TWiV 629 Coronavirus update, pandemic sitrep

This Week in Virology

Hosts: Vincent Racaniello, Dickson Despommier, and Alan Dove

Guests: Daniel Griffin and Chuck Knirsch

Aired 20 June 2020

Vincent Racaniello: This Week in Virology, the podcast about viruses, the kind that make you sick. [music] From MicrobeTV, this is TWiV, This Week in Virology, Episode 629, recorded on June 19th, 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: The week seems to go by quickly, Daniel.

DG: [laughs] Does it? I think it does.

VR: You don’t, huh?

[laughter]

VR: Also joining us from New York State, Chuck Knirsch.

Chuck Knirsch: Hi, Vincent. Hi, Daniel.

VR: Daniel, are you still well? Are you still working hard? Will you take some time off?

DG: I am still well. I think as people listen to this, I’ll be just about to head into another 12-day stretch. Lots of work and no time off, but no I’m staying healthy. I’m doing well. I realized I was watching– I don’t know if you guys got a chance to watch the PBS Frontline special. I noticed, boy, I looked like I need a little bit more sun and more sleep. [laughs] Chuck, I could take your advice to heart.

CK: Two hours a night is not enough, Daniel. That’s what I was scolding you for last time.

DG: Yes, I’m getting bags under my eyes, it’s terrible. [laughs] I’m going to start balancing things better, just in case they do another Frontline special and I have to appear, I don’t want to look so tired.

VR: It looks good, it looks like you’re working hard.

DG: Yes. Well, someone made a comment because I said that. They said a lot of the other people are not seeing patients, so many hours. I actually asked one of my staff to go through how many encounters have I had since the beginning of the pandemic with COVID patients. It was– you want to guess?

VR: Let’s see. I’m thinking of how many you had in the hospital at any given time. I don’t know, I’m going to throw out 1,000.

DG: It was 1,735 COVID encounters. Some of these are the same patient that I saw repeatedly, like the Irish patient, who I saw about 50 times. I was shocked at the volume, it’s averaging seeing more than 20 patients with COVID a day.

VR: Not every patient you saw so many times? I would guess.

DG: Yes, a lot of patients, I think we talked about this, I would see once. I would go through the whole thing. I would go through with the hospitalists and I’d say, “Hey, if you got a question for me, just let me know.” I’m not going to necessarily go physically see the patient again. Now I know the whole story. Call me at 1:00 in the morning and I’ll give you my take on what we need to do next.

CK: I think that’s why training, especially expertise, is something that leads to better outcomes for patients. That amount of volume led you to decipher a lot of different interventions. Steroids, IL-6 anticoagulation, as we’ll probably get to a little bit later in this talk.

DG: Yes, no, I think that that was really helpful. You do need to see a lot of patients to start picking up on patterns, getting insights, hopefully coming up with those observations that then can form the basis for clinical trials. I was reading some recommendations recently. They had qualifications for people writing the guidelines. It was they had to have actively seen the patients that the guidelines were addressing. It’s tough when I see these talking heads, and the majority of them have seen no COVID patients. I always thought that was really hard, for people to be making recommendations about the care of patients that they had never actually seen and managed.

VR: Daniel, in many parts of the U.S., cases are increasing as people get back to their lives. I’m wondering what you’re seeing here, in the New York area.

DG: Yes. I always try to prepare, “What are the things that we’ll talk about each time?” This is a fine place to start. What I like to tell people when they ask are two things. One is, I say we closed the front door, but left the back door open. We remember early on, it was, “Oh, my gosh, we can’t have flights from China,” then it was, “Oh, we can’t have flights from Europe.” People start asking me, “Do you think they’ll shut down travel in the U.S.?” I was like, “They probably should, but they won’t.”

What happened is, it was actually an interesting article, a lot of people actually moved out of New York City and haven’t come back. I think it’s like 7% or 8%, maybe even more. Just left the city, and they moved to Miami or somewhere else, some out to California. As things got under control in New York, and they really have gotten under control in New York, things have gotten much, much better here.

If you look at the curves, the number of new cases is really low, the number of deaths is below 100, that’s fantastic. For instance, a couple of the cases that I saw this week, one was a gentleman who winters with his wife in Florida. Now it started to get too hot in Florida, so he and his wife flew back with a stopover in Boston, and then a couple days later, ended up admitted to the hospital with COVID. He’s on high-flow oxygen, and he already started on steroids, we’ll talk about that.

We’re considering giving him Tocilizumab at this point, as well. People get on an airplane, here’s a state where the numbers of cases are rising. A few hours later, they can be back here in New York. The other was a young man– this is like a euphemism, I think, goes back to clean out his college dorm room. Of course, he went there, he wore a mask, gloves, went only into his room, packed up all his stuff, then immediately came back, unscathed to the family– shared a house in the eastern end of Long Island. I’m not sure how accurate that description is.

What I’ve seen, basically, is people go back to colleges and their buddies are there. They get together, the social distancing is put on hold for a period of time, but this was another case of this individual. The week before, the family was going to do this house share out on the eastern end of Long Island. He had gone back to college and cleaned out his dorm room and now he ended up getting sick. By the end of the week mom, dad, aunt, uncle, the whole family gathering is now COVID-19 infected. That back door is wide open. People can jump on a plane from any one of those states and come right back here to New York. It’s really parsing words or playing around with the language.

People always ask me, “Will there be a second wave?” As people have probably heard, “Well, this first wave hasn’t really gone away.” As the numbers go up, “It’s not a second wave, it’s just the second peak of this wave.” I think it’s semantics, at that point. We got up to almost 40,000 new cases per day when we peaked, it was early on. Early on meaning just a couple months back. We’re now seeing about 26,000 as a weekly peak day. So yes, we went down. The deaths have actually gone down quite a bit more.

At one point we were seeing between 2,500 and 3,000 deaths per day. That has now settled down to less than 1,000 deaths per day. I think we’ve come down low enough that as things rise, I’ll call it a second wave. I know a lot of people are going to say, “Well, no, there isn’t a second wave because they said there wasn’t.” I remember we used to climb Mountains in Colorado, and we would define how many peaks were above 14,000. For two peaks to be truly separate peaks and not just part of the same mountain, you had to have a dip, a saddle that went down a certain point. I think we’ve, at least in New York, have a saddle. We’ve gotten it down.

As the numbers rise, I think we’re going to do okay in New York for a little while, here it seems like it. We’re going to have the snowbirds coming back from high-risk states: Arizona, Florida, California. We’re going to see cases, as mentioned, I’m already seeing cases due to that. The rest of the country, the number of cases dropped from a high in the upper 30s to a low in the mid-20s. That’s not a huge drop, we’re still tracking along.

VR: Well, Tony Fauci said we’re still in the first wave. [laughs]

DG: Yes, [laughs] it’s semantics. It hasn’t gone away. It’s starting to get worse again in certain places, so yes. What were the other things we should talk about? Preparations for vaccinations for the fall. We’re getting ready because that’s a big issue that we’re worried about. This is still on the same concept of, “We expect there to be an increase in the fall. We’re hoping that we can get more uptake on the flu vaccines this fall.”

It’s almost a triage or a Bayesian analysis if you think about it. If a person calls and it’s say end of October, November, “I’ve got a fever, I’ve got a headache, trouble breathing, I don’t feel well.” If they’ve had their flu shot, then it’s higher likelihood that we’re dealing with COVID. If they didn’t get their flu shot, then it could be the flu, it could be COVID. It makes it a little bit more of a challenge. We know the flu vaccines are never 100%, but we’re going to need everything we can.

Our chief of the Division of Pediatrics, Jay Berger, has been working on this. Dr. Larry Shulman, the head of our ProHealth COVID Team, has been really letting people know, “Start prepping. Hopefully, we’re going to do more vaccinations this fall. That’s going to help us.” People who maybe didn’t get flu vaccines in the past, maybe this is the first time, that would be great. We’re going to get to steroids, but I’ll just talk about telemedicine because I know we have a lot of doctors listening. You wonder what do you do with telemedicine. I’ll say telemedicine is here to stay. We just need to sustain this model and understand how it complements our other abilities to deliver care.

It can’t replace all traditional in-person visits. I still see a percent of patients in-person even “outpatients.” The Centers for Medicare & Medicaid Services, so CMS, they’ve actually been very supportive of telemedicine with reimbursement and other flexibility. They’ve extended that support out until September. We expect a hybrid model in the future. This pandemic is going to forever, I think, leave its mark to have an innovation on the extension of telemedicine. Maybe this was good timing because people are a little bit more flexible and forgiving with telemedicine because it’s a necessity at this point.

Once you’ve actually had one telemedicine visit with a patient, I find that the repeat visits are so much easier. Their computer’s set up, the microphone’s turned on. That’s been helpful. This is why I was so excited to have Chuck on here. I was hoping we would talk about steroids.

CK: The RECOVERY study.

DG: Yes.

CK: You had predicted this. I think it was about two months ago, you were talking about actually a dose of steroids or a trial of steroids before you would go to an IL-6 inhibitor. Given the long half-life, given the sever immunosuppression of IL-6, it turns out you’re right, Daniel. That’s the expert opinion of the bedside, I think. The RECOVERY study is actually very innovative design. It’s a multi-arm adaptive study where you can add arms to the study in midflight. Each arm controls for itself, including having a standard of care arm. Indeed, in hospitalized patients, it looks like giving six milligrams of Dexamethasone actually reduced mortality by 35%, which is a whoppingly big number in these types of trials.

DG: It is. It’s dramatic. I thought this was maybe a good time to walk people through, “What was the whole steroids story? What happened?” Because people probably remember– I remember this was even before we talked about masks, people were saying, “Oh, don’t give steroids to these patients.” I thought I would maybe walk people, our listeners, through “What was the story? What happened? Who said what and why was this so controversial for so long?”

It’s really interesting because February 15th there was an opinion piece that was published in The Lancet. That’s okay. I know it’s The Lancet, it’s had some issues. [chuckles] It was an opinion piece out of a group of writers from Edinburgh. This is Edinburgh, Scotland. These are folks that they’ve not seen any patients with this disease. Basically, they just said, “You know what? We’ve reviewed the literature, we looked at SARS, we looked at using steroids in other respiratory illnesses. We just think it’s a bad idea.” There’s no clinical data that exists to indicate that you should be using corticosteroids in this disease.”

People very quickly said, and WHO actually got on board with this and said, “No steroids. We recommend no steroids.” About two weeks later, there was actually a correspondence response back to The Lancet. This is from physicians in Wuhan. They said, “Of course, we oppose the liberal use of corticosteroids, but we do recommend short courses of corticosteroids at low dose. Use prudently and only in the more severe cases. We do believe that this is something that should be studied.”

It’s interesting, that first correspondence to The Lancet, there was no data. There was all this discussion about, “Well, they said this because if you give it in the first week, you’re going to double mortality.” There really wasn’t a lot of data to support that. There was a lot of thinking. A couple of actual studies popped up on the preprint servers because the mandate was you may not use steroids in these patients, it’s contraindicated. We all read the opinion piece in The Lancet.

There was an “Early, low-dose and short-term application of corticosteroid treatment in patients with severe COVID-19 pneumonia: a single-center experience from Wuhan, China.” This actually showed that, “Hey, there may actually be some benefit to using steroids. You may get a faster improvement.” The people that we gave steroids to, they’re only in the hospital for 8 days versus 13 or 14, they’re requiring less oxygen. It was at about this point when some of us started to say, “You know what? We are seeing so much inflammation in these individuals that it makes sense.”

Another study came out, and I think this is where we really started to see an increased use. This was the “Early Short-Course Corticosteroids in Hospitalized Patients With COVID-19.” This was actually a COVID-19 Management Taskforce based at Henry Ford. Here, actually, they show that you had increased death. What they did is they said, “We think this might make a difference, so we’re going to do a before and after.” Before, they said, “This is what’s happening right now. Let’s introduce this short-course steroid protocol.” They’re using an intravenous, about a milligram per kilogram of SOLU-MEDROL, and we’ll talk about that.

They saw once they introduced the protocol, that the percentage of people that were dying went down, percentage of people that were requiring intubation went down. The percent of people that were escalating to require ICU-level care went down. About this point, we started using it quite a bit more broadly. Again, it was going against dogma. People were quite upset. How could you possibly do this? I think I remember it on one of the TWiV, there was a, I will say, a more senior ID doc who came in. “What was this patient doing on steroids? Don’t you know?” [chuckles] It was actually a colleague of mine, an ICU doc. He’s like, “Well, look, there’s this data here and we’re seeing all this inflammation.”

We started noticing when you’re doing something that reduces the mortality by 30%, which now we’re seeing confirmed in the study, that’s something you can see in real-time. The interesting thing about this study is, I think, that when people saw this come out, I read a bunch of reactions to it. This is why I hope Chuck will be able to help with this. The same, “Oh, this is just a press release. We can’t do medicine by press release.” I’m actually going to point out that this isn’t really medicine by press release. This RECOVERY Trial, we have more data and more information on this than you usually get in a publication.

We had plenty of time to see about how the RECOVERY Trial was set up. We have all the methods, all the statistical analysis, there’s an independent data analysis group. What we’re really seeing here is the entire paper was, in a sense, written ahead of time with, “Here’s the results, here’s the methods, here’s everything you need to know.” What came out here is the results section of this trial with 11,500 patients enrolled in 175 NHS hospitals in the UK. This arm of the study was 2,000 patients in the treatment arm and over 4,000 in the comparator arm, so in the control arm. It made statistics that are really impressive.

The reduced deaths in the ventilated patients was a p-value of 0.0003. This was so dramatic a difference that the number needed to treat, I don’t know if people are familiar with that. For every eight people you treat, you’ve saved a person’s life. They followed this data out this isn’t one week, this isn’t two weeks, this is out to 28-day mortality. People say, “Oh, these people are going to just go on. They’re going to end up with bacterial infections. They’re going to die anyway. All you did was protect them for a little window.” No. This is out past discharge. This is really impressive. I think I’ll say practice-changing landmark. Really, the first drug showed improved survival in COVID-19 in a proper randomized control trial.

CK: I think just the other thing to comment on, this is the Oxford Clinical rial group. These are leaders in the field of innovation and clinical trial design. This study in itself is innovative the way they can add arms to the study, and they have second-wave randomization to Tocilizumab if you’re progressing poorly. I think the studies that were withdrawn are different. They’re observational studies. It’s big data. Well-trained epidemiologists with a computer that has significant power can get a dataset and analyze it. It’s not the same thing. Those types of findings compared to randomization in an excellent clinical trial unit.

VR: These are all hospitalized patients, is that correct?

CK: Yes.

DG: These are. I think it’s important to point out, there really were three groups that they looked at. There was the group of patients that were mild, didn’t require oxygen, so required no respiratory intervention. Those people, there was no benefit. I think that that was what we’ve been talking about. Don’t do anything unless you need to. These people had mild disease, no evidence of the significant inflammatory component. The patients who required oxygen, and the patients who actually required ventilation, both those groups had really significant benefits.

This is not something you give to people the first week, it’s not something you give to people who are doing just fine. This is a therapy for people with that inflammatory response to the point where they’re actually becoming hypoxic, so their oxygen level is low and they’re requiring oxygen, all the way up to patients who are so severe that they’re requiring ventilatory support.

VR: If you did give this early on, it would be detrimental because you’d be suppressing an antiviral response, right?

DG: I still suspect that. There’s no benefits.

VR: Was there any harm in giving this? Did they report any of that? I didn’t see it.

DG: You want to jump in on that, Chuck? This will be interesting to see, the details that go through the dramatic reduction in death, but we’re not seeing details in what percent of the people that survived had required antibiotics for a secondary infection, etc.

CK: I think the full details of the paper, we need to look at. I think some people said that. This is such an important result that I don’t think withholding it– and the amount of detail they gave, as you mentioned, Daniel, was good. This will be in probably The Lancet within a month.

VR: Is this the first outcome of the RECOVERY Trial?

DG: It’s the second, actually. The other arm of their study that they stopped was this group also looked at hydroxychloroquine in hospitalized patients. They basically said, “We’re not seeing any benefit. Let’s just stop doing that.” This group, I think that was the solid data saying, “We’ve looked at in hospitalized patients, and we don’t think it makes a difference,” versus the retracted paper.

VR: They have other arms still in progress, basically like Tocilizumab and convalescent plasma. We’re presumably going to hear about those in the future.

DG: Exactly. I think Chuck mentioned that. That’s the next step. We’ll hear about that in the coming weeks– is the people who got steroids, they’re then going to randomize a certain percent of those to go on to get Tocilizumab or not. We’ll see. Is the steroids giving us this dramatic mortality benefit? Is that enough or does the Tocilizumab add something to people that are progressing? We’ll learn from the RECOVERY group, we’ll also learn from the large French study that’s going on.

All right, next. [chuckles] This was a good week, I have to say. The other is prone positioning. We finally got a paper that actually– We’ve been seeing this and it’s pretty dramatic. I say it’s almost like you turn up the oxygen on the vent. Oh, wow, now they’re not hypoxic. This was the prone positioning. JAMA published a paper looking at a number of critically ill patients right here in New York City. This was actually done during April. Basically, they were able to show that when you put these people and you prone-position them, within an hour, you see a significant improvement in the serum oxygen. The hypoxemia improves dramatically with this intervention.

Actually, this intervention just again today, that gentleman I described who came back from Florida, initially, he got the steroids. He seemed like he was plateauing, and then today, his NLR, so his neutrophil-lymphocyte ratio had shot up, starting to have more difficulty breathing. I went in and I proned him, took a rolled-up bedsheet, put it behind him to get him more comfortable, not quite completely on his belly, but as close as he was willing to get. It doesn’t have to be completely laying on your belly. If you can lay on your sides, somewhat prone, and then maybe switch to the other side after a number of hours, that whole shifting seems to help with the ventilation profusion mismatch. The shunting that we’re seeing in these people.

The other is just an update on anticoagulation. We’re still waiting for more studies specific to COVID-19, but this is now becoming universally recommended. We really realized we’ve observed that almost half of the patients in the hospital end up with thromboembolic complications, so clotting complications if we don’t do something. Now, there’s a lot of studies looking at what’s the right dose, what’s the right medicine? There’s even some outpatient ones, because I think as we’ve tried to point out, people who ever even end up sick enough to get into the hospital during the first week or two, we were seeing those patients have strokes come in during week three and four.

This is just the other where now that we can do more, it becomes really important to make that diagnosis right up front so we know who has COVID-19. Make sure they’re connected to care. I talked to that gentleman who came up from Florida. I asked him, I said, “You went to an urgent care, you were diagnosed. What did they tell you to do?” He said, “They told me to go home and die.” [chuckles] I was like, “Okay.” Please don’t do that. Don’t tell people, “Just go home and die.” If we follow these people, we now know, if they get to the point where they require oxygen, we have an intervention that can reduce their chance of dying by 30%. The prone positioning helps, there’s a lot of things, anticoagulation.

Let them know that now we know you have it, let’s keep in touch. Let’s make sure we can step in as we need to. Even if they don’t end up in the hospital, there are trials ongoing so we have a better sense of what would be the best anticoagulation to use. This anticoagulation recommendation, this risk period, is extending out probably 30 to 90 days, so it looks like a pretty long increased risk of clotting issues.

VR: You said 50% of patients have clotting issues?

DG: Yes. Different studies, one showing 40%, one showing 60%, so really, really high. I think I shared some of the frustration I had early on where we would get a patient through that cytokine storm, they were doing better. We would be starting to plan for discharge, and then they’d have a pulmonary embolism and sudden death on the floor. We just were beside ourselves, because you felt like, “Oh my gosh. We thought this was a win.” Now, we’re realizing that there are things we can do to intervene and prevent those horrible outcomes.

VR: Is that the most common complication you’re seeing?

DG: I guess you’d go through steps. The first week, I don’t know if you call it complication. It just felt crummy. The second week was the hypoxemia requiring oxygen support. Usually, now, because we’ve gotten better at not requiring intubation in most cases. If we did not do something to address the thromboembolic issues, we were seeing DVTs, we were seeing arterial clots, and people losing limbs. We still see that week four and sometimes we see people come back. They’ve been discharged, now they come back with bacteremia or some sort of a bacterial infection. We see that in people that never even ended up in the hospital, who’ve never got steroids, never got anything that touched the immune system. This seems like there’s a post-viral risk of bacterial infections.

VR: At what fraction of patients, Daniel?

DG: We don’t know yet. We’re still waiting to see what number. Actually, interesting, we may see part of this data come out of the Tocilizumab trial. I got some of this feedback about that. That’ll be interesting. It looks like the rate of bacterial superinfections is a little bit higher, not fatal. Most of the people are able to be treated, they get these but it may be a little bit higher. It looks like it’s a little bit higher in people that receive immunomodulatory therapy. That data will give us what percent are having infections in control group versus treatment groups, so that’s going to be helpful. One thing we do know is that the minority of people when they come in the front door have bacterial infections. It’s 90% of the time just the COVID virus is enough to cause this.

CK: The bacteremia is similar to their post-influenza staph?

VR: Yes, it’s really similar. We’re seeing staph, we’re seeing E. coli.

CK: You’re seeing E. coli too, okay.

DG: Yes, the stuff I think I was expecting, and now every time I see someone with staph bacteremia, I take a very thorough, “Have you had COVID?” And I check serology. The majority of the time they do. Then again, I’m in New York. So let’s see update on the late-stage issues. Still a growing number of people that I’m taking care of where they just never get better, where the fevers continue for weeks and weeks. The interesting thing, and I described this last time and seemed to be consistent, is that bi-phasic nature where people tend to get better. Maybe this is that trough and the second bi-phasic wave of the illness, but then they feel worse.

Again, as mentioned, antibiotics usually don’t play a role in this. Just generically give them antibiotics but some people, as mentioned, might have a bacterial superinfection. These people need to either be seen or get a chest x-ray or evaluated. The most common is this chronic chest tightness burning described as waking up in the morning, and your chest just feels like it’s burning and on fire, trouble breathing, stiff joints, muscle pains, and low energy.

It’s almost like a rheumatological where there’s usually a 30 minutes to two hours rough start in the morning. Things get somewhat better during the day, and then in the evening, it starts to get worse again. A growing number of these individuals and I’m not sure exactly how to deal with that.

VR: Anything else, Daniel?

DG: No, well, let me thank everyone for their support of Parasites Without Borders and FIMRC, that continues to be really impressive, so thank you for everyone reaching out. I know people who maybe haven’t listened before, Parasites Without Borders is supporting the FIMRC Bududa Clinic in Uganda. If you go to parasiteswithoutborders.com and contribute, we give twice whatever you give to Parasites Without Borders to support this clinic. FIMRC is an organization that is, I guess, the people who run it there’s a number of individuals who run the organization, but the Bududa Clinic is completely run by local Ugandans. Really, this is flowing through and supporting the local Ugandans who are really having a tough time as people might imagine with this pandemic.

VR: Hey, let me ask you a few listener questions. The first one from Kayam, “What should a convalescent patient be on the lookout for in terms of a possible second phase late rebound? Any sign of age or pre-existing conditions as rush factors for this?”

DG: Yes. I am going to say if you had COVID-19, you do want to be in regular communication with your provider because there can be complications in the various stages. You run through these as; the first week you feel crummy, the second week as we see that high risk of pulmonary complications with the cytokine storm– This really tails into second week– into third week when we start seeing the highest risk of the thromboembolic complications so the clotting.

You want to be talking to your provider about, “Do I have coronary artery disease? Am I limited as far as mobility?” Because there are certain antiregulation things you might do, there also is just a generic, try to be as active as possible. Moving is going to decrease the risk of these clotting complications. During that trough period, as mentioned, there is an increased risk of bacterial infection. If you don’t feel well, you want to get evaluated. You don’t want to just get antibiotics because you might have a pneumonia, you might actually have something as serious as bacteria in the blood. Unfortunately, during this late phase, I’m not sure we know how to treat it if it’s just COVID-related.

Some patients are finding that Tylenol is very helpful with fevers. We’re getting a little bit more relaxed about taking non-steroidal anti-inflammatory medications. At some point, we’ll talk about that, but again, that was the whole never use aspirin, never use Ibuprofen or Naproxen was again just a letter. An opinion piece from some doctors in France saying like, “Yes, we’ve seen some stuff. We’re a little worried about this.” It is pretty dramatic, actually, if you have a patient, they take just one Ibuprofen, and oh, my gosh, the relief they get it can be impressive. Coordinate with your doctor before taking anything.

VR: All right. Opha writeshe heard you, Daniel, mentioned you’re starting to see some reinfections– that’s eight episodes ago. He wants to know if patients coming in with reinfections are also positive for antibodies.

DG: I guess I’ll clarify. I don’t know if we’re actually seeing people with COVID reinfections yet. I don’t think that’s been documented. We certainly saw, and I had a gentleman in the intensive care unit who actually was one of our longest patients who died last week. Actually, one of the last of the originals who came in initially, went through the whole process, got better, they did the clap out, and he went home, everyone was excited. About two weeks later he came back with worsening pulmonary symptoms, and he ended up in the intensive care unit, ended up intubated. He was on mechanical ventilation for well over a month until he finally succumbed to this.

He’s one of those gentlemen who was PCR positive for a very long time. By the time he died, he was PCR negative. I don’t know if we actually– I would say there is no clear documented COVID-19 reinfection yet. We’ve certainly seen what people have described where people are PCR positive become negative, have a worsening of symptoms, the PCR turns positive, but we don’t know if it’s a viable virus. We don’t even know if it’s related to the virus or if this is related to an immune perturbation.

VR: Margaret wants to know, she read an article in Elemental Magazine, which says that COVID-19 is a blood vessel disease, not a lung disease. She wants to know if virus reproduction in blood vessel cells can explain all of the symptoms like the hypoxia, clots, and so forth?

DG: I don’t know. I love this article. This was actually a very good article I’ll say. People who haven’t read it. Dana G. Smith does a great job, but all the things that we were seeing early on led us to think of this as a model. I think we talked about it on TWiV— the idea that endovascular that’s associated with endovascular dysfunction or endothelial dysfunction, and so it’s really acting that way. I do not know if the virus is actively replicating in endothelial cells.

It’s limited as far as information on that, but the activation of the D-dimer, all the thromboembolic complications, I think there’s a lot of interesting science that needs to be worked out relative to all the different stages. We understand, I think to some degree, the early viral replication phase, we’re getting a better understanding of the cytokine storm phase, but don’t really quite understand the mechanics underlying the whole thromboembolic endovascular part of this.

VR: I have looked and I cannot find good evidence for viral replication in endothelial cells as you say. In this article, they linked to a Lancet article, which is entitled, “Endothelial cell infection and endotheliitis in COVID-19.” If you read the paper, it’s a two-patient study where they have some electron micrographs, what look like virus particles, but there’s no identification of them as SARS-CoV-2. They conclude that it’s a virus reproducing there, but I’m not convinced I would agree with you. We just don’t know yet what’s going on.

DG: Yes. It is fascinating though, I have to say.

VR: I bet in the end it will turn out to be immune effects of some sort, and not virus reproduction there, but we’ll see. None of the animal models, especially the non-human primate models, I haven’t seen any endothelial cell reproduction. Two more, two short ones. One is from Beth who has Graves’ disease. She’s never had a thrombotic event. She’s worried if COVID will trigger APS, and she’ll get critical. Should be worried or is this just late-night Internet-induced medical terror?

DG: Yes, if you go on the Internet, you will certainly die of all horrible things usually by morning. Just to translate a little bit of this, Graves’ is actually an autoimmune disease that affects the thyroid, and it is an autoimmune disease. The antiphospholipid syndrome, so APS, is you form an antibody that interferes with the clotting system and it can lead to an increased risk of thromboembolic complications. Putting this all together, I think that I could see why your Internet search could get you quite concerned.

We are seeing only evidence of lupus anticoagulant in a minority of people. I think I’ll clarify, let me explain what this means. We can actually do assays where we measure, “Are there antibodies to cardiolipin or phospholipids?” You can measure them, that’s great. You can also do functional assays where you say, “Okay, I’m picking this stuff up, but is it really functioning as a lupus anticoagulant?” This is really fascinating. There’s a silicon base, but I like the traditional, there’s a Russell viper venom test. You take this viper, a Russell viper and you actually get the venom. You’re really there are snake farms where they have all these Russell vipers.

The way that venom works is it causes blood to clot in the presence of lipids. If you’ve got this antiphospholipid antibody that is functional, it actually will block the dilute Russell viper venom from causing it. You add a little bit of excess lipids, and boom, it clots right up on you. Early on, and I don’t know if people know this, but early on the epidemic, I brought up all the Russell vipers in the world. No, I’m joking. We were doing this test early on and we noticed this issue that people are publishing like, “Oh, look, they’ve got this lupus anticoagulant.” But we were doing functional assays to basically say, “Yes, it’s not always functional.”

This may just be part of this diffuse polyclonal B-cell activation, and all these immunoglobulins are being produced. Yes, you can measure them, but they don’t necessarily have the antiphospholipid syndrome. There’s no actual activity. I’m going to say that there isn’t compelling evidence that you should be more worried than anyone else.

VR: Beth is a novelist and you can find, she’s got a link to her work there. I’m just amazed that the different kinds of people we’re now attracting with TWiV in the time of a pandemic. All right, one more, Daniel, from David who heard you on 621 talk about early advice from Chinese doctors to use ventilators, and he says, “Is it the chicken or the egg? Does being on a ventilator itself cause problems or would their outcomes be terrible anyway?”

DG: Yes. I’m trying to figure out which is the chicken and which is the egg, but I will say this was something that we watched really closely. We would notice that there would be a person who was becoming hypoxemic, and then we would put them on the ventilator, and they would rapidly get much worse. The ventilator itself seemed to be triggering an acute worsening. We would maybe have them on high-flow oxygen or whatever we were doing to keep them off the ventilator, they were saturating and in the high 80s.

We had a limited, we’re trying to figure out what to do with our ventilators. We weren’t using them willy-nilly. We would say, “Okay, this gentleman looks a little bit more stable here. Let’s not intubate him now. Let’s just watch him.” This gentleman over here, let’s intubate him because he meets all the criteria, right? This is early on in the pandemic. When we would intubate the person, suddenly we would have to turn the oxygen up to a 100%. They would become much worse and this neutrophil-to-lymphocyte ratio of the ferritin, the ESR, the D-dimer, the procalcitonin, and all the inflammatory markers would acutely rise right after intubation.

It was actually, it looked like the ventilator itself, that positive pressure was actually driving worse inflammation. It’s a very hard thing I would say to study. Yes, we’re noticing that just right with the intubation this would happen. What we started doing was delaying intubation, and if you could delay intubation, and just use other methods, you seem not to trigger that acute spike in the inflammatory process.

VR: What is the process where you take the blood out and oxygenate it outside, then return it?

DG: Yes, that’s ECMO, extracorporeal membrane oxygenation, which I first actually learned about with the Hantavirus outbreak. I was in medical school back then, and actually got to meet the original doctors and hear the story firsthand. This was I think the first time a lot of people heard about ECMO, and this is where the blood would actually come out, would go through a machine. This extracorporeal, outside the body, oxygenation device, and it would oxygenate the blood, and then it would go back. We’ve used that a little bit in COVID-19. We’re usually using it to people already on ventilator. It’s added to a ventilator [crosstalk] instead.

VR: I see. Because I wonder if you do that instead of a ventilator, then you have this pressure issue. I just wonder if those patients would do better or if it’s not enough oxygen to help on its own.

DG: Well, we actually talked a little bit about your field. The iron lungs with maybe instead of what we’re using now is positive pressure ventilation where you’re putting– Using the negative pressure where you basically expanded the chest and help them breathe that way.

VR: Right, right. Interesting. All right, always interesting. All right, Daniel, thank you again and for coming with us.

DG: No, a pleasure as always.

VR: See you next week. Chuck, thank you.

CK: Good talking with you both.

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