TWiV 704 COVID-19 Clinical Update #44

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 08 January 2021

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

VR: From MicrobeTV, this is TWiV, This Week in Virology Episode 704, recorded on January 7th, 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: Clinical update 44, the first for 2021, Daniel.

DG: It is and I’m hoping that this is a better year.

VR: I was just going to say, Daniel, is this going to be a better year?

[laughter]

DG: Yes, it will be.

VR: Let me put it this way: is it starting off in a better way? [laughs]

DG: No, no, it is not. It’s arbitrary that 2020 ended on a specific date but the pandemic doesn’t respect that. Let me start with my quotation and then we’ll get right back to how bad things are. Maybe as I read this, people will recognize it. “I will respect the hard-won scientific gains of those physicians in whose steps I walk and gladly share such knowledge as is mine with those who are to follow. I will apply for the benefit of the sick, all measures that are required avoiding those twin traps of overtreatment and therapeutic nihilism. I will remember that there is art to medicine, as well as science, and that warmth, sympathy, and understanding may outweigh the surgeon’s knife or the chemist’s drug. I will not be ashamed to say ‘I know not’ nor will I fail to call in my colleagues when the skills of another are needed for a patient’s recovery.”

VR: I know what that is and I’m not a doctor. [laughs]

DG: Vincent, what is that?

VR: The Hippocratic Oath.

DG: It is. Now, this is the modern version and this was actually written in 1964 by Louis Lasagna, the Academic Dean of the School of Medicine at Tufts. It’s updated. If people ever go back and read the original, it’s a little interesting, it’s not what we think of. I wanted to throw that out there.

VR: Your background has changed a bit. I see some viral flowers, right?

DG: Yes, this is actually a gift over, I guess, this shoulder. I’m backwards so this shoulder. Let’s see if I can . . .

VR: No, it’s the other shoulder.

DG: [laughs] But over my shoulder is a bouquet of pathogens and this was actually created by my wife’s youngest sister, Genevieve. It’s got– there’s the coronavirus that perhaps people recognize in there, there’s HIV, there’s syphilis, there’s tuberculosis, we’ve got Yersinia pestis, it’s a whole bunch in there.

VR: I like it.

DG: People always wondering how I got the books up there, but I think the books have all fallen, right? They’ve all fallen off.

[laughter]

VR: It’s a good thing. It’s a good change for the new year, Daniel.

DG: Yes, they’re on the floor. People probably know that things are tough and it’s really hard for us to take care of patients and provide the same level of care when numbers rise. The latest reports I think people have probably heard reminded me of a conversation that, actually, it was Rich and Allen were reaching out with words of advice, things to do when we were running out of oxygen in New York. I don’t know if people remember that. I know Northwell has been in the press, sort of negative stuff lately, but one of the things that they did at some of our local hospitals is they really upgraded the oxygen system.

We have a lot of oxygen supply capacity that we did not have a year ago. A lot of things that were happening a year ago, we were running out of oxygen, we’re actually wheeling in mobile tanks to some of the rooms to keep up with the demands. We actually got to one point when we were discussing, “Maybe we’re going to reach out to the aviation industry, out to the airports, what can we do to get more oxygen?”

Right now, at least in New York in some of the hospitals where I’m working, people thought ahead and they put in the money, they upgraded the oxygen. We’re able to keep a lot of people off of ventilators, we’re able to keep people’s oxygen at a good level by doing a lot of high-flow oxygen delivery techniques that we couldn’t do before, but this requires a lot of attention. I mentioned the art of medicine. There was a woman the other day and the nurse was calling out, “I need a doctor.” I went in and it was an older woman, she’s actually one of the other infectious disease doctors, Dr. Fatima Johari was taking care of her, an excellence, nice to have the help of such high-quality colleagues.

This woman had had the BiPap on, which is somewhat suffocating. She’s an older woman and she’s frightened and she feels ill and she’s alone because of the isolation of the COVID. It really was a question of me sitting there holding her hand, getting her to take deep breaths, getting her to relax, getting her to allow the oxygen to stay on. We still need to do that. These are human beings. You can’t just check off a box and walk out of the room and have systems and things take care of them. They need people at the bedside.

As the numbers rise, how are you supposed to hold the hand of a frightened woman requiring oxygen and this claustrophobic-feeling device when you’ve got so many other people? As we’re seeing the horrors of LA, where they’re telling the ambulances, conserve your oxygen, because if the person requires too much oxygen, let’s triage, don’t bring them here. It’s really, I have to say, well, it is very troubling just to say that. Numbers are bad here.

One of the things that I point out, one thing that really was devastating in the first wave here in New York, about 50% of the deaths, about half of the people coming into the hospitals were coming in from nursing homes, from group homes. We published on this. A lot of people have asked, “How do you keep those people safe?” A lot of them died during the first wave. We’re not really seeing those. In the first wave, we had about, say, about 80 when we maxed– about 80 community-dwelling people with COVID, we’re now up to about 90 or 100 community-dwelling at one of the hospitals where I was actually this morning.

We’re seeing more of the community, but we’re not seeing those nursing home individuals. We’re starting to get them vaccinated, we’re keeping them safe, there’s testing other measures. We’re not sending infected, infectious people into those settings. Well, we’re going to probably pass 4,000 deaths per day this month, but we were pretty darn close yesterday. We’ll see what the numbers are today. Things are not going well.

Now, why did I start off with the Hippocratic Oath? It’s because I wanted to bring us back to, I think, the paradigms I talked about, the eminence, the vehemence, the eloquence, the diffidence, the nervousness, and then the evidence-based medicine. But I also want to throw a second thing in that I think people will maybe think about and maybe they’re starting to already get this flavor as I talk.

There’s actually two splits that I’m going to say in practice style. One is derived from Hippocratic philosophy, but as you may have noticed, it was not in the Oath and this is the, “First, do no harm,” the primum non nocere. That’s really this idea of, don’t do something unless you know it’s going to make a difference. There’s a second style and I want to be respectful, which is, if we think something can help, let’s go ahead and try it. Now, we’ll say in calmer times, the less is more, the “do not treat your patients with untested therapeutics” has been more of the common approach, has definitely been more of the academic approach. This is the philosophy behind having an FDA, restricting the use of prescription medications to highly trained licensed professionals.

You certainly wouldn’t take anything off the bench, no concoction, nothing that you think would work, and then put it into a patient without doing safety and other trials, but there’s a gray area. A lot of the medicines that we use, we’ve been using for many, many years, but never really actually doing those randomized control trials that we have required or set or are the gold standard. I clearly am of the school where I respect the randomized control trials, but I just wanted to point out, there’s two different styles here. I learned from actually watching both styles. There certainly are a lot of individuals that try things at the bedside, and I watched that and learned from it. Sometimes this actually leads to us going ahead and doing those randomized controlled trials.

I just wanted to throw that out as we started because we have some new information and I’m going to jump into a lot of vaccination arms here. One thing I want to talk about is passive vaccination. What are the two types of passive vaccination that we know about? Well, I’m going to get to monoclonal antibodies, but we had a study out of Argentina funded by the Gates Foundation, Early High-Titer Plasma Therapy to Prevent Severe COVID-19 in Older Adults. This was just published in New England Journal of Medicine. I want to say this was done the way I think going back to March, April, convalescent plasma should have been studied.

What they did is they took convalescent plasma, they identified convalescent plasma that had high-titer neutralizing antibodies, and they gave it early. They gave it within the first 72 hours. This was a randomized, double-blind placebo-controlled trial of convalescent plasma with high IgG titers, neutralizing antibodies against severe acute respiratory syndrome coronavirus-2, SARS-CoV-2, in older adults given within 72 hours of the onset of COVID-19 symptoms.

They’re still in that first week, they’re in that critical viral replication window. One hundred and sixty patients underwent randomization. Severe disease developed in 16% people with convalescent plasma, 31% in people that got placebo. A relative risk reduction. Basically, about by half, by 50%, and they didn’t see any significant adverse events, which makes sense. You’re giving this to healthy outpatient people that have not gone into the second inflammatory phase.

I think this finally builds on trends that we saw on a lot of other trials. The idea that high titers, neutralizing antibodies given in the appropriate window, not giving it late, all the issues that we saw there. Hopefully, this is going to guide people who are looking at using convalescent plasma. Many parts of the world, the monoclonals I’m about to talk about may not be available. We talk about convalescent plasma being a resource-intensive therapy, but it’s not quite as expensive as the monoclonal antibody. Let’s go into the next passive vaccination area. I have some I’ll say, really, I think positive developments here.

Bamlanivimab, that’s really the monoclonal antibody that were being used the most. That’s the Eli Lilly product, the Regeneron product also has EUA. Hasn’t quite got as much attention but the Mayo Clinic which has treated over 2,000 patients, and Houston Methodist, which has treated over 1,000, they’re doing about 70 patients a day there. They share their experience. A lot of clinicians were concerned about monoclonal. It’s got EUA with just looking at 100, 200 folks, little over 200 folks in each of those trials. People were saying, “How can you really go ahead and make this standard of care without more experience?” Now we’ve had thousands of people, a post-EUA experience, not in a formal trial.

Here the reports were a very similar safety profile. Actually, went over this with the people at Eli Lilly about a week ago, and that’s what we’re seeing at the Mayo in Houston and about a 70% reduction in people progressing to require any hospital-level care, any oxygen, and ER visits. I look at this, I say this is pretty impressive. Here is a therapy– steroids, what, 2% mortality benefit? Here’s a therapy that if you give this to people in the first week of illness, earlier the better, about a 75% reduction in those people going on to require any medical care, keeping these people out of the hospital.

The Mayo people actually suggested that they were starting to see evidence of decreased mortality, and actually suggesting that this will eventually lead to a peer-reviewed publication. I think that’s exciting. I’ll throw in here the issue that we’ve seen across the board. It’s just like the vaccines. It’s only 20%, 30% of the doses are getting to people, the rest of them are sitting there. We just opened up our United in Research. I’m going to be doing a– It will actually be a trial. Seventy-five hundred individuals will get Bamlanivimab and we’ll actually get more data.

Really understand the timing, the safety profile, and the efficacy of these therapeutics. Find out and look into this more and make sure that this is something that if you feel like it’s appropriate for your patients, you know how to access the programs.

All right. The early inflammatory phase. I’ve skipped right over the vaccines but let me throw it in here before we get there. The whole idea is to keep people from even getting to this point. The vaccine rollout has been incredibly frustrating. I think that people have heard about this. Only 20% to 30% of the vaccines that have been distributed have gotten in people’s arms.

I was having a conversation today about the latest– Instead of asking, “How can we help?” It’s, “We will punish you if you don’t do a better job.” I’m not sure that’s helpful.

We shared some of the experience about when ProHealth received the vaccines, how basically by the end of the next day, 90% of those were in people’s arms. I have to say, this was not easy. We were told that eventually, we were getting vaccines. The vaccines arrived. That’s how I knew they were coming. No one picked up the phone the day before to say, “They’re in the mail, they’ll be there tomorrow, they’re being shipped.” I’m sure that occurred. Really, it was Tuesday, 1,200 vaccines just showed up and then we were basically trying to get those in arms. It was the week after Christmas, a lot of people are on vacation, it’s a challenge.

I think we need to do a better job. We’ve really cut the Departments of Health out of the equation here. This is what they do. They were ready. They were ramped up and ready to go. We need to do a better job there. I’m just going to leave that. If people are listening, we all want to do a better job. The hospitals are not failing to vaccinate on purpose.

Instead of governors reaching out and saying, “We’re going to fine you,” why don’t they reach out and say, “How can we help make this happen? Are there HIPAA issues or is there red tape in the way? Do you need– issues? Do you need help getting IT stuff uploaded? What do you need? Let’s make it happen.” Because I’m sure there are some IT workers and other folks out there who are ready to help. My request, change the paradigm if you can, and maybe all our listeners can help push that forward.

The early inflammatory phase, I mentioned before we’re running out of oxygen, what do we have? Well, we do have Remdesivir and a little subtle change here. I don’t think any of us have gotten more and more excited about efficacy, but there have been several studies now saying you don’t really have to worry about renal function. This is being given to people with end-stage renal disease, people on dialysis. It looks like it’s safe in people with renal disease, it looks like it’s tolerated in people that have pretty significant LFT abnormalities up to 10 times upper limit of normal.

At this point, I’m not saying we have any more efficacy data. I’m just saying that we no longer have to not give it if there’s a renal function issue or LFT issues. I’m going to tell people they should listen to TWiV 703, Vincent, because I think you did a great job. The group did a great job. I was going to spend a little time talking about CT values. I’m just going to talk a little bit about CT values. Not all our hospitals, as I mentioned, have access to this. Some of the machines don’t give CT values. You could save a little money and buy a “yes or no” machine. There were some interesting studies that came out that were talked about.

One of the things is that someone comes in, and timing again matters, we’re not looking at peak-level virus. We’re saying seven days out, we’re saying the time at which someone decompensates, and someone shows up at the hospital, if the people have a very high level of virus at that point and they have yet to mount an antibody response when they’re sick enough to require hospitalization, those people are much more likely to die. We’re looking at a patient today in the ICU who I do not expect to survive, who came in with the PCR positive.

It was into the second week. Antibodies had not developed yet. These are people that are not doing well. How does that help us clinically? I don’t know if it does. Some of the things we’ve seen is that people that are going to do poorly tend to decompensate earlier. Some of my discussions were well, it makes sense the virus is still high because they’re coming in earlier. You come in at day 14, I expect a lower viral level, I also expect there to be enough time for the antibodies to develop. We’ll learn more about that but this is potentially now that we’re talking about CT values, something that’s going to help us on the tail end.

I do a lot of consulting and I’ve people know about this for the entertainment industry and sports. I had always been a zero-tolerance, but now with CT values, we actually had a discussion that if both CT values– Because there’s often two primer sets. If both CT values are greater than 34 and the person has been well for more than, we’ll say, 20 days to be conservative, I really think that that may actually be reasonable for us to start looking at, at least for me, to start loosening up my zero tolerance for some of those settings.

Secondary infection phase. There was a Tuesday morning conference at Columbia and first, it was the pulmonologist, then it was the infectious disease physicians, and they were doing some case reports and it was a discussion about invasive pulmonary infections. Aspergillosis, that’s one of our molds that we worry about.

It’s interesting. I’ve seen several studies and I always hate when they throw in the judgmental word “low” or “high”. There was a recent publication, Occurrence of Invasive Pulmonary Fungal Infections in Severe COVID-19 Patients Admitted to the ICU. They said, “We have seen very few. Only 4.8% of our patients have a fungal infection.” Well, one in 20, I’m not sure I would say very few. Other series have suggested higher. We have not seen that many in the hospitals where I have worked.

We have seen some, but this is just when you’re in that secondary infection phase. Not only are we worried bacterial infections, now we’ve seen more and more multi-drug-resistant bacterial infections. You put them on what we thought was broad-spectrum antibiotics, and actually, it’s ineffective because of the rising rates from the antibiotic overuse, but you also have to be thinking about fungal infections as well. Discussion about sending off the Fungitell, the Aspergillus galactomannan serum test as well as BAL specimens to try to sort all these out.

Got a very interesting call today, which hopefully I’ll get more development on going forward, but an individual at one of our local hospitals who sounds like he is being admitted with a multi-system inflammatory syndrome in an adult, a gentleman in his early 30s. I’m also concerned that this person may actually have a strongyloides hyper infection as well. We’ll get some interesting things there, but that’s just something that we see.

Often people leave the hospital and then they come back in week three or four with just sky-high ferritins, D-dimers, massive amounts of inflammation, and the challenge to sort out is, is this someone that you treat with IVIG and steroids, or is this someone who has a massive infection? There’s overlap here. You want to try to somehow make a really tough decision here and we’re working with the CDC and the physicians there. Hopefully, that’ll end up with a positive outcome in this young gentleman.

The other thing that I want to close on is to talk about long COVID. I make sure I always talk about this. I’ve been doing that since I think about April. There was a recent study. Cognitive deficits in people who have recovered COVID-19 relative to controls. This looked at over 84,000 individuals. What I really enjoyed about this is the fact that you were able to see that the severity of disease was predictive of the severity of the cognitive deficits. People who were sick enough that they ended up on a ventilator.

The cognitive impact in them was basically equivalent of about being 10 years older. Have an IQ drop of 8.5, but on a specific testing, you were seeing cognitive deficits, even in people that had mild out-patient disease, not quite as severe. The severity of your disease, whether or not you have significant respiratory symptoms early on, significant amount of oxygen support, whether or not you’re ventilated. The sicker you are, not only the higher likelihood you have of getting long-term cognitive deficits, but also predictive of more severe cognitive deficits.

A little more data on the loss of taste and smell. We’re actually seeing about 86% of people by six months are getting their taste and smell back. That means about 14%, 15% of people six months out still are chewing on cardboard. I’ll end it there. I want to try to keep it a little short today. I ask you to continue to come to Parasites Without Borders and help us support the Peace Corps, their HIV and AIDS programs. I just want to point out, we’re immersed in COVID, we’re drowning in COVID, but we come out the other side of this, we have so many other issues and we’re hoping to be here to help educate and support all these other causes.

VR: All right. Daniel, three quick questions. One is from Dr. O’Brien who writes about your update on the use of “BamBam”. “In the first week to lower the incidents of hospitalization, when I reached out to our local hospital officials, they seem to be limiting this treatment to very high-risk patients. Could you give us further information about the specific criteria for emergency use of this drug? My staff members seem quite sick at home, but do not meet the criteria set forth by the hospital. It seems to be that ‘BamBam’ might be beneficial in a much wider group of patients sick with COVID-19.”

DG: I share this. This is like the vaccines. We’ve made it so hard to access things that no one gets them so they sit there on the shelf. Some of the hospitals, I’ll say in Minnesota, for instance, the experience I had there was that they’re basically trying to give out as much per day as it is coming in so it’s not just sitting there. They will first target the people that are highest risk. That would be people who have a 10% or higher likelihood of ending up in the hospital. This woud be individuals who are 65 and older, 55 plus a certain list of comorbidities. There is a Bamlanivimab FDA fact sheet which is available online to look at. I’d glance at it.

The third category is very complicated. It’s any of the following, and it’s a long list of severe diseases which significantly increase your chance of ending up in the hospital. They go through that triage. I think it makes sense. This is a therapy that the reason it has EUA for the 10% or higher risk of hospitalization is that’s where it makes sense, but it would seem to me rather than letting it sit on the shelf, it is probably beneficial in people beyond that group, and I’ve actually seen people outside of that group get it very quickly bounce back, quicker than we would expect with the natural history.

Then again, as I started off with my evidence-based medicine, that population was not specifically studied so you’re stretching it a little bit, but it tends to be a very safe therapy. As we move forward with more studies, hopefully, the use of this will expand.

VR: All right. The next email is from Alan who writes about his wife who has severe asthma and some years ago in preparation for a chest X-ray, she was given intravenous iodine contrast and she went into anaphylactic shock and they had no idea that she was allergic to this contrast agent. He asks, “How are we supposed to know if we are allergic to any of the ingredients in the vaccine if there are a bunch of compounds that we have no clue about? More specifically, are any also found in iodine contrast?”

DG: This is an excellent question. When the MMWR just came out with recent report on the side effects seen with the vaccines, and reported about one in 100,000 people are having an anaphylactic reaction. That means 11.1 people in the first million that got vaccines– these people were treated with Benadryl, some of them received epinephrine and then all recovered.

This is not a vaccine that has zero risks. It is an effective agent, but who had those reactions? The initial recommendation, the current recommendation is someone who’s had a prior significant vaccine reaction and that would be an anaphylactic reaction to a vaccine, someone you’d have heightened concern about. It’s not a food allergy, it’s not an iodine allergy. I’m doing a talk for an allergy group next week.

There is a paper that came out. It was actually published by a group out of Harvard. Looking at PEG 2000, Polyethylene Glycol. The idea is that maybe what is triggering these immune reactions, these anaphylactic reactions, and there is some investigation into trying to figure out if there’s some way to do maybe skin testing to figure out who that one in 100,000 person is. I have to say the way I weigh in on this is the recommendations, all the sites giving vaccinations should have a vaccination reaction kit which involves Benadryl, the epinephrine, which is supposed to have enough for three people at each site. Also, intravenous formulations of the antihistamine as well as the oral, and Famotidine. Intravenous, other H2 Blockers, and the ability basically to get someone to a higher level of care as needed.

We’re talking about a million people vaccinated, 10 reactions. It’s actually quite uncommon, but you need to be ready for those, because again, if you have this reaction, you have this reaction.

VR: Okay. Our last question is from Laura who writes about her 66-year-old mother who was recently updating her advance medical directive and included a note saying, “If she were to contract COVID-19, she does not want to be placed on a ventilator as she believes she would be unlikely to survive and regain the ability to live a full independent life. I did a quick search to see if I could find any literature on long-term outcomes for COVID-19 patients on ventilators and I found one study considering whether patients would survive to discharge, but no other end points. I’d appreciate your insights on longer term outcomes for ventilated patient either from the literature of if research on the subject has not been published. Your impressions from your own patient population.”

DG: Our own patient experiences were actually published. Early on, you saw data out of New York Presbyterian, Columbia, you saw data out of NYU, you saw data experience at Northwell, so the different hospitals where I see patients. The initial experience was that people who ended up on the ventilator, their early experience was less, like single-digit survival then got up to15% survival, but consistently people who end up on ventilators have a very poor prognosis. They have a limited chance of surviving. It continues be—we, as much as possible, try to keep people off the ventilators. Our experience, which I think is consistent with the literature, is once you get on the ventilator you’re probably not going to survive.

I say probably, but again each individual case– people make these advanced directives but you want to look at the whole picture. What’s the age in the individual, what are the comorbidities? Now we’ve talked a little bit about the ability to look at viral levels and antibodies and inflammatory markers and neutral lymphocyte ratios, so you can even make this more customized to an individual. That’s potentially another way to nuance it to look– talk to your mom’s healthcare provider about specifically for her, which is really what it is.

At this age, maybe this is one of the people that would survive and come off the ventilator. You want to have those discussions. Make sure that, as we say, your goals of care are consistent with the treatments.

VR: Daniel, if you do survive after a ventilator, do you have any long-term issues?

DG: In most cases, I think we’re seeing, yes. As I discussed today, high incidence of about a 10-point IQ hit on average.

VR: Wow.

DG: You’re seeing long-term disability. People who survive, and I think this is really important, just surviving COVID doesn’t mean you bounce back to 100%. A lot of times it means now you’re going to have significant morbidity.

VR: Got it. That’s COVID-19 clinical update number 44 with Dr. Daniel Griffin. Thanks, Daniel.

DG: Oh, thank you so much. Thank you everyone. If you can push, help us get those vaccines into arms. Thank you so much.

[00:32:18] [END OF AUDIO]

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