals. Just to start to lay the framework for people, people are probably starting to hear about Phase I, Phase II, and Phase III trials. Phase I are the safety trials, these are small trials. Just seeing like, “Are people okay or is there some stimulation of the immune system?”

Phase II, these are the expanded trials where you move up to hundreds of people, broader age, and again looking at safety and immune stimulation. As our listeners probably know, one/two has become the paradigm for COVID-19. We just jump right into the deep end. Phase III is the true efficacy trial. Give me neutralizing antibodies, give me surrogate markers, etc., but what we really want to know is, “If I get that vaccine, am I less likely to get sick?”

Those trials are firing up and to do these trials, the FDA is involved in the U.S. and they’ve got to give you permission before you can go ahead and perform these trials. We’re already starting to enroll volunteers for these trials, more trials are about to start to enroll. There’s going to be several different options out there for, and I’m going to talk more about this next time, just to put the path in the brain here. We’re going to have whole inactivated and attenuated whole virus vaccines, replicating and non-replicating viral vector vaccines, DNA and RNA nucleic acid vaccines, protein subunit, and virus-like particle protein-based vaccines.

Next time, we’ll go a little bit more into this, but I’ve been asked to do this for UnitedHealth Groups so I’m double-timing. I’m going to use the primer that I’m creating for the patients and clinicians there and share it. I think we’ve got exciting stuff on the horizon. The reason I think this is so important is as I started off with, we’re going to need patients and physicians willing to support this effort so we can fill these trials. Because vaccines are not something you learn by doing, this is something that really needs proper trials.

VR: Daniel, you said something interesting, you said these Phase III trials are ramping up. Just this week, the CDC said we’re going to have them licensed and ready to go by November 1. How is that possible? Every vaccinologist I know says it’s impossible, what do you think?

DG: It’s called magic.


DG: I was having a conversation with Dr. Kaplan, he’s the head of the ER out at Plainview. He’s a gentleman who actually got COVID-19 back end of March, early April. I’m probably violating his HIPAA, but sorry, Dr. Kaplan. [chuckles] He got quite sick and then he had an antibody test four weeks later, nothing. Had another antibody test because he just couldn’t believe it, nothing. This guy was PCR positive. He was out of work for weeks.

We were talking again today, he’s like, “Daniel, I couldn’t even watch TV I was so sick.” That’s what you do when you’re sick, you watch TV. He’s like, “I couldn’t even look at a screen.” He was basically saying, I want a vaccine. I don’t care. I was so sick last time. I’m willing to roll the dice. I’m not sure that’s so prudent as I try to lay things out. Some vaccines have already started, already did start trials in Brazil and other parts of the world, in Europe.

The approval process outside the U.S. is a little bit quicker, and this is the thalidomide thing that we always learned about where sometimes something gets out there and everyone thinks it’s great and then you realize a year later, “Oh, my gosh, what a tragedy?” The thalidomide, our listeners may not know about this, but this was a medicine that was used to treat pregnant women with nausea, with vomiting, and the impact it had was when the babies were born, a certain percent of them were born without lips. Their hands and feet were just basically attached at the trunk. It interfered with development and this was just tragic. These individuals spent their life with hands and feet attached to the trunk.

That’s not going to happen with vaccines. Vaccines are not going to, I don’t think, cause these things. As a lot of our listeners probably know, the virus, you always say on that catchline, “Viruses, the ones that make you sick.” Coronavirus, it’s the immune response that makes you sick. What we’re doing with these vaccines is we’re giving you the immune response and then we’re just hoping it’s not the immune response that makes you sick.

Are you going to have antibodies that are going to cross-react with your vascular, with your blood vessels? Are you going to end up paralyzed? As we saw when people developed antibodies, suddenly they couldn’t walk and they need to be on a ventilator. We may start to get some preliminary efficacy data in the next few months but we’re not going to get the safety data. It takes time. Things take time.

I know we’re in the “I want my information now” generation. Just like my quote from last week, from one of Mao’s compatriots, Joe Stalin, it’s going to take time. We will not know by November how safe these vaccines are. I think that that’s a little frightening to a lot of people I talked to that these vaccines are going to be out there, people are going to be encouraged to take them, and we already have enough people who are anti-vaccines. The last thing we want to do is if you have a disaster and you expand the anti-vaccine population, it’s a disaster because vaccines work when enough of the population get it.

There was a recent survey where the headline was, “Majority of Americans Say They Are Willing To Get A COVID-19 Vaccine,” and it was in small print, “53% are onboard.” That’s not enough. You drop any lower, that 53%, you’re already not enough. You drop any lower, you’re really not enough. So if you rush this, you can end up really being in a bad situation.

VR: When the CDC director said we’re going to do it in November, for sure he said, we’re going to do it. It makes me think that they’ve decided to release them based on the animal studies and the Phase I and II that have already been done, and that seems like a bad idea. As you know, Gerald Ford rushed a swine flu vaccine back in 1970 and it ended up giving people, hundreds of people, Guillain-Barré.

DG: Yes. I don’t know if people have ever seen Guillain-Barré, but I’ve seen this in a lot of individuals. We saw it quite often in COVID-19, where an individual would start to get better, the antibodies would come up and now they’re paralyzed. What is incredibly frightening, you can’t move your legs, you start having trouble breathing, and it’s an ascending paralysis.

It starts with, I can’t move my feet, I can’t move my legs. This disease, the antibodies against spike protein, we think, trigger this. We also see cognitive impacts. We see what looks like– when those antibodies come up, people have issues with cognitive function. We see vasculitis, we see the antibodies cross-reacting and destroying platelets. This is very worrisome.

VR: I’m making a point of this because I think clinicians and scientists need to speak up and object because it seems like CDC has already decided. This is really inappropriate as Peter Hotez and Michael Osterholm and many others have already said.

DG: Yes. They already have a plan for who gets it first. The idea is first, it’s going to go to the “vulnerable populations.” They’re going to kill off our nursing home patients and then we’re going to kill off our healthcare workers because we’ll get it next. I’m not excited. I was frightened back when everyone was drinking bleach and swallowing flashlights, this is more frightening. It’s more frightening because I think actually reasonable people will think it’s okay because the government has okayed the vaccine. Not to be partisan but people, really think it through. Don’t just take something because you could do permanent damage. All right.

Understanding the course of COVID-19. I’m finding that for my patients it helps that providers actually understand the clinical course. There does seem to be this whole specific pattern of people get better, they have a sort of a lull where they feel like it’s all good, and then there’s this second hump when people get a lot of symptoms. We actually admitted a person this week, it really was– Well, it hit several things.

Here’s a gentleman, who’s a security guard at the hospital and he was relaying to me how over the winter he worked night shifts. His job was, the morgue was full and his job was to figure out how many of the bodies he could cram into the limited freezer space. What a horrible job he does for months, right? He’s doing this every night and the death toll was really high in New York to the point where we had an overflow of the hospital freezers and we had refrigerator trucks outside. This gentleman does not get COVID, he makes it all the way through. He protects himself, he wears his mask, he uses all the right proper preventative precautions, but what’s his other job, he’s a custodian at one of the schools.

They open up the school, he goes to work, and the guy he works with gives him COVID. He almost ends up intubated three times, barely able to stay off the ventilator. He feels better and then he has this second hump where he develops severe abdominal pain and the inflammatory markers go up again. It helps, I think, for people. We submitted a woman with this today where they get better and then they have this hump where the hair falls out, the fatigue, the trouble breathing, the muscle pains. I think it helps for people that we understand the clinical course, that we don’t just think they’re malingering.

There’s a few things we’ve actually learned that seem helpful. It would be great if we had some more studies here, but Tylenol was surprisingly helpful for some people, particularly for the prolonged fevers. We have some folks having fevers eight, 10 weeks out, but it gradually moves down. Your week moving average just keeps getting a little bit lower. Mucomyst or the Acetylcysteine has helped quite a number of people early on, or when they get these thick pulmonary secretions.

Antihistamine sometimes help with sleep, sleep is often an issue, but also this weird where they say, “Oh my gosh, I feel like I got too much sun today,” this histamine reaction. The non-steroidal anti-inflammatories, I feel terrible that we held them back for a lot of people. The muscle aches, all the myalgias, just taking an Alevebefore bed or maybe twice a day, taking Naproxen or ibuprofen or aspirin or Indomethacin. Whatever one you want to take, people really seem to be responding well.

Occasionally, we do a low-dose short course of steroids when people tend to have the second hump flare. Again, it would be nice to study this, this is all sort of shared experiences. I’ll also say to be positive, there was some articles recently about the COVID tail in children and it is much less common in children. There’ve been a few reports, but that’s what it is, it’s a handful of reports. I check in with the head of our pediatrics program here Jay Berger, who’s a TWiV listener and fortunately, kids are also usually spared of that. I think that’s it for my clinical update.

VR A couple of questions, quick questions for you. I think the first one is from Chuck who wanted to know how to get in touch about the Testinator Program, but I think you gave us that information. We’ll provide Bonnie Simmons’ email, right?

DG: Bonnie Simmons. [crosstalk] It’s in our show notes now. Reach out to her, flood her with your requests for coordination for access to testing.

VR: Okay. A number of listeners have written in asking for your opinion on this Bradykinin Hypothesis, which was published in eLife not too long ago back in July. They’re wondering, the paper is “A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm.” What are your thoughts on that?

DG: It’s interesting. A friend of mine, colleague, Alex Shalshin, he’s a pulmonologist, and he and I took care of a lot of COVID patients together early on. We would quiz each other like, “Okay, do you think it’s COVID or not?” Waiting to see who had the highest percent success of figuring out if it was COVID or not. The nice thing was as time went on, you basically could be like, “Yes, it’s COVID. It’s all COVID.” [chuckles] Until he actually got sick, he got sick himself, but he’s doing better.

He never had a lot of hair to begin with, it’s just he and I have a very similar frequency with which we need to go to the barber, but he sent me the Supercomputer Analyzed COVID-19, the Bradykinin hypothesis. It is very interesting because when you look at all the impacts of Bradykinin– I feel like I’m going to have to give people some context here. There’s a system that is tied into both inflammation and blood pressure regulation. This involves renin, it involves the angiotensin-converting enzymes, and it actually ties in with, not only constriction or dilation of blood vessels, but also their permeability.

When you start looking at all the different things we observe in COVID-19, a lot of them could be explained by a direct impact of Bradykinin. There was a paper that was published, actually, a little while back, took a little while to get attention here, I think it was published in July maybe, where they actually took lavages from patients who were sick with COVID-19 and they did RNA analysis to look at gene expression. It actually suggested that there was this Bradykinin over production dysregulation.

I know there’s a bunch of different early studies looking at this, and this stuff, I think, is great. One day we won’t care, but we’re not there yet. But the different phases, when they come to us in the hospital, the virus is usually on the way out. The antivirals, things like remdesivir, even if remdesivir was super potent, the horse is out of the barn. Now we’re dealing with this whole cytokine storm, now it’s being suggested that part of this storm is the Bradykinin storm. I’m fascinated for looking at, are there ways to modulate this inflammatory response? Not just for COVID, but this may be an issue for other people that have this acute respiratory distress syndrome or other inflammatory responses.

VR: Okay. One more from Stephen Bickel, who’s the medical director at the Flagler and Volusia County Health Departments. “Dr. Griffin, you recommended confirmation of positive results when doing surveillance screening testing. A, is there a rough community prevalence level you use to guide this, or just anytime you’re doing surveillance testing?”

DG: Yes, there is a rough prevalent. Really, it’s the “What is your pretest probability going into this?” I’m going to go back to May, people have to listen to TWiV, we were probably in the teens back then, 16-17 maybe. You’re going to have to Google, people, Google, “Positive Predictive Value” on TWiV.

I talked a little bit about you take a test that is 99% specific. That doesn’t mean that 1% of everyone that comes back positive, that you’re missing or getting. You have to take that number and look at it in the context of what percent of the people that you’re testing are potentially positive? Your prevalence in your testing population. It’s not necessarily just your prevalence in your community, but it’s prevalence in that particular population.

When you get to a prevalence in the population, you’re testing of less than 1%, the majority of those initial positive tests, over 50% will be not true positives, so they’ll be false. When you’re less than 1%, then you’ve got to do an orthogonal approach. You’ve got to do a confirmatory test. Once you get to up to about 5%, now you’re going to say 80% of those positives are true positives. Those are your numbers or break-offs. Less than 1%, you need orthogonal testing. Greater than 5%, you’re going to be positive most of the time. That, I think, helps you. As far as what is that second test? It could be the same test in all honesty. Because it’s an issue with the test design, it’s not an issue with the person.

Some people prefer a different test to be used. That’s fine. I think that’s more aesthetic than actual science. What we prefer to use is a rapid test that second time because you don’t want to say like, “Oh, you may be positive. I’ll tell you in a day or two or three.” You want to hopefully, within eight minutes, be able to say, “We just checked you, it’s negative.” This is probably the best way to do this. I think any time you’re going to have a testing program, you need to have an approach to, “What do you do if a test comes out positive in potentially a population with a less than 1% prevalence?”

VR: Finally, he says he’s trying to calculate sensitivity and specificity for contagiousness versus sensitivity and the specificity of diagnosing the infection. Because my guess is that the antigen tests are very slightly less sensitive, but actually a fair amount more specific for contagiousness. Have you or your colleagues tried to estimate these values or have any studies been published?

DG: I think we talked about it last time. The white paper that I wrote up for UnitedHealth Group that we shared, and, actually, we’re trying to put this together into a model. One of the problems with the tests that detect very low levels of RNA is you’re detecting for weeks, months in some cases, past that infectious period. The question of contagiousness, the antigen tests are much more specific for contagiousness, particularly if you do anterior nares.

I will say, saliva actually in the studies I’ve seen, seems to have very similar levels of RNA to middle turbinate, so I’m okay with saliva as well. I think the specificity is pretty similar between the two different platforms, in that 99%, 98.7% range, but the ability to recognize infection versus overdiagnosis people with low levels of RNA, the antigen tests are better. They’re better tests for answering certain questions.

VR: All right. That’s our weekly COVID-19 update with Dr. Daniel Griffin. Thank you, Daniel.

DG: Thank you.

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