This Week in Virology
Host: Vincent Racaniello
Guest: Daniel Griffin
Aired 09 August 2020
Vincent Racaniello: This Week in Virology, the podcast about viruses, the kind that make you sick. From MicrobeTV, this is TWiV, This Week in Virology, Episode 651, recorded on August 7, 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, everybody.
VR: How’s it going, Daniel?
DG: It’s going well, it’s going well. We were just starting to talk a little before this started about our big storm that we just had here.
VR: Yes, a couple of days. It was a Tuesday, right?
VR: We had a lot of high winds and rain. You probably had the same thing since you’re not far away from us.
DG: Yes, the biggest thing was, you should have seen the sailboats because the sailboats were all out there and the wind was blowing. Even sailboats that are attached to these huge moorings were actually being dragged around the bay.
DG: It was quite something.
VR: Well, we have no power. We lost it yesterday and it will be out till Sunday, Monday, so I came in to do my pods today. I got a TWiV in yesterday and then the power went out so I had to reschedule TWiEVO. I came in today for TWiM and now the Daniel part of TWiV.
DG: All right, so let me start with my traditional quotations. These are both by Winston Churchill. “It’s a fine thing to be honest, but it’s also very important to be right.”
The second, I modified this a little to make it– Winston Churchill says, “men,” but I changed this to people. “People occasionally stumble over the truth, but most of them pick themselves up and hurry off as if nothing ever happened.”
VR: He was great, Churchill was great.
DG: He really had some great one-liners. I should make sure before I get into the thick of it that I let everyone have an update on our current fundraiser. I wanted to thank everyone for helping us supportFIMRC.
We’ve now started– August and September, we’re going to be helping to support Floating Doctors, which is an organization that I’ve actually worked with down in Panama. It’s an organization that, I’ll say a friend of mine, Ben LaBrot started many years back. They’re in the northeastern part of Panama. What they do is they go out by boat– Sometimes it’s four or five hours across the open water to these tiny little isolated villages where the indigenous people live and they set up mobile clinics and provide medical care.
Unfortunately, because of COVID and everything else, they’re having more issues with medical problems. The people are actually starving, so it’s really a tragic situation. I think of all these people that I got to know personally in these small villages, moms, dads, children, and now they’re suffering. Floating Doctors really need our help. If people can go to parasiteswithoutborders.com and donate, we’re going to do the same thing. For every dollar donated, we’re going to double it to help Floating Doctors, so help us with that.
VR: Before we go on, Daniel, I want to show you– A couple of weeks ago you made a comment. You wanted a Masks Are Cool t-shirt, and there you go.
DG: That’s awesome.
VR: Masks Are Cool, This Week in Virology, you can find it at cafepress.com/TWiV. It’s a nice design, isn’t it?
DG: I want a whole bunch.
VR: Sharon Isern, a virologist down in Florida designed it.
DG: This is great.
VR: There you go.
DG: I love this. All right, so we’ll start off with, where do things stand? Not great. I think as I said last time, my wife keeps saying, “Dan, you’re just a bucket of sunshine.”
We’re now past 700,000 people that have died from COVID-19 and many think this is actually an underestimation. In the U.S., we’re still averaging over 1,000 deaths a day and we’re actually seeing a bunch of cases in kids in the immediate area here. Part of it is they’re having these delayed prom parties, graduation parties, and sometimes it’s more than 50 kids at these gatherings. They’re all piled together. You see these group photos with people without masks.
This is a bit of a disaster. I’m just going to say that outright. It’s a bit of a disaster what we’re seeing. Actually, the last 24 hours, for me, has been a little bit of a challenge because I think I mentioned I’ve tried to help with a couple of the programs in the area. We had some positive tests, but actually when we retested it actually turned out these were false positives.
I was going to start to talk a little bit about testing and quarantine. What exactly happens here? This is a very– As my wife says, “It’s excessive but it’s excessive because of the biology, not because of anything beyond that.” When initially we were concerned that these were true positives, in these different programs the kids were in cohorts. You actually think of this almost as a classroom. There’s a limited number of kids, eight kids in a situation where if one of them is positive and shedding virus, you potentially have eight kids who could have gotten infected. We’d consider that a high-risk exposure.
We have a lot of guidance on this from the CDC and they actually have a great web page if you just Google “CDC and quarantine”. They actually have calendars that run you through this.
Let’s talk a little bit about it because I think, when the ideas of quarantine were put in place, people were thinking about adults. If you’ve had an exposure, the recommendation is for 14 days after the exposure, you need to quarantine because you’re in the incubation period. If you get a test right away, that’s great, you’re negative right away. You get a test two days later, you’re still negative, but anytime during those 14 days, you can become sick or start shedding virus.
Here’s the challenge, because with kids, in particular, they don’t necessarily get sick. They don’t necessarily show symptoms, so at any point during those 14 days, they can start shedding virus with or without symptoms.
Now, that’s one thing if you say, “Oh, this is a 42-year-old man, he’s going to be in a separate room, he’s going to wear a mask, he’s going to use a separate bathroom.” Now imagine what we started talking about, you have your nine-year-old daughter and your nine-year-old daughter just had an exposure. Now, how does quarantine work in a situation like that? It’s quite difficult.
I was on the phone last night with several people and in one situation, it was the mom and the dad. The mom was like, “I am spending the next 14 days with my daughter, period. I’m the mom and that’s just what I signed up for.” The dad is meanwhile saying, “I’m older, I have some health issues. If our child starts shedding virus and I get the virus, I might actually die.”
This is all pretty tricky when you start thinking about, now you open a school which is sort of a microcosm what we’re seeing now, and your child is off at school. They come home and say, “You know what, just found out one of the kids in my class is positive.” Theoretically, they’re quarantining for 14 days. I don’t know how realistic that is for a young child. One of the parents is going to be taking care of them. Anytime during those 14 days, they might become sick, they might start shedding virus. Now the quarantine restarts for everyone in the household at that day for another 14 days. It starts adding and adding and adding and it becomes the never-ending quarantine.
We talked about the cost involved in testing people that prevent stuff like this happening, you can already think about the cost of our current model where people are out of work for weeks and weeks, people are getting sick and ending up in the hospital, that’s not cheap. We’re seeing a long tail and disability with COVID. That’s not cheap. Not only is it not cheap in financial terms, it’s not cheap in the human impact.
Challenges ahead of us. I know with testing, there’s been a little bit of a push to limit testing which is interesting. I try not to be political but I was reading an article where they said there was a lack of a national testing program and my response was, “Well we do have a national anti-testing program.”
I apologize if that is taken as political, but the way we responded in our local areas is we were having the problem that– I actually just heard Anthony Fauci talking about where, in certain areas, you might perform a test. It might be a week or longer before you get that result. As he mentions, and that’s basically the equivalent of not having a useful test.
VR: You had such an experience yourself right here, right?
DG: Yes, we were out to eight days. Actually, that was an issue for us because when we were setting up this, we had the idea that there’d be periodic testing going on. When we had an eight-day turnaround and we realized that adding more tests to the system was not going to be helpful, we delayed. We’ve now gotten our resulting back to somewhere between 12 to 36 hours, depending upon the priority level.
Instead of us doing less testing, we said “Okay, the problem is that we’re having resulting delays. I’m going to say at least, at ProHEALTH New York, so all the ProHEALTH doctors that are listening, congratulations for helping us make this happen but we’re rolling out a lot of– We’re working with BD to get access to those strips. We’re doing Abbott ID now. We invested in a Hologic machine. We’re coordinating better, I think, with Quest and LabCorp and we’ve got our turnaround time down to about 36 hours or less. That’s huge but that’s a big issue. You do a test and you find out eight days later. “Oh, by the way, that child was sick.” Just think of the challenges for contact tracing. It’s a disaster.
VR: This is where a daily cheap test would be useful, especially in a quarantine situation where you have an exposure, you could test daily and see when they first start shedding, right?
DG: Yes. The nice thing at least for us, with this experience, was we tested– Fortunately, they turned out to be negative when we re-test them, so they’re false positives. At least the children tested positive. Thank you to the hurricane, we had no sessions and so the children did not return to camp. It could have been that they were infectious.
Fortunately, but that’s what you need. I think the impacts of not doing this– I know our schools in the area, we’re waiting to hear what their result is. I think we talked about it last time. There was the comment that, “Well if we open the schools, it will be a certain percent of children that will get sick and die. It’s only going to be 14,000.” Putting ‘only’in front of 14,000 children dying is just not acceptable. We need to do better here.
Again, this is not a partisan issue. This is, we all want to and we all need to do better so let’s work together and make that happen.
Masks and eye protection. I put here, “Why are we only hearing about this now?” We’ve heard about physical distancing. Some people call it social. We’ve heard about face masks and we’ve heard about not only do face masks protect others but maybe they protect you. There was an article that came out, Physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19, a systematic review and meta-analysis. I think now we’re getting a little more data on this.
It has come on TWiV several times, I’ve always included eye protection as part of droplet protection because eyes are mucus membranes. You really don’t want people coughing, sneezing, spraying into your eyeballs. I think now this was a good systematic review and meta-analysis that there is data actually that protecting your eyes is a useful thing. We say not glasses, we say goggles because that’s what’s studied but glasses are better than nothing. Contacts, not so great.
I know, I think I talked on the last TWiV when my dad is hoping at one point the gyms will open and I told him, “Only with goggles, a face mask, the full repertoire of protection.” I think we’re hearing about it now because we’re starting to get a little bit of data on this. I’ll say actually it’s people who work with me out of Plainview Hospital, in February was when I was walking around and making sure there was eye protection on all the floors for all the staff so that this was part of the personal protection that we use there.
Four, this is understanding the full impact of COVID 19 by-systems. I like to point out to people, a lot of people get on their computer and they look at the different websites. I want to say COVID is more than just counting cases and deaths. There was a quotation at one point where someone said, “Well, with COVID-19 you either live or you die.” But it’s actually much more than that. A lot of people live and there’s significant, what we term in the medical profession as, morbidity.
I wanted to go through each system talking a little bit about what’s the impact because unfortunately, a lot of people do a little more than just get over COVID-19. Starting from the top to the bottom, outside to inside, the dermatological impact. So we’ve talked a little bit about hair loss. It’s in my list if you heard it first on TWiV. There’s actually a little bit of a controversy about what exactly is going on with the hair loss. The initial idea was that these are some big words but we’re going learn telogen effluvium.
This was the idea that after a significant amount of stress your hair follicles go into a state of really just a rest. They just stop, they’re not going to grow. A period of time will go by and then the hair will start growing back. One of the things we’ve actually seen is a significant amount of hair falling out. Some people are suggesting there is a component of anagen effluvium and this is where you’re losing hair during the growing phase. Instead of the hair growing in, it’s falling out. A lot of dermatologists are actually describing that the individuals are coming in with a gallon-sized Ziploc full of hair. It’s almost like they brought in a wig.
This is something I think, I described in our patient in the ICU recently, where the nurse was saying, “I like her hair.” You look down and the pillow is covered with hair. It’s not that you’re losing a normal amount of hair and it fails to grow in, you’re actually losing hair at a significantly faster rate and it’s not growing back in. This virus just loves to give us everything.
VR: Too late to call it a little hair loss?
DG: The timing is interesting. We start to see this about a month after symptom onset. Interesting. I think I always mention I was waiting for an immunologist to sort out what is going on. The virus is long gone. What exactly is triggering this? It tends to be women more than men so this is my, “Wear your mask now or your wig later.”
We see multiple rashes. Everyone knows about the COVID toes. I have special COVID socks with red toes, just my COVID toe socks. We see all different rashes and the COVID toes is something we refer to as pseudo-chilblains. This is as if you were to put your toes into hot water and pull them out and the toes are red. It looks like that and this was, I think, people started noticing early on.
Nurses noticed it more than doctors, interesting enough. When I asked doctors, “Oh, I don’t know about that?” I asked nurses “Oh yes,” and then they would show me all the different patients.
Neurological impacts. We’ve discussed many of the acute impacts of COVID-19 which included the confusion, the delusions, the paralysis, the Guillain-Barre we’re seeing about four weeks in. Now, we’re actually getting more data on the longer-term post-acute COVID impacts on cognitive function. Many a patient of mine have been reporting issues with concentrating and their attention span.
I actually mentioned one of the local neurologists who’s seeing if maybe ADHD medications can be of help because of the shared characteristics, but there was a paper that came out, The Landscape of Cognitive Function in Recovered COVID-19 Patients by Z-H-O-U, Zhou, Zhou et al, in theJournal of Psychiatric Research and he actually was reporting that, much like was seen in SARS-1, COVID-19 patients who had residual issues with poor concentration, memory, and other neurological issues.
This seems to be the case in many of these patients and actually corresponds with the CRP, the c-reactive protein. The amount of inflammation that we’re seeing early on may have some predictive value with regard to the cognitive function that we see later on. So interesting. A couple of reports on a possible link between foot drop and COVID-19, so peroneal nerve palsies. Plenty there in the neurological department.
Cardiovascular impacts. So there appears to be a risk of acute myocardial issues. Acute issue with heart failure, arrhythmias but we’re also seeing evidence of longer-term myocardial inflammation. There was the paper, Outcomes of cardiovascular magnetic resonance imaging and patients recently recovered from coronavirus disease 2019. That was in JAMA Cardiology. I didn’t know there was a JAMA Cardiology but they actually were showing that the majority, about 78% of the patients, month or two out were actually showing inflammation of the heart. Pretty high significant amount there.
I don’t know if people in the news, if we have some baseball fans, the Boston Red Sox pitcher is out for the season due to COVID-19-related heart issues. This is the Red Sox lefty southpaw, Eduardo Rodriguez.
VR: We’ve talked about athletes and how you really need to be careful because a little impact on your performance can make all the difference and this is much more than a little impact, right?
DG: Yes, this is and it’s really difficult, I think. If you think about an athlete, the risk for an athlete, I think a lot of the leagues think about, “All these cases, we may have to shut down.” But I think about it on the human level, think about an individual who has worked this hard to get to that point and their dream’s gone. We don’t know. I want to be honest here, we don’t know what the long term is and whether these people will be able to make full recoveries. It’s a frightening prospect as a professional athlete.
VR: That’s why it’s probably not a good idea to have Olympics next summer.
DG: Yes, that seems like a bad idea.
Pulmonary impacts. There was another– And this was about two months post-recovery from COVID-19 and this was, Persistent Symptoms in Patients After Acute COVID-19. The majority of previously hospitalized patients are still reporting trouble breathing and fatigue. There was another article, Impact of coronavirus disease 2019 on pulmonary function in the early convalescent phase.
They’re detecting imaging pulmonary functioning abnormalities in the majority of patients a month after discharge. We’re seeing cases, publications, severe fibrosis. I see these individuals, they survived, but you do a CAT scan of their lungs and their trachea is pulled over to the side with this traction from the fibrosis. I think people probably remember where you had an individual undergo a double lung transplant. The pulmonary impacts I think are pretty significant.
Vascular thromboembolic impacts are well established, increased risk of pulmonary embolism and thromboembolic complications. These can lead to death, stroke, loss of limbs and digits, so pretty significant issues.
The gastrointestinal manifestations. Probably some of our providers– And I know if you look at some of the COVID support groups, not only can there be nausea, diarrhea, intestinal and organ ischemia as some of the acute issues but there can be a chronic diarrhea that lasts for weeks to months. That’s actually plaguing a lot of individuals.
Kidney damage. I think we talked early on about this progression from pulmonary to cardiac to kidney damage. Sometimes this is severe enough that the patients are actually requiring dialysis. Actually, if you look at different series, in some series this may be up to a quarter of hospitalized patients are having some kidney impact. It’s even higher when you look at the high-risk patients that end up requiring intensive care support.
Some of the autopsies on the individuals who did not survive are actually showing acute kidney injury with acute tubular necrosis, with lymphocyte and macrophage infiltration. We’re actually seeing the immune cells invading in and once you see renal failure actually, your risk of mortality goes up significantly.
The other thing, if you take care enough of these patients, you’ll start seeing conjunctivitis in a few percent. We say it’s about 1% to 3%. It’s not common but it’s actually, I often see these patients and they’ve been given different eye drops, they’ve been treated for their bacterial conjunctivitis but this is often just part of this. If you look at the eyes there isn’t a thick purulent, it’s a clear, it’s a watery discharge that we’re seeing in these individuals.
VR: This is early on or later on you see?
DG: No, we see it at all points but it’s usually later on. This is usually part of the, we’ll say, the long hauling part of the COVID-19.
VR: I want to make it clear. It’s not reflecting entry of virus in the eye and conjunctivitis there, right? It’s later.
DG: Yes, I don’t think. I really don’t. It’d be interesting if there was the idea– I’m going to say this is not the case, that you failed to wear your goggles and the COVID got in your eye. No, that’s not what we’re seeing. This tends to be a later inflammatory post-viral part of the COVID-19. All right. Those are my updates.
VR: We have some questions for you, as usual. I always have to pick some because there are a lot, Daniel. The first one from Charles, he wants to go back to TWiV 648where you talked about tocilizumab and you said, “We give tocilizumab without steroids, IL-6 shoots up from the 40s to over 3,000.” You’re blocking the receptor which creates this problem. Charles asks, “Okay, tocilizumab binds the receptor. What about siltuximab, which binds IL-6? Could that make a difference together with tocilizumab?”
DG: I don’t know. These are the great questions that people come up with that help guide us forward. That’s interesting. The MABs, this means these are monoclonal antibodies that we’re talking about here. Siltuximab is an anti-IL-6 monoclonal antibody. It’s actually a chimeric mouse one, so it’s made from a humanized mouse. It binds directly to IL-6 so it’s interesting. That’s an interesting thought.
In many ways it makes more sense and I think the reason that we started using tocilizumab was the experience in the cytokine storm of some of our CAR T-therapy in situations like that. This is probably not being tried by us just because of the lack of experience, availability, the rest but it makes so much more sense when you think about it. Why don’t we just directly target IL-6 and neutralize it rather than blocking the receptor with the potential result?
VR: Now we have one from John in Cambridge, England, who presents some numbers about the weather which are quite puzzling to me. You could read them in the show notes.
VR: All right. The first is about sensitivity. Remember Daniel, the last time you said, “I’m going to challenge the concept of sensitivity”? He says he agrees. He also wants to challenge the concept of specificity. “If specificity means not indicating the presence of viable virus when no virus is present, the clinical PCR tests have poor specificity if their results are interpreted as indicating the presence of viable particles,” or in other words infectious, “In the same way that we would give arbitrary sensitivity to Abbott ID Now by our choice of reference, test samples could give a clinical RT-PCR test in arbitrary specificity when tested against a cell culture reference. Again, specificity in the established sense makes little sense.”
What does specificity mean Daniel, we’re talking about these tests?
DG: These are great. We’ve spent a lot of time– I think this is good that people understand. Sensitive would be the question of, if it’s there, can you pick it up? Specific is the relationship of when something is positive, can you trust that? Is it only going to turn positive if the person has COVID-19 or if the person only has SARS-CoV-2 RNA in their system? If something was not specific it would, “Oh, any of the coronaviruses will turn it positive,” lack specificity.
The things he bring up here is, I think, great. As far as sensitivity, there is an issue. The PCRs are, as we’ve mentioned, too sensitive. People who are not infectious are being told they’re positive. They’re positive in that they have maybe 80, 90 little bits of RNA but what we really want to know is, are they infectious? They’re overly sensitive. They actually have an issue with specificity.
I like this argument here because when someone goes and gets tested, “Oh you can’t come into the workplace because you’re a PCR positive,” the assumption is, “You must be infectious.” The test has horrible specificity for determining who’s infectious. The antigen tests are better in terms of specificity. They’re going to pick up a lot less non-infectious people.
VR: He has two comments on units. He said when you talk about IL-6, goes from 40 to over 3,000, he wants you to say what units.
DG: These are picograms per deciliter, I think, is the units that we’re using. Remember Michael, who was working on the bivalvesin the lab, he used to always say, “You clinicians, you just use numbers and you never give us the units.” There’s so many darn units that after a while we’re just referring to like this. But then it’s an issue if we’ve got someone listening in the U.K. versus someone down there in Houston, the units are different.
Actually, I should say, there was a little comment about creating a table. Actually, we put that table out in the newsletter. Parasites Without Borders puts out a monthly newsletter, so if people go to Parasites Without Borders and sign up for that, they can actually get that monthly newsletter. There’s one specifically for clinicians which has a little bit more than what goes out in our normal newsletter.
VR: Can you get the back ones with the table in it or is there a table in every one?
DG: You know what I’ll do, I’ll make sure that the next big one that goes out we put that in there, because, yes, a lot of people have asked me about that. I’ve started including that in some of my talks. I wonder if he did this on purpose, that EGSC and then had a whole thing there and you’re like, “What is he talking about? Can he translate that into something intelligible?” Maybe that was a clever way of saying, we say picking up 90 bits of RNA cycle CT39. We’re trying, I think here, to translate our testing into something that makes sense to people. You’re infectious when you’re in the millions. Our rapid cheap tests are picking up 50,000 or more. They’re plenty, plenty sensitive. They’re more specific for picking up people who are infectious, so these are excellent points.
VR: Both John and several other listeners had written in asking for that table, so parasiteswithoutborders.com. Sign up for the newsletter and you’ll get it. It’s in there. Is that correct, Daniel?
VR: John also wanted to know when you talk about pieces of RNA what you meant? Pieces.
DG: Yes. That’s really what we mean. We mean the As, the Cs, the Gs, the Us, basically these little sequences. They’re fragments where when we do these amplification methods, these nucleic acid amplification tests, we’re actually looking for small, 120 or less base pairs. The reason we do short ones is because anyone who’s done PCR in the lab is familiar with the three cycles. You heat it up and that’s when you separate, then you drop it down to an annealing phase, and then you have the midpoint which is you’re extending.
With a lot of these PCRs, a lot of these amplification approaches, if you use a short enough sequence while it’s annealing, it’ll actually quickly finish off the elongation. You can remove the third phase, so you can have a two-cycle and you can speed up your amplification process. These are little short pieces and they’re not testing for a viable virus in any way. All they’re testing is for little bits of RNA, 120 or shorter in length.
VR: All right. One more from Dr. Mary Bowden, who is at BeatheMD in Houston, Texas. “I’m a solo practitioner in Houston. I have tested almost 6,000 people for COVID since March, primarily saliva through MicroGenDx.” Are you familiar with that one, Daniel?
DG: No, not really.
VR: “My facility is unique in that I’ve been testing asymptomatic people from the start. I’ve never restricted who gets tested and since the lockdown ended, I’ve tested many people who need clearance to travel or go to camp. I’m in the process of analyzing my data but one trend that really stands out is intrafamilial transmission or lack of it. When I looked at many families I’ve tested, I cannot find a single family where every member tests positive. I have faith in the sensitivity of my test. I just finished a six-week run of 13% positive test rate, and I understand that T cell immunity is part of this. Wondering if you could direct me to research in this area, as I’d like to explore it further.”
DG: No, this is interesting. Dr. Bowden brings up a few interesting things here. I quickly Googled the MicroGenDx. They’re actually using a DNA sequencing to accurately identify COVID-19, and so that’s another– We got so many bits of technology out here.
VR: That would be PCR followed by sequencing probably, right?
DG: Yes. We see these, too, where we’ll test the whole family, whether it’s our nucleic acid amplification testing approach or whether it’s serology, and you’ll see 80% – that tends to be a number we see quite a bit – where 80% are positive, but you’ve got someone who’s negative. You wonder, did this person not just get infected, or did this person get infected but they’re one of these people without a serological response, for instance, if you’re looking at serology testing?
I know this was actually I think, a conversation I mentioned I had with Jay Berger, the head of our pediatrics, and he was saying, “We would love to start looking at T cell immunity, doing some of these cell assays to get a sense.” Maybe there are just people who don’t respond as far as the antibodies go, but maybe they’ll have a T cell response.
As I think was discussed on immune, there may be people who really just do neither. There tends to be type-1 with, I don’t know if I’ll get the numbers right, but who have a nice T cell response. There’s another group that has a nice B cell response. There’s a third group that just doesn’t seem to care. They get the virus, it goes away, not much of an immune response at all. Those people may be the people who do the best.
VR: I’d be surprised that there isn’t a single family where everyone’s positive, but to have many where not everyone is, is not surprising to me at all. I think if you look back at some of the early clinical reports out of China, there were examples of very common.
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