TWiV 645 Lions and tigers and zookeepers (oh my)

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 25 July 2020

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

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From MicrobeTV, this is TWiV, This Week in Virology, Episode 645, recorded on July 23rd, 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.

VR: Hello again, Daniel. It is a week later already, time flies, and Chuck can’t make it tonight. It’s just you and me and a COVID-19 update, what’s going on?

DG: I wish for the day, I hope for the day, when I say, Vincent, I think we’re done. There’s nothing more to talk about, but every week, there’s so much to talk about. I try to organize like, what will I leave out? What will I focus on?

VR: Yes, I worry about that day coming too because I’ve been enjoying this on the other hand, when you say there’s no more, that means it’s good, so, we’ll have to accept it.

DG: Yes, so, it’ll be mixed. We will celebrate. Well, actually, we will be ultimately happier, but I’m going to start with a quote, and this is my quote. I don’t know if we have any Matt Smith or David Tennant or BBC fans, but this is my quote, “Masks are cool. The doctor.” We’ll see if any of our listeners get the reference.

VR: Wow. That’s great. I like that.

DG: I think it is, masks are catching on. I’m just going to talk a little bit about masks before I kind of get into the meat of things. It was actually back in March, Vincent, when you had Ian Lipkin on, and he had just come back from China. People remember, and people should go back and listen to that, because it’s really entertaining, I think from my perspective, where he says, “I had some viral thing for about a week. Then I got the COVID.”

Now we know that pattern, you have a viral thing for a week, and then boom, you get the COVID cytokine storm. On that episode, you and Ian talk about masks, and Ian brings up, there’s some data out there. You know, masks are not something without some support, and you both talk about this back in March. I was being interviewed I think maybe the day after that episode came out. I was being interviewed by someone and we were talking about social distancing, and they basically were saying, “I don’t really want to be six feet away from my friends. Maybe I could be three feet. Isn’t that enough?”

After we finished the report, I was, “Do you have anything else you’d want to add?” I said, “We just talked all about social distancing, but do you want to talk about masks?” Because I really think someone’s got to talk about masks. Now, and this was back in March. That was, unfortunately, probably my most famous viral quotation when I say, you should wash your mask as often as your underwear. If you search the Internet, unfortunately, Dr. Daniel Griffin masks, the whole underwear quote comes up.

VR: That’s the way the Internet works.

DG: It does. Apparently, that was very catchy and proceded. Yes, that was about cotton masks back in March, and here we are. It only took a few days, months for people to catch on, but yes, masks are cool. Wear them, do the right thing. This is not a partisan issue. I think hopefully we’re all coming together on that. This is about stopping the spread, this is so we can get back to school and back to work and back to getting together with people we care about, so wear those masks.

VR: By the way, I spoke with Ian yesterday. I asked him, “Are you completely recovered, or is there any lingering?” He said, “I am always exhausted.”

DG: It’s so tough. I mean, I think that we talked a while ago, we started talking about the long haul, the fact that a lot of people with COVID don’t just get better. I think we’re beginning to realize that may be more the rule than the exception. There’s a lot of people. If you really get sick with this, you try to go up a flight of stairs, you try to go out for a run. You notice it, there is a pretty significant tail to a COVID infection for a lot of individuals.

VR: Do you know if that was the case for SARS?

DG: To some degree, but I don’t think we had the numbers to really to see this.

VR: Yes, with only 8,000 global infections, you’re not going to see kind of more rare things happening, right?

DG: Yes. Case numbers, deaths. I think as we’re sort of warning people what’s going to happen, when you’re sitting here in the US with over 70,000 new cases a day, the deaths are going to go up, and the deaths are now, I think it was 1,200 deaths yesterday alone, the numbers have gone up. This does not bode well. The only part of our country right now that seems to be doing OK is this little pocket here in the Northeast, and OK is the right word because we’re starting to see a creep. I admitted a gentleman this week who is from a group home. This is where individuals who are not able to be on their own or together, one person got sick in the group home, then he got sick in the group home, and this just brings back bad memories of the spread within the group homes. Things are not going in the right direction.

Transmission/testing, I want to put these together. I’m going to tell a little bit of a story at the end about a particular patient, and go through what we should know and how things should go differently than they went for this one patient. I’m going to continue to harp on transmission and testing, because I think we all really care about this. Why do we care so much? Why does it keep coming up? Why is it in the media, and I think, particularly for those of us that see many of these individuals such as doctors, nurses, hospital employees, waiters, security guards, people that just leave their house ever. This is all of us. With 70,000 plus new cases, and we say we’re only diagnosing about 10% of the folks, that means millions of people, this is we all care about.

Just to reiterate I think what we’ve been saying all along, there is some degree of contact, most of it is droplet, you’re within six feet of someone who’s coughing, sneezing, speaking, singing, and there’s some certain circumstances where you have airborne. We know this, and I think the best way to protect yourself is to stay outdoors, outdoors is a great place, this virus transmits much better indoors, but stay six feet away. Protect your eyes, protect your mouth, protect your nose, help protect your neighbor’s eyes, mouth and nose by wearing a mask.

We hear about super spreader events all the time. A lot of people email me actually about this. Every time there’s a super spreader event, they think, “Well, that must mean that there’s airborne,” but just to define for all our clinicians who get asked about this, what is a super spreader? It sounds much more exciting than it really is. I mean, it’s all based upon the reproductive number. We have what we call the 80-20 rule. The idea is about 80% of people just spread it to one or two other people, but with a lot of respiratory illnesses.

Instead of that 1.4 to 3.9, there are some few people that spread it to more, and for SARS, one, the definition was eight or more people you spread it to. This is, fortunately, we just had a call from one of the clinicians a little farther east who just had three new COVIDs today, and they were each, they had gone to a party, which one was a graduation party with more than 50 people, and that was this weekend, and now they’re sick.

Another individual, it was just, I don’t know what was being celebrated, but again, about 50 people altogether, and we’ve been to parties. There’s always that guy, I always say that guy, but that individual who’s just really excited and has no sense of six feet, and you feel that excitement, or just hear the excitement. Yes, you don’t need to be aerosolizing. Someone gets this in your eyes and your mouth, people are not wearing masks. Little recap of what’s new, because there’s a little bit of new as far as guidance from the CDC. The CDC couched this and said, “This is guidance. This is not a rule.” But they’re trying to somehow figure out what to do relative to testing.

There’s actually, I’ll say, they are discouraging repeat testing during the first 90 days after a positive test unless there’s a specific reason to do it. And so, what are their changes? What are they saying? They have a duration of isolation and precautions, and they’re saying for most people with COVID-19 illness, isolation and precautions can generally be discontinued generally 10 days after symptom onset and resolution of fever as long as you have at least 24 hours at that tail end, where they are fever-free without any medications to make them fever-free, and the other symptoms have improved.

They do point out that that’s for that chunk of people with mild outpatient illness, and then, for the number of people who have severe disease, that they may actually produce replication-competent virus beyond 10 days. We’ve actually seen the ability to isolate virus from folks out as far as 20 days. They basically say, once you get outside of that sort of limited mile, then you want to involve an infectious control expert, or infectious disease physician to sort of help you. For persons who never develop symptoms, they’re actually basically saying, let’s start that clock 10 days after the first positive PCR, right?

Because for them, you don’t have a symptom onset. Giving you a sense of what to do. Now, in New York for instance, if you’re going to send that person to a group home, a nursing home, a facility where there’s high-risk individuals, we’re still doing the PCR testing. As mentioned, with all the issues that come with that.

VR: The 70,000 cases you mentioned a day in the US, are these mainly people who are symptomatic and go for care? Or is there a certain amount of random testing in there as well?

DG: I don’t have, and I don’t think anyone actually has the exact breakdown of the stuff I would love to see. Which is, who’s symptomatic, who’s not symptomatic? Then, even, we’d love to see the values, how symptomatic. Then I’d love to see sort of how far are they from time of onset of symptoms.?

VR: I’ve seen in some parts of the country people in cars getting swabs, so they’re just going to get it. I don’t think that’s normal, that’s probably a rare occurrence, right?

DG: It’s changing in certain areas. I’ll say like the New York area for instance, there’s a lot of people who are getting tested for surgery. They want to go to surgery, for instance. There’s a lot of screening for situations like that. As mentioned, we do a number of tests prior to people going to a facility. We also do testing on pretty much everyone who comes in to the hospital to determine what sort of isolation precautions to use. In certain places, there’s different protocols for who gets tested.

One of the things they do say, and I think this is important, is they say, the role of serological testing, and basically, it has no role in sort of isolation precautions. I get this question all the time, “But wait, if someone has positive serology, I probably don’t even do that PCR because we know they’re negative. We see people who come in with positive serology and positive PCR.” There’s a somewhat sophisticated calculation you could do with information we don’t have access to. If you had access to the level of their antibodies, and the level of the virus in the test, then there is some literature suggesting you could probably do an individual calculation, but we don’t necessarily have that information.

VR: You’re talking about the cycle threshold for the genomes, right?

DG: Yes, and I’m going to talk about that, so let’s jump into that. I was thinking about this. I’m thinking about going sailing this evening, and if I ask someone, I say, “Hey, I’m thinking about going sailing. What do you think, should I go or not? What’s the weather going to be like?” They say, “Oh, it’s going to be in the 270s Kelvin, and we’ve got a zephyr at 14 knots.”

Most people would just look at that person. You feel like you’re on Charlie Brown talking to the– You’re the grown-up. You’re like, “Yeah, is that good? Do I want to do that?” I was talking to Buddy Simmons, who runs the 30 urgent cares we now have in the area, so we’re growing. I was like, “You know what, let me just translate CT values into something that makes sense. Something like Fahrenheit, right?” Like if someone said, “Oh, it’s going to be in the low 80s, and we got a breeze coming out of the north at this.” People are like, “Oh, OK. Now I know what to do.”

I did. I actually brought the envelope with me, right? Because I did these back of envelope calculations. Then I’m like, “It’s easier if I just talk to Siri and have her do the math.” But I wanted to talk to people a little bit about, what are these CT values that keep getting discussed? What do they mean for us, and what do they mean for testing? I actually went through this a little bit, so talking a little bit about, what are the tests that people are getting?

One of the classic tests that came out right upfront was one of the nucleic acid amplification test. This is the RT-PCR. This can be either a quantitative or a qualitative. It can give you like, “Yes, we found some.” Or it can tell you how much virus was there to begin with based upon when the technology could detect it. I’m going to say, when Tony Fauci was on, he was like, “If you get a positive test, you can always just pick up the phone, call the lab, ask them what that CT value is. Ask them how much virus is.” Yes, you can’t do that.

You can’t for two reasons. One is, no test is FDA-approved as a quantitative COVID test. They’re not allowed to tell you actually per the FDA. None of the tests, and so, Anthony in FDA, if you give him a call, because I know he listens to TWiV, so he’s going to jump on this for us. I think that would be helpful, interesting information for a lot of us.

The other is that, a lot of the technology does not give you that quantitative number. I’ll go through a little bit as we talk about the test. If you’re in a research lab, and, boy, I used to do, I don’t know, about a thousand these a day in these trays that had hundreds per tray. Actually, I didn’t have to do all of them, later on I had a masters student who was there for the summer. She did these where we’d end up with figures with thousands of data points.

When you’re doing a polymerase chain reaction, so the PCR that we keep talking about. Every cycle, you’re basically doubling. You start with, we’ll say 1, and then you have 2, 4, 8, 16, 32, 64, so on, all the way up. You start with 100, then you go 200, 400, so and so. When people talk about CT, each CT is each doubling until you get to a point where you can actually detect the signal and the machine can say it’s there.

In our fancy research labs, we can actually sit there, and I would do this early on when I was very anxious for the result. Waiting for that signal to come up and cross the threshold, but a lot of the machines that are now in use, they don’t check to see if there’s a signal there until they hit cycle 39. You’re getting, basically, a plus or a negative. You could call that lab person all day, and one is, most people are going to say, “It’s a black box. All it does is tell me at cycle 39 yes or no. I can’t get that number.”

Let’s talk about, what do the CT values actually mean? The most sensitive reverse transcriptase PCR machines that came out initially, they can detect about 80 pieces of RNA in a milliliter sample. You stick a swab in someone’s nose, you stick it in the mouth, you stick it wherever you’re going to stick it. You put it in that little vial, you put it in the machine, and if there are basically 80 little bits of RNA, and this doesn’t necessarily mean virions. This is just RNA, it could be fragments, etcetera. Just little pieces of RNA. You are going to pick that up basically by cycle 39 with some of these machines.

At what point, at what amount of virus do people become infectious? I think we know that now. You basically need to have so much virus that if someone sticks a Q-Tip in your nose, they’re going to pull out about 1,000,000 pieces of RNA on that Q-Tip. You pull that out, and I think Ian, what did he come up? In the 20s, right? He was talking?

VR: He did it in his lab so he could get the number.

DG: Yes, that’s someone who’s infectious. If your cycle threshold is 24 or below, you got a lot of virus. You got millions or more per milliliter on that Q-Tip sample. Those are the people we want to detect. The PCRs, as I mentioned, these super sensitive machines, they can pick up when you have 100 on there. What about the Abbott ID NOW? We had a paper that came out, and this is sort of the history that sort of killed us. The paper comes out, first as a pre-print, then it gets published. It was “Performance of Abbott ID NOW COVID-19 Rapid Nucleic Acid Amplification Test in Nasopharyngeal Swabs.” I’ll stop reading, but this paper was another one of those things that kicked out our legs. “You can’t use it.”

If you look at this, the sensitivity of the Abbott ID NOW, it can pick up anyone who has 5,000 or more bits of RNA on that Q-TIP. That’s great. If you looked at anyone with a CT value of less than 33.5, it picked them all up. It picked up everyone who was infectious. What they did is they basically said, if you crank up, if you start looking at people who have just a few hundred, or people who have only about 80 p– You’re going to miss all those people.

If someone comes into the hospital and they’ve been sick for two weeks, and they’re now in the tail end of their cytokine storm, OK. Maybe that RNA level is pretty low. I need to know it, not because I’m worried they’re going to spread the disease, but because I’m trying to figure out about steroids or anticoagulation. But when someone shows up in the urgent care clinic or the office and says, “I’m not feeling well. I got a fever, I got a cough. I’ve been sick for a day or two.” That kind of person, they have millions, if not more, in that swab.

The sensitivity of the PCR is down to about 100. Sensitivity of the ID NOW is about 5,000, the sensitivity of these quick, cheap antigen tests, it’s about 50,000. Again, it’s going to pick up everyone who’s infectious.

VR: That was basically Michael Mendez’s message, that what we need to know is when someone is infectious, right?

DG: Yes. I think people need to understand this. I think this is really critical. If you show up at the urgent care center, you show up to the doctor’s office, you don’t feel well. If you’re someone who’s got enough virus that you’re going to infect your neighbor, your coworker, you will have a positive test on one of the antigen detection systems. You’ll have a positive test on the Abbott ID NOW. Of course, you can have a positive test on the PCR, but you know what, you’re going to keep probably having positive PCRs on that PCR thing for a long time, because it’s going to pick up like 80 little fragments on a Q-tip.

VR: The ID NOW and the rapid antigen test, you’ll get a lot quicker than your PCR.

DG: Yes. Oh my, you’ll actually know that that person is infectious before they infect everyone, which is really what we need to know. If you’re going to go into the office, if you’re going to go into schools, you don’t want to send the kid in and then find out a week later, “Oh, by the way, we sent a bunch of infectious kids into the schools.” I think that this is important, and the technology is there back in actually May 8th. Quidel got approval for a rapid test, BD got approval back actually just on the second of this month, July 2nd. OraSure has this little plastic thing with a white part that comes out, and you just put in your mouth, it’s a quick saliva test, and it’s going to be like a pregnancy one.

You just hold it up and you look and, do I see my two lines? The technology is there. A lot of it, we have to change the mindset. I mentioned the 30 urgent cares that we have, we have Abbot ID NOWs at all these different urgent cares, but there was a hesitancy to use it because people were told, are you going to miss cases? You’re not going to miss cases we care about. The cases we care about, you’re going to pick them up in about 10 minutes. You’re going to know, and you’re going to be able to do something to stop transmission. Let’s all get on board. Masks, as I mentioned, I’m going to hit that again. This really seems to be making a difference.

There was actually a nice article where they looked at where in the hospital setting, they started to have the patients wear the masks, and that actually made a big difference, because the patients talk and some of them sing, most of them don’t sing. It’s a great way of. You have to wear your masks correctly. I saw my parents for the first time in quite a while, we had a socially distanced dinner last night. My dad’s got his mask on, and then he puts it down and then he puts it back on inside out, and I’m like, “Dad.” I call him pop. I’m like, “Pop, if you were actually using that mask properly and someone spoke or coughed and you got virus on the outside of your mask, what you just did is turned it around and put the virus in your mouth.”

You got to wear the mask properly. I guess he was protecting me, but I was like a good 8 to 10 feet away. If you’re going to wear those masks and they’re really gonna protect you, pay attention. Right.

VR: Daniel, the good news is, last week, at least the president finally said wearing masks is patriotic. Which is not great, but it’s better than nothing.

DG: Yes. It will hopefully cease to be a partisan issue, because it’s not. We want Democrats, Republicans, libertarians, democratic socialists of America. We want everyone to be healthy and safe, and everyone wants the economy to come back. I think everyone wants the schools to come back.

VR: Yes. For sure.

DG: Let’s all work together. Now I’m going to talk about a specific case as an example, and then I’m just going to go through the clinical presentation and what we understand about phases. I’m even going to throw out a little new data. We have a little new data that I just was discussing today, which was helpful. There was a woman, this is a real case, but I’ll leave out the names and personal identifying. She is an older woman, Hispanic descent, and she’s living down in Florida, and she starts to get sick. The daughter realizes, “My mom is getting sick. We’re in Florida, I’m worried about her. I think it’s the COVID.”

She packs her mom in the car. What does she do? She drives her up to New York, because here in New York, we got the experience, we know what to do. She drives her up and she goes to an urgent care center. It’s not a ProHEALTH urgent care center. They see the woman, they’re actually able to do a test and they say, “Oh, look, it is COVID. You’re positive for COVID, you have now been sick for,” at this point it was about seven, eight days. They say, “OK, so, we’re going to do a couple of things. First, we’re going to give you augmentin, which is an antibiotic which has the wonderful side effect of diarrhea, because you’ve gotten pneumonia and you need antibiotics for your viral pneumonia.

Then two, we’re going to set you up with a home nebulizer, because, you know what? If your daughter isn’t already sick, we want to aerosolize the virus in your home so that she can bring some into. The first two missteps, this is a viral disease. Viral pneumonias do not improve with antibiotics, if anything, you might cause harm, and this woman ended up with diarrhea, which her daughter cleaned up, which increased her exposure there, probably. You really want to be careful with nebulizers. We’ve talked about the ability to get this in the air and have other people breathe it in.

If you give someone who has active COVID with positive PCR, a nebulizer, you are now basically aerosolizing the virus, so that was not good. Now, the woman then actually recovered, and then at about week three and a half, she started developing bruising and ended up getting admitted to the hospital, which she actually had developed where the antibodies that developed from the COVID attacked and took out her platelets. Her platelet count, which would normally be about 200,000, was down at about 10. Anytime they would try to even just draw blood, she could just bleed from those places.

Go through a couple of things, just one more thing to worry about when we have COVID, but we have a pre-symptomatic phase. This woman was probably infectious and had a high virus level before she even developed symptoms. Then she had her viral phase, which was when the daughter drove her up to New York. Then the trouble breathing, which is probably about what was happening when she showed up in the urgent care and got her nebulizer was the beginning of the cytokine storm phase. What is cytokine storm? We use words and I think it’s important to define them and give their history.

Cytokine storm, we did not invent in the time of COVID. It actually first appeared in the medical literature in the 1990s, and it was actually used by a group in Boston in reference to graft versus host disease and the significant cytokine release there. Then it ends up in 2002 in a discussion of pancreatitis. Then in 2003, it’s actually described in the context of influenza. There’s actually a really nice review in 2007 by Ian Clark, and the NIH National Cancer Institute actually came out with a nice definition.

This is really, so what is a cytokine storm? It’s a severe immune reaction in which the body releases too many cytokines into the blood too quickly. This hyper cytokine anemia is something we’ve gotten quite familiar with. The RECOVERY trial had that really nice outcome with regard to steroids, but we were talking about steroids today. 20% reduction in mortality, but when that 20% is 40% of your patients die, but now only 32% die. That’s a 20% reduction, but we still have a third of our patients dying. That was, we’re chipping away at the iceberg, but I don’t want people to feel like, now if you come in, we’ve got this one, because we don’t. Another paper just came out, and actually part of the Northwell consortium, it was Montefiore.

As I think people probably know, early on in March and April, doctors were split. Some doctors were using steroids, some healthcare systems were saying, “Oh, no, no, don’t use steroids, bad news.” There was a split. They looked at about 3,000 patients, and they actually looked at, some got steroids, some didn’t get steroids, and this paper in my stack here, “Effective Systemic Glucocorticoids on Mortality or Mechanical Ventilation in Patients with COVID-19.” Actually, it was Marla Keller, was actually the ID doc as the first author, 75% reduction in people ending up on a ventilator if they got steroids.

Just a little more, we’re getting. This is not a randomized controlled trial. It’s randomized to which ID doc was consulting on you probably. So, it’s just nice seeing a little more support to the role. Again, if you give steroids to everyone, if you give steroids to young people who come in, who have no oxygen need, who don’t have significant inflammation, you’re not being helpful. They actually showed that in here. If you measured C-reactive protein, an inflammatory marker, people without inflammation, people who are probably coming in a little bit early, you give them steroids you may make things worse. Again, steroids, certain people, the right time, not for everybody.

We’re still doing hypercoagulation targeting. Have a woman right now, unfortunately, who is dying on us in the ICU. I’m not sure we’re going to be able to interrupt that progression. Her D-dimer that we’ve talked about is now up 13,000, 12,000. We’ve actually got her on intravenous anticoagulation. We’ve escalated. She’s prone. She’s on high-flow oxygen. Not doing well. As you and I talked, not only is there a late hyperinflammatory phase where we see the vasculitis, the Guillain-Barré.

Now, I’ll introduce the immune-mediated thrombocytopenia, so the ITP. Sometimes that happens, not only with COVID, but other viruses. Then, there’s this tail, and it looks like a lot of times COVID has a tail. I think there are a number of physicians in the UK who actually are suffering from that tail. We’re seeing this be vocally recognized as significant and an issue. If you see a patient who has this– Then the last thing I’m going to get at is infection control, because as I mentioned, we’re starting to do some COVID testing not just in the drive-through urgent cares, but in the office.

If you’re going to be doing this testing, make sure you wear proper personal protective equipment. For the ProHEALTH physicians listening, I created a nice video. Adam Fiterstein stars in this, and I direct it from the back. Stacey Goldberg, our PR person was involved, and it’s high quality. If you get sick, you can’t take care of anyone else, so protect your mouth, wear that mask, cover your mouth and your nose. Glasses are not enough. You need actual proper eye protection, so goggles or face shield.

Wear gloves, wear the full gown, try to limit the time in the room, so, go in, get the test, because we don’t want you to get infected. As I mentioned, that woman that I spoke to, she had three different positives today. You really want to make sure that one of those three positives doesn’t make you the fourth positive. Oh, thank everyone. We’ve almost reached our goal, Vincent for the-

VR: That’s great.

DG: parasiteswithoutborders.com, support FIMRC.

VR: Excellent.

DG: We’re actually only a few hundred dollars away from reaching our goal to be able to support them with a donation of $40,000. Everyone, please go to parasiteswithoutborders.com. We’re almost to the end of July and we want to reach our goal.

VR: All right. Daniel, the woman who drove her mother from Florida to New York, did she get infected?

DG: We don’t know. Sounds like probably that she did not get sick. I’m not actually taking care of– Did she get infected?

VR: Who knows?

DG: When you look at the whole scenario, I’d be hard-pressed not to have been infected with.

VR: All right. I have a couple of questions from listeners. This is from Ian who is recovering from immune system side effects of lymphoma chemotherapy treatment, and one of his side effects is neutropenia. He writes, “I heard on TWiV that a high greater than four ratio of neutrophils to lymphocytes has been associated with statistically worse outcomes for those who are infected with SARS-CoV-2.

My ratio is currently in the safe zone, but looking back in past months, it was low.” He would like to know, basically, “I’m not expecting to shed any light here. I’m hoping for a small summary of how these two components of the immune system work and change together in response to viral infection, in this case, SARS-CoV-2.” He’d like to know why we get a rising neutrophil count and a falling lymphocyte count.

DG: This will be my plug for– I’m waiting for a long-overdue Immune episode, Vincent. [chuckles]

VR: Oh, I have to announce that one of our co-hosts had a baby last week, Stephanie.

DG: Oh, congratulations, Stephanie. That’s fantastic.

VR: That is why we are delayed a bit on Immune. [chuckles]

DG: Okay. All right. That is well worth the delay. That’s great to hear. There’s a bunch of interesting issues here. When the human body, when the immune system responds to certain things– I’m going to say certain things, because it’s not always an infectious agent. There are several different ways that it can respond. Actually, I think this came out to TWiV too. Early on, immunologists could count, and so they said the first type of immune system was a Th1, so a T helper type 1 and/or you could have a T helper type 2. T helper type 1 was, I’ll say the proper way for responding to intracellular pathogens, so viruses, other things like that.

Th2, we think of more as an antibody type. Then they forgot how to count, they went right to Th17, and then the numbers keep going. [chuckles] They bounced around. What really happened is they went from counting one, two, et cetera, to referencing them based upon signature cytokines. A Th17 is an IL-17. Actually, one of the significant cytokines there can be IL-6 as we’re seeing, which is not really what you want when you’re responding to a virus. What seems to be happening in SARS-CoV-2 infection, people who have COVID, is that they’re responding in a certain way where they’re interfering with lymphocyte survival, so that’s the lymphocytes are going down.

Actually, there was a nice paper that just came out where a group, a very small number, and there wasn’t as much immunologists as I would like, but they were giving IL-7, which is a lymphocyte survival cytokine, and actually seeing that they could raise the lymphocytes up. One of the ways that SARS-CoV-2 is doing this seems to be cytokine-mediated. When you give Tocilizumab, when you give steroids, sometimes you can actually see that the lymphocytes start to come up. That’s one component.

The neutrophils going up, that’s actually a broad acute phase reaction. Again, cytokine-mediated. It’s a combination of things. Some people just follow the lymphocytes, and you can do that because it avoids doing any math. When you see the combination of rising neutrophils and dropping lymphocytes, that ratio actually can be more predictive. It’s really what we’re having here, is a dysfunctional, improper, non-effective.

One of the nice things I’m going to say about vaccines, with a vaccine, one of the TWiVs, I don’t know if it was Rich or Alan, but someone commented that adjuvants just basically make the immune system angry, but they can make them angry in certain ways. [chuckles] That’s one of the things, you can in a vaccine not just teach the immune system that there’s something that they should respond to, but you can actually educate them how to respond. That’s why I’m not as pessimistic about– I’m actually very optimistic with the ability to make vaccines that don’t cause a dysfunctional immune system like we’re seeing described here.

VR: All right. Michael is a physician who said he wants to ask Daniel. Has anyone looked into steroids or Tocilizumab on long-haulers? I’ve looked for studies of clinical trials but I can’t find them. Not sure quite how to parse the search terms.

DG: No, I haven’t seen data on this yet, and I’m still working through. We have a growing number of these people who are still suffering through the tail that I see. I’ve described a number of them get better. They have the trough, and then there’s this second hump that they’re just struggling through. Anecdote, just sharing my experience. A couple of times I’ve gone ahead and done a short course of dexamethasone or prednisone. I’ve had a couple of successes where it broke that.

Had a woman who, and I think the quote was, “After 16 weeks, I finally feel there’s light at the end of the tunnel,” and it was. We reached a point and I said, “Listen, we don’t have guide. We’re in a data-free zone here. I think with the data we’re seeing on steroids, you’re in the second heat, second bump so to speak, second hill. Actually, a week later she said, “Hey, I feel better.” Then, she’s actually hopefully going to be returning to work.

A second individual, again, these are still anecdotes at this point, where again, this was an older gentleman. Initially, we talked about it. We decided not to do it, but then a week later he said, “Yes, let’s give it a try.” Will there be a role? I don’t really know. We’re still trying to understand. There are a number of setters that are gathering large numbers of these patients, and that’s what you need. You can’t one or two. It’s hard to know, are they going to get better either way. As we have a larger number of these and 10, 100, then we’ll get a sense. At this point, we do not know.

VR: Channeling your clinical cases on TWiP, have you done labs on these individuals? Is there anything out of the ordinary that you see?

DG: Some of them, yes. Some of them, when they get into that second peak, we actually can see some of the inflammatory markers coming up.

VR: Good. All right. One more from David, our friend and a professor emeritus at Penn State Hershey. He says, “There’s been recurrent mention that immune responses fade with aging. What about immune regulation? Might it also be disrupted? I know that counteracting immune regulation is an important part of the latest cancer therapies. Are there therapeutics that boost immune regulation rather than reduce it? Such agents might provide a complement to therapeutic immune suppression. As a non-clinician, I love Daniel Griffin’s reports. If Vincent is America’s virologist and Fauci is America’s infectious diseases expert, then Daniel is America’s clinician. I’m keeping up with the blizzard of TWiV content. The quality remains unparalleled. Stay safe and keep on TWiVing.” [chuckles] Thought you would enjoy that.

DG: David, that’s very, very kind. I would agree that Vincent is America’s virologist.

VR: Oh my gosh. No. So many people will be mad at that. [chuckles]

DG: Who’s going to be mad?

VR: Oh, everyone else who wants to be America’s–

DG: America’s virologist.

VR: That’s why I call myself, Earth’s Virology Professor. Make it very clear, I’m just a professor.

DG: I have to say, in the field of what we like to call edutainment, really communicating the science. Vincent, you’ve done an outstanding job. To be honest, I think because of that, thousands of lives will be saved, so fantastic. David, I echo your sentiment. A lot of respect for what Vincent continues to do here. Keep it up, Vincent. Stay healthy so you can keep it up. Let me answer this. There are reasons to be optimistic during COVID as many reasons as there are to not be optimistic. Our understanding of immunology is still really crude, and particularly crude when it comes to what we do therapeutically.

When I see a study where, “Oh, we’re going to give Interleukin 7, we’re going to do something to the IL 6 receptor,” when I see us starting to do real sophisticated immune modulation in the clinical setting, I think that bodes well for the future, because, most people get over infections because their immune system handles it properly. It’s that percent of people where the immune doesn’t respond properly, if we can actually learn from COVID-19 how to modulate and have people respond properly, I think we’re really going to make– This will be one of those leaps forward.

The way NASA brought us forward in a lot of ways. The way HIV brought us forward in a lot of ways in understanding the immune system. I think that we’re going to come out of this with a much better understanding of the immune system. Not only are we going to be able to treat COVID-19, we’re going to be able to treat a lot of things better.

VR: I agree. I think a lot of good information’s going to come out of this, although maybe not immediately. It’s going to take some time. Maybe even after we’ve got vaccines controlling things, but I agree with that.

DG: I would say even clinicians, right? When did clinicians discuss cytokines? Their eyes would glaze over. Now they care. Now they’re like, “I saw this paper about IL-7”. Physicians are getting more sophisticated, the science is getting more sophisticated. The light at the end of the tunnel is not a train. It’s going to be increased understanding of the immune system.

VR: That’s right. All right. That is your weekly COVID-19 report from Dr. Daniel Griffin. Thank you so much, Daniel.

DG: Pleasure. Thanks

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