TWiV 716 COVID-19 Clinical Update #48

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 06 February 2021

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

From MicrobeTV this is TWiV, This Week in Virology, Episode 716, recorded on February 4th, 2021. 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: Daniel, January is over. You said it was going to be the worst January. Did that turn out to be true?

DG: It certainly did. The only good thing is it is now over and we have passed my favorite day of the year, Groundhog Day, and so it sort of means at least we could start looking forward to a better spring. It’s been a horrible January and I sometimes feel like we’re are U.S.-centric. In the U.S., I feel like we’ve crested or we are in the process of cresting a huge wave. The case numbers I think are coming down after the holidays but the deaths, we’re seeing the deaths from all those cases still so still a lot of deaths. There’s still a lot of patients in the hospital but I think we have better days ahead in the U.S. but I’m going to make sure I hit on this.

We can’t forget about the rest of the world because no one’s safe until everyone is safe. Let me start with a quotation, we have a lot to do today. “How very little can be done under the spirit of fear?” That’s Florence Nightingale and just a couple of things I really like sort of in swell a very inspirational woman who really advanced nursing. A couple of things it brings– makes me think up, one is just how critical the nurses are in taking care of patients and how critical I think they are in the culture of medicine. They bring a real warmth and a caring to patient care.

Just this pointing out that people work better in a cooperative, in a supportive, in a culture of generosity and kindness and in a lot of ways over the last year that has been forgotten. There’s been a lot of rigidity and rules and, “this is how we are doing it.” I know hospitals are struggling financially but you can’t lose sight. We’re not there primarily to make a dollar, we’re there primarily to take care of people and the almighty dollar has to come second to patients’ life, patients’ care.

All right, we’ll start off with the pre-exposure period with my three rules. I’ve actually started to see this echoed a bit in the media which is great. “Never miss an opportunity to vaccinate, never miss an opportunity to test, and never waste a precious vaccine dose.” Today, I’m going to be talking about mutations, vaccines, and some very exciting anticoagulation updates.

Active vaccination, in this realm and it really goes into several of the different phases or stages of COVID-19 but I’m going to try to talk a little bit about these in a context that makes sense for clinicians. What are we as clinicians? How do we understand this language and what is going on here? I’m going to hit up some important highlights but just a little background, we’re on TWiV.

This is science-heavy and that is good. This is an RNA virus so there’s going to be changes to the genetic code being randomly introduced when this virus replicates. An infected person has a large number of replicating virulence – so not every single virus in a person is exactly the same. Sort of a quasi-species people talk about sometimes in the world of HIV. Now, I am going to over-simplify a little but a change in the genetic code can be silent or they can actually result in a change in amino acids for which the protein is being coated.

I said this is simplified because RNA itself can have some functionality so, as clinicians, why do we care about mutations?

We all enjoy science fiction but why do we actually care in our day-to-day? One is the specter that it changed the genetic code of the virus and mutation can make the virus more transmissible. We want to give that just a little bit of context. It’s not as though the change in the genetic code makes the virus fly through the air more quickly, nothing like that.

Maybe I think as Anthony Fauci said in his first, we’ll call it the post-Trump giddy news conference, it could affect the ability of the virus to bind tightly to its target receptor – today’s two receptors, for instance– so it might be more transmissible and that it’s easier for a smaller exposure to result in an infection.

That could potentially change the virulence. It could either make the virus more or less virulent. Then as clinicians, a big one for us is, are these changes going to impact our therapeutics or the immune response? Is it going to affect for instance our drugs, our monoclonal therapies, or our vaccines? Just to give people a little bit of language here, the changes we care about are mutations or deletions.

These are inevitable, variants are thus expected but it’s really the biologically significant changes that we care about. For each variant of concern, we can ask this question about the genetic changes, the mutations, the deletions, potentially even some additions, but we won’t really go into that today. Most of the changes– actually all the changes I’m going to talk about today are going to affect the biology of the spike protein. So, just a little bit about the spike protein. I always try to use visuals to get people to think about this and sometimes my visuals are more of the cartoony but the spike protein is a protein, it’s made up of amino acids.

Amino acids come together to make a protein. This protein is 1,273 amino acids long, in general we’ll say the Wuhan reference strain. That spike protein, this is for our clinicians to really put this into your mind and a terminology you can remember on the fly, there’s really two important parts of that spike protein that we’re going to talk about. The N-terminal domain NTD, it’s not neglected tropical disease, and the receptor-binding domain, the RBD.

I’m going to ignore some of the others just for simplicity because there’s a lot of complexity here. There are areas where this could be broken down, cleaved, protease is the rest but just for today, the NTD, the N-terminal domain, and RBD. I want people to think about this as the analogy of a hand and we’re going to get back into that, the hand and the arm.

Just some of the terminology, what are these crazy numbers and letters? I know we’ve been told don’t call it the U.K. strain, don’t call it the South African strain so people have now thrown in the numbers and said, “Originally isolated in the U.K.,” so I’m going to acknowledge that.

As I mentioned, the spike protein is 1,273 amino acids long, don’t tune out it’s going to be okay, you’re going to make it through. This is critical stuff to know. What are those numbers? The numbers start with the N- terminal domain, that’s where 1 is and at the far right, think of this in your head that could be 1273. The deletions are going to be the same thing so when we hear a number, we’re talking about a particular amino acid that has changed. When you talk about, I’m going to give some concrete examples, when you talk about an N501Y, that means we are talking about a change in amino acid 501 and the N has changed to a Y.

What is an N? An N is a code, help us use a one-letter code for amino acids, so an N is an asparagine, a T is a tyrosine, and so the N goes to the Y. I have to look those up, I’ll be honest, but just let people get a sense here. When you hear an N501Y, when you hear an E484K, that’s 484 the E has changed to a K so we’ll talk a little bit about this. If you hear deletion, del69-70, that’s going to mean those amino acids 6970 were deleted. A little trick here to help people, just think because this is going to become a number soup going forward. Every one of those 1,273 amino acids can change or be deleted.

The N- terminal domain that goes from about 14-306 and the RBD, I could use the palm of my hand analogy. The RBD, the receptor-binding domain that grabs onto spike is 330-528, so 331-528 to be exact. Anything that affects the palm of the hand is going to affect the ability of the spike to grab its receptor and I’m going to say the NTD, think of that as affecting the back of the hand. It’s not right in the binding pocket but it may affect the modality of the binding pocket. Hopefully, this allows people to get a little sense of, what are these numbers? What are these letters’ soup?

Let’s just talk a little bit about each of the described strains. Today, I’m going to talk, briefly, don’t worry, we’re going to go to other stuff, about the B.1.1.7 strain, originally described in the U.K., the B.1.35 strain described originally in South Africa, the Cal.20C that we’re seeing now in California, and the B.1.28 detected in Brazil and Japan.

VR: Variants, Daniel. Variants.

DG: Am I going to call them variants or strains?

VR: Variants. That’s variants of concerns remember.

DG: Let’s talk about that. This is great. Variant versus strains, what is the difference? This is why This Week in Virology, we have Vincent chaperoning. A strain is when we have convincing biological activity change. A variant is when we have a change in the genetic sequence. Calling something a strain requires a higher bar. The B.1.1.7, I’ll use a variant of concern here, originally described in the U.K. It has that D614G that we’ve been hearing about for a while. It’s got a couple of deletions and it has the N501Y which is suggested to maybe allow that spike to bind better.

The B.1.35 variant of concern originally described in South Africa, this has that D614G also. It’s also got the E484K. Now, why do we care about that as clinicians? We care because there is some experimental evidence suggesting that that may affect our monoclonal antibodies, a couple of them. The Bamlanivimab and Indevimab. There’s also a K417N in this variant of concern that we are concerned may decrease the monoclonal Casirivimab efficacy. This also has that N501Y which we think may allow it to bind a little bit better. Cal.20C, that’s got this L452R, which we also think decreases the efficacy of our BamBam, and also may be associated with decreased plasma effect.

Maybe there’s some impact upon someone who has been previously infected. I’m just going to mention the Brazil one last and then just try to put this all together for people in a way that they can think about it. The B.1.28 detected in Brazil then Japan, that has the E484 which we talked about. It has the N501Y. Now, just to put this in people’s mind, you’re going to hear all these numbers. One of the things you could do is when you hear the number say, “Is that somewhere in that 331 to 528? Is that affecting the palm or the hand? Might that affect the ability of the spike protein to bind to the receptor?”

If it does, this is a sweet spot, we think, for a neutralizing antibody. It may potentially impact some of our monoclonals. I do want to say the sky is not falling. As people may know, and I’ve mentioned several times, I’m involved with Eli Lilly and helping get their monoclonal antibodies to folks and trials. Also, with Regeneron as well. I guess the caveat with that, they don’t give me any money but I’m happier with that. Maybe it would be a conflict of interest if they did. We follow these because we are concerned. The other side is they have a lot of monoclonal antibodies in the pipeline, ones that can cover these.

If you’re in an area where we are concerned about Bamlanivimab efficacy, Eli Lilly has data we’ve talked about on a cocktail. There’s also the Regeneron cocktail. If you’re concerned about the Regeneron cocktail, the other way, and then there are other monoclonal antibodies in the pipeline, so to speak. I envisioned some point, Vincent, in the future, this will be on my board exam where they’ll have these up there posted, and I’ll have to remember which one, just like I have to with the HIV mutations and which drugs I can and can’t use. I’m working on some memory tricks, the “Nervous Nelly 501Y”, that was the one in the U.K.

The “Eek 484K”. Am I really worried about that affecting my monoclonal Bamlanivimab and Indevimab, that lousy 452, does that affect my Bamlanivimab? The “Kite 417N”, so that’s the K417N/T is that going to affect Casi?

I think as time goes by, we’ll get a better sense of where all these come out. There was a really nice paper out of the David Ho lab, Increased Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7 to Antibody Neutralization. A lot of things described here. You have to use more convalescent plasma about 11-33 fold increase for neutralization with convalescent plasma about a 6.5-8.6 fold increase in vaccinee sera.

From a clinical standpoint I mentioned, I don’t think the sky is falling. On a positive note, we have various monoclonals that are already FDA EUA – Emergency Use Authorized – out there that we can use. We have others in the pipeline waiting to go hopefully quickly through the FDA if needed. This is something I think that we can stay ahead of. I’m not concerned that the sky is falling. If that decreases our number of TWiV listeners, because I’m not saying the sky is falling and saying, “stay tuned for exciting news,” I just want to be honest and reassuring. As a clinician, I think that we have the tools and the technology to stay ahead of these things.

Do you have any comments, Vincent? Do you think the sky is falling or does this seem reasonable now?

VR: No, I don’t. We’ve talked about this a lot on TWiV. I don’t want to usurp your-

[crosstalk]

DG: No, no, please, usurp. I think that the benefit of this is having you as well. Jump in.

VR: Originally the B.1.1.7 variant, which originated in the U.K., they originally said, “Oh, it’s 50% more transmissible,” but you know what? Since then, it’s gone to many other places and it’s not doing 50% more transmissible. It’s a lot more subtle. It’s a lot more nuanced than just transmission. I like to think of it as these changes affecting fitness. Fitness is the ability of a virus to get to a new host. It doesn’t just involve going through the air. It involves the amount of virus shed by someone, the ability of the virus to take hold in the host, maybe to evade immune responses, maybe to reproduce better.

I think sometimes these changes give the virus a little edge and it takes off, but it’s not really transmitting better. It’s just spreading and displacing another virus in the population. That whole idea doesn’t bother me. I think a more realistic concern is, are the changes that can aggregate monoclonal effectiveness and vaccine effectiveness as you’ve talked about? Because if you do your masking and distancing and all that, it doesn’t matter except for the antibody resolving an infection. That’s my take on this.

DG: I get questions and I don’t know if this is a good time to throw this in, butpeople are asking, “Oh my gosh, with these new variants. I hear they go right through the masks.”

VR: No, no.

DG: I think a lot of people’s perception is when they say, “oh, increased transmissibility or increased transmission”, they view it as almost like a bullet and that someone coughs or sneezes and things have somehow changed their shape and can penetrate the fibers of your mask. You now have to use Kevlar masks. I think time will tell, right? I mean, you and I are being recorded.

VR: Of course.

DG: In March, right, people will go back to these episodes and get a better sense.

VR: The 1.1.7 variant is in many other countries and in Scotland, it hasn’t taken off, in California, it’s been there since November. It has not displaced the existing variant. Something else is going on. It’s not just about going through those droplets. That’s what I want people to understand.

DG: It’s complicated. The great thing is we have the science and the scientists who are on top of this, and so we’re going to get out of this. We are not going to have another January like we just had.

Sputnik V, so in the Lancet, we got Safety and efficacy of rAd26 and an rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of randomised controlled phase 3 trial in Russia. These were the results that we were waiting for, randomized double-blind placebo-controlled phase three trial in 25 hospitals and polyclinics in Moscow, Russia.

This vaccine group of 16,501 placebo, group was smaller, 5,476. Then the numbers don’t quite add up because they say 19,866 received two doses of vaccine or placebo. You lose a few folks there between the whole trial and everyone getting that boost. This was interesting, from 21 days after the first dose– basically, they started counting the day people came in for their second dose or booster. They saw that 0.1% of the vaccinated got COVID-19, 1.3% in the placebo group. These are small numbers, but that gives us an efficacy of about 91.6%. They’ve got another one of these. These will be the curves that I’ve heard are now on T-shirts. Immunity works. We show the placebo group in red and just the number of confirmed COVID-19 just keeps going and keeps going where the vaccine it goes up, and then once they’ve reached a level of protection, it levels out and stays pretty flat for a while. With the data here, they have actually mentioned that they’re going to do a single-dose trial which will be interesting as well.

Then there’s been some discussion on the main This Week in Virology about some of the other data.

More exciting news on vaccines, but let me hit a bunch of Q&A, questions and answers on vaccines. This is actually– I spend a lot of my time. Julie, my partner today, and she’s saying, “what are we going to do when COVID is over?” Because we spent so much of our time addressing COVID-related questions and vaccine questions?

“If the vaccines still allow for milder symptomatic COVID and mainly prevent severe COVID, what about getting a mild case and the risk of developing Long COVID?”

That’s an interesting question. Just to be honest, we do not know but this is a very interesting question. If a person has been vaccinated, they go ahead and get a mild case of COVID. We are hoping they’re less likely to develop the Long COVID but we still don’t know. Actually, this is a pretty important question, I would say. As I get into some of the other questions, I will say I’m optimistic about this. It looks like when people do get infected, the limited data we have that they end up with milder symptoms, they end up with a shorter course. They end up with a shorter period of time that they’re actually shedding the virus or I should say, that they’re RNA PCR positive.

They also end up at much lower, usually about two logs lower. I’m optimistic, but I think that this is a question that we’ll keep our eye on. It sort of goes right into this next one:

“Any more information on vaccinated people being less able to transmit the virus?” This gets back to Dixon’s idea that he doesn’t want a healthcare worker coming and taking care of him who’s not vaccinated because now they’re more likely to give him the virus. I always like to use scenarios and I get a lot of questions here about scenarios. We have some adults over the age of 75. They’re about to get their second dose.

They’re already starting to ask, “Well, now that I have my second dose, what can I do? Can I go visit my friends in Florida? They’ve also been vaccinated. Can I fly to go visit my adult children? What about all the other activities?” I just want to bring up some more data we have, so analysis of PCR-positive swabs in the U.K. population suggesting that the vaccine may reduce transmission. We’ll get a little bit farther into that because I want to hit on some really specific scenarios.

“Anything new about people who previously had COVID getting vaccinated?” Peter Hotez weighed in on this. There’s some research we’ve got some papers out, Robust spike antibody 1 responses and increased reactogenicity in seropositive individuals after a single dose of SARS-CoV-2 mRNA vaccine. This was out of Mount Sinai. They actually found, and this is something I think we’re starting to see and now it’s nice to have it quantified. They found that getting that first vaccine dose in someone who had COVID before was very similar to that second dose in folks who did not have COVID before. A similar reactogenicity profile but also what looks like a similar boost in the antibody levels.

What we don’t know, and we’re not going to know quite yet, is what’s the durability? What are the kinetics of those antibody responses? The other paper, Single Dose Vaccination in Healthcare Workers Previously Infected with SARS-CoV-2. This is out of University of Maryland. They really found about the same thing. It looked like that one dose of the mRNA vaccine was giving these elevated antibody titers similar to the boost we would expect from the second. We’re not encouraging people at this point to only get one shot. We may actually end up at some point having people get even a third shot, who knows.

This is interesting stuff and is helpful. We’re learning more. I think it does feed to, boy if you’ve had COVID before that first shot, maybe a bit of a doozy, maybe what most people are getting the second time.

I don’t know why I still get this question but, “Is it a good idea to keep millions of vaccine doses in the freezers to make sure that second dose is given right on schedule?” Well, unfortunately, I think everyone is aware that millions of doses of vaccines are sitting in freezers and not getting into people’s arms here in the U.S. Despite requests by the White House, by Andy Slavitt to get those vaccines in arms, many large hospital systems have freezers full of doses.

Oddly enough, some rules only allow for vaccines to go to sites that have the ability to have those freezers. In my world, you wouldn’t be allowed to have vaccines if you had a freezer that could hang on to them for more than those 30 days. Now the CDC has updated their guidance on COVID mRNA vaccine interim dosing to include a grace period. You can get it four days earlier than the three or four weeks. Then out to six weeks if it is not feasible to adhere to the recommended interval. I’ll give the qualified statement just to quote right off, “CDC is not advocating for people to delay getting their second dose but the data from clinical trials supports this range” of either four days early or out to six weeks in if you need to.

My answer really is in line with the Biden COVID Task Force that no, it is not a good idea to remove two-fifths of the available vaccine doses from potentially giving them to people freeze them away just because you want to hedge and are worried that there might be a slight delay in the order of days of getting the second vaccine doses into patients. People have probably heard how we’ve approached this at ProHealth where we get our vaccines, we put them– 100% of those end up in arms as soon as possible. If everyone would do that, I think that this would go much quicker.

VR: Is the supply now flowing from Moderna and Pfizer or is it jerky?

DG: The supply is flowing. We’re getting 200,000, 300,000 doses a week to New York. Some of the states, I have to say like our Riverside partners, every week they get a consistent supply because there, it’s going directly to our clinics where we’re giving everyone the vaccines. In New York, there’s still this hub model where every week, you put in as a provider, we would like “this many” to “this many” sites. Even though there’s a constant flow to the state, that flow is still going to large hospital systems, healthcare systems with lots of freezers.

Every time one dose is given another is stuck in the freezer for three or four weeks later. Yes, it’s flowing. Moderna actually increased by 33% the amount of vaccine it’s sending out. Pfizer is increasing their production. The government and the pharmaceutical companies have made it clear this is flowing. If somebody gets their dose delayed by a few days, that’s not as much of an issue as millions of people not getting any vaccine at all.

“If a second dose of a two-dose vaccine is delayed, will it be less protective?” I think there’s two things here.

One is, person is watching the clock, “I want to get that second dose so I can then count the clock to when I’m at that 100% protection from severe disease.” There’s also that concern too, is if it’s delayed by a period of time, will that mean that it’s less protective? We are starting to get some data on that and we had recent data from AstraZeneca where they actually—interesting to have demonstrated improved efficacy with longer intervals between doses with higher antibodies and a broader antibody response with a boost given at 12 weeks rather than six weeks.

Vaccine efficacy rising from 54.9% with an interval of less than six weeks to 82.4% when spaced 12 or more weeks apart. We still recommend adhering to the studied intervals. This understanding of immunology, now we’re getting data, really goes along with what we’ve learned over many years with vaccine research. Certainly, there’s a critical, minimal interval before the boost to allow the effector cells to mature into memory cells. A slightly longer interval may be associated with a higher and broader boost of antibodies. I don’t know if we know enough yet as far as T-cell responses, whether or not they’re enhanced.

I think our basic understanding analogy would suggest that most of the benefit here if you stretch that out a little, it’s going to be antibodies, but definitely not a diminution.

“Now that I have been vaccinated, can I do the following?” The science is developing here but let me run through a few scenarios. I want to be careful not to get above the science, but also to be reasonable in what we say. I’m using my parents as an example. My parents will soon have reached two weeks past their second vaccination. Yesterday, my wife helped my mother get to her second vaccination. My dad pretty much can do it all by himself. The two of them went and my mother reported a penicillin allergy so they made her wait for a prolonged period of time because I don’t know why, but fortunately was not very crowded. I think they said in the entire time they were there getting vaccinated, four people got vaccinated. They were two, there were two others. My dad wants to start going back to the office. What was my advice? My mother’s, “He can’t go to the office. He’s going to get COVID, he’s going to bring it home to me.”

We had a couple of conversations. One is, as I said to my dad, “Dad, you have not gone to the office in a year. You, in two weeks, will be protected. I do not have a problem with you going back to the office.” Will he wear a mask? Will he be careful? Yes. Am I worried he’s going to bring it home and my mother will get COVID and die? Again, no. My mother has also been vaccinated. I think I can answer very clearly here. Two older individuals, both over the age of 80. Sorry about that, mom. You look younger and dad, you definitely look younger too. I have no problem as a son, as a physician, being okay with them, with my dad going back to the office.

Now my mom wants us to come over to the house for Sunday dinner indoors after she’s been vaccinated for two weeks, is that all right? Now, this is a tough thing. This gets into what does the science tell us? Are we underselling, are we overselling the vaccine? My mother will have reached her two weeks past the second dose. My father will reach his two weeks past the second dose. Is it okay for my wife and I, and my oldest daughter will be off of college, but for my other daughter Eloise, and Barnaby to go over for Sunday dinner?

We haven’t had indoor dinner with them in a long time, is it okay for the five of us to eat indoors?

I’m going to say, I think it’s okay. I worry about my mom. I worry about my dad, but they’ve now been fully vaccinated. My dad’s going to and from work and that’s it. He and my mom are not suddenly socializing with big maskless parties. I’m sure it will be just the two of them watching the Super Bowl this weekend. Yes, I think it’s okay until they reach that point though, I do not go into their house without a mask and even if I do go in with a mask, I stay for limited periods of time.

Now my in-laws when they are fully vaccinated, they want to start flying around the country. They’ve been up in Cape Cod, being really careful staying by themselves. They want to fly down to Florida. They want to see their vaccinated friends there. They want to fly out to Utah to see their daughter. Is that safe? For them, yes. I actually think if they’re flying down to Florida, if they’re staying at a hotel and they’re going to be outdoors with friends in Florida, I actually see really minimal risk. I see that being a reasonable risk-taking activity. When they go out to see their daughter in Utah, we are hoping that the data will pan out. I expect the data to pan out that people who are vaccinated are less likely to transmit to others but we’re still waiting on the science on that.

That then is going to be, is it a risk for the daughter? Is it a risk for the daughter’s boyfriend? Daughter has a boyfriend. Is it a risk for the malamute that they have, the dog? For the vaccinated parents, my vaccinated in-laws, they’re actually going to be much safer.

Passive vaccination. We just talked a little bit about the monoclonals. The Eli Lilly product, a Regeneron cocktail, the Eli Lilly cocktail, and the past monoclonals are still being underutilized but as I mentioned, they’re ready to go. They’re here to meet the challenge of any changes in the genetic code of the virus.

All right. Now, this is the bulk, as that we haven’t already done the bulk. Lots on anticoagulation this week. I don’t want to keep this too long, but let’s hit this. This is really critical because now we have new information that is actually changing some of the decisions that I’m making and some of the recommendations I’m making in the hospital. Based on the interim results of more than a thousand patients admitted to the hospital, findings from three large randomized control trials showed that full doses of blood thinners in addition to being safe were superior to the doses normally given to prevent blood clots in hospitalized patients with moderately severe COVID-19.

These trials compliment the findings announced in December that the routine use of full-dose anticoagulation, when started in the ICU in critically-ill COVID-19 patients, was not beneficial and may be harmful. Just to break this down, before I go through the weeds. You’re a critically-ill patient in the ICU with lots of lines, severely ill. The evidence that we have to date is favoring prophylactic dosing. Doesn’t really necessarily go along with what we were thinking, but your floor patient who is maybe laying there in bed, who is on oxygen, they actually are at lower risk of bleeding and they actually do better with full-dose anticoagulation.

How does this fit in with our guidelines and how do we move forward and what are the actual studies? The current guidelines from the American Society of Hematology are, “the ASH guideline panel suggests using, these were made a while back, prophylactic intensity over intermediate or therapeutic intensity anticoagulation in patients with COVID-19-related acute illness who do not have suspected or confirmed VTE.” Then we mentioned, this is a conditional recommendation based on very low certainty in the evidence about effects. Then add it to this:

“The panel acknowledges that higher intensity anticoagulation may be preferred in patients judged to be at high thrombotic risk and low risk of bleeding.” Then we actually add, the interim data from these studies will eventually be available in peer-reviewed articles, but right now let me run through all the data here. The three clinical trial platforms spanned five continents, more than 300 hospitals, and together were able to test whether there was a greater benefit of full doses of blood thinners to moderately-ill hospitalized patients with COVID-19 compared to the lower dose typically administered to prevent blood clots in hospitalized patients.

Let’s go through the studies. We have the ATTACC, this is the Antithrombotic Inpatient and Antithrombotic Therapy to Ameliorate Complications of COVID-19 with 58 sites in Canada, the U.S., Brazil, and Mexico. We have ACTIV-4a, Therapeutic Anticoagulation; Accelerating COVID-19 Therapeutic Interventions and Vaccines-4, and this was 60 sites in USA and Spain. We have REMCAP, Randomized, Embedded, Multi-factorial Adaptive Platform Trial for Community-Acquired Pneumonia, 290 sites. This is very robust in Canada, the U.S., U.K., Ireland, E.U., Saudi Arabia, Australia, New Zealand, Nepal, India, Pakistan.

I have to say, this is impressive. There was a collaboration between all these studies and they agreed to create a multi-platform randomized controlled trials with harmonized protocols. They all agreed to use common primary, common secondary, and safety outcomes, and also to have common combined prospective superiority and futility rules. All the enrollees in all sites had to have signs and symptoms consistent with COVID-19. This is all symptomatic COVID-19. Then they were randomized within 72 hours of admission.

The primary outcome was organ support-free days, and then they had several key secondary outcomes.

From the safety, they were looking at major bleeding. From efficacy, they were looking at mortality, intubation, major thrombosis, stroke, MI, length of stay in the ICU and hospital. Then this is critical because I’m going to get back to this. They restratified. They thought they were restratifying people based upon the D-dimer level. You looked at people with D-dimers that were low, less than two times the upper limit of normal and then they looked at people that had elevated D-dimer, so greater than two times the upper limit of normal. The reason I want to point this out right here is that this did not impact the recommendations.

I’m going to have to say this several times because people– it’s very hard to get away from this. We as clinicians, we love to measure stuff. We love to have something objective to guide us. We think of D-dimer as an indication of people developing a thrombotic complication. I just want to point out here whether the D-dimer was low or high, the recommendations still stand. When you put all this together, the primary outcome of organ-free support days favored full-dose anticoagulation for moderate COVID-19. As far as secondary outcomes, mortality was lower with full-dose anticoagulation for moderate COVID-19.

Major bleeding was seen with full-dose anticoagulation but was less than 2%. Thrombotic events were less common with full-dose anticoagulation. But to recap the other side for severe COVID-19, those patients requiring ICU-level support, the probability that routine use of therapeutic anticoagulation was inferior, was 98.5%. Mainly you were seeing major bleeding complications of 3.7% in the ICU patients which really backfired against us with that full-dose anticoagulation. Your floor patients, the science currently suggests full dose but if you’re in the ICU, you want to watch the bleeding complications.

I know we’re going to probably getting near our limit here, but I want to make sure I discuss guidelines and what they are because we had a lot of conversation about this last time at the ASH guideline meeting. What we’re discussing is we, unfortunately, people have not really understood what guidelines were and guidelines have changed in the time of COVID. I think a lot of people have been promoted to positions of responsibility where they’re forced to make these decisions, but they themselves never served on a guideline committee before. Maybe they never helped construct guidelines but now they’re putting these in place. We talked a little bit about how this was a challenge.

We’ve already added language actually to the ASH website. Trying to clarify what a guideline is and how is it expected to be used. These are not rigid rules for patient care. We do encourage people to individualize their management decisions, to tailor them to a specific patient. We’ve added an individualized assessment of the patient’s risk of thrombosis and bleeding is important when deciding on anticoagulant intensity. Clinicians should weigh the potential benefits and harms based on the most up-to-date available evidence in caring for their patients. We’re trying to communicate that these are only guidelines.

They’re established to help direct physicians to deliver the best care for their patients and even though these are living documents updated on a regular basis, by their very nature, they will not be the most up-to-date based upon available evidence. I’m just going to hit three scenario cases, examples. Case one, what would we do? This is a police officer in his 40s. His oxygen saturation is 88% on room air. He has no significant medical problems. He’s standing up, he’s looking out the window. “When can I go?” He’s being treated with Remdesivir and steroids. That’s an individual I still might stick with just prophylactic dosing. He’s ambulating, he’s low-risk.

Case two, we have an obese 75-year-old man. He’s somnolent, he’s on six liters nasal cannula. He has coronary artery disease, CHF, and diabetes. That’s a man now I’m going to recommend full-dose anticoagulation.

Case three, a woman, she’s in ICU, she’s intubated, she’s proned. She has low Hct, she’s on medications to maintain her blood pressure or pressors. She has staph aureus bacteremia and multiple IVs. She’s got a central line. This is a woman that I’m going to recommend prophylactic dose anticoagulation.

I’m going to make sure I just mention the tail phase but then I’m going to update people on our fundraiser. As we move into our fundraiser, I’m going to use an analogy from my honorary cousin Peter Dates about oxygen masks in airplanes, and how they always tell you, when those oxygen masks come down, put them on yourself first. But then the point I’m going to say here is, once you have that mask on, you make sure that you put that mask on other people.

Throughout the months of February and March, we’re going to be making donations to the ASTMH. Donations made to Parasites Without Borders will be matched and doubled by PWB and donated to the American Society of Tropical Medicine and Hygiene.

This money’s going to include scholarships for women from low-income parts of the world to travel to the annual meeting. We’re going to pledge a– hopefully, we’re going to get up to a maximum of $40,000, but we are going to donate a minimum of $20,000 and part of that is going to go for these scholarship travel awards to basically prioritize females from low-income countries who otherwise might not be able to attend.

It goes back to where I started. We are not safe until everyone is safe. We’re seeing vaccines roll out here in the United States. That all may be exciting but we’re not safe till everyone’s safe. Let’s not forget about the rest of the world.

VR: A couple of emails for Daniel, if you want to send in a question, daniel@microbe.tv. The first is from Debbie, who wants to advise a friend on sending daughters back to school in Maryland, where they’re living in an underfunded school district, has an incredible plan to bring students back, small cohorts, air filters, distancing dividers at desks, et cetera, but she says, the only thing that’s missing is testing. “I thought nothing is perfect, but air quality, cohorting, and testing were what I thought of as deal-breakers. Your thoughts.”

DG: Yes. This continues to be a really frustrating challenge is that people leave testing out. All these other things cost money too, right? You start smaller class sizes; you start doing all these mitigation strategies and then they leave testing out. One of the things Debbie, I’m going to suggest you do, let’s see where you are. You’re in Maryland. What I’m going to say is reach out to one of the local provider groups in the area because a lot of times we’ve done this at ProHealth New York. We’ve done this at Riverside. We’ve created the whole Let’s Get Back Program. Sometimes the schools just leave this out for some reason.

If they do, there’s no reason why parents and teachers, organizations can’t jump in and we can’t create something. In my local town, it’s actually one of our ProHealth providers who has been working with the school and it took a long time, but they finally introduced testing. Testing is really, I think, part of creating the best possible solution. President Biden has said he really wants to get the teachers back. He really wants to get the kids back and in-person. That’s fine and all, but we’ve got to make sure we do everything to make it safe. This is a safe decision and I think testing is part of that.

VR: Terry in Orlando has a 100-year-old mom who got her first dose and is preparing for the second. Terry wants to know, “is there anything that we should do to prepare her? And how long should someone stay with her afterwards to monitor her?”

DG: Yes, the nice thing about older individuals, and I know this was discussed on the last TWiV is they either have less side effects or they just complain less than young people, right? Young people are,” Oh, so horrible. I had to take pain medications.” No, I think your healthy 100-year-old mom is actually going to do very well. The observation period we recommend is really 15 minutes after the vaccination. No one really needs to stay with your mom. It would be nice if you stayed with your mom but again, you want to weigh, are you vaccinated? Is there a risk of exposure? She’s getting so close to being out the other side of this.

Ask her doctor, whether it’s safe for a 100-old-woman with whatever medical problems she has to use something like ibuprofen or Aleve or Tylenol but no, I think that there’s nothing too much that I would worry about here.

VR: She has one more question. Her daughter is breastfeeding her 10-month-old grandson. Is there any chance if she is still breastfeeding when she is vaccinated that any protection will reach the grandson and how far down the road do you think will be the earliest we expect one-year-olds to be vaccinated?

DG: Yes, so breastfeeding and I think I posted my friend, Vanessa, one of my coworkers who she’s a breastfeeding mother who is vaccinated. That’s one of the things. Vaccinating a breastfeeding woman is really vaccinating two people. We anticipate, and this has been true for all our other vaccines that when a woman starts making antibodies, those antibodies are then in the breast milk. If she is vaccinated, once she starts making those robust levels of antibodies, we anticipate that those are being then transmitted to the 10-month-old grandson.

There are some trials looking at younger individuals. It’s probably going to be a while before we look at one-year-olds. I know there was a question about, “Okay, if you say this is allowable for this, are you allowed to stretch beyond that?” For instance, I’ll say the J&J vaccine has been given hundreds of thousands of individuals, will it be okay to give those to children? Unfortunately, it may be quite a while before we have any science to guide this. There may be judgment calls at some point.

VR: All right. One more from Carson, “You’ve said that people who recently had COVID should still get vaccinated, but also that anyone who’s had monoclonal therapy needs to wait 90 days because the monoclonals could prevent the person from mounting a sufficient immune response to the vaccine. Why isn’t that the case for someone who’s been infected and presumably developed their own antibodies?”

DG: This is an excellent question. I’m going to bring two things. I had a conversation with my partner earlier today, I had conversation with Fatima Johari, one of the infectious disease doctors I work with at Plainview about these two topics. One was, it was a husband and wife, and the husband had been vaccinated and he’s well– just like so many, he got infected before his second vaccine dose. He meets criteria for monoclonal antibodies, but he doesn’t want get the monoclonal antibodies because as he explained, “It was so hard to get the appointments for the vaccine, if I missed this, I’ll never get another one.”

I try to explain that if he gets the monoclonals, we have the impression and actually the evidence that those are going to be in his system for 90 days. In a sense, instead of waiting for that second dose and another two weeks for the antibody, so three weeks from now, within an hour, he could instantly have that passive immunity that lasts three months, and at the end of those three months, then he can go ahead and get his vaccine, and get that boost. But what about this? This is this issue. What about someone who’s already had an infection? Why not just wait three months just like you did with antibody therapies? You’ll hear different advice on this. This, for me, gets back to the rule, “Never miss an opportunity to vaccinate.” If someone is ready and willing right now to get vaccinated and you can give them that protection, which we have well-studied, which we’re familiar with, which we are learning more and more about the durability, and all the science suggests that it is even better than natural infection, that’s why I’m saying there’s no need to wait. Three months, maybe that person’s lost interest and they decide they don’t want to get vaccinated so you’ve just lost the opportunity to immunize. For us all to get out of this, for us to see the death count drop, we want to see as many people vaccinated as possible.

VR: That is COVID-19 clinical update number 48 with Dr. Daniel Griffin. Thanks again, Daniel.

DG: My pleasure. Everyone, be safe.

[00:51:19] [END OF AUDIO]