TWiV 853 COVID-19 Clinical Update #97

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin                                

Aired 15 January 2022

pdf of this transcript available (link)

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 853, recorded on January 13th, 2022. I’m Vincent Racaniello, and you’re listening to the podcast all about viruses. Joining me today here at ‘The Incubator,’ Daniel Griffin.

Daniel Griffin: Hello, everyone. Hello, Vincent. That’s good.

VR: Hello, Daniel. Again, next to each other.

DG: [chuckles] This is always nice.

VR: Good to see you here. We also have Dickson here for TWiP later. That’s really exciting.

DG: This can be exciting. It’s a good day. All right, let me start with my quotation, and then we will move forward. This really is reflective of the update, “The miserable have no other medicine, but only hope.” That’s William Shakespeare.

VR: Don’t they have vaccines?

DG: [laughs] Actually, they do. My wife was talking to me the fact that, “Dan, you really need to have a split-screen. This is, we’re talking to the vaccinated, this is we’re talking to the unvaccinated.” When I give the update, and I say, “Oh my gosh, we’re setting records across the country, we’re setting records here in New York, more people in hospital than ever, we’re having days with over 2,000 people die a day.” This is 95% when you look across the country, this is the unvaccinated. That’s what the unvaccinated is experiencing. The vaccinated is experiencing the omi-cold. It’s really a different experience.

There is some subtlety here. I think we’ve always tried to talk about this. We don’t want to leave out those individuals under five who don’t have access to vaccines. We don’t want to leave out people who are immunocompromised. We’re going to talk a little bit about the things we can do to help those individuals out. It is largely, but not exclusively, currently a pandemic of the unvaccinated. There also, unfortunately, are people who are at high risk. Also, unfortunately, we still have people who developed long COVID. Those individuals continue to suffer.

A few points from last week that people were excited about. The CDC does offer a testing option for ending isolation. There’s been a lot of mixed things there, and we’re going to talk about a paper today where we talk about how infectious actually are people when you get to day six. Maybe a little bit of the mismatch between viral load and what that really translates into as far as viable infectious virus that might go on to others.

People also got a little bit excited, CDC now recognizing for 90 days the viral infection-induced survivor immunity, what people have called natural immunity for the first 90 days when people are making quarantine decisions. Some people are excited here. Our testing advocates are excited. People who’ve been infected before are excited, I guess.

The Omicron update, we’re going to discuss some U.S. data here. As we discussed last week, in all the different areas where Omicron is sweeping through, we have been seeing less hospitalizations, we have been seeing less deaths; South Africa, Scotland, Denmark. We’re going to talk a little bit about what are the numbers here in the U.S.?

Let’s go down to the preprint, “Comparison of outcomes from COVID infection in pediatric and adult patients before and after the emergence of Omicron.” This was posted by Wang, etc. These were the results of a retrospective cohort study of electronic health records, so EHR data looking at 577,938 first-time SARS-CoV-2 infected patients from a multi-center nationwide database in the U.S.

Just to point out right there, we’re not looking at re-infections. We are just looking at first-timers here. Unfortunately, as I’ve shared, that’s now become part of my history. Have you been vaccinated? Have you been infected before? We’re going to remove, at least in the study, any sort of that survivor immunity when we’re looking at the impact here.

They reported that after propensity score matching for demographics, socioeconomic determinants of health, comorbidity, medications, vaccination status, the risk in the Omicron cohort outcomes were consistently less than half those in the Delta cohort. We’re seeing a relative risk reduction for hospitalization, 0.44%, so about 56% reduction. Relative risk of 0.44%, we’re seeing about a 56% reduction in people ending up in hospital. Where does that 56% come from? I will point out that they estimated this study about 60% of the people in the study were vaccinated.

Really nice. This is preprint, so it’s not behind any paywall. You can go there, you can actually look at the comparative acute outcomes in these matched patients. You’re actually seeing a risk ratio reduction here. Now, I do want to actually also introduce here, so we are seeing less hospitalizations. So far, we’ve seen less deaths. That is a lacking indicator, so we’ll see where we end up with that.

We did hear from Henrik Ullum, the director of the Statens Serum Institut, Denmark’s public health agency, in a press conference. One of the things we’ve been trying to sort out is, “Is this apples to apples? Are we comparing different things? If you are unvaccinated, is the virus itself less of a risk?” Here was his quotation, “It is primarily young in vaccinated people who are infected with Omicron. When we adjust for this, we see no evidence that Omicron should result in milder disease.”

The other day I was hearing a talk by a clinician to a large group, and his comment was, “You know, we’re not quite ready to be recommending those Omicron parties.” I was a little taken back. I’m hoping we’re never recommending people actually get infected and risk getting the virus versus vaccine, but Vincent, any thoughts on–

VR: Well, this illustrates how hard it is to figure out the virulence of any variant. We heard last week the South African data were compromised because they looked at different fractions of comorbidities compared to earlier in the outbreak, and they conclude we really can’t tell. The fellow from Denmark says the same thing. I got the impression from your clinical observations that you thought people are getting seriously ill with Omicron.

DG: Yes, I think that’s critical. People are getting seriously ill with Omicron. People are dying of Omicron, over 2,000 people a day on some days here. This isn’t something to take lightly. One of the suspicious correlations has been when we look at whatever percent reduction in hospitalization that always tracks with the percent of your population that’s vaccinated. Vaccinations are clearly a tremendous way of reducing your risk of hospitalization, severe disease.

A couple of unknowns. Is there actually a difference when– Will our statisticians be able to tease out that if you’re unvaccinated, one variant was associated with a lower risk of hospitalization or death? The other, what about long COVID? What is the risk of long COVID with Omicron?

Vaccines, a lot of really great data, doubling down. Go out there if you haven’t been vaccinated, get vaccinated. If you’ve got a friend, somebody you care about, have that conversation. We’d much rather have people get vaccinated, maybe get a little bit of reactogenicity, than get COVID, potentially end up in a hospital, potentially lose their life, potentially survive, and then have their life diminished.

VR: I think it would be great if Omicron were less virulent, but I don’t think we have the data to say that yet. What does it matter if you’re vaccinated? It’s not a problem. I think that’s always been the bottom line.

DG: Yes, I think that is the bottom line. We would love at some point for the virus to become less pathogenic, less virulent, but I don’t think we have the data that you should go out there and take a risk.

VR: Have you ever known a virus to become less pathogenic over time, Daniel?

DG: [laughs] Not personally.

[laughter]

DG: Yes, there’s really not a lot of selective pressure for that to occur. The virus is focused on fitness. That’s how evolution works.

VR: As far as the virus can focus, right?

DG: Yes, as far as the virus can focus, we’re anthropomorphizing. Viruses don’t care about us. [chuckles] They don’t care. All right. I also wanted to highlight another preprint, and this is a nice one. “Infectious viral load in unvaccinated and vaccinated patients infected with SARS-CoV-2 WT, Delta and Omicron.” In this preprint, the authors report on the assessment of nasopharyngeal swabs of COVID-19 patients for quantitative infectious viral titres, that’s IVT infectious viral titres, by focus forming assay that’s very similar to plaque assays. Can I say very similar, Vincent?

VR: I think so, yes.

DG: Okay. Compared to overall virus isolation success, and RNA genome copies. Now, I have to say this is going to be my favorite preprint that we discuss this week. They assessed infectious viral titres during the first five symptomatic days in a total of 384 patients. Unvaccinated individuals infected with pre-variant of concerns, SARS-CoV-2, they had 118 Delta. They had 127 people who were vaccinated got infected with Delta, they had 121. Then Omicron, they had 18 individuals there, vaccine, then you get Omicron. What did they find?

First, they reported, and I think this is really important. I’m going to give you four bullet points here. First, they reported that the correlation between RNA copy number and IVT, remember that’s our infectious viral titre, was low for all groups. I got to repeat that. That’s RNA copy number, that is not viral load. That is really interesting, really important RNA copy number is not a measure of viral load. We’re going to even go a little deeper into that.

Second, no correlation between this infectious viral titre and age or sex. We always want to say that they’re saying, “Oh, if you’re young, if you’re old, if you’re in the middle, man, female.” Third, I think this is also, they observed higher RNA genome copies. Higher RNA copy numbers in pre-varying of concerns, SARS-CoV-2 compared to Delta, but significantly higher infectious viral titres in the Delta infected individuals. Again, a disconnect there.

This is going to be big and I’m going to talk a little bit with– I’m going to pull Vincent in on this. Hopefully, there’ll even be a deeper dive on the other two. In vaccinated individuals with Omicron infections and those with Delta infections, there were comparable IVTs, Infectious Viral Titres. I don’t know if this paper– If you got a chance to look at this?

VR: I did. I think this is one of the most important papers of the pandemic because they measure infectious virus. Here we are almost two years into it and it’s one of the first studies where they’re measuring infectious virus and they don’t just take one-time point. They take five-time points over time, and they point out, as you have said, it’s not good enough to do PCR.

Do you remember that CDC study out of Provincetown where they did one-time point and they concluded that vaccinated people shared as much? It was meaningless yet it dictated the policy of masking and distancing and so forth. This goes to show that if you do the right experiments, measure infectious virus, you get the right answers. I just think this paper is beautiful because you get the correct data and we’re going to do a deep dive on TWiV tomorrow.

DG: Okay. I will be listening. Everyone, listen. I know sometimes people only listen to the clinical updates. Go ahead, listen to that deep dive, because I’m going to agree, this is a really critical paper. One of the things that when you look closely at this paper is that particularly an RNA copy number and your vaccination status. It’s not the same. When you start looking at the infectious viral titres and you get out to a day six or so, if you follow these people out, the vaccinated people, those RNA copy numbers are not really representing a significant amount of infectious viral titre. I think that that was a misinterpretation of the P-town study.

Yes, vaccinated people may have significant RNA copy numbers, but they are not teaming with infectious virus. I think if anything, really encouraging data. We’re getting from the efficacy of our vaccines, not only in preventing infection, new superpower, not only in preventing hospitalization, severe disease, not only preventing long COVID, but actually really reducing your risk of spreading it to others. This will be a great paper. I look forward to that deep dive.

VR: They make a statement in the discussion, which I think is really important to bring up. They say that infectious viral loads that you’re shedding are clearly important for transmission, but it’s not the only thing. What else is important? Human behavior. How about that? Masking, how many people are getting together, all the things that we’ve been saying for so long, they all come together. It’s not just about how much virus you’re producing.

DG: Yes. This is a great paper. I think it really hammers some– You got to be doing the right science. Unfortunately, I remember someone early in the pandemic said, “It’s not great science, but it’s the only science we have.” No, no, you don’t put those two words together. Bad science is not science.

All right, children, COVID, and mental health. I think everyone’s aware of this point, we continue to have lots of kids in the hospital. We’re not doing great with vaccinations in our youngest. When you start getting below the age of 18, we’re dropping down to about 50% and lower as we go down. COVID is putting children in the hospital. Every week, more children are dying here in the United States, from COVID. Vaccinations are incredibly safe.

If you look at that lower dose in even our younger children, we’re not seeing myocarditis, we’re not seeing all this serious adverse events that people are concerned about, that we are seeing if your child gets COVID. Let’s protect our children.

All right, pre-exposure transmission testing. Never miss an opportunity to test, but I’m going to say, think about, do the right test at the right time. There’s a lot of, I’ve been seeing a lot of anti-rapid testing stuff going on on social media. If I can imagine that. Yes, if you pour orange juice on your test, it’s going to– I don’t know. Anyway, how are those rapid antigen tests actually doing against Omicron? What is the science here?

There was a really nice preprint, “Direct Comparison of SARS-CoV-2 Nasal RT-PCR and Rapid Antigen Test (BinaxNOW) at a Community Testing Site During an Omicron Surge.” This was posted as a preprint. Here the authors looked at 731 persons testing at a walkup San Francisco community site, January 2022. 97% of this was the Omicron variant. We’re talking about the Omicron variant. And they had simultaneous nasal rapid antigen testing with the BinaxNOW and RT-PCR testing. They actually had a 40.5% positive test rate by RT-PCR.

Let’s see, how did the rapid antigen show up, and again, this is done right? This was done, right? They gave us the two bits of information that I always want to know when someone is evaluating the rapid antigen test. I want to know CT thresholds because the antigen tests are really designed to pick up those folks with CT thresholds of less than 30. A million-plus RNA copies, we also want to know, is this during the first seven days?

We’re trying to figure out who’s got acute COVID, who’s potentially contagious spreading to others. What were the sensitivities? The sensitivity of a single antigen test was over 95% for a CT threshold of less than 30 when we added on time. We said, what about CT threshold less than equal to 30 symptom onset? Less than seven days, the sensitivity was 97.6%. When you actually looked at youngest, right, “Oh, we’re going to miss all these kids.” The age was less than 30. The sense that they picked up 100% sensitivity, 100% at least in this sample.

Here’s what we’ve been saying. The other day I got an email from my buddy, Jay Berger, head of our pediatric division at ProHealth. “Dan, it’s a disaster, 30% of our antigen tests that have come back negative are coming back with positive PCRs.” I’m like, “Jay, the world is not ending.” I think that number should be 35% based upon this study but no, if you have no threshold, if you don’t care about time, PCRs are so sensitive that you’re going to pick up COVID. You’re going to pick up SARS-CoV-2 from November. You’re going to pick it up from December.

What we really want to know is that kid coming in right now, that individual coming in right now, is this COVID? Are they contagious? A person comes in– One of the things we have seen is a little bit of a difference in symptoms now coming before a person becomes contagious and test positive. You give them a day, “Are you not feeling better?” Okay. It’s day two, let’s get a test. As we’re seeing here, over 97% sensitive for picking that up. Sometimes people don’t turn positive for a few days later.

What makes us sick? Not the virus. It’s the symptoms. It’s our immune response. Had a woman in the hospital and they put her on quarantine. They locked her in a room with someone who probably had Omicron. I got a little bit of a history and the woman said, “I got COVID over Thanksgiving. I even got treated with monoclonals. I don’t have COVID. Why are they?” She was very upset that she was locked in a room. She was there with a finger infection. We were able to get a CT number. It was over 38. We were picking up with that CT an infection from November. Now, this woman was upset because, yes, unfortunately, she was put in a room with someone who probably has Omicron. She went home with a sore throat a couple of days later.

Right test, right time. The rapid tests are really continuing to work well. PCRs are overly sensitive. A lot of discussions, a lot of education that we need to get out there. We need to be moving away from PCRs. PCR is not a great test for saying someone can return to work, saying someone can return to school, etc. They are too darn sensitive.

VR: I want to know what is the positivity of the antigen test when the CT is over 30, over 35? They’re doing less than, which is okay. Could you take these numbers and get that from it?

DG: Yes, you actually can. If we just forget about timing and we just say, “Okay, let’s do under 30,” you’re picking up about 95%. When you go, your threshold 35%, 82%. When you say no threshold at all, you’re only about 65%, so about 35% you’re missing. When you get to higher thresholds, just doing it the opposite way, like Dan instead of less than 30, what about over 30? You’re starting to miss, initially, do the math in my head 25%, then you’re missing 35%.

It really goes up and, actually, that’s the other side, which I think is important. People want a negative antigen test before they let people return to work. Again, you’re picking up people who are not infectious. If you’re vaccinated, and you’re feeling better at day six, even if that antigen test is positive, you’re probably not infectious anymore.

VR: It’s important because even at high CTs, you’re getting a fairly good over 50% positivity in the antigen test. There’s no way you’re infectious, so the antigen tests are not as robust as we thought in the sense that they’re still going to give you a positive even when you’re not infectious.

DG: Yes, and I think that’s a problem. I was talking with one of the hospitalists this morning when I was over seeing my folks in hospital, all of them with COVID– we perhaps should have the ability to order different sensitivities to our COVID PCRs. Maybe have a high sensitivity where they run it up to 40, but then just have a normal where they stop it at 30. We really don’t need to be picking up people who are not infectious, people who had COVID weeks, months ago.

VR: What would you say would be the cut off? It’s hard to do because it’s variable, but would you say 30, 35?

DG: I like 30, I think 30 is reasonable.

VR: Should we only run 30 cycles?

DG: It would be reasonable if a clinician could order that. If you’re going to fly something like that, 30, it’s plenty. That’s going to pick up the people who are infectious, it’s going to help us with that 2% or 3% we missed with an antigen test.

VR: Okay, CDC, you’re listening?

DG: Yes, hopefully they are. Yes, go CDC. Just the last thing I will throw and this is just the ‘on the street’, what do you do? What does a provider do when they have a negative antigen test? They’ve sent off that PCR for some reason. As we’re saying here, with a million people getting infected every month, well, every day pretty soon, what about 10% of Americans positive? You’re going to be seeing a lot of these. You’re going to have to use your clinical judgement there. The big thing I’m going to say, use your clinical judgement. You don’t have to send off that PCR test unless it makes sense. We’re going to be over-diagnosing there.

All right, couple updates. FDA shortened the interval for the booster dose of the Moderna vaccine to five months. They listened to you, Vincent, because Vincent was saying, “Why is one six and the others five? Couldn’t they just be the same?” I would have liked it if they were both at six but okay, five is what we’ve got here. This is one of the nights I was in a meeting. I was like, I think that and oh, no, it’s been updated. Everything changes every day.

A couple of exciting things here. T cells, we’re going to talk about T cells. We’re going to hit this a couple times. “Cross-reactive memory T cells associated with protection against SARS-CoV-2 infection and COVID-19 contacts,” this was published in Nature Communications.

Just to briefly go through because there’s another I’m going to hit a little deeper dive on. What did they report here? The authors reported that they observed higher frequencies of cross-reactive and nucleocapsid-specific IL-2-secreting memory T cells in contacts who remained PCR negative despite exposure when compared to those who convert to PCR positive. No significant difference in the frequency of responses to spike and observed hitting and a limited protective function of spike cross-reactive T cells.

I just bring this up because this is interesting. We’ve certainly noticed situations where a person particularly is maybe even vaccinated, they are in a setting where, my gosh, they have lots of exposure. They continue to stay PCR negative despite these high exposures. Not everyone ever ends up with that positive test even despite pretty significant exposure. We’re seeing a little more than just those B cells and I wanted to bring that up.

VR: Daniel, you’ll see in the end, the T cells are going to be what are protecting us contrary to what everyone thought.

DG: Michel Nussenzweig is not going to enjoy that conclusion.

VR: No, he doesn’t like that idea.

DG: Michel, if you’re listening, we love the B cells, don’t you worry. Pre-exposure period, right? I always feel like I need to keep going through this because. unfortunately, maybe the memory is short. Remember, pre-exposure period. There’s a lot of ways for us to keep ourselves safe. Those non-pharmaceutical interventions, they continue to work. It’s not like suddenly the virus has gotten so incredibly small that it’s popping through those masks. Masks continue to work, surgical masks, cloth masks, are very good if everyone’s wearing them for source-control if you really want to protect yourself, really increasing the supplies of those N95, those proper masks.

I saw a headline, I thought it was a little bit disturbing, Vincent. CDC was discussing whether or not to recommend high-quality masks. [laughs] I was like, “It’s very interesting.” I recommend high-quality masks. If you are an individual who is at higher risk, and we always talk about individuals who despite vaccination continue to be at higher risk, you can protect yourself with a proper fitting, an N95, maybe a KN95, if that’s something you’re willing and able to wear. Continue with those vaccinations, active and also passive.

We’ll talk a little bit about passive here in a moment, but what about active vaccination? As I keep trying to say, never miss an opportunity to vaccinate, but we need to stop scaring the wrong people. A lot of people really liked the discussion of the paper, “Risk Factors for Severe COVID-19 Outcomes Among Persons Aged Greater Than 18 years Who Completed a Primary COVID-19 Vaccination Series.” That was when they looked at 465 healthcare facilities, United States, December 2020-October 2021.

This is where the data suggested that the baseline risk for persons after two doses of mRNA vaccine, one dose of the J&J vaccine, was actually quite low and that over time, this seemed to be maturing. It was even more reduction in risk of severe COVID as we got out past six months despite the waning antibody levels, all right.

VR: Contracting.

DG: Say that again, contracting?

VR: We like to use contracting. Waning sounds like there’s a problem.

DG: Contracting is actually the proper immunological term. I know breakthrough is also supposed to be a proper term, so some proper terms I like, some proper terms I avoid.

VR: Especially in a pandemic, breakthrough sounds bad, so we shouldn’t be using it.

DG: It sounds bad, yes. Contracting, that is normally what happens. Nothing scary, nothing bad, waning does suggest something bad is happening. One of the things people want to know about other things, we talk about hospitalizations, we talk about deaths. Maybe people can hear the sirens in the background. I’m hoping that was just some criminal activity and not someone being rushed to hospital with COVID. What about other things? And here, let’s talk about MIS-C. “Effectiveness of BNT162b2 (Pfizer-BioNTech) mRNA Vaccination Against Multisystem Inflammatory Syndrome in Children Among Persons Aged 12-18 Years – United States, July-December 2021.”

This is that multisystem inflammatory syndrome or MIS-C. This came out as an early release in the MMWR and here, the author’s looked at the effectiveness of two doses of the Pfizer-BioNTech vaccine against MIS-C, both incidence and severity. They looked at 24 pediatric hospitals, 20 states, fairly large survey during this period of time when most of the MIS-C patients could be temporarily linked to the Delta variant. They reported that the estimated effectiveness was 91%. I will say, in addition to the reduction, we’re also talking about severity here, all of the MIS-C patients that required life support were unvaccinated.

Really great protection as far as reducing risk, but also great protection as far as reducing severity. They concluded, rightfully so, that the vaccine was associated with a high level of protection against MIS-C. Again, just highlighting another reason for vaccination among all eligible children. I still want to see more data on long COVID. I want to see a long COVID to add to this, just to really hammer that home. So far, encouraging, but everyone wants to see that kind of stuff.

All right, so I think I said one of the other articles was my favorite, but this might be my second favorite. My equally favorites. It’s like my children, I love them all equally. I love this one as equally as that other one, that is my favorite also. This one, “Vaccines Elicit Highly Cross-Reactive Cellular Immunity to the SARS-CoV-2 Omicron Variant.” This was posted as a preprint. Here, the author’s instead of looking at antibodies, they looked at T cells. They assess CD8(+) and CD4(+) T cell responses in individuals who are vaccinated with either the adenovirus vector-based J&J vaccine (had 20 of those folks), the mRNA-based Pfizer BioNTech vaccine (they had 31 of those folks). I have to say, it’s all in the figures.

This will be put up on the Parasites Without Borders website. I encourage everyone to go and look at these figures. Let’s go through, what did they find? Well I lied, they did look at antibodies and the antibodies were contracting. If you look at month one to month eight, they were contracting. But what you were also seeing, if you did just a total antibodies ELISA, or if you did a neutralizing antibody titer, you saw that they were the highest for the wild type, lower for Delta, lower for Beta, lowest for Omicron.

Then, let’s talk about the good stuff. I thought this was interesting. I was listening to the most recent TWiV and the question was, “Well, why did they look at CD4 and CD8 separately?” I’m like, “Why wouldn’t you?’ Immunologists, we’re splitters, we want to see each compartment. We want to see what is going on, and so they looked at the CD8 T cells. They looked at the CD4 T cells separately, so these were the interferon positive.

What did they see? Levels at one month looked great with both the J&J and the mRNA vaccines and, actually, were increased. When they went out to eight months, it was getting better. What is the opposite of contracting? Expanding. Just like the Universe, the protected T cells were expanding. I have to say, and then interesting enough, what did they do? They boosted folks and the T cells went up even higher.

Encourage everyone to take a look at this, loved the figures. These were beautiful figures, and I got to go through this twice because my computer crashed. I made all these notes copied in all the figures. It crashed, I got to do it again. I was not frustrated. It was like discovering it the second time.

Now, speaking of boosters. This week also marked the New York booster requirement for healthcare workers. Our governor, Governor Hochul, additionally announced her plan to require that all covered healthcare workers previously required to receive a COVID-19 vaccination must now receive a COVID-19 booster within two weeks of becoming eligible, absent a valid medical exemption. Then the New York State Health Council went ahead and actually supported this decision.

All right. I did mention that we would get to passive vaccination and we have gotten to passive vaccination here on the ground. We’ve started to be able to give EVUSHELD, I spell it S-H-I-E-L-D, but EVUSHELD. This is the AstraZeneca long-acting antibody cocktail. These are for individuals who, for some reason, can’t get that protection that we would normally hope to give them with vaccination and boosting. This is actually an easy lift. There’s a number of places that do it. You’re basically giving this person two intramuscular injections, 150 milligrams, boom, 150 milligrams, Q six months. This is something you’re only doing every six months. This is really nice.

We have millions of individuals out there who, despite the availability of vaccines, don’t have the ability to produce these protective antibodies. At least we can do this. We’re still hoping that a lot of those individuals, despite not making their own antibodies, may also have some degree of T cell protection. This is not a substitute for vaccination. This is an augmentation to the vaccination.

VR: Do you think that people who don’t want to be vaccinated would instead take monoclonal infusions?

DG: I have to say the approval for– here for EVUSHELD, it is not for the unvaccinated. It is not as a substitute to vaccination. I think that’s important. Now the person has detectable viral replication, maybe they have viral symptoms. We’ve talked a little bit about, and I’m not sure if there’s any intrinsic change in the virus or if this is just that people’s immune systems are primed and they’re responding sooner, but we’re seeing symptom onset and then the tests don’t turn positive until the next day.

That’s important for us. I’ll say on the ground, boots on the ground. When do you do those tests? Because boy, there are not as many tests as we would like. This is the time we say for monitoring, maybe the time for monoclonal, and we’ll get a little bit into that, but it’s also now the time for oral antivirals. PAXLOVID, everyone in their different area is hopefully getting aware like where, which pharmacies have them and in Nassau it’s a few of the CVS locations in Suffolk. That’s Eastern Long Island. It’s a few CVSs. In New Jersey, apparently, it’s Walgreens. I was thinking about in Connecticut, they’re giving it to the hospitals, which a lot of my providers up there don’t understand. I mean, this is really, it’s an outpatient medicine. You want to send people to the pharmacy. You want them to be able to get this because time matters. You really want to get this within the first five days.

We’re having good success. People seem to be tolerating this. I did hear a story about one of the first individuals out west in Washington had some GI upsets, stopped after two-and-a-half days. We seem to be doing pretty well. The providers are getting on the phone with the pharmacist, you need to know why you’re giving it, what puts the person at higher risk. You need to know what other medicines they’re on, so you can discuss with the pharmacist. You need to know their kidney function.

For some individuals, that’s easy. For a lot of individuals with multiple medical problems who are at high risk, this is something the primary care doc will usually have a current kidney function assessment. If they can’t do the PAXLOVID, they’re dropping down to the molnupiravir. Instead of that 89%, 88% reduction in progression, only about 30%. And we’re starting to get better access to the sotrovimab. That’s the monoclonal that works.

Unfortunately, a few places are still giving out the REGEN-COV cocktail, and I just don’t really understand the thought there. I mean, it’s very clear that does not work. That’s a waste of resources. Also, come on, the ERs in different places where they’re doing this, they’re already taxed. These are people who are highly-infectious, contagious. I’m not really sure that makes sense. Inexcusable, perhaps I would say. We did hear that on Tuesday, 1/11/2022, the U.S. government ordered another 600,000 doses of the sotrovimab. Encouraging there.

I will reiterate, this is not the time for steroids. This is not the time for antibiotics. I saw a woman the other day, I didn’t quite understand, she had been triple vaccinated. I’m like, “I don’t understand how you ended up in the hospital. I would’ve thought you would be fine.” Well, her helpful friendly physician had given her a big whopping dose of steroids to help with that sore throat she was experiencing. Why would we shut down her immune system?

Why do we even bother vaccinating? If instead of letting that vaccine protect people, our friendly, helpful doctors are giving you steroids and shutting it down when it’s trying to control the virus. So don’t do that. Steroids are not during that early viral replication phase. We do it when there’s that early inflammatory phase to help shut that down, and the antibiotics come on, we’ve done this, we’ve looked at this.

I know some of the nursing homes, people are still getting treated with doxycycline, not helpful. And I think I discussed this study where I actually saw higher mortality in the doxycycline than in the not-doxycycline. Don’t harm our patients. Keep your hands in your pockets. I know how hard that is to do or go ahead and do something that is helpful.

I’m going to jump ahead to the tail phase, long COVID, and post-COVID. This is really post-COVID here that I’m going to be talking about. A lot of folks end up in the hospital, and now there’s a decision about discharge anticoagulation. There’s no great consensus here. We don’t yet have guidelines from ASH on this, the American Society of Hematology. There are a number of studies that were looking really at this issue in hospitalized patients before COVID. There was the MAGELLAN, there was the MARINER, these people do a great job of naming their studies.

Really trying to say, is there a certain subgroup of patients who are at higher risk? Who might actually benefit from being sent home on some sort of an anticoagulation or blood thinner as people like to call them? And now we have the publication of the MICHELLE study.

I’m going to pronounce this big long name, “Rivaroxaban versus no anticoagulation– so that’s one of these oral direct, oral acting– anticoagulation for post-discharge thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE): an open-label, multicenter, randomised, controlled trial.” I’m not sure where the MICHELLE comes from. This was published in The Lancet and in this open-label, multicentered, randomized trial conducted at 14 centers in Brazil, 320 patients hospitalized with COVID-19 at increased risk for venous thromboembolism.

They did IMPROVE. This is International Medical Prevention Registry on Venus Thromboembolism, VTE scores. They had to have greater than or equal to a score of four of 2-3 with a D-dimer greater than 500 nanograms per milliliter, and they were randomly assigned 1:1 to receive at hospital discharge the rivaroxaban 10 milligrams per day, or no anticoagulation for 35 days.

Basically, what did they see? They saw a relative risk of 0.33. What they’re basically concluding, and I think this is really important in patients at high-risk. This isn’t everyone. High-risk after hospitalization due to COVID-19, the thromboprophylaxis for 35 days was associated with improved clinical outcomes compared with no extended thromboprophylaxis. I think as we need to be clinicians here.

This is not just, “Oh, my healthcare system says everyone goes home on a DOAC on this kind of a medicine.” You want to make sure that we’re giving it to patients that it will help because if you give this to everyone, you’re going to potentially harm folks who don’t need to be on this. I remember the list price is $500. I’m not sure every single COVID patient ever admitted in the U.S. needs to go home with a $500 30-day supply of medicines and it gets a little bit extra because it’s 35 days. I think it’s important here. Did you figure out what MICHELLE stood for?

VR: I have it here for you, Daniel. The M is Medically Ill Hospitalized Patients for COVID, all right, that is the M-I-C Medically Ill COVID and then the H for COVID-19 thrombosis, they took the H not the T, they took the H. And then the E is Extended Prophylaxis with rivaroxaban and the L comes from Prophylaxis and then the last E, I don’t know where the second L comes from. There’s no second L. The second E comes from therapy. That’s such a stretch to make MICHELLE out of that, right?

DG: I don’t know. [laughs] Well, all right, I will say– and we like to continue to have a global perspective here. No one is safe until everyone is safe. We’re having trouble here in the U.S., we’ve got over 2,000 people dying on some days. We’ve got more people in hospital than ever, but a lot of the world does not have access to these vaccines and I know the WHO has said, “Stop saying Omicron is mild because it’s killing lots of people every day throughout the world.” A lot of these individuals would love the opportunity to have access to vaccinations, just keep remembering no one is safe until everyone is safe.

In our effort to continue to support MicrobeTV, for the rest of January, this is winding down, we’re going to continue to accept donations and we’re going to double those. I’m going to say past $40,000. We’re going, actually, to give MicrobeTV a bit more this year. They’ve been doing a great job, Vincent. If you want to get that Virology textbook, I think it’s $1,000 is the donation and Vincent will sign you a copy. We’ll actually pay to send that out to you.

I also want to bring up another thing in closing. We still have our global health coordinator internship opportunity. This is a paid internship and it’s asynchronous. It’s going to be 10 to 20 hours a week. We do want to look at someone in the New York area because there will be some commitment to coming in. We are looking for a dynamic, committed individual with a passion for global health equity, science communication, just someone who’s excited about our mission and who would be willing to work with us and really learn a lot about what we do. If you’re interested, send your CV, send a cover letter to–

VR: Daniel@microbe.tv. This description you have, we should post this on Parasites Without Borders.

DG: We can definitely do that.

VR: Let’s do that.

DG: I’ll send this to you with the show notes.

VR: Please do, we’ll take care of that. It’s time for some email questions for Daniel and I have one that is not in the notes today but someone asked if we could explain why we sit next to each other without masks. My answer would be not civil, so I want you to answer it.

[chuckling]

DG: No, actually I think that’s good. I think we’re at a point now where people need to start really thinking this through. I am doubly vaccinated, I am boostered, I am asymptomatic, I am reasonable as far as my risk tolerance. Vincent, sitting right next to me is also double vaccinated, boostered, whether he or Paul Offit liked it. I think they went together. No, I consider this a low-risk activity. I’m a healthy individual. I don’t know if I’m quite an ideal body weight, I’m working on that.

No, I would say and I think this is important for me, let’s say the unforeseen happens. Vincent, he goes out to a bar with his unmasked friends, engages in risky behavior, gives me an infection. I end up with COVID-19. I do not expect that to be something that puts me in hospital and I think people need to start looking at this. I think the Singapore data was really interesting. What was it? People who had just two shots of Moderna, the risk of death from COVID was one in a 100,000.

VR: Yes, I also think that the transmission is widely misinterpreted. As we saw in the paper today, you’re shedding much less virus when you are vaccinated, so your likelihood of transmission is going to be very low. Perhaps only in the first day or so. I don’t think that we’re fomenting transmission either looking at the data.

DG: Yes. Hopefully we’re sending a reassuring message. I would say probably the people who listen to our show are those individuals who are doing all the right things and can they get together with their buddy without a mask and spend some time discussing science? I think it’s safe.

VR: We have vaccines that work, folks, we have to use them. All right, Kevin writes, “Thanks for doing this podcast. We live in Switzerland, which royally screwed up getting under 12-year-olds vaccinated and only slowly started rolling it out in the last week. Slow to approve the vaccine, failed to order in time, poor logistics, etc. A couple of weeks ago we did what many parents here are doing and crossed into a neighboring country to get our kids vaccinated. Germany in our case, but I have friends who have taken their kids to Italy and Austria. As well as vaccinating our six-year-old, we were also able to get our four-and-a-half-year-old and two-year-old vaccinated.

All children were vaccinated with BioNTech 10 milligrams. Vaccination center we visited could also have given them a half-dose, but we wouldn’t have been able to do the three milligram dose that is currently being evaluated with seemingly ‘meh’ results so far. I don’t think off-label vaccination is something you’ve talked about on the show before, maybe it’s not even allowed in the U.S.? I’d be interested to hear your thoughts on it. Would you add a caveat to your mantra ‘Never miss an opportunity to get a vaccine’?”

DG: It sounds like you’re going to, would I do that if I lived in Switzerland and vaccines were available just across the border, Vincent? If my child was 11, I could go across the border and get a 10-microgram vaccine. I would actually. I don’t know if there’s any sort of legal issues with coming and going in situations like that. Here in the U.S., the Pfizer adult vaccine is fully-licensed. That gives U.S. physicians a lot of discretion to use clinical judgement, but some of the other parts, for instance for the younger individuals, it’s under EUA, which is still pretty strict. You got to follow the rules in those age groups.

VR: Kevin gives a post-script. He says, “You might get a laugh out of this. The school’s kindergartens here pretend to be ‘safe’ places because they implement the following test schedule every week. Tuesday, pool PCR tests for each class. Wednesday evening, results of the pool test. Thursday, collect samples from every kid/teacher in a positive pool, run individual PCR tests. Friday evening, maybe get the individual results from the lab, often parents are never told the results. Monday, the kid that caused the positive PCR test six days ago finally stays home.”

DG: Oh, my. I’m trying to understand.

VR: It’s crazy. This is Switzerland.

DG: Well, actually, I’m thinking that by the time day six comes around with the new rules, they can go back to school.

VR: There you go.

DG: Yes, this makes no sense.

VR: All right. Mason is an MD PhD student in Chicago. “My question is regarding PAXLOVID. I’m a little concerned that the drug is co-packaged with ritonavir as a potent CYP3A4 inhibitor. Ritonavir will impact the metabolism of many drugs other than the nirmatrelvir it is packaged with.” Nirmatrelvir, is that the real name?

DG: Yes, that’s the actual name.

VR: Oh my gosh. “The EUA for PAXLOVID mentions many of these drugs in the fact sheet for healthcare professionals, which include Warfarin, Amlodipine, Prednisone, and several statins just to name a few. Does this lengthy list of drug interactions prevent the use of PAXLOVID in the high-risk populations who need it most? I’m curious about how many people who qualify as having high-risk for progressing to severe COVID take one of these drugs and if they can be safely treated with PAXLOVID?

Would many of these patients be limited to only receiving monoclonals or the less-effective molnupiravir? Is this a concern you’re facing in the clinic or is it simply a thought in a naive medical student’s mind?”

DG: No. Mason, I think this is really important. I was asked this question, actually, just yesterday. I was talking to, I’ll say, a member of the press about this because people are concerned they hear all this. At least the nice thing about the current model, and this is actually a nice way that we’re going to ease into this, is the physician is picking up the phone and they’re talking to the pharmacist and the pharmacist is walking them through this.

This is what pharmacists do is they go through, they understand drug interactions, and it’s great with the physician on the phone because you can go through. Let’s say the person is on a medicine for cholesterol if it’s Crestor/Rosuvastatin that’s okay. But if it’s Lipitor/Atorvastatin, that’s not going to work. You can have that discussion. Is it okay to stop this medicine? Is it okay to adjust this medicine?

At least at this point, there’s a little bit of a dialogue. Pharmacists are right on top of this. There’s in each jurisdiction only a certain number of pharmacies that are doing this, so those pharmacists are really on top of– and that’s why I say. When you call that pharmacy, have a list of what medicines the patient is on. Know why they’re on that medicine, so you can understand. Can you stop that Lipitor for five days? They’re going to be going to the pharmacy anyway, maybe this is a time you switch them to that Rosuvastatin.

If it’s something else, you go through this, there have been times– actually an oncologist colleague of mine, we just had a patient who was late yesterday, was a drop-down to molnupiravir because there was some medicine they weren’t comfortable stopping. Sometimes the anticoagulants for instance. No, in general, this is something which will be a problem sometimes is usually surmountable. It would be great if there was a drop-down to something that had better efficacy than the molnupiravir. Sometimes you’re switching over and saying we really got to pursue that sotrovimab, that monoclonal therapy.

VR: Phillip writes, “I try to rinse my nasals daily using a Neti Pot with a saline solution, not necessarily for COVID. Would a nasal rinse before a nasal swab for COVID test lead to either increase in false negatives or reducing false positives?”

DG: This is a good one. sometimes people are testing positive repeatedly. We’ve had these issues. Sometimes, when I actually get involved, boots on the ground, I wonder, has this person ever blown their nose? Like how long has that stuff been staying in their nose? Before you do a COVID test, you actually probably want to blow your nose, clean out your nose, because we’re not trying to pick up RNA that’s there from some, say, nasal secretions, nasal remnants that haven’t been washed out. When you actually, Vincent, when we get tested here at Columbia, they have you blow your nose then you go ahead and do a sample.

VR: You might have just walked through a cloud of COVID.

[laughter]

DG: Don’t think that’s what it is, but okay.

VR: The last one is from Allie who’s a school nurse for a middle-high school, “My husband is a family practice PA. We have noticed that antigen testing seems to be more accurate on day three to four after symptoms– even more so with Omicron. In general, day one of symptoms, the antigen tests are not picking up positives. In this week’s TWiV clinical update, you stated that the viral load is likely to be highest on the day before, day of, and one-day post-symptoms. If the antigen tests pick up a viral load, why are they not showing positive at this early stage of virus and picking up fairly routinely on days three to four?”

DG: This is a great chance to hammer this home. Things have changed. Things are different now. We’re not sure we know exactly. Michael Mina was discussing this just the other day. It was, “Are we seeing this change in the testing because people are now either previously exposed or they’re immunized?” Just as you start to get a little bit of antigenic stimulation, you start feeling those symptoms. The symptoms now seem to be starting before we’re getting the positive tests, before those PCRs even become positive, before those antigen tests become positive. Thus, the recommendation in-line with what you’re saying.

Particularly in a vaccinated person, you don’t test on that day one, we’re seeing the peak of those viral RNA copy numbers, which do not necessarily correlate particularly well with infectious virus. We’re not seeing those tests turn positive necessarily that first day, not necessarily the day before, but maybe that second, third day as you described. Don’t waste that test. Wait. Give it that time.

What I would love to say, I don’t know if I’m ever going to see, Vincent, I would love to see them follow people and do symptom checks, do antigen. And the PCR with the CT and also do the infectious viral titres and show me vaccinated, show me unvaccinated shall be unvaccinated never previously infected with negative nucleocapsid antibodies and see how much of this is explained by the virus, how much is explained by the immune system.

VR: You could do that.

DG: [chuckles] I’ll add that to my list.

VR: That’s COVID-19 clinical Update number 97 with Dr. Daniel Griffin. Thank you, Daniel.

DG: Thank you, Vincent and thank you, everyone, and be safe.

[music]

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