TWiV 621 An Era of COVID-19 Poppycock

This Week in Virology

Hosts: Vincent Racaniello, Dickson Despommier, Alan Dove, Rich Condit, Kathy Spindler, and Brianne Barker

Guests: Daniel Griffin and Chuck Knirsch

Aired 31 May 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 621, recorded on May 29th, 2020. I’m Vincent Racaniello, and you’re listening to the podcast all about viruses. Joining me today from Fort Lee, New Jersey, Dickson Despommier.

Dickson Despommier: Good afternoon, Vincent. It’s a hot and humid and muggy day out there.

VR: Why is it called Fort Lee, by the way?

DD: It was named after a general.

VR: Okay. Robert E. Lee?

DD: No, no, this was a general in Washington’s army.

VR: Oh, way before.

DD: Way before.

VR: Okay. Also joining us from Austin, Texas, Rich Condit.

Rich Condit: Hi, everybody.

DD: Hey, Rich.

RC: We’ve got just a gorgeous day here. It’s 85 degrees, partly cloudy, no mosquitoes. I’ve been sitting out on my back porch gazing over my garden and cramming for TWiV. Cool. All good.

VR: Why is it called Austin?

RC: Because of Stephen Austin, who was instrumental in the settling of Texas early on. Okay.

VR: From Western Massachusetts, it’s Alan Dove.

Alan Dove: Good to be here. It’s called Western Massachusetts to distinguish it from the area with the high cost of living.

[laughter]

VR: Is that right?

AD: Well, because it’s on the Western side.

VR: Is it cheaper than the Eastern side?

AD: Oh, vastly. Yes.

VR: Yes, but The Berkshires are not cheap, right?

AD: Depends on where you are. There are some very, very nice areas up there and resorts and that kind of thing, but then there’s also a lot of just rural area.

VR: Yes. Got it. From Southeastern Michigan, Kathy Spindler.

Kathy Spindler: Hi, everybody. Ann Arbor is named after the wives of the two founders of the city.

DD: You mean Ann and Arbor?

[laughter]

KS: Also because of trees.

VR: Ah, it’s not named after Arboviruses?

KS: No. Did you make that a question on your exam?

VR: No, I will though. The next exam, this summer, I’m going put that on.

DD: That’s right. That’s one of the choices that’s–

VR: That’s very good. From Madison, New Jersey, Brianne Barker.

Brianne Barker: Hi, good to be here. It is 81 and sunny, and I’m pretty sure Madison is named after the former president.

DD: Yes.

BB: Who is a character in Hamilton, as is General Lee, who I think is the namesake of Fort Lee.

DD: Exactly.

VR: You know, there’s a Clinton, New Jersey, and during the impeachment hearings, they wanted to change the name of the town.

[laughter]

DD: I think that was named after DeWitt Clinton, however.

BB: I would assume it was.

VR: Yes, it was named after, but this is how people think.

DD: It’s true.

VR: Some people are Covidiots.

DD: Or that they don’t think.

VR: What do you think?

BB: I forgot to tell you the temperature here. It’s 60, which is about 19 Celsius.

VR: 60, oh.

BB: Yes. It dropped considerably. I think you have some cool weather coming your way.

KS: I hope so.

AD: Look forward to it.

VR: Speaking of temperature, sometimes in the morning, my wife will say, “What’s the temperature gonna be today?” I look at my phone, it’s in Celsius. I tell her and she gets really mad.

[laughter]

VR: I don’t do the conversion.

AD: You keep doing it?

VR: Yes, but I never learned after–

BB: Have you taught her the simple conversion of 16 to 61, 28 to 82. That could make her a little happier.

VR: Then I have to go to her phone, which has it in Fahrenheit, because I don’t know how to convert. I want to learn in Celsius how it feels. Right?

DD: Yes.

VR: Because you’ve spent your whole life learning in Fahrenheit. That’s 32 fields, etc.

DD: That’s right.

VR: I can say yes, 20, that’s room temperature. I got that.

DD: I’m retired. I’m not doing that. [crosstalk] There’s too much effort. I avoid things that involve too much effort. [chuckles]

VR: Also joining us from New York State, Daniel Griffin.

DD: Hello, everyone.

VR: Welcome back. How’s your week been?

DG: You know, it has been a good week. I got a little time off this weekend just before I went into this 11-day straight stretch that I’m now in the midst of. No, it’s good. I guess I’ll be relating all that to our listeners, but, yes, it’s been good.

VR: Also joining us as a guest tonight, he’s a member of Parasites Without Borders, clinical researchers, and was last on TWiP number 30, Chuck Knirsch, welcome to TWiV.

Chuck Knirsch: Thank you, Vincent, and hello, Daniel.

DG: It’s good to have you here, Chuck. Usually, when the three of us get together, we’ve got Dickson in tow, and we’re over at Coogans, which is a local Irish, what is it? Sort of restaurant-tavern?

VR: Yes, which is no longer.

DG: Oh, is it just temporarily or has it–

VR: They’ve announced they’re out of business.

DG: Oh my gosh.

VR: We can’t go there anymore.

DG: That was a landmark. That is really a disappointment. That’s sad.

VR: Yes. It is too bad. It was good to get together, and I assume there’ll be something else. We’ll just have to do that. Daniel, it is time, it’s been a week since we last spoke, time to have a clinical update from you.

DG: Okay. Well, a lot of clinicians listen to this, but I know a lot of non-clinicians listen as well. I’ll try to give a balance here, make sure I don’t get too technical. I’ve started, in my head, titling these little clinical updates. This, I’m going to call, “The Good, The Bad, and The Ugly.” The reason I do that is I always promise that I’m going give good news, and if I don’t give it right up front, I just don’t. [chuckles] I was talking to my mom via phone. She’s been evacuated out of the city since actually the end of February when I had this crazy idea there might be a pandemic on the horizon and I wanted them safe. She was saying, “Just give me good news, make it up if you need to.”

[laughter]

DG: That was the traditional Irish. I remember my grandmother saying, “Never let the facts get in the way of a good story, Daniel.” [laughs] I will start with some good news. I will say that all the shelter-in-place and all the social distancing and all the social cohorting and the quarantining and all the many other measures that were employed in the New York area were effective. The numbers are definitely down. The number of patients in the hospital with COVID-19 is really down. Many parts of the country certainly are seeing increases, but I could definitely say, you know, from a bit of good news news, we are doing well in the New York area. The number of deaths are down. That’ll be my initial bit of good news.

My second bit of good news is that people are starting to look, in the New York area, at opening up. Actually, across the country, there’s a lot of opening up that people are doing and looking at doing. This is all state-by-state variations. I’m starting to get a lot of questions now from clinicians. So, I’ve put some information about, how do we handle this? How do we handle opening back up? How do we handle people going back to work?

A couple things I will say is that CDC still has the two tracks. One is the non-test based paradigm, and one is the test-based paradigm. Most of the clinicians got very used to the non-test based paradigm, and a lot of this had to do with access to tests. If you start saying, “Oh, everyone needs a test followed by another test 24 hours before they can leave quarantine, go back to the workplace.” What was happening is that was really creating a problem because, how do you access those tests? The turnaround time was quite lengthy. It was actually out to about seven and nine days at one point.

Very quickly, people got used to a non-test based paradigm. Initially, it was, “If you’ve been sick for more than seven days and you’ve had three days or more of no symptoms, then good to go.” That got a little bit extended out to 10 days. Then we started getting this return to a test-based paradigm. I think part of this was as we were seeing numbers go down. Now, I get a lot of questions. Here’s a person, they maybe were never even tested up front, but the diagnosis was made clinically.

Now the employers are starting– And I think this is interesting. The employers are starting to request that the person have a PCR negative. Interesting enough, some employers are starting to request serology testing, which is very interesting. I will comment on what you’re supposed to do. In general, the CDC is giving us guidance. That’s great, but if the employer is demanding a PCR test and basically telling the patient that’s required, there is a CDC guidance on the PCR testing.

In the hospital, actually, because of the executive order from Cuomo, which we talked a little bit about last time, a lot of the facilities are requiring a negative PCR test before they’ll accept people back. I’m going say, as I mentioned, I listen to the other TWiV episodes once I tune off. It takes me about a week because it’s like little snippets when I get a bit of time. We’re running into a bit of resistance as we return to the contact tracing paradigm, and this is the Tetris. So, the test-trace-isolate paradigm. And part of it is that people are actually fearful, they’re afraid that if they submit for a test, once they get that one positive test, then a couple things are going to happen.

One, now they’ve entered into the testing paradigm, and it’s going to be required that they get a negative test before they can return to work. They’re also worried, and I had a firsthand conversation with this just recently, that the Department of Health will track them down, and will actually then track down their contacts, will restrict their freedom, will prevent them from going to work, which a lot of people really are desperate to do now. It’s been interesting in that clinicians are starting to hear when a patient calls and they’re concerned, they get pushback sometime if they say, “Oh, this sounds concerning. I think we should get a test.”

The patient may say, “No, let’s not, because if you test me and it’s positive, I’m worried.” Early on, when this first started with healthcare workers, we would have the issue where you might get a phone call and it was, “Oh, you’ve had an exposure, you need to now go home and self-quarantine and not work for 14 days.” People are worried that that’s going to happen. I had one of my colleagues, who’s an infectious disease doctor, they got a call a few days back, Dr. So-and-So, preserve their anonymity, “It seems as though you may have had a COVID exposure.”

Their response jokingly was, “Really? Just one?” There was silence, and then, “This is not a laughing matter.” They’re like, “Okay, oh my gosh.” There was almost this police-type enforcement. This story, here was a person, initially who was PCR negative, then was PCR positive, and now they had this exposure, and there was this concern about, “Okay, are you going to go back to that paradigm?” We are now going to tell this infectious disease doctor that they need to go home for 14 days to quarantine. People are worried about the Tetris approach. This will be interesting, and hopefully, we have some Department of Health people listening.

We’re going to need a little bit of communication with the public, so that this fear doesn’t go awry. Also, we moved away from a testing paradigm at the guidance of the CDC and a lot of physicians saying, “The testing needs to be prioritized. It’s limited.” We’re starting to see these longer periods of time between the test being taken and the result. That also creates an issue too. Just things are opening up and sliding here into the bad.

The next would be the silent spreaders. We’re starting to worry about this. As people are getting tested for surgery, we’re starting to realize people without symptoms, quite a number of them, are coming up positive. That’s beginning to increase and reinforce this message about, “There are people out there who never have any symptoms, but you test them and they’re positive.” We’re seeing this even in the hospital, creates an infection control issue. Here’s someone who came in for something else, but the decision is made to send them to a rehab facility, they get a PCR test, because that’s required. Now it comes back positive, and the whole question is, “What’s going on?” That’s a challenge.

VR: That’ll give you an idea of how many people are infected.

DG: Yes.

VR: Do you have any sense of numbers so far? What fraction of people coming in for electives are positive?

DG: The number I heard was, it was about 10 or 15% of people who we were just screening are coming back positive, so it’s at this low rate.

VR: Wow. Wow.

DG: It’s a little higher than you would think. It’s actually similar to what they told us was infected so far in the population from some of those early serology assays, but we’re going to get to those, because in “The Bad and Ugly,” we’re going to get into some of the issues with the serology testing. An update on the late stage issues, and this is where I always feel like, “Okay, things are getting better,” and I’m an optimist for a moment, but then, in adults, we’re seeing this issue that we brought up several times with really prolonged PCR positivity, where if you’re trying to get someone out of the hospital, out of quarantine, we’re seeing the PCR staying positive out to two months.

We’re also, as I’ve discussed, we’re continuing to see the late-stage symptoms such as the joint pains, muscle pains, leg pains, we’re seeing this thick mucus, we’re seeing prolonged fever. I actually got a call from one of the infectious disease docs, who I’ve coordinated with in the last few months. He’s an older gentleman. I was taking care of his COVID patients in the hospital with the associated high exposure, with that, and then he was doing a bit of outpatient follow up and telehealth for me. He was saying, “Dan, I’m seeing people six, seven, eight weeks, they just keep having these low-grade fevers, 100, 100.8, 100.9, and it’s going for six to eight weeks.

I said, “Yes, that’s what we’re seeing too.” There was a recent paper where they say people that have mild symptoms, fevers might only last about eight days, people who get a little sicker might last about 14 days. Unfortunately, there’s a nice enough chunk of people here who continue to have a fever for two months, which is really a long time. There’s also a late-stage chronic diarrhea that my gastroenterology colleagues are seeing. We do all the testing, and it just is this chronic late-stage diarrhea that we don’t quite understand. The other thing — Yes, Chuck.

CK: Just a follow-up, just a follow-up question, because we’ve been trading some papers on the subject, and you’re at the frontline seeing a lot of these patients. Do you think it’d be worth getting some of these later stage people, especially the people with fever, and getting them close to a facility that might have a BSL-3 laboratory and seeing if there’s any correlation between the prolonged RNA PCR and actual presence of virus after you sample various tissue spaces?

DG: I would say, yes. This is a perfect issue that– We’ve seen in a bunch of people, and we just had an issue today, and I’m trying to clarify this, where people seem to have gotten better, and then they get worse again, and the PCRs are positive. We had a gentleman who was sick for quite a while, then he improved, was PCR negative twice, 24 hours apart, was moved out of the intensive care unit, was in a regular room, and now his white count is coming up, his inflammatory markers are coming up, he’s not doing very well, and his roommate just came back PCR positive for COVID, and his roommate came in 10 days before COVID negative.

So, we’re starting to worry about this issue. We keep saying there’s no second phase, we’re hoping people can’t be re-infected, but I’m actually quite concerned about, we’ve been using PCR, which I think people on TWiV have been really excellent about pointing out, this just tells us that we’re detecting genetic material, but still detecting genetic material 55 days after symptom onset with the second peak, which seems to have a rebound of all the inflammatory markers.

And now, I’m not sure what to make of the exposure here. The individual who is now COVID PCR positive was on a COVID-free floor, so we think his roommate was someone that had been negative for PCRs and now is having this rebound. There is a little concern, I’ll actually have to say, and I would love this BSL-3 approach to happen is, we really need to know, is there a rebound of the virus during this late stage, or can people become re-infected? I think those are two really critical issues.

VR: You’re going to have to do some infectivity assays?

DG: Yes. That’s what they have to do. They really have to do the plaque assays, do the viral culture, do all the confirmatory stuff, because with just the PCR, we don’t know. And this is critical for us to know because if we’re really taking people that maybe go through a low where the virus replication goes down but then rebounds, or people become re-infected, and then we’re putting those out in what we think of as a COVID negative region, or sending them back to the nursing homes, that also is a potential disaster. Because we thought like, “Oh, we’re doing a better job now.” We need to know.

The other thing, and this is “The Ugly,” this is what really I found upsetting, and we’re still trying to get a handle on a couple of late-stage things. People went home, they were doing better, some people never even got sick enough to come in the hospital, and now, I’m treating a large number of people with bacteremia. This is where bacteria is in the blood. I think I mentioned the first time I saw this, was like, “Oh, maybe it’s the steroids. Maybe it’s the immune modulators.” Now, we’re seeing people that never even came to the hospital, received no therapy at all, and now we’re seeing quite a bit of E Coli bacteremia, staph aureus bacteremia, so really a bit of an issue.

We saw an increased incidence thing, an eight-fold increase incidence of staph aureus pneumonias after influenza, but not necessary bacteremia. This is a concerning issue. Some of these bacteremias have been fatal. So, fatal and non-fatal bacteremia at about week three or four. These people have a consistent story. Some of them were never PCR positive, but they have a nice IgG serology test that gives us the connection along with the story.

Some people actually were in the hospital, had a PCR positive, and now here they are, three to four weeks later. We seem to add this to our stages of the disease. The next, and this is going to be interesting to see how true this is, but the issue with potential linkage to second trimester miscarriages, and so, there was actually a paper, it was a little bit back, in German. I watched it and I’m waiting to see how this pans out. Thrombotic issues, they say viral detection of the placenta, but again, it’s PCR.

We’re still seeing the pediatric multi-inflammatory syndrome. I’ve been in touch quite a bit with the pediatricians trying to come up with protocols for what we’re going to do going into the fall for dealing with– In fact, pediatricians are great. They see the kids no matter what. Somehow our pediatricians had an incredibly low rate of getting infected with Covid-19, like lower than the population average. But the pediatric multi-inflammatory syndrome, just to keep it on everyone’s radar, these kids tend to have fever. The median age is about 10, right?

We’ve seen it very young. We’ve seen it up to 20. A little bit more than half of them get this skin rash and the swelling of the lymph nodes in their neck. Most of them end up with conjunctivitis. The red eyes. The red and cracked lips in most of them. About a third of them are feeling kind of mentally not so there, a little fuzzy. Only about a third, a minority of them, have any respiratory symptoms. Most of them have the nausea, the diarrhea, the abdominal pain. The majority of them have some heart involvements, some left ventricular dysfunction, if you look.

VR: You said last time this was pretty rare, right?

DG: You know, I think that is reinforced. It’s still rare. These are small numbers at our local pediatric hospital, Cohen’s out here, 40-50 kids, which is several times higher than we would see normally of people having these vasculitides, but still, fortunately, a minority relative to the large number of cases we’ve seen.

CK: It looks like response to therapy is pretty good in a limited series we’re seeing so far, right?

DG: Yes, and that’s fortunate. The acute response to therapy looks really good. These people are getting the pooled IVIG, which people claim they don’t quite understand how that works. Yes, it is complicated.

[laughter]

DG: Also steroids. They tend to do both. In Classic Kawasaki’s, there’s usually a distinction and the Kobayashi criteria for all our Start Trek thing for trying to determine who will require steroids or not. Here, it looks like most people are just treating them with like IVIG and steroids. Yes, as you said, Chuck, these are good responses in general.

CK: It’s so important to make the diagnosis, so that they’d have access to the therapies.

DG: Yes, and that is key. That’s why there has been all these alerts going out, so that the diagnosis is made, these people are treated, and then they can do well. You don’t treat these people, and then, we’re worried about long-term impacts. An update on the virus and the serology testing, more bad news about the serology testing. CDC basically came out with a blanket statement, “About half of the test results you’re getting, you can’t trust.”

That’s a bit of an issue. We notice, I think I pointed out, that the healthcare system out here, that you’re able to report to the board. We did great, so a few of our employees got infected, and that a few of us were like, “Well, yes. But how come so many people were PCR positive and out of work?” It was issues with sensitivity. Actually, now the CDC has put on their website a whole little chart trying to educate us about positive predictive values. Which, good luck to them, I don’t think that’s going to succeed. [laughs] People seem to find it very challenging, like, “I already got sensitivity and specificity, and that took a lot of brain power. Now you’ve got positive predictive values based upon prevalence.”

It’s a bit of a challenge. They point out that even if you have a test, and they use a test, which is sensitivity 90%, specificity 95%, and they say, “If the disease has a prevalence of 2%, your positive predictive value is only 27%.” What they’re actually trying to do here is introduce, I think, the concept of orthogonal testing. I don’t know how familiar a lot of our listeners are to that. Orthogonal is ortho, meaning in alliance. You do one test and then you repeat the test. You’re using the results of the two tests.

If you have two positive tests, now your predictive value is up in the high 80s. Also, the negative predictive value is going to improve. That’s part of our– Before we send someone out, someone has been ill, they’ve been PCR positive, they’ve had COVID– What we like to do before we send them out, the COVID area, is two negative tests a little more than 24 hours apart. That’s our orthogonal testing. Add that to our list of things. The other thing [crosstalk] in testing. I know that this has been brought up, the issue about, “What happened to those oral tests? And what about those tests at-home?” There is the Robert Wood Johnson test. That’s FDA approved, the saliva test.

There’s a bunch of people that are hoping to be able to use this in part of the ‘open up phase.’ There’s also a few at-home tests that are now, you can actually go online this moment. You can click a few things and go to Everlywell. You can go letsgetchecked.com. You can actually go through, and for about a $100, you can get a test sent to your home. These are swab tests. Those are nary swabs. These are not oral tests, but trying to improve access to testing because that continues to be a challenge.

CK: You mail these back in, is that how it works?

DG: You do. You go online, they send it to you. You can get it normal mail or overnight. You go through, collect your sample, and then it gets sent back out. Yes.

VR: What’s the turnaround, do you know?

DG: I do not. I do not. They claim you could pay extra, and within 48 hours of the lab receiving your sample, you’ll get it. You could say overnight to you, you do your test. Overnight back, 48 hours. About four days, if everything goes as promised.

VR: Last week, Dickson said he went into a CVS and had a saliva test, which they’re doing for you there. You can do that as well. He said it was negative.

[laughter]

DG: This was Dickson, right?

VR: Yes.

DG: [laughs] Yes.

VR: How about you, are you still negative too, Daniel?

DG: I am still negative.

VR: Zero negative, right?

DG: Zero negative. Actually, I’ve tested a couple of different– A part of it, I tested just to test the process to make sure this is really working. Yes, I’m going to get tested again.

[laughter]

DG: I keep testing. We do warn people, “Don’t use those tests to tell people they’re immune.” I was on the phone just yesterday, it was with, it was a family where the daughter was positive, the son was positive, the father was positive, and the mother was negative. I was like, it was very awkward because I had to explain that she just didn’t love her children.

[laughter]

DG: Yes, you never even know with these serology tests, and also, since we don’t know about the reinfection potential, they’re right now out in the grey zone and we’ll eventually figure out what to do with the results. The last, just so I don’t drag on for too long here. Just an update on management from door-to-door. We’re still using the risk stratification when people come in, where we look at the lymphocyte and neutrophil, so the neutrophil-lymphocyte ratio. We still look at respiratory rate, oxygen saturations, procalcitonin, ferritin, C-reactive protein, and D-dimer.

We’re still seeing that same pattern where the first week is this viral. The second week is when we see the potential surge. We’ve started to use a little of remdesivir, and then we ran out of it. There’s limited supplies. But at least we feel like we have a little bit of direction on the tiny impact it has. It looks like the population that we’ll try to target is the patients who are requiring oxygen, but not very much. So not the people that are on ventilators, not the people that are on high-flow, but it looks like there’s a tiny little benefit.

We say it’s like spitting in the ocean, you’re not going to move your chair back, but at least there might be some benefit that we do there. There was a study on hydroxychloroquine and macrolides. Hydroxychloroquine and azithromycin, and, I think, finally, this is going to put to rest– A lot of the hospital systems created these COVID order sets, which as people remember, I was pulling my hair out, now I have none. Didn’t have much to begin with. People would come in, and you could kind of go click, click, click, click, you get your three liters of intravenous vitamin C or hydroxychloroquine and azithromycin, and then I would try to stop them, and we’d end up with some issues.

Now, I think we’ve really said that we’re not clear that there’s a benefit here. There may be even association with increased mortality given late. The nicest thing I liked about that paper, it was a paper in The Lancet, he really got things broken down, and you saw that there’s a benefit to being female, you saw the association with certain ethnicities. We’re starting to get some sense of who’s at higher risk here for poor outcomes. I think that’s going to be about it.

VR: Chuck, any thoughts?

CK: No, I’m looking forward to some of the randomized control studies. These observational studies are very important, but I think that until you have the randomization from the RECOVERY study, or even some of the studies that you’re involved with Daniel, the final answer will need to wait.

DG: Yes, it is tough. I have to say, I feel like early on, everyone was desperate, every night like, “What did we learn today?” I worry that the quality of the data is not the quality of the data we really want when we’re making decisions about how to manage people.

VR: All right. We have a couple of quick questions from listeners. We have one from Will, who’s an electrical engineer from England, he says, “Daniel Griffin recently commented it might be good to be sufficient in vitamin D at the beginning of illness, but deficient later on. This made me wonder about drugs like leflunomide or methotrexate, which people take for rheumatoid arthritis. The immunosuppressant nature of these drugs has led people to be cautioned that they’re at extra risk from COVID-19, however, might have turned out to be the case that such drugs actually reduce the risk of second week complications, and thereby reduce the overall risk. Might it be they’re actually a low-risk group rather than a high-risk group?” He wants to know if you have an opinion, and whether you’ve ever treated people who are existing users of these drugs?

DG: Yes, I have an opinion. I have always plenty of opinions.

[laughter]

DG: The first thing I’ll say is, “I’m hoping when we see stuff like that big study about these observational trials, where it looks like people who got treatment did worse than people that you just stood back from, I always hope that we learn our lesson. That, ‘Do no harm, stand back.’” When I saw the vitamin D, of course, my worry is that people are going to start overdosing on vitamin D because the news cycle, like all the people that started buying Pepcid and everything else that they thought might somehow make them better. I’m hoping that there’s a little bit of sanity here.

Yes, there’s a lot of stuff that needs to be studied, but please don’t run out and take a lot of vitamin D. Early on, there was this idea that, oh, maybe people with rheumatoid arthritis who were on Plaquenil, people who were on– People on different therapies trying to get a sense of, did they do better or did they do worse? One of the discussions we actually had today, which I thought was an interesting discussion, was about people who got tocilizumab or steroids, and the issue that you’re giving something that calms down the immune system, but it lasts for a month or two.

Ideally, when we start coming up with ways to modulate that cytokine storm, which I think we’ve been characterizing, we want something that just lasts very briefly, and then we could turn right back off. Methotrexate is not necessarily something that is able to be turned off so quickly.

VR: Mona wants to know about proning. Her husband was a Navy Corpsman during the Vietnam War, and she said, before that, he worked at a Marine Corps Base Hospital, and they treated those with pneumonia or other respiratory problems by turning them onto their bellies, and turning them 90 degrees and hanging their lower bodies off the sides of the beds. Then she listened when you were talking about proning and Rich asked the idea where proning came from. She asks, “I wonder, why hasn’t this been used from the onset? We’ve known about proning for 50-plus years?” She also wonders whether doctors in countries with less money would use proning routinely? They don’t have ventilators.

DG: These are excellent questions. Proning has been around for decades. I think 30, 40 years people have been doing this. This was something that was discovered, and part of the reason I think it was discovered is because you can get such quick feedback. Early on, we got advice from China on how to manage a lot of things. I’m not sure how much of it worked out, and one of the early bits of advice was early intubation. You don’t want to wait, you want to get these people intubated early. I think most of us feel like that was not helpful advice, and maybe bad advice.

Because, when we started waiting, we started realizing these people may become hypoxic, but, even though they met criteria, once you put them on a ventilator, the outcomes were awful, very high mortality. We started basically doing other things, saying maybe not all this advice is gospel. The proning was part of our saying like, let’s actually try things that were not in these recommendations that we initially got. I think it was in March, that was actually one of the first publications I saw out of Wuhan. It was just a small series, it was about nine people, where they did proning in the context of COVID-19 and saw a clinically significant improvement in the oxygenation status.

We very quickly jumped on, I think, if you go back through the TWiV episodes, early on, it was, I think, the Irish patient, who, unfortunately, I should point out is now back in the hospital with bacteremia. Just as mentioned, a late-stage complication, but he’s doing all right, by the way, but not as alright as if he’d stayed out of the hospital. It was one of those things that you could do with rapid feedback. I think that this is interesting. We tried to jump in pretty quick. I think as soon as we started saying like, “Hmm, we may want to come up with our own approaches and not just follow the guidance that came out of China.” I think this has actually gotten widespread use.

VR: Brin writes, and this is pretty funny, “Let me be honest about my layperson’s status, and even admit that I took meteorology and oceanography in college to avoid the hard sciences.” Here’s a question about deciding to send her children back to school in the fall, “My husband and I worry about our son who had apnea at birth, requiring a NICU stay. Chronic bronchitis that turned to pneumonia twice, reactive airway disease. Should parents with kids who already have lung issues be more worried? I feel like there’s precious little data on the impact on kids, even with Kawasaki-like syndrome. Many parents are trying to make big decisions without enough data, friends whose children have asthma are just as concerned about whether or not schools will be safe.”

DG: These are excellent questions, Brin. I was on a web-type conference, they have these Zoom conferences now for UC Santa Barbara. I’m going to actually do a presentation for William and Mary, and I get asked to weigh-in on issues like this, and I always try to just focus on the stuff that I can comment intelligently about. So, the science of it, the clinical aspects of COVID, because a lot of these decisions are beyond that. Fortunately, the biggest predictor of good or bad outcome in COVID-19 is age. You can really see that the curve starts to go up. As long as you’re under the age of 50, your chances of dying of COVID-19 is well under 1%.

Once you get up to 80, you’re up to about 15%. And when you get down to these lower ages, it is quite a bit lower, but now let’s add a little bit to that. If you’re going to make a decision and the risk of death for your child is 0.1, so one in a thousand chance. Then they have some lung issues. We know a little bit, we could say, “Okay, that might raise it 0.2, so two chances in a thousand. There is a little bit we’re starting to learn about how you can adjust that. The Kawasaki-type syndrome is still quite low, but again, we don’t have the follow-up. So, this is a later complication, one that we’ve only started to recognize. The reassurance can be that the risk of death, the risk of complications in children is still low. We’ve been surprised that asthma has not been a significant issue where COPD and being a current smoker currently was. These are going to be tough decisions because, I know, I won’t even mention their name, but one of the famous TV doctors was saying, the price of starting schools is, a certain percent of children are going to need to die. That paradigm doesn’t work for me. I think that what each individual is going to have to do is make a decision about, “What are their risks? What risks are they willing to take?”

Because we know there’s harms to sheltering-in-place, we know there’s harms to schools being closed. I think I described the increase we’re seeing in drug overdoses and suicides and mental health issues. These are complicated decisions that I’m glad I’m not going to be the actual one making the decision. School can be made safer, but there’s no way we’re going to be able to make things 100% safe for quite some time here.

VR: Last one from Steve, “It was hot news last week here on the BBC that blood clots are a major problem. You guys have been talking of these for some weeks. That’s because we have Daniel, right? [chuckle] Now the hot news is T-cell count is low in severely-affected patients. Is this news to you?”

DG: No. [chuckles] This is something, I think, if you go way back, I tried to point out early on. This was this concept that we started seeing, and this was helping me get a sense of who to worry about, but the neutrophil-lymphocyte ratio. We were seeing the neutrophils go up. I think I always made the point, is always when someone does a complete blood count and they tell me what the white blood cell level is, I’m like, “Would you tell me which white blood cells are up and down?” It’s like going to a restaurant and they say, “We have food.”

What we say early on in COVID was that neutrophils would go up, but the lymphocytes, which are your t cells and your b cells, that these would actually go quite low. The lymphocytes dropping is associated with clinical worsening, associated with worse outcomes. When we see that neutrophil-lymphocyte ratio get above six, we start to worry. This is actually one of the ways that we track people. As the neutrophil-lymphocyte ratio comes down, as the lymphocytes, so the t and b cells start to rise, that’s associated with a person doing better. I guess it was news to us two months ago.

VR: You hear it first on TWiV, and then it gets to the rest of the world, right?

DG: Yes.

VR: All right, Daniel, thank you again.

DG: Pleasure as always.

VR: Chuck, thanks for joining us.

CK: My pleasure. Be well, Daniel.

DG: Thank you. Good to connect, Chuck.

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