TWiV 677 Does antibody really know what time it is

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 1 November 2020

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

[music]

VR: From MicrobeTV, this is TWiV, This Week in Virology, Episode 677, recorded on October 29, 2020. I’m Vincent Racaniello, and you’re listening to the podcast all about viruses. Joining me today from New York, Daniel Griffin.

Daniel Griffin: Hello, everyone.

VR: Who else at the beginning of every Friday TWiV for some time now?

DG: I was looking back. It goes back to March of 2020.

VR: Wow, that’s a long time.

DG: Yes, and you’ve been great, Vincent. You’ve been consistent every time. I was going to say you’re looking good. I think you must have discovered that Zoom feature where you click on it and it makes you look more handsome.

VR: That’s it. Certainly isn’t me, but, Daniel, they say, “Consistency is the last refuge of the unimaginative.” That’s a quote for you.

DG: I also think consistency during these times is something that’s nice. I think a lot of people have gotten into a ritual. Every Sunday morning they go, and they find our podcast.

VR: For sure.

DG: I’m going to say our TWiV.

VR: You bet.

DG: They listen, and I think that hopefully, this is something helpful. Hopefully, this gives people something that gives a little structure, reliability, predictability to what has become a very unpredictable time.

VR: You bet. Okay, let’s go.

DG: Okay. I guess when this drops it will be November 1st, right?

VR: Yes.

DG: Let me start with my quotation. “To everything, there is a season, a time to every purpose under the sun.” Perhaps some of our listeners will probably know where that comes from, but I’ll leave that. People can email in. As we go forward, people will get a sense of why I’m starting off with that quotation. I even sent out a little Twitter teaser for this episode, for my little intro, so people can, if they don’t follow me on Twitter, they can track me down. There’s a little graphic that you can look at, maybe help gives a little bit of context for why I picked that quotation and some of the stuff I’ll be talking about today.

I’m going to start off with a patient update that actually, a friend of mine, I think I’m actually going to mention him another time during this episode. He’s my honorary cousin, Peter Daytz. He and I sail together. We race sailboats usually during the winter. I don’t know why we don’t sail much during the summer, but traditionally, on Sundays, when I’ve been less busy before the pandemic, we would race sailboats out there on the frozen waters on Sunday. My honorary cousin, Peter Daytz, was relating some stories about, it was really a friend of his who went camping in the Dakotas over Labor Day Weekend.

Both he and his friend ended up getting infected, getting COVID-19. Unfortunately, his friend died, but the other friend of my cousin actually ended up getting treated. Has not died, but he was curious because here we are now, and I think people who listen to TWiV have a sense of what the standard of care is becoming. But what I was shocked by was here his friend was given first hydroxychloroquine, a little bit of azithromycin thrown in there, and basically told, “Hey, there’s really nothing else we can do for you. Good luck with that.” I think we’ve come quite a long way.

Maybe just, if you listen to TWiV, I know someone referred to themselves as the quivers of TWiV or something along those lines. I try to do my best to disseminate what is the latest that we know, my physician update just here in the first 20, 30 minutes of the show. I’ll try to keep doing that. Hopefully, we can get people, I don’t know, up to speed with what we’ve learned because we have learned a lot. We shouldn’t be treating people now the way they were treated back in March. I’ll start off. As we’re recording this, we’re recording on October 29th, it’s my wife’s birthday.

Everyone can donate to Parasites Without Borders in her honor. Where are we? Just pulling these numbers off the front page of the New York Times. Yesterday’s numbers, we had 81,457 new cases. A 41%, 14-day change. We’re up 41%, and we had over 1,000 new deaths. That was a 9% change over the last 14 days. This is not great. For all the nurses, all the other people I work with, wear a mask. Let’s move back into the schools. Now, I’m not sure if I’ll ever get tired of discussing schools and COVID-19 while I have school-aged children.

Those of us who either have school-aged children, or were affected by school-aged children, or where grandparents and our kids have school-aged children. One of my earlier quotations, and here I’m quoting myself from TWiV 635 Mask Hysteria, which was released June 5th. Apparently, it’s quite a popular one. It might be the title. My quotation at that time was, “Open the schools not the bars.” I want to use some real-life examples of how this can be done safely, and why I think even as the numbers seem to be going up, we can actually have kids in schools safely.

I’m going to start with your Alma Mater, Cornell, Vincent, which I actually think is a great example of how testing can allow a university to, and I’m going to quote the headline of this article or the name of the article, “Chalk up a rare COVID-19 containment victory.” This was a nice article that was actually in Bloomberg News about this success. We’ve talked a bit about Cornell, I think partly because Vincent you have a personal connection, but also as my honorary cousin, Peter Daytz, his two daughters, twin daughters, actually graduated from Cornell.

He keeps me updated. Cornell University reopened its sprawling Ithaca, New York campus to a population of about 24,000 people in late August. This was unique as no other of the Ivy League Schools had attempted to bring back its entire study body all at once. Not every student came back. There were certainly students that opted to attend the fall virtually. Just as the doomsayers expected, people show up and a cluster of cases emerge just days before classes were to begin. They jumped in with testing, and they’ve been doing testing including pools.

Pools up to 24 at a time. I think they’ve really actually had a tremendous amount of success. Here we are, when this airs, we’re going into November now, and they’ve been actually able to continue to educate our students. It just shows you what you can do at a university level, at a college level. I just want to make a distinction that there are two real different scenarios. There’s the K through 12, and there’s the college/university, right?

VR: Yes.

DG: I enjoyed reading this article because they use some of the visuals that I use. The cruise ship on land, these college campuses. The other side of this is the K through 12, and that’s actually a little bit different. I want to reinforce the data, which is demonstrating repeatedly that there is very low or negligible risk of transmission inside the schools when correct measures are put in place. I’m going to knock on wood, create some sound background for you there, Vincent, when I say this. Last time I spoke about my friend, Scott Bersin, who’s down at one of the South Shore Long Island schools, Seaford High School.

They’ve not had to close for a single day. What did they do? They did a few things. One, which I thought was pretty creative, I was out walking the dogs early today in the pouring rain, the hurricane is now reaching us, and one of the things they did is they have half of the school go to class in the morning, half of the school go to class in the afternoon, avoiding the really high-risk activity of feeding and having people eat in a setting. Because, as we know, when you’re eating, when you’re drinking, off come the masks. They’ve also done all the distancing.

They have the students six feet apart. They have them wearing masks. I’m always a little shocked when I hear about mask breaks, which is, we don’t do that in the hospital by the way. I’m not sure it should be done in schools. We keep our masks on. It keeps us safe. It keeps other people safe. They upgraded the ventilation systems. They’re keeping windows open. They’re probably going to spend a little bit more this winter on the heating bills. If you do it right, when someone ends up testing positive and you ask that question, “Has there been an exposure?” The answer for the school should be, “No.”

When you find out that someone in Johnny’s class tested positive, you should say, “Johnny was not within six feet for more than 15 minutes without a mask. There was no exposure.” We should be able to continue to educate our children. We should be able to continue to do a lot of things. We have learned a lot. This is just like the story I mentioned in the Dakotas. We should not be treating situations the same way now as we did in March. We have learned quite a bit. I’m hoping here, in Port Washington, in my local schools, they’ve actually gotten one of my colleagues, Dr. Wilkins, onboard to help guide the process here. Hopefully, they’re going to stop shutting down every few days, and my kids can go to school because I love my kids, but I love my kids even more when they go to school every day.

[chuckling]

VR: Wonderful.

DG: Let me go into some treatment updates. What I want to do is I’ve been talking for a while about our phases, how a bunch of us have been using different terminology. We’ve been trying to get together on the same page. We just submitted to Annals of Internal Medicine, our paper, “The Stages of COVID-19,” 30 authors from around the world. You can imagine how much work it took to get 30 people to agree on the same terminology. Some of us had to part with our beloved terms, other people gave and took as this went on.

What I’ve been noticing, and I think this is positive, we are learning a lot. There does seem to be a growing appreciation that there are two major periods of COVID-19. A viral replication period, and then a second inflammatory period. It gets a little more sophisticated than that. I tweeted a little bit of this out there, so people can actually find my Twitter feed. We tried to get together, and we actually accomplished a framework where we try to identify clinically-relevant stages of COVID-19 and come up with three periods and five phases. As I go through in future episodes, as I talk about different strategies, the when will be relative to these periods.

The periods are the pre-exposure period, the incubation period, the detectable viral replication period. Then come the phases of the disease. The viral symptom phase, the early inflammatory phase, the secondary infection phase, the hyperinflammatory phase, and the tail phase. The early inflammatory phase, this is a compilation of what some of us were calling the cytokine storm phase, some of us were calling the pulmonary phase.

This is also when the hypercoagulation begins. We’re beginning to realize that even though we didn’t really see the thromboembolic complications till a little bit earlier, they were actually, at a small level, involved in the pulmonary and the cytokine storm manifestations. Our hope is that this common terminology is not only going to serve as a framework to guide therapeutics, but it’s also going to help when we do trials because we’re going to talk a little bit about some trials that gave us some negative information. Not because the therapy I think was wrong, but the timing was off.

Let’s start with the period of pre-exposure. What am I talking about when we talk about when 30 authors agree on this pre-exposure period? This is when you have susceptible individuals, and this is your opportunity to employ a variety of measures that can minimize the likelihood of an exposure to potential infection with SARS-CoV-2. This is thanks to people like Vincent, educating people about the virus and what we could do. This is also something we as physicians could do on a regular basis to educate our patients. The best thing you can do is not get exposed is, during the pre-exposure period, do everything you can to reduce your risk.

What do we do during this period of time? We have masks, distancing, ventilation, cleaning, hygiene, keep washing those hands. Potentially, chemoprophylaxis, minimizing contact with potentially-infected individuals. Testing can help to identify those, and, actually, optimizing management of pre-existing conditions such as diabetes, hypertension, asthma, COPD. In a sense, we’ve been falling down on that latter part. A lot of patients are afraid to visit the doctor. You might want to balance that against poorly-controlled diabetes, about not controlling your hypertension, about putting on those pandemic pounds.

Being in good health is a great, great thing to do should you be at exposure. This is also a time for active and potentially passive immunization. By passive immunization, I’m touching a little bit on those monoclonal antibodies to which I’ll return. One day, we have visions of chemoprophylaxis, where pre-exposure prophylaxis, where maybe you’re going to be taking medications before you’re exposed. We see this in other diseases. I do want to bring up what is perhaps controversial to many of our listeners, and this is about vaccines.

This is when you want to get vaccines out there. I’ve been called a vaccine pusher, and that’s okay. You always say, “Call me anything you want, just call me.” This was something that actually was in the news recently. I’m going to read a quotation from Marion Gruber, people can Google who she is, “But we are concerned about the risks that use of a vaccine under an EUA will interfere with long-term assessment of safety and efficacy in ongoing trials, and potentially even jeopardize product approval.” Continues, “And not only the first vaccine but maybe even follow-up vaccines.”

There’s a lot here. I’m sure people will, when they start to think about this, they’ll start to realize what is being talked about here is delaying EUA of vaccines. We’ve gone back and forth on this. First, there was a rush, “We’re going to get them out there soon as someone comes up with an idea.” To even when we start getting efficacy and preliminary safety data, realizing that if we release those, that’s going to be an issue moving forward looking at other vaccines. Just to throw that out there, all four of the major vaccine trials are ready to be fired back up.

We actually are anticipating interim results to follow in November, December. Novavax actually delayed the start of their protein-based nanoparticle vaccine Phase 3 trial. They’re having production issues. Flu vaccines, flu, we’re going to vaccine push here. Get your flu shots. There are some regional short supplies, but it looks like nationally we’re okay. It’s a distribution issue here that we’re trying to work through. Having that flu shot, having less flu circulating around, is going to be a huge boon for us this year.

Let’s move into the incubation period. Now, this is a tough window because once you’ve had the exposure being within six feet for 15 minutes, and that’s cumulative, you can’t just step away and reset the clock, you may or may not be in this period. You don’t know if you were in the incubation period until afterwards. You have this presumed incubation period when perhaps you’re quarantining because at any point during the 2 to 14 days, you might get sick. We’re hoping that actually, this is a period of time when we can start jumping in with therapeutics. When I get to the monoclonals here in a minute, this is actually something in high-risk individuals we might consider looking at.

There are some discussions about trials there. Then you move into a little bit more understandable phase, the period of detectable viral replication. This is followed soon thereafter by the viral symptom phase. This is really our chance to keep people out of the hospital. Here, I’m going to bring up the Solidarity Trial because a lot of people found issue with this. They went through, and basically, it was a study where they said, “Ah, nothing really works,” and included in there was remdesivir.

When you look closely at the remdesivir, for instance, a lot of people are a little concerned that they’re giving remdesivir to people who are in the ICU, they’re on ventilators. They actually broke down their data a little bit into people who are on ventilators, not on ventilators. You could see a lot of the data, if you give remdesivir to someone already on a ventilator, it’s not helpful. If anything, you’re better off not giving them remdesivir. Toxicity, liver toxicity, no clear benefit.

One of the things is you hate to spend, and this was millions and millions of dollars. Not just one or two, millions and millions. You hate to do that and see them look at a drug at the wrong time, and then basically come away with, “Oh, it doesn’t work.” This period here, the period of detectable viral replication, the viral symptom phase, is also the time when we think that the monoclonal antibodies might play a role. People have probably noticed, it was a little bit in the news about this lately, where, again, they said, “You know what? We looked at giving monoclonal antibodies to people who were already in the ICU on ventilators, and we stopped that trial.”

That’s a good thing. Doesn’t mean monoclonals don’t work. It just means, really bad idea to give an antiviral therapeutic after the virus is mostly gone. I’m glad that they stopped that, but I hope the takeaway from that is, again, not the solidarity, “Oh, nothing works. We’re back in March.” We started actually talking about monoclonals back on TWiV 611, back in May. This was Corona and Crowns. Since then we’ve had a little more developments on this front. We had talked back then about a conversation I had had with the people at Regeneron. They had started a trial back then, where they were giving monoclonal antibodies to what stage of disease? The inflammatory stage, people in the ICU on ventilators. At that time, we said, “This is a terrible idea.” They said, “But we don’t know how to do those other trials. We don’t know how to do trials in the outpatient setting.” We said, “All right, let’s make this happen.” Fortunately, those trials have been ongoing, and now we’re seeing the fruits.

Let’s talk a little bit, what are antibodies? This is a little bit tricky, but that’s okay. This is a very complex protein that is made by your B cells once they differentiate. I always think of Richard Nixon. He’s got the two fingers up, and he’s shaking his jowls. He’s basically trying to educate the American public about antibodies. Good job, Vincent.

VR: He used to do it double. He was bivalent.

DG: Yes. Actually, the nice thing is a lot of these companies are studying the right hand shaking one and the left hand at the same time. Eli Lilly has a couple of these going on. Some of them are coming from human. Some of them are coming from the $120 million humanized mouse. We’ve got Regeneron. They’re studying their combination of two monoclonal antibodies. “The Regeneron” that our President received. We actually have Vir, GSK is working together, and they’ve actually got one where they’ve modified the hand part of the stalk part where it gives it a slightly longer half-life.

Once you give someone the therapy, it may continue to protect them a little bit longer. The data I have to say is really pretty compelling, and a couple of these companies are going to the EUA. We’ve talked a little bit about this, but if you give these to high-risk individuals, someone over the age of 65 with even a single comorbidity, we’re looking at a greater than 70% reduction in this person ever needing any medical assistance, ever developing hypoxemia, ever going to an ER hospital. They’re going to price them accordingly because that’s pretty huge.

Pretty huge if we can take our high-risk population and the majority of them never end up in the hospital. I look at Vincent because I’m wondering if he’s thinking about how does this work. I’m involved, actually, full disclosure, helping Eli Lilly do really a post-marketing type study if the EUA goes through. What we’re going to do is we’re going to use Optum Infusion. If someone has a positive test, we’ll send the nurse right to the person’s house. They’ll put a little IV, they’ll get the medicine. That’ll be it. We’re going to be using couriers to help improve access in the older adults.

I’ve been told not to use the word elderly. Improve the ability of older adults to get testing right in their home, and actually have these therapies “delivered to the doorstep.” These are the individuals that are highest risk, and if we can keep these individuals from ever needing to go to the hospital, this will be tremendous. Very encouraging stuff here. I’m going to jump ahead to convalescent plasma. I’m going to try to keep this short today. I think I mentioned to everyone this is my wife’s birthday. Convalescent plasma, this was another I’m going to say failed trial published in the BMJ.

“Convalescent Plasma in the Management of Moderate COVID-19 in Adults in India.” It was an open-label, multicenter, randomized control trial. A cute name, the PLACID Trial. 464 adults over the age of 18 admitted to the hospital with confirmed moderate COVID-19. 235 were assigned to the convalescent plasma and then compared to standard of care. They didn’t find any benefit in this study, but a couple things I’ll say. The role of plasma remains uncertain. In this study, 79% of the patients enrolled already had detectable antibodies. They’re giving this to people after the stage when we think it’s going to make a difference.

Again, I’m going to repeat. These are big expensive studies, and I’m going to argue, as many of my co-authors do in the paper we have out, that we’re spending huge amounts of money on trials that are doomed to fail and provide misleading results If we’re looking at the wrong phase of the disease when we do our trials. Let’s move into the early inflammatory phase. This seemed to be the tocilizumab week. There was a flood of papers. I don’t know if people are following. Actually, I took my notes on this section, and I redid it about four times because there were so many papers that were flooding through.

I’m going to pick one paper to discuss, which was actually our experience at the Northwell hospitals. This was where we used a combination of steroids, where we would give steroids, and then give the tocilizumab. I think our regular listeners perhaps recall that this has been my bias of a background of steroids first. Then you add toci rather than giving toci without this background of steroids. Tocilizumab is an IL-6 receptor inhibitor, so we’re trying to interfere here with the cytokine storm during the early inflammatory phase.

In this paper, which is actually out on a preprint right now, “Comparative Survival Analysis of Immunomodulatory Therapy for COVID-19 ‘Cytokine Storm’: A Retrospective Observational Cohort Study,” we see good and bad things in the title. I love the cytokine storm terminology. You notice it’s not really in our faces, it’s hidden in there. I really love the cytokine storm terminology. The nice thing here is this study looked at over 3,000 patients. They looked at people giving steroids and then tocilizumab. What happens when you did it in that context in this experience?

The patients treated with a combination of tocilizumab and corticosteroids, and it was steroids followed by tocilizumab, their hazard ratio for basically dying dropped down to 0.46. They had improved hospital survival compared to standard of care. This translates into a 54% mortality reduction over standard of care. Steroids alone gave you a hazard ratio of 0.7, so about a 30% reduction in mortality, which was consistent with other studies. Steroids drop your mortality by 30%, and then when you add tocilizumab afterwards, the mortality reduction was 54%.

I thought this was pretty impressive. If you go to Figure 2, there’s a nice Kaplan-Meier plot in this paper. You can see different approaches in how they did. Anakinra, that was an IL-1 inhibitor that was being used in a lot of the hospitals in the Northwell system. If you got monotherapy with anakinra, your survival was about 30%. If you got steroids alone, your survival went up to 45%. If you got steroids followed by toci, the survival was 60%. This was data after 30 days. Let’s caveats here because I don’t want people to think I’m a cheerleader for tocilizumab.

This was retrospective, it’s observational. We do get to see this combination of steroids in toci, but now we need to see steroids-toci randomized control trial. There are at least five additional randomized control trials evaluating tocilizumab in patients with COVID-19, currently underway. The interesting thing is going to see a study where this approach – I think tocilizumab all by itself, we’re seeing a lot of data saying that’s not a great idea. Steroids, still being widely used. I think here we had another bit of data that was on the lines of that making a difference.

We’re routinely using prophylactic dose anticoagulation, and then escalating this to full-dose if we feel like the risk-benefit warrants that. In the U.S., we tend to use low-molecular-weight heparin in places with more limited resource. It’s an injectable heparin. We’re also using a couple of these direct oral anticoagulants. Now, there was actually an interesting article about aspirin. Certainly, a lot of context where people don’t want to do this, and they decide they want to use an alternative.

This was actually an article, “Aspirin Use Is Associated With Decreased Mechanical Ventilation, Intensive Care Unit Admission, and In-Hospital Mortality in Hospitalized Patients With COVID-19.” Title basically says it all. In this study, only about 25% of the patients who didn’t get aspirin, were receiving heparin. This is, in most cases, looking at people that did not get an alternative. This was a retrospective observational cohort study. Still not at the level that ideally we’ll like, but just a little bit of support for people that are using aspirin.

Suggesting that it’s better to use something than nothing during this coagulation phase, which is starting during the early inflammatory. Then, after the early inflammatory, we move into the secondary infection phase. This is really straightforward. This is that high-risk for pneumonia bacteremia, bacteria in the blood. We have learned that staph aureus is a particularly common pathogen during this period of time. People usually don’t need antibiotics when they walk in the door. Only about 10% of people have a bacterial process with the virus, but this is a time when we start seeing the bacteremia and pneumonia. The time when antibiotics might play a role. The hyperinflammatory phase, this was originally the multi-inflammatory syndrome in children. There’s now a multi-system inflammatory syndrome in adults as well, MIS-A. The hope we have is that earlier innovations will prevent progression to this phase. There’s an overlap here with the study I’m going to talk about, the tail phase. Growing appreciation of the tail phase.

There was an interesting article looking at auto-antibodies that seemed to hit all the major news media, where they basically are finding broadly targeted auto-reactivity is common in severe SARS-CoV-2. What did they find? They found consistent tolerance breakdown. Normally, people’s immune system tolerates themselves. That’s better than a lot of people. Not sure how well everyone tolerates us, but our immune system seems to tolerate us, Vincent. What they looked at was something that maybe our listeners are familiar with, something called ANA, antinuclear antibodies.

What are these? These are basically antibodies against the nucleus, so anti-nucleus you could almost say, antibodies. This is something you normally shouldn’t be doing. You normally shouldn’t be making antibodies that target your nucleus. They basically were finding that a high percent of people not only had these, but a significant number had them at high titer. They also found reactivity against rheumatoid factor, phospholipids, prothrombin, the ancas. When they looked at the different types of ANA, there’s different patterns, they found what they said was predominantly speckled pattern, about 50% of people.

What does that mean? Homogeneous is when you do the whole nucleus. Speckled is you see it going after just certain areas, but not the whole nucleus. These are what we say as targeting extractable nuclear antigens. Just to make it simple, it’s a pattern we see in lupus, in rheumatoid arthritis. There’s nucleolar and centromere as well, but I’m going to leave it here. Just to say, it looks like we’re starting to see a little bit more interesting information about maybe the mechanism behind the tail phase, and a lot of the arthritis, and the fatigue, and all the other symptoms that we’re seeing.

It’ll be nice too, perhaps, if this will give us a little ability to do some objective testing because I know a lot of these people are suffering and not being taken seriously. A lot of times when you’re trying to work with them as far as their workplace, and unemployment, and issues like that, it’s nice to be able to have some objective measures. That allows us to do a little bit more objective testing there. I’m going to finish there for my part. I guess I’ll ask you, Vincent, if there are any emails that we hear, any other topics we should talk about?

VR: There are, but maybe in the interest of your wife’s birthday, we could skip the emails this time. Does that work?

DG: We could do a couple if they’re nice.

VR: If they’re nice? All right. I wanted to bring up two points quickly first. First, did you hear that in Russia, they have a masking mandate now?

DG: I heard that Vladimir is the first international leader to have a national mandate for citizens to wear masks. Kind of crazy, right?

VR: Interesting. Yes, there’s a lot of talk about this. The Biden campaign is saying that they would want that, but they recognized there would be legal challenges to it in the U.S., so probably is not going to happen.

DG: Yes. We live in a country that really favors our freedoms.

VR: Yes, for sure. The other thing, Daniel, let me share my testing results with you. Columbia does random tests of people who come here to campus. Last week, I was selected to come, and on Thursday, a week ago, I went. They have a lovely system set up here in the atrium, in front of alumni auditorium. You go in, they give you a tube with your name on it. You sit down on a desk, and there’s a procedure where you swab yourself and put the swab in the tube, and so forth. Then it gets sent to the Broad Institute for PCR. They are doing a one primer pair PCR to the nuclear protein gene.

Friday night, I get a phone call from the person directing this program, and I’m having dinner. My wife says, “It’s for you.” I say, “I don’t talk to people on Friday night.” She said, “I think you better talk to this.” I’m positive.

DG: Oh my gosh.

VR: What would be the first question you ask, Daniel?

DG: Whenever we do a test like that, I always want to know the pre-test probability. Is there any reason why you should be positive, Vincent? Is there anything you’ve been doing that put you at risk?

VR: It’s possible, but what I asked her was the CT value.

DG: [laughs] I like that.

VR: She told me it was 34.

DG: I was going to guess that it’s in the 30s.

VR: 34.7.

DG: I’m hoping this is negative, Vincent.

VR: 34.7. Friday, she said, “You need to isolate.” I said, “Fine.” I went in my office in the basement for most of the weekend. I didn’t eat with my family. My wife went to a different bedroom. Everybody is wearing face masks. I thought it was a false positive.

DG: That’s my highest suspicion, Vincent. We’ve talked about this on the show. I would consider that, in someone like you, as a screening test, to be a false positive and would do a repeat test. Did they offer you that? Did they offer confirmatory testing?

VR: Oh yes, sure. She said, “Come back.” I went back on Tuesday. I went in, did it, went home immediately. Then yesterday, so yesterday, Wednesday, it takes about 24 hours to get the results or 36 hours, and she said it’s negative. That’s the story, but it just goes to show that, you get a high CT value, you really need to repeat it, right?

DG: Any time you do a test where the positive predictive value is less than 50%, requires confirmatory testing. For you, you could do what you needed to do, but for a lot of people, could you imagine if this was your 11-year-old son? You have to wear a mask, you have to stay in your own room.

VR: Yes, true. True.

DG: I think a couple issues with that story, Vincent, why aren’t we doing it at Columbia? Why are we sending it to Boston to see that?

VR: Oh really, truly I agree. Yes.

DG: The second is, when someone is positive, you want to have rapid confirmatory testing to sort that out.

VR: Right, yes. No, I agree. You asked me, did I have any risk? Now, no. I’m mostly home, and I come here to my office two or three days a week. I don’t do anything, so, there would be no reason. Now, there’s just one possibility, which they brought up. Now, they haven’t found many positives on these random screens, but the ones they have, have been in labs with plasmids encoding SARS-CoV-2 genes.

DG: Oh, that’s interesting.

VR: That’s what they think is going on.

DG: That’s an interesting twist, right, in this kind of a testing scenario?

VR: Yes, all the positives have been in labs with plasmids. Now, my colleague, Amy Rosenfeld, who you know, thinks that’s nonsense because she said she hasn’t had the plasmid around for months, but these things can linger I think.

DG: That’s interesting. No, that’s really, really interesting.

VR: It’s interesting for labs working on plasmids. You have to be careful if you’re doing random testing, right?

DG: Yes. The other thing, which is interesting, I asked you that, of course, to put you on the spot on live podcast, live YouTube, whatever you want to call it, pre-recorded, you could always edit this out. No, a lot of times when someone has a positive test, and it was “screening,” and I learned this from the days of sexually transmitted infections, you say, “Hey, it was positive, so, do you want to share a little bit more than you shared with me before?” Then people are like, “Yes,” and then there’s the ugh and you find out. I think this has been –

Actually, I don’t know how they get this data because I understand how I get the data as a physician. There’s a trust, there’s a confidentiality, but a lot of people say that they’re wearing masks. They say they’re doing all the right things, and then push comes to shove, like, “Yes, I’m just getting tired of washing my hands. Me and a bunch of the guys did whatever.”

VR: I have to say, I was good. I isolated and did all the right things even though I didn’t think it was anything. What are the possibilities? False-positive, but it could also be I’m at the very beginning of an infection, right, before we get much RNA amplification?

DG: Yes, or the tails.

VR: Or at the very end, maybe I had an asymptomatic infection, right?

DG: Yes.

VR: It could have been either. That’s why a rapid second test would be good. I should have come the next day I think.

DG: No, that would have been more helpful. The other thing you can still do is you could do an antibody test, now and in two weeks, and that gives you a sense. If it was at the tail, the antibodies should start to come up by now. If this was at the beginning, then your antibodies would be negative. Sometimes it’s actually helpful, diagnostically, to have that confirmatory PCR and a serology test to help sort out what might be going on.

VR: Anyway, I thought that would be fun to talk about.

DG: Yes, I’m glad you’re okay. I worry about you, Vincent. You be safe.

VR: Oh yes, I’m in a risk group. I’m okay, but I have Blood Group O.

Dr. Griffin: Yes, I’m A+, so I’m a God.

VR: All right. Let’s do one email because this is a cool one about testing. This is from Will, who writes, “I am a Captain Paramedic for a large city, north of Detroit. Kathy’s meteorological report is the same as mine. I’m in charge of Macomb County’s Hazardous Materials Response Team. I teach paramedic curriculum to new students and CME to paramedics. I began listening to TWiP after my son had a crappy encounter with a little parasite by the name of cryptosporidium five years ago. I quickly became a fan of MicrobeTV and have been using info from your podcasts to aid in my teaching ever since.

I’m concerned with the second wave and how the emergency response community will handle it. As with most HCPs, we were dealing with PPE shortages in the beginning. Now that grant money has alleviated this issue, we’ve turned our focus to building a reliable testing regimen and preventing an outbreak within our department. I plan on utilizing UHG’s testing simulator to help accomplish this. The access to testing sites and the type of tests they use have been very unreliable and inconsistent. Here’s a breakdown of testing results for our 100 fire fighter/paramedics.

PCR or antigen positive since March 12, antibody-positive since March 9. Not all 12 went for the antibody test. We have been using PCR for guidance on when someone can return to work. The New England Journal paper on rethinking test sensitivity made me reconsider that. We have one firefighter who was PCR positive with mild symptoms last week in August. He went for PCR and serology test last week. Both of those were positive. He’s currently asymptomatic. Here are my questions for Dr. Griffin. Is his current PCR positive test likely showing post-infectious shedding of RNA from the last week in August rather than a new infection, possibly a false positive?”

VR: You want to take these one-by-one?

DG: Yes, let’s take them one-by-one. These are helpful because I think these are questions that a lot of people have. I appreciate your story because you used isolation and quarantine properly, Vincent, or at least you used the word isolation. When someone who does not have severe disease gets infected, we recommend, from the onset of symptoms, or from the time of a first positive test because not everyone’s symptomatic, that they isolate for 10 days. Then, at the end of 10 days, if they’re symptom-free for 24 hours, you’re really done.

We now have millions of experiences that support that. The second is if someone has more severe disease, they end up in the hospital, then it’s 20 days from either that first test or from the onset of symptoms. We no longer recommend, in most cases, that you do a test-based return to work paradigm. We really don’t think you need to do that. This works properly. For instance, in this individual, I’m going to say I don’t think you need to do the PCR test. We require two negative PCRs for entrance to a nursing home, and actually, our nursing home study, I think is going to soon be published in Emerging Infectious Diseases.

We used a really strict, yet to be negative PCR for the NHL experience, but in general, this is I think excessive. I wouldn’t continue to have this person get tested. Repeat infections, so far in the time span we have, are very rare. We think we’re starting to see more here in New York as the incidence goes up, but we’ll see. Within 90 days, we don’t recommend that someone continue to be tested.

VR: His next question is should he get an antigen test because the city will not pay for two negative PCRs 24 hours apart?

DG: Yes. I don’t think you need to do this. I think you can stop the testing and move forward.

VR: He asked, “Can you provide resources for obtaining rapid testing equipment and supplies?”

DG: The entire Optum Network is basically moving to try to create access places for everyone to do all the testing. Optum Care writes a whole network, all the Optum urgent cares. If you’re having issues, we’ve even done this over time, is partner. You don’t have to reinvent the wheel. When we were having this ramp up, we’re doing about 150,000 tests a day in New York, and ProHEALTH is doing the bulk of those. We can’t do all those ourselves. I think I had mentioned we have a line of airplanes at Teterboro, and we fill those airplanes with samples. Then Quest runs them for us in North Carolina. Reach out, partner with people. There’s ways to get this done. Don’t feel like you’ve got to try to shoulder all this. That would be my advice.

VR: All right. He said he plans to move to a higher frequency testing model utilizing rapid tests to minimize false positives and unnecessary quarantine of our members. He thanks us for being a reliable resource. He signs off, “Your friend in science, Will.” That’s great.

DG: No, I think that is great. The one thing I’ll just make sure I throw in there, if you’re going to be doing a lot of testing, have confirmatory testing. We have, in our calculator, and we show if you don’t have the ability to do a confirmatory test, you’ve got lots of people that end up sitting in quarantine, I’m going to say, or isolation, right?

VR: Isolation, right.

DG: Testing positive.

Vincent: All right, that’s our weekly COVID-19 clinical report from Dr. Daniel Griffin. Thanks again, Daniel.

DG: Yes, I’m going to thank you, but before I go, let’s not leave money on the table. I’m going to say, we’re right here in the middle, right? It’ll be November 1st, the middle of our MicrobeTV fundraising.

VR: Yes.

DG: Go to Parasites Without Borders. Your tax-deductible donation, we’re going to double it up to a total donation, which I think we’re going to hit $40,000 to go to MicrobeTV to help Vincent and the team do what they’re doing.

VR: Wonderful.

DG: Parasites Without Borders.

VR: Thank you.

[00:46:13] [END OF AUDIO]

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