TWiV 758 COVID-19 Clinical Update #63

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 22 May 2021

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 758, recorded on May 20, 2021. I’m Vincent Racaniello and you are listening to the podcast all about viruses. Joining me today from New York, Daniel Griffin.

Daniel Griffin: Hello, everyone.

VR: Daniel, this is clinical update number 63. How will we know when the pandemic is over, Daniel?

DG: Actually, that’s a great question. When will it shift from being a pandemic to just, “Hey there’s still COVID-19 around.” And you know, it’s become less of a pandemic. Vincent, maybe you’re the person to answer that question because what was the point when polio ceased to be a pandemic and started to be just something we were trying to get rid of?

VR: Polio was around before we had this word ‘pandemic,’ so we never got to call it a pandemic, but Daniel, would you say we’re still in the middle of an HIV/AIDS pandemic?

DG: Yes, and I try to make that point. A couple of people have reached out and said, “Oh, you know, would you like to write a book?” I am working on a book that Chuck Knirsch connected me with about– sort of what happened with the vaccines and what was the rollout like. But the whole idea about writing a book– about “Oh, we’ve survived the pandemic.” I’ve known other people have written these books and it reminded me of a movie and it was surviving the pandemic and it was about HIV.

I remember talking to my buddy Joe McGowan and I was like, “I don’t understand, it’s not over. There are over 30 million people infected with HIV. We see another 50,000 new infections every year in the U.S. We see half-a-million to a million people every year dying of HIV. Explain to me how we’re not still in the midst of that pandemic?”

VR: That’s right. Daniel, before you start, what’s on your bow tie today?

DG: It looks like a coronavirus, doesn’t it?

VR: Yes, it’s very nice.

DG: The virus with the little coronas there.

VR: All right.

DG: Our listeners may not know this, but just about every one of my bow ties is an infectious disease, and whenever I appear on Friday, it’s always a sexually transmitted infectious disease.

VR: When you take care of patients, do you wear these infectious bow ties?

DG: [laughs] I do, I do.

VR: Very good.

DG: I started doing it in part as a teaching thing for the residents’ medical students. Actually, my socks match, I won’t show those now, but they match the pathogens, so maybe I’m wearing one with little red snappers so they’re supposed to cue them, that it’s tuberculosis, I have anthrax, I have several others.

VR: Great, love it.

[laughter]

DG: All right, let’s jump right in with my quotation. “We are drowning in information, but starved for knowledge.” And that’s by John Naisbitt. I think this is so relevant because really this fire hose of information, we’re seeing it all around COVID, but this is just the modern world. We’re always struggling to make sense of what does all this information mean? How do we actually get from information to knowledge? Hopefully, we play a part in doing that. Let me start with the updates. How are things?

Things are really much better here in the U.S., here in New York. One of our local hospitals I discharge to, I think is, at least for the moment, there will be no COVID patients left in the hospital after this gentleman goes home. He’s probably home already with his wife and twins, so that’s very exciting. Other big hospitals in our area are down to single-digit numbers of COVID cases. My partner Anuja Leejust admitted someone today with COVID and as you can imagine, this is a woman who did not get her vaccine, diabetic who really should have been taking that opportunity. That’s what we’re seeing now, we’re seeing younger individuals, we’re seeing people who did not take the opportunity to get vaccinated.

The numbers really exponentially seem to be going down. I continue to have that optimism that we’re going to be in a really great place across the country in July. There certainly are areas with poor vaccine uptake and you worry about those areas starting to see a rise when people get back indoors either because it got so gosh darn hot, they’re in for air conditioning, or when it gets cold again and people are indoors for the warmth.

Around the world, parallel with HIV, we are in no way at the end of this pandemic and until we are more generous, until we’re able to get everyone in the world vaccinated, we are not safe. I was joking today about first world problems where people complain about their chair is not as comfortable as they would like, there’s plenty of places in the world without chairs, and I think that’s the vaccine story at this point.

I will say as we get into this, we certainly have evolving recommendations, have people’s heads a little bit spinning, but that’s actually what we wanted. We wanted to learn, we are not where we were a year ago. A year ago, we did not know much. We actually know a tremendous amount now and as we learn more, as the science comes in, then we can actually revise what people are being told to do, what we know is safe, what we know is not safe, so we’ll go through that.

I’m going to start with children and COVID, this is always the crowd-pleaser or not. Paul Offit appeared on the podcast Track the Vax with Serena Marshall, that’s another one of the podcasts that I enjoy listening to. I actually was on, I was a guest on their 13th episode of Track the Vax. Serena is wonderful. I miss that it wasn’t as raw, I think, as TWiV is because at one point, she asked me a question and I replied and she just started laughing to the point where she had to actually stop the recording and she edited that out, I thought that was great, but not all my jokes are bad. [chuckles]

This episode with Paul Offit was the May 18th episode, I’m giving a little plug for them, called Next Up in Line for COVID Vaccines: Kids. It was really a great discussion between Serena and Paul. Paul Offit brought up the fact, really that I try to reinforce on a regular basis, that yes, kids are actually at some risk. It’s not huge, it certainly is lower. The reason we’re recommending vaccination to adolescents at this point is not for the greater good, it’s actually to protect them. It’s like putting a seat belt on them, putting a helmet on them, and let me quote Paul Offit, what he said during that discussion, “You have at least 300 children who’ve died from this infection and estimates are could be as high as 500.” He’s talking about just right here in the United States.

He also pointed out that we did a really great job, I like to reinforce this, initially, of protecting our children early in the pandemic with only 2.4 % of those total infections in the early months being in children. Now, things are changing. Now children account for 24% of the infections. My colleagues, as I mentioned, are admitting adolescents to ICUs– a number of articles and releases about the shift into younger ages. I’m also going to add here that per the CDC, the number of confirmed multisystem inflammatory syndrome cases in children, so that’s that MIS-C, is approaching 4,000 and there are many more that are still under investigation, including about 500 just right here in New York State.

I don’t want to blow that out of proportion because I like to say children are at low risk, they’re not at no risk, but there are things we can do to keep these kids safe. It has been really difficult for a lot of these children, actually, I will say for us parents, to have schools closed, to have a lot of these other social and other opportunities closed. There was another MMWR publication hot off the press today as we’re recording this, “Characteristics of COVID-19 sases and outbreaks at child care facilities,” District of Columbia, July through December 2020.

Here, the authors were reporting on 469 child care facilities in the District of Columbia. As far as facility-associated outbreaks, they occurred in 5.8% percent of the facilities. The other flip of that is you could say over 94% of the facilities had no outbreaks. The child care facilities in D.C. were able to adhere to many of the recommended prevention measures and reporting requirements, and basically, they did a good job. The kids were able to be in these settings and they reported that really similar to what had been observed in other studies. The rise in the COVID-19 cases and outbreaks correlated with level of community spread, so I think that’s really a positive message here.

We can get these kids out in these settings, we can do it safely, we’ve learned how to do that. We now have the lowest positive test rates across this country, actually, ever. Early on, when we started testing, I remember in New York, 80% of the tests were coming back positive. A recent article that I tweeted out– maybe I should tell people, just follow my twitter @DanielGriffinMD because I try to get a lot of these articles out there– but really, showing how a lack of testing plagued us early on.

Now, we are doing a lot of testing and you know you’re doing enough testing or you’re doing a lot of testing when you’re getting a positivity rate of down in the 1% or 2%, nationally. Really, going in the right direction here for improving the risk for our children. I should probably tell this story here. I always try to be careful when I talk about risk and I talk about no risk. My wife asked me yesterday, she was going to give Barnaby a sandwich with Swiss cheese, turkey, and mayo, and it had been in an insulated thing and there was a blue ice thing in there, but now the blue ice thing was no longer cold, so she wanted to know if it was still okay for Barnaby to put in a new blue ice pack.

I had not taken off my work hat, so I said, “Oh, that seems like a very low-risk decision going ahead and letting him have that.” My wife’s response was, “I don’t want a low-risk, I want no-risk for our son, Barnaby.” I was like, “No, no, it’s fine. He can eat that sandwich. He’ll be fine.” I know we want absolutes, but even when it comes to sandwiches, we don’t have absolutes. All right, pre-exposure transmission.

On Friday, May 14th, the article, “Interim Estimates of Vaccine Effectiveness of Pfizer-BioNTech and Moderna COVID-19 Vaccines Among Health Care Personnel,” 33 U.S. Sites, January-March 2021. This is hot off the press, this became available as an early release, and on the last TWiV clinical update, Vincent had asked mainly to address questions from our audience about how we knew about safety and efficacy of vaccines beyond the initial large RCTs.

We were talking about the latest adolescent trials. There’s like 2,000 people in there. But what are they doing over time? So I brought up theirs, but here, this is one of these trials that continues to give us information after those RCTs. Here are the authors’ report on a case control study of mRNA COVID-19 vaccine efficacy, VE, with HCP, healthcare personnel, being enrolled at these 33 sites across the United States.

These were healthcare personnel with the potential for exposure to SARS-CoV-2 through direct patient contact or for indirect exposure. Think about it, these are people who are exposed, so you’re getting an exposure here. They had case patients, they had control participants, and these were being identified through routine employee testing performed on-site through their occupational health practices.

They went ahead, and the healthcare personnel with a positive SARS-CoV-2 PCR or antigen-based test result and at least one COVID-19-like illness, were enrolled as the cases, and then we had the negatives being those who did not have a PCR. It didn’t matter if these people had symptoms, they had something else going on, as long as they did not have COVID. As of March 18th, 2021, 623 case patients, 1,220 controls were enrolled, and they gave us an effectiveness estimate of a complete two-dose regimen of these vaccines at 94%, which is really actually consistent with the clinical trials.

I should say, surprisingly, we were not expecting– the real world is usually not as good as what we see, but what are the limitations here? First, testing for SARS-CoV-2 infection among healthcare providers was based on occupational health practices at each facility, and vaccinated people may have actually been less likely to go for testing, possibly underestimating the efficacy, thinking, “Hey, I’ve been vaccinated. I’m not as worried about a little bit of sniffles here.” That is one issue, and the authors comment on this as well.

Second, again, limited sample size. We love our 10’s, our 20’s, or 30,000’s, this was not as big a sample size, and third, it’s not clear that you can generalize this to the entire U.S. population. Different races, different ethnic groups, age, we’ve certainly started to get a sense that the vaccine has different efficacy based upon age, good data starting to support that, and fourth, the healthcare personnel with a known past SARS-CoV-2 infection were excluded. We’re vaccinating those individuals, giving them protection.

Again, are those people going to get better or worse protection than people who did not have that exposure prior to vaccination? We think that they may actually be even more protected. That 94%, another reason why maybe even underestimation. Now, this was actually the data that came out the day after our last TWiV, and the headline, making comments by the current CDC director about vaccines and masking. I certainly have gotten a lot of questions, so I’m going to spend a little bit of time discussing that in this context.

What was that all about? I think there were several points that that was based on, and I think the CDC director has been really clear that the recommendations were science-driven. What is that science? Well, one of the bits of science that has just been building, and this was another brick in that wall, is that vaccines can be incredibly powerful at protecting a vaccinated person. The person vaccinated, as long as they have an intact immune system, as long as they can mount a response, they can have a tremendous amount of protection. I will be talking about people that can’t get that.

The second, and this I think is an important point, growing evidence that an asymptomatic vaccinated person is at very low-risk for transmitting to others. Incredibly low chance that they’re even going to turn PCR positive, and then we have data suggesting that if they’re asymptomatic and PCR positive, that is at such a low level that it may actually be below level of transmission. That was the second part.

What are the other caveats, I think, that need to be put into this whole situation? 4% of people in the U.S. have impaired immune systems due to disease or medications, so that’s about 10 million people that are unable to protect themselves with active vaccination. They are relying on the kindness, the decision to get vaccinated, the masking, the non-pharmaceutical, and the vaccine mitigation measures.

The other is what about children 11 and under who do not have access to the vaccination and the protection that this could offer? That’s another 50 million people here who are at risk if someone is unvaccinated, infected with SARS-CoV-2, and walking around. The other point that people are bringing up, and I think is relevant, is children 12 to 15 just got access, so millions of these kids who have not had time to get that second shot, not had time to get to that full protection. Many, many, rightfully so, in the U.S. worry that unvaccinated people will be dishonest and take their masks off around vulnerable people and infect them, giving them COVID. I think there’s a lot going on here.

The only state that I’m aware of with any sort of real robust verification system is New York, here, with our Excelsior Pass, which is already being used and already planned for use for sporting events to verify that you get to sit in that vaccinated section, etc. Remember, the CDC is not the police, they are a public health agency, and this is the science. The police saying– that’s going to be someone else’s job.

Now, one of the things that comes up in this context is people who say, “Well, I don’t know if I need to get a vaccine because I already had COVID. I should be fine.” What about that? How much protection against reinfection do you get with prior infection? Boy, have we come far in a year. A year ago, there was the whole discussion, “Is reinfection even a thing?” Well, I think we’ve moved past that and now really the question is, “At what rate are we seeing this?” If you’ve been infected, what percent does that protect you relative to vaccination, for instance?

I’ve always been shocked that there’s a group of people out there who would somehow prefer natural infection to a vaccine. I’m seeing a lady now who got chickenpox, instead of a vaccine, and she has this recurrent zoster all over her face, she actually has to wear a mask. She keeps having issues trying to get employment because at job interviews, this is an issue. Polio, I think, Vincent, right up your alley, if you could get a polio vaccine or just take that chance of maybe a little bit of paralysis for the rest of your life, I’m always shocked here, but here’s some data.

This was the study, “Risk of SARS-CoV-2 reinfection in a university student population,” published in CID, Clinical Infectious Diseases, and they reported on a retrospective analysis of 2,021 students with prior infection, and 14,080 students without previous infection. These were aged 17 to 24, and they reported an 84% lower risk of infection compared to the unvaccinated students over a study period of four months. I just want to give a comparator here. Remember, this is an age group with almost 100% protection with vaccination, and here, only an 84% reduction with prior infection, and this is just in that window, just the four months.

My takeaway here is we saw dozens of reinfections in these young adults in this short period. Prior infection is not vaccination. Testing, never miss an opportunity to test. We are back into the realm, I want to remind everyone, of the indeterminant test. We now have rates that are dropping back so low that we are back to those issues, “Of what is the positive predictive value and what is the negative predictive value of a test?”

If our listeners remember that far back, but I’m glad that we’re circling back to there. This is the situation where I’ll start with sort of the high numbers. Back when we had a disease prevalence of 30%, if you use-to-test that was 80% sensitive, 99% specific, we’re thinking of like PCR, some of our antigen tests here. If a person had a positive test, 97% of the time that was truly positive, only 3% of the time was that false. If it was negative, your negative predictive value is up in the 90s as well.

What happens when we dropped to where we are now? What if the disease prevalence is down at 1%? Using that same test, if it’s negative, okay, it is negative with even higher certainty than we had to begin with. But what if it is positive? The false-positive rate now is going to exceed 50%, it’s going to be at 55%. Now, it’s becoming really important at a lot of our testing sites to have that second test ready to go. If you get a positive, or what I will say an indeterminate initial result, you want to be ready to employ a second test to determine if that’s really a true positive. This is also going to be a little bit of communication with each state’s Department of Health. Do they want that indeterminant reported? How are you allowed to respond?

All right, active vaccination, never miss an opportunity to vaccinate. And I will call this perhaps, “Patience is a good thing.” We saw the preprint results of a study looking at extended interval boosting of the Pfizer-BioNTech vaccine entitled “Extended interval BNT162b2 vaccination enhances peak antibody generation in older people.” Can you guess what they saw? Yes, this is the secret of a well-crafted title. It’s all right there. The authors reported on 175 people over the age of 80 and found a peak antibody response that was 3.5-fold higher with an extended interval of 11 to 12 weeks versus the standard three weeks, so 3.5 times higher by just waiting that extra point.

I think this makes sense. We did our studies at three weeks, at four weeks because as I tell my daughter Eloise, 95% is good enough, we don’t need 98. These older individuals– where maybe we don’t have as robust responses as we might like, also start thinking about those people with immunocompromised where there were issues, maybe an extended interval even. We’ll talk in the future about some of these heterologous or mix and match boosting approaches.

For a population, we may be getting where we need to be because I think it was quoted on the last TWiV, a little bit of discussion there with Kathy and Alan and Rich and the gang about if someone gets vaccinated, we’re only seeing your chance of dying only, and I think I’m going to use the word only here, is 1 in 500,000 people. And that includes all these people who come back with a negative antibody test, come back with a low titer antibody test after vaccines. The vaccines are incredibly effective. I don’t know if we need 3.5 higher, but at least it says that if there is a weight depending on your vaccination strategy, you’re not getting lower antibody, so you’re actually getting significantly higher.

Three, the period of detectable viral replication, the viral symptom phase, as I like to say, the time for monitoring and monoclonals, and remember, NSAIDs are fine for symptom relief. I’m going to combine pulling passive vaccination and the early inflammatory phase here together. And part of it– I’m going to bring up the issue that timing matters. What am I talking about here? We finally saw the peer-reviewed results of the RECOVERY Trial results onconvalescent plasma in patients admitted to hospital in The Lancet. As people may know, I feel like that’s a little bit late, right? We’re waiting until the early inflammatory phase. We’re not getting convalescent plasma in during that first week. Let’s see what we saw here.

The title was, “Convalescent plasma in patients admitted to hospital with COVID-19,” RECOVERY: a randomized controlled, open-label, platform trial. At this point, our listeners are perhaps familiar with the RECOVERY Trial out of the UK. What do those letters stand for? This is a randomized controlled, open-label, platform trial. Randomized Evaluation of COVID-19 Therapy. Looking really at several possible treatments in patients with COVID-19 in the UK.

The trial is still underway at 177 NHS hospitals from across the UK. This is the trial that introduced steroids at the right time in the right patient at the right dose as the standard of care. We also got some significant results from RECOVERY on the potential harm and lack of benefit of HCQ. And most recently, the compelling data demonstrating the mortality benefits and other benefits of adding tocilizumab to steroids for the treatment of COVID at the right time in the right patient.

This paper describes the results of patients who are randomly assigned one-to-one to receive either usual care or usual care plus high-titer convalescent plasma. The primary outcome was 28-day mortality, and it was analyzed on an intent-to-treat basis. Between May 28, 2020 and January 15 2021, 11,558 individuals were assigned to either the convalescent plasma group or the usual care group. What did they find?

They reported no significant difference in 28-day mortality between the two groups, 24% versus 24%. The 28-day mortality rate was similar in all prespecified subgroups of patients, no significant effect on the proportion of patients discharged from the hospital within 28 days. Again, 66% in the convalescent plasma, 66% in the usual care. Among those not on invasive mechanical ventilation at randomization, again, no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death.

In summary, this was a robust, well-powered study using high-titer convalescent plasma early after admission, so they were getting it in within, it was median of two days after admission, no benefit was observed. If anything there was, I feel like I’m quoting Mark Crislip, a non-statistically significant trend toward a 20% higher rate of mechanical ventilation, if you look closely at figure two. That means that yes, there was a trend there, but they did not actually find benefit anywhere. There was a little bit of a suggestion that maybe if you had a larger study, you would have started to see harm actually.

They also did a meta-analysis of the 10 major trials to date and I will say here, again, the totality of data, putting all these trials together, did not support a benefit to convalescent plasma for hospitalized patients. Now, the authors did comment that recovery only included patients admitted to hospital, so this trial doesn’t really address whether or not there’s maybe a narrow window early in disease where convalescent plasma might provide some benefit. That question has not yet been robustly tested in a sufficiently large randomized control trial.

They actually did reference a trial that we’ve discussed here, which was The New England Journal trial. This was, Early High-Titer Plasma Therapy to Prevent Severe COVID-19 in Older Adults.” That was that small study with 80 patients in a geriatric unit in Argentina who got plasma within 72 hours. There was a report of some benefit on disease progression, so just putting, I will say, the hospitalized patients– really robust data from this trial as well as a meta-analysis of 10 other trials, really a labor-intensive approach, and we’re not seeing data here to support it.

Is there something that’s similar that can be given during that first seven to 10 days? What about those monoclonal cocktails? We got another press release, this was actually presented at a conference, but what was the press release? This was from Regeneron. Phase III data that was also presented at the American Thoracic Society 2021 meeting, REGEN-COV, so this is the casirivimab with imdevimab, reduced risk of hospitalization or death by 70% in non-hospitalized COVID-19 patients. This was a Phase III randomized, double-blind, placebo-controlled trial, evaluating the Regeneron cocktail in 4,567 high-risk patients with COVID-19.

They studied two doses, the currently authorized 2400 milligram dose and a 1200 milligram dose, so half the dose. They evaluated all these patients for efficacy. They all had one of the risk factors to include them in this study, and the REGENERON-COV cocktail met its primary and all secondary endpoints with similar efficacy for both doses. They saw this for 1200 milligrams or 2400 milligrams, so 70% and 71% reduced risk of hospitalization or death through day 29 compared to placebo for both doses, a four-day shorter time to symptom resolution and reduced viral load, and that had a p-value of 0.0001 for both. Great safety data as mentioned– these are thousands of individuals, one person had an anaphylaxis reaction that resolved with therapy.

A little bit more on monoclonal. This is, again, another exciting week, updated and expanded emergency use authorization for the monoclonal cocktails, now including more medical conditions and the BMI has been dropped down to only being greater than 25. Just to give a sense of what that means, for men, my height 5’10”, I would only need to weigh 175 pounds or more to be allowed to squeeze in under BMI alone, so this is really expanding down to many of us except maybe those really fit athletic people like my son Barnaby, who keeps getting new personal records in the mile.

We also had, and I think this is critical too, updated info on efficacy relative to different variants. This is what worries me about the variants is the impact on monoclonal therapy. In these new updated FDA EUA documents, there are a couple of tables. There’s a table looking at the variant substitutions and their impact on the Eli Lilly cocktail with the B117, no change in susceptibility, but when we get into the B1351, originally described in South Africa, we are seeing a 215-fold reduction in susceptibility.

When we look at the P1, originally described in Brazil, we are seeing greater than 46. Remember, both of these have very similar key substitutions, so the K417N/T, the E484K, and the N501Y. Then the B.1427 and the B.1429. Originally described in California, we have the L452R, about a nine-fold reduction, and the B.1526, that’s New York City’s, that also has the E44K, that’s about a 31-fold reduction of susceptibility. In contrast, the Regeneron cocktail did not show any fold reduction in susceptibility for any of these key substitutions or for any of these variants. It now becomes, I’ll say, pretty critical when you’re deciding which monoclonal cocktail to use to have a sense of what variants are prevalent in your area, because you may be having reduced benefit to your therapy if you’re giving it to a patient who has one of these key substitutions.

Still in this section, remember this is that early inflammatory phase, so if those oxygen saturations drop below 94, that’s when we have data that steroids, dexamethasone 6 milligrams a day for 10 days improves outcomes, is associated with a mortality benefit. Be careful with higher or longer doses. Remdesivir, minor impact at huge expense. Still recommending anticoagulation for our hospitalized patients, at least prophylactic dose is associated with improved outcomes.

Mortality benefit, we still really need better studies in this space. Oxygen and pulmonary support as we’re seeing in India, so critical to have that ability to deliver oxygen. Antibiotics, not helpful for treating viral infections and can be harmful. As we mentioned, tocilizumab can be added to steroids in a certain subset of patients, appears to have a mortality benefit if used appropriately early in patients not responding to steroids.

We’re going to get into our tail phase of our discussion, our long COVID part. Finally, we have the paper, I could say finally because this was preprint, now it’s published in BMJ. I spent some time going through this. The paper is “Risk of clinical sequelae after the acute phase of SARS-CoV-2 infection: retrospective cohort study,”and this was in the BMJ. This was generated really from a huge data set of 266,586 individuals with SARS-CoV-2 infection aged 18 to 65, so I sort of encourage that we’re looking at a younger group of patients here than some of the other studies.

At minimum, I’m hoping Vincent will post this on Parasites Without Borders for people to link into, but I encourage listeners to go there and to, at minimum, look at Figure 2 in this paper. There’s a few takeaways from this paper, one of them is that 14% of adults aged less than or equal to 65 who were infected with SARS-CoV-2 had at least one new type of clinical sequelae that required medical care after the acute phase of the illness, so we’re seeing about 14% here in the under 65. The people at higher risk were those people that had been in the hospital.

Just a shout-out to some of the authors, actually, a couple of these authors are friends of mine. I work with them at UnitedHealth Group. Sarah Daugherty, we’ve been working on a bunch of long COVID stuff, and Ken Cohen, we published a paper a little while back together. Let’s just hit a little bit about why am I telling you to look at Figure 2. One of the really difficult things is that people who get acute COVID can end up with a number of other clinical sequelae at significantly higher levels. What are those?

Not surprising, interstitial lung disease, the hazard ratio for that is greater than 7.5. This is really troubling. And I know I come back to this a lot, but encephalopathy, this has a ratio of greater than 6 and this is really difficult. You see a lot of really high-functioning individuals who now are having difficulty on so many levels and actually being told, “Oh, it’s all in your head, etc..” Well, I guess it’s all inside the skull. Yes, it is, damage and impact on the brain.

We’re also seeing cardiomyopathy, and that has a ratio of about 3. We’re seeing heart failure, we’re seeing arrhythmias. We’re seeing memory difficulty, amnesia. We’re seeing these people being more than twice as likely to develop a stroke, peripheral neuropathies, a lot of these are small fiber issues affecting gut motility, and other things, so really a tough space and a lot of people are trying to jump in and understand and we’re looking forward to the CDC guidance on this.

I guess I should say we’re still waiting for that really good data on people with long COVID and the impact of vaccines. I’ll say a friend and colleague of mine, Akiko Iwasaki, up at Yale, she used to actually come on Fridays to our Steve Goff weekly lab meetings, so I got to know her then. She has a long COVID study, so people can just email [email protected], if you have long COVID and you’re thinking about getting a vaccine, that’s a great way to connect and then we can start getting some really good data. We continue to see this, anecdotally, which you know, the plural of anecdote is not data, it’s anecdotes, and so we really want to get this quantified. We want to get a sense of who gets better, the timing, etc.

I’m going to close there and I’m going to say, thank you, everyone, for your incredibly generous support, going to Parasites Without Borders, and helping us support FIMRC and all the great work Foundation for International Medical Relief of Children continues to do throughout the world. These are tough times and no one’s safe until everyone is safe.

VR: Time for some questions for Daniel. You can send yours to [email protected]. Patricia writes, “One topic I have not seen anywhere is drug metabolism. I seem to be a poor metabolizer of drugs. I’ve been like this my whole life, even Aspercreme can put me to sleep, NyQuil I’m out for 24 hours, these are just two examples. At age 58, I feel getting vaccinated is important, but I don’t dare try because of how I always react to drugs. If I can handle any, it’s a child’s dosage at best. Can you point me to more info on this? I can’t seem to find any discussion on this topic, as it relates to vaccine, or if the answer to whether it would be safe for me to get vaccinated that would be helpful too?”

DG: Okay, well, I’m going to encourage you to get vaccinated first off, but let me explain what I know. Usually, I tell people, “Oh, these are vaccines. They’re not something that gets metabolized,” but there is a little bit of detail here and I’ll go into what do we know about this. People who are on particular medications that are metabolized by the liver, so the hepatic cytochrome CYP 450 system, we actually can see sometimes and we think it’s cytokine-induced. You get your vaccine, there’s that reactogenicity. Sometimes, if anything, it can increase the metabolism of certain medications and we want to know about stuff like this.

If someone’s on warfarin, okay, no interaction there. Some other medications, what actually is happening here, it’s improving the metabolism, it’s speeding up the metabolism with certain medications. Most of the studies in this area have not suggested that it’s of significant or clinical relevance, but yes, there is a little bit of a subtle issue here. If you are a poor metabolizer, well temporarily, you’re going to be a slightly better metabolizer.

VR: Victoria writes, “I’m the parent of a 13-year-old daughter who has Down syndrome. My family has been careful during the year working and schooling from home, reducing our risk, but this has come at great cost to our 13-year-old’s schooling and social development because remote school has been pretty much miserable and ineffective for her. My household awaits, with great anticipation, the news that we can have our daughter vaccinated when Pfizer is authorized, but I can’t help wonder, will the vaccine be sufficiently effective for people with Down syndrome or is it likely that my family should expect that the vaccine will not offer our daughter substantial protection? I suspect there is scant empirical evidence. What might you predict based on your knowledge of the immune system of folks with trisomy 21?”

DG: This is a great question. We are starting to expand from just the “Oh, how does this group of 30,000 people respond?”– to looking at some of these other populations. We discussed the last time about people with transplants, people with other immune issues. Now, a couple of things I’m going to say, I’m going to say I am actually quite optimistic from what we know about these vaccines and what we know about the immune system that an individual with Down syndrome will get excellent, I’m going to say excellent, and an adolescent with Down syndrome should get an excellent response.

We saw in the trial of adolescents, 100% protection against even a positive PCR test with Pfizer, and that’s pretty amazing. Let’s say that you drop that down to 90%, that’s still really impressive. If it’s not a negative PCR test, is it going to at least be should there be a positive PCR, its lower level? I would optimistically say, I would go ahead. I would get that vaccine. The efficacy looks really impressive. Even if it’s a little bit reduced in someone with Down syndrome because of the issues there, we have a lot of margin of reduction here.

VR: Mike in South Jersey writes, “The day after receiving the second dose of Pfizer vaccine, I developed an irregular heartbeat. I have had symptoms the past six days, which tend to be worse at rest. I have yet to determine if I also have myocarditis. After going to my primary care physician and cardiologist, I was surprised to learn that this is becoming more and more common. Can you please discuss this issue? Do you have any idea what might be causing it? I’m a 42-year-old male who exercises regularly and eats healthy.”

DG: I think this is great, I want to try to put this in context. Right now, we’re getting to the point where the majority of Americans have gotten, at least majority of adult Americans, have gotten at least one dose of vaccine. It’s almost like in the history of every patient when their vaccines were done. It’s pretty soon going to be uncommon that someone was not vaccinated. Do we see myocarditis? Yes. Do we see myocarditis at a higher rate in people that are vaccinated? I’m not sure that’s true.

Speaking to one of my cardiologist colleagues today about some, basically, things they’re noticing. One was the issue, oh, this individual had low platelets. In their mind, they had made a connection. This is being actively looked into, particularly, with the Pfizer vaccine. For instance, do people who get the Pfizer vaccine have a higher incidence of really anything, particularly myocarditis, arrhythmias? So far, we’re not seeing that looking at the vaccine reporting system, looking at all this robust tracking.

We still see what we see. People get vaccinated. They get bitten by dogs. They get bitten by cats. They get in car crashes. They have arrhythmias. Basically, all these things that we see, we still see. It’s not clear that the myocarditis, the arrhythmias are actually at a higher level. Certainly, that doctor will say, “Boy, of the last so many people I saw, 60% of them had been vaccinated,” but you know what 60% of all people have been vaccinated. It’s sort of tricky to actually look at what you’re seeing and then really use a robust system to determine whether or not there’s any causal link here.

VR: That is COVID-19 clinical update number 63 with Dr. Daniel Griffin. Thank you, Daniel.

DG: Thank you so much, and everyone, be safe.

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