TWiV 721 COVID-19 Clinical Update #50

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 20 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 721, recorded on February 18th, 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: This is our Update 50, Daniel. Almost a year’s worth of updates. How about that?

DG: Yes, that’s quite something. Yes, I guess 50 is an important number, but let’s march through. Let’s not make this 50 minutes long.

Start off with my quotation. “In nature, nothing exists alone.” That’s by Rachel Carson from Silent Spring. I just keep using it, bring people back to the fact that we talk a lot about things in the U.S., but we are part of the global community. If we don’t address this virus at a global level, it is not going to go well for anyone. We are part of the world, no walls that are going to keep this virus out.

My three rules, “Never miss an opportunity to vaccinate, never miss an opportunity to test, and never waste a vaccine dose.” Still pains me when I hear that doses are being thrown in the trash because people are worried there’ll be legal consequences.

Let’s go through our stages. The pre-exposure period. There’s a lot of coverage on the CDC guidance on school openings. The CDC, you can go there, there’s a lot to read there. Couple of criticisms people have, is there may be not enough focus on ventilation. For the first time, what I am really seeing is a lot of the school opening plans are introducing testing, and it looks like there’s federal support for testing. Testing saves lives. I know early on, a bit of controversy about testing, and a period of time when some politicians were trying to get people not to test.

I am not talking just about at the federal level, but we’ve moved past that. I think we all now realize, and this is embraced, testing saves lives. Don’t let the testing numbers go down. We need two million tests a day to keep making the progress we’re making, to keep an eye on what’s going on. You got to keep testing.

Active vaccination, a little bit more out of Israel on the impact of vaccination on viral load, and I think this is a little bit better than the data that I discussed last week. I was not impressed with a single CT value change, but this was posted as a preprint.

Decreased SARS-CoV-2 viral load following vaccination. It reminds me when I say that, and Vincent, maybe you remember we had a big discussion, are we going to ever discuss preprints, or are we going to wait till things hit the peer review? I guess we embraced we will be preprint reviewers and discuss the data critically. In this study, they looked at CT values of positive samples collected 12 to 28 days after vaccination. They compared these to CT values of positive samples taken during the first 11 days following vaccination.

I felt this was apples to apples. They reported the differences in mean CT values calculated for these two time periods. Basically, it looked at three different– They looked at RdRp, that’s the RNA-dependent RNA polymerase gene. They looked at the gene E, they looked at gene N. Just to give you a sense, they were seeing here about a two CT value difference, so, decreased from about, or I guess the CT value is increasing, the viral load is decreasing. I got to keep that in mind here. The CT value was increasing by about 2 from 25, up to about 27.

We’re looking at an RNA copy number going from about 1.5 million, down to about 400,000. That’s going in the right direction. We’re trying to build a case, and I’m sure this will come up at the end, about, if you’ve been vaccinated, are you less likely to carry a high level of virus and transmit it to others? I think the data is starting to support that story.

The period of detectable viral replication, I get a lot of people saying, “Dan, where are the antivirals?” I want to say this is an excellent question. We really just have as far as what we think of small molecules, remdesivir, weak evidence, minimal impact.

Maybe shortens our hospital stay by a few days. No compelling mortality data there. But monoclonals, growing amounts of data, and evidence there suggesting that there’s even a mortality benefit as well. There is convalescent plasma, but remember, the compelling data there was on high titer used within the first 72 hours. I had a discussion today at our hospitals, a lot of the centers around the country don’t titer their convalescent plasma.

By the time someone shows up in the hospital, they’re usually past those first 72 hours. When you compare apples to apples here, if you have a choice between convalescent plasma and monoclonals, the data is more compelling on monoclonals. Right now, our best antiviral therapeutic is monoclonals, but don’t miss your window. This is a numbers game, don’t say, “Oh, you look like you’re doing well, let’s wait.” If you wait, you can miss your window. One of the nice little bits of news here is we just got approval that we’re going to be able to start offering monoclonal therapy at our urgent care centers throughout the New York tri-state area, so, improving access.

We’re going to have the ability, through the Catholics, to get it in the ERs, through the Northwell system, to get it in the tents, through the ProHealth Riverside and ProHealth Connecticut, to get urgent care centers, and through United in Research, we’re going to keep doing in-home infusions, and down to 16 minutes per the FDA. I know folks are still taking an hour to get it in there, but we have approval now for 16 minutes.

Early inflammatory phase, there was another interesting paper put up on The Lancet as a preprint. I actually think this is interesting.

This is a paper that I’ve already seen is changing people’s practice. This was a vitamin D paper. Yes, Calcifediol Treatment and COVID-19-Related Outcomes by a group in Barcelona. This followed on that pilot study that I discussed on October 4th, on that TWiV. They’ve done a pilot study. Now, this was the prospective open-label, randomized control trial. They had just under 1,000. They had 930 participants, and they were randomized to either receive oral Calcifediol treatment. That was 532 micrograms on day 1, 266 on day 3, 715, 30. They started this right at the time of hospital admission.

Then the controls were not receiving this, so I jokingly said, I think, in the past, that nobody is going to do a study with a vitamin D deficient control arm, but apparently, they do that in Spain. In the intention-to-treat analysis, 6.5% of the folks treated with vitamin D died, compared to 15% in the control arm, giving us a p-value of 0.001. The adjusted results actually showed a reduced mortality of about 60%. Relative risk, 0.40.

What we’re already starting to see, at least in hospitalized patients if people were not listening to me and Fauci and a few others, and they’re not taking their vitamin D and showing up deficient, a lot of folks are actually starting vitamin D when they get admitted. Just a few basics here, just to remind people, this study looked at Calcifediol treatment, but a lot of us in the U.S. are using ergocalciferol and cholecalciferol. The cholecalciferol is that vitamin D3 that were taking 1,000, 2,000 different recommended doses per day. The ergocalciferol is our vitamin D2 that is often weekly.

Our D3, usually animal origins, so, oily fish, egg yolks, meat. Your ergocalciferol is going to be from certain vegetables. Things get a little bit complicated for us here because we don’t quite have the same formulations used in the study. A lot of us here in the U.S. are just using the vitamin D3, the cholecalciferol, 4,000 IUs per day. I do want to point out, check those vitamin D levels. I had a patient today, maybe he listens to too much TWiV, his vitamin D level was 138 at admission, normal would be less than 80, a 30 to 80 range– 138, that’s too high, so, he and I actually had to have a talk about not taking so much vitamin D.

I’ll say, in some of the hospitals, it’s been fairly standard to give people vitamin D, a thought, maybe a benefit, no significant concern for harm. Some of the hospitals, though, this is new. We had another study, actually, on zinc and vitamin C. This was not as positive. This was the effect of high-dose zinc and ascorbic acid. That’s vitamin C supplementation versus usual care, and they were looking on symptom length and reduction among ambulatory patients with SARS-CoV-2 infection. This was the COVID A to Z Randomized Clinical Trial, and it was published in JAMA.

This was only 214 patients so by the time you break them down, you’re looking only about 50 folks in each group. They looked at basically the amount of days before they reported a 50% reduction in symptoms. Usual care, they’re saying about 4.4. The folks who got just zinc said 4.9, vitamin C, 3.7. The group that got vitamin C and zinc, 3.4. A lot of overlap here, so, no real compelling difference. I mentioned this is a small study, and there was the issue that the folks who got zinc were reporting a metallic taste, dry mouth, gastrointestinal intolerance. The people in the vitamin C group, actually, there was differences in the amount of nausea, diarrhea, stomach cramps. Small groups don’t compel us in any way. More information there.

Another paper on anticoagulation. Here was really the focus, and I think this is an important paper.

It was demonstrating a mortality benefit to doing anticoagulation versus not. Maybe this reminds people of the COVID wars that we discussed about, where we were seeing about 30% of the folks not on anticoagulation having major events. There was a tendency to want to use at least prophylactic and the thought of maybe studying prophylactic versus high dose. This was actually looking at prophylactic versus none. There was a 27% decreased risk for 30-day mortality. Really concluding here that early initiation of anticoagulation, compared with no anticoagulation was associated with decreased 30-day mortality.

They did not see a significant increase in the risk of serious bleeding events in this trial. Just to put this in the context of our other trials, there’s now data to suggest that the optimum dosing for our moderate floor patients is going to be full dose, lower risk of bleeding there. In our ICU-level patients, we’re going to back off a little to prophylactic dosing, just because we have an increased risk of bleeding. This does still leave out a little bit. What do we do with those outpatients? We still don’t have as much data as we would like, so that’s going to be a lot of a judgment call, looking at each individual patient.

I just want to do a deeper dive into the tocilizumab data that I mentioned hot off the press last time. I want to say this has already resulted in the revisions of a lot of hospital guidelines. Tocilizumab has now been reintroduced, and this was based upon the recovery data. We discussed this a bit last time, Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial. As I mentioned last time, this study looked at over 4,000 patients, and the Tocilizumab was given in a weight-based dosing regimen.

If you’re greater than 90 kilograms, you’re going to get 800 milligrams. If you’re between 65 and 90, it’ll be 600 milligrams. Four hundred milligrams if your weight is greater than 40k but less than 65. Then you drop down to an eight milligram per kilogram if the weight is less than 40. Then a second dose in this study was given 12 to 24 hours later, if, in the opinion of the attending clinician, the patient’s condition had not improved. Here, we basically saw that there was a 14% reduction in 28-day mortality, p-value less than 0.007, and about a 20% reduction in the risk of being intubated there, with a p-value of 0.01.

This builds on the REM-CAP data, but I want to be clear on where this fits in. This isn’t, everybody gets tocilizumab. This is a background of steroids is critical. We have a lot of studies showing that if you give the IL-6 receptor inhibitors without a background of steroids, even in the recovery trial, there was a trend towards higher mortality. You don’t want to do that. It also looks like the benefit we’re seeing here is in the early inflammatory phase. We have a lot of trials showing that if you give an IL-6 receptor blocker, so, a tocilizumab to someone, week 3 in that secondary infection, that late phase, that that actually may increase infections, not provide benefits.

What we’re doing here at a lot of our hospitals, I’ll say the Catholic Health System has actually been our standard approach for some time, but some of the other hospitals, they’ve updated. Basically, a person comes in, they’re on oxygen, they’ve been started on steroids, but now they progress to a high level of oxygen support. Then tocilizumab is considered.

Secondary infection phase. Again, I always like to point out the timing of that is, most people with COVID come in without a secondary bacterial infection, but then a lot of folks, we see either they stay in the hospital and then week 3, they have this, or they go out and they come back. In a differential, one of the things that can drive that readmission can be a secondary infection.

Finding the Ferritin-to-Procalcitonin ratio that my buddy Lee Shapiro has championed to be quite helpful, fairly predictive. If you take the Ferritin divide it by Procalcitonin, numbers less than 844, suggestive of bacterial. Numbers higher than that, particularly up in the thousands, suggesting your procalcitonin elevation is being driven by the inflammation.

Our multi-system inflammatory phase. I’m actually going to spend a little time on this because we have a little bit more data now.

I want to point out again, there is an early inflammatory phase, and then there’s this later multi-system inflammatory phase. There’s a bimodal inflammatory nature, and either for some folks, this is a readmission. As we saw with children, this may be the first time it comes to attention. An update on the multi-inflammatory syndrome of children. The number of cases now reported, the CDC is keeping track of this, is over 2,000. We’ve had about 30 confirmed deaths. This is a little bit of ….and this is different, the number, or I’ll say the percentage, of the pediatric cases that are now coming in requiring ICU support, it used to be about 50%.

It’s now greater than 80%. I’m not sure I understand exactly what the difference is with the severity there. We also understand a little bit of these 2,000 cases, the peak of this tends to be in the five- to nine-year-old rage. There now is a nice case definition for the multi-system inflammatory syndrome in children. The first distinction is this is someone under the age of 21. If they’re over the age of 21, it might be in adults, and we see that as well. They have to present with fever, laboratory evidence of inflammation, evidence of clinically-severe illness requiring the hospitalization with multi-systems, so, greater than two organs being involved.

This could be cardiac, renal, respiratory, hematologic, gastrointestinal, skin, or neurological, and no alternative explanation. Then ideally, from the case definition, you have positive evidence for either current or recent SARS-2-CoV infection. You could be doing your PCR serology, antigen tests, or a good story of a COVID-19 exposure within the four weeks prior to the onset of symptoms. The CDC now has a nice link where people can go.

The tail phase, I want to spend a little bit time here. Just before we got on the air, Vincent and I were chatting about an individual with Long COVID who had what sounded like a very negative encounter.

They went to the emergency room, tachycardia, swelling in the legs, continuing to suffer from COVID, and they basically were told, “Hey, this is what your life is going to be like. Get used to it.” Not acceptable. There are a lot of us, I have to say, who are really keeping an eye on Long COVID, taking care of a growing number of patients. I have a lot of frustration here. As I think I mentioned here, we’ve had a lot of research on our vaccines. We’ve had a lot of research on the care of hospitalized patients with COVID. We still don’t have robust data to guide us in the outpatient management.

We don’t have robust data to guide us in the care of long COVID. There’s a lot of centers that really are set up by, say, rehabilitation specialists. Basically, let’s condition these people back up. As we know, with our experience with other chronic illnesses, that’s not always acceptable. A lot of people have post-exertional malaise. There’s a lot of stuff going on here, we’re still seeing increased infections in these individuals months and months after the acute period. Something is going on here, and a lot of us are really actively trying to understand this.

Those of you out there listening with Long COVID, you’re not forgotten. We’re trying to understand and provide better therapies. One of the things that actually we’re quite interested in is, if you get a vaccine, are you less likely to get Long COVID? Some people I know who are younger think about the vaccines, and they say, “I’m not going to die of COVID. I have very low risk of dying of COVID, but I am worried. I might be in my twenties, thirties, forties, if I get COVID, I might end up never better.” We’re tracking those individuals. We’re also tracking, I have a study fired up on this, where we’re looking at people that got the monoclonal antibodies. Not only is that going to keep people out of the hospital, but is it going to prevent people from developing Long COVID? A lot going on here.

Then I will close, before we get to emails, by reminding people to go to Parasites Without Borders, and help us support the American Society for Tropical Medicine and Hygiene. For the months of February and March, we’re going to donate a minimum of $20,000, hopefully, up to $40,000, matching what people send us, to help bring some early-career investigators, scientists, physicians from less developed parts of the world.

Women. We’re going to be sexist here. We’re only going to be helping women, but I think that’s right. Fifteen percent of the leadership in medicine, in global health, is made up of women. There’s an equity issue there, and we want to jump in, we want to make a difference, so, help us do that.

VR: All right, time for some questions for Daniel. If you have some, send them to [email protected]. The first is from Chris. “The CDC is now saying if someone has been fully vaccinated, two weeks after, they do not have to quarantine when directly exposed to someone with COVID.” Chris wants to visit his infant grandson. Neither of his parents are vaccinated, won’t be anytime soon. “If I have to quarantine before I visit, what is the minimum amount of time to ensure a good amount of safety?” Chris has been fully vaccinated.

DG: Yes. Chris, and I alluded to this a little, the CDC talked about someone who’s been exposed, and then saying, “Hey, we’re going to treat people who’ve been fully vaccinated like someone who had a recent infection with COVID.” We’re going to believe, and they are stepping a little in front of the science, but the science is starting to get there, that these individuals are less likely to become infected, less likely to transmit. We know about a 95% reduction in symptomatic. We don’t quite have a solid data on the impact of asymptomatic, but now we’re starting to see lower viral loads.

I’m going to basically give you the information to make the decision here. I don’t think quarantine is going to be something you need to do. You want to continue to engage in low-risk activity. Just treat this as this possibility that you could be exposed, could have low-level asymptomatic, and not be aware of it, or you could have pre-symptomatic. It’s a 95% reduction, not 100%. Don’t forget about testing. Testing is still another thing. We talk about the Swiss cheese approach, multiple layers. You got your vaccine, you get your test, you look at different exposures and how to do things safely.

But I think that we need to start basically being honest and not underselling the vaccines. The biggest risk for older individuals was that they would get COVID and die, but there’s been a tremendous burden, a tremendous social isolation. That would be my advice on this. Vaccination is great, but don’t forget about testing.

VR: Javad writes, “As a primary care physician who works both in the clinic and hospital and is faculty at both the med school and residency, I’m disappointed at the lack of guidance there is for COVID management and primary care. There is clear guidance for how to manage COVID patients in the hospital, based upon a fair amount of research. There’s almost nothing for primary care doctors.” Javad goes on to talk about monoclonal antibodies, which are underutilized in his system at the University of Minnesota.

“Even though we have far more COVID in the community than in the hospital, basic questions of whether to use anticoagulation and/or aspirin have not been answered. Therapeutics that are logistically more feasible are not known. A small study showed fluvoxamine could be a game-changer in terms of limiting hospitalization, but a larger study is in its early stages. What would you recommend in terms of outpatient management? We are doing a lot of testing and monitoring, but it would be nice to have better research and guidance as to what more can be done.”

DG: Javad, you bring up some excellent points. First off, say hello to my buddies there at University of Minnesota. It’s a fantastic place, by the way, except it’s cold. I spent a winter visit there in the end of June once joking about that. But no, you are completely right. What the COVID pandemic has really pointed out to us is what a poor system we have for rapidly studying outpatient therapies. The monoclonals almost didn’t make it to market because they were studying them in week 3 ICU patients. We really need to change that.

We need a robust ability to study outpatient therapeutics and to point out 80, 90% of folks with COVID are managed in the outpatient setting. What do we do? There is limited data. Let me go through what there is. A person gets diagnosed, one of the first things, you mentioned monoclonal antibodies, that’s critical. If the person qualifies, and hopefully, this is going to expand as far as access, monoclonal antibodies are a game-changer. We do not recommend starting steroids in that first week, but I’ll tell you, in the New York area, a lot of times when you get to week 2 when people start to drop their sats below 94, we’re starting steroids in the outpatient setting.

We’re actually doing home oxygen and pulse oximeter. We have actually programs where we’re managing a large number of patients that, in other parts of the country, probably are in the hospital. What about anticoagulation in that context? Is it aspirin? Are we using things like the Eliquis or Xarelto? Gave you some brand names there, I apologize. In some situations, yes, we do have some limited data on aspirin providing a benefit as well, but no, you were totally right here. I saw the SSRI study, the fluvoxamine study, and that is very interesting.

Where’s the rest of the data there? Where’s the data, as I think we’ve joked about, of giving people vitamin D and seeing if that keeps people out of the hospital? These are inexpensive therapies that we would love to have the answers to, and we don’t. It’s a year later. I see all this data coming out of the U.K. What would we do without the U.K.? We wouldn’t know the benefit of steroids, and we wouldn’t know the benefit of when to use toci. Yes, we need to do a better job.

VR: William writes, “Is it safe to receive COVID vaccine if you are incubating COVID-19 or ill with COVID-19?”

DG: William, we don’t recommend vaccinating people if they’re ill with COVID-19. Basically, we’re treating them with other therapeutics. We’re waiting until they get better. Then the CDC is saying there’s no minimum time to wait. Once you get over COVID-19, don’t miss your opportunity to immunize. If you wait three months like I know some people recommend, I feel like you’re missing that opportunity, and who knows what that person is feeling like in three months? Maybe they don’t want to get vaccinated, then you’ve lost that.

We certainly have seen a lot of folks who come in, they don’t get tested, they get their COVID shot, and they were incubating COVID. Actually, a woman I’m taking care of today, and as I expressed to her, most of the patients that I’ve seen, unfortunately, I’ve seen a lot of folks where they got their COVID shot, three or four days later, they’re not feeling well. They’re thinking, “This reactogenicity, it’s just a little bit rough.” Then they get a test, and they realize, “No, I actually was incubating COVID when I got vaccinated.” These people, I have to say, tend to do quite well.

I don’t know if it’s that we’re giving them a nice boost of the spike protein response, but when I’ve discussed with colleagues, they’ve shared similar experiences. We don’t intentionally vaccinate people who are incubating COVID. I’ve actually encouraged a lot of the centers, particularly with the high rates that we have, of testing people when they come in for vaccines if possible. Too many situations where a group comes in and everyone gets vaccinated, and one of those people in the group has COVID. Then they find out a day or two later, and then we know everyone there got COVID riding to and from in the car. So, I’m going to encourage people to continue to test.

VR: One more, Daniel, from Stefan whose mother has had a long difficult problem with COVID. Starting out on Long Island, in fact, and has taken a long time to recover. Now, he’s in Florida, where the doctors say she can be vaccinated, but he’s not sure. She’s suffering from PTSD, has difficulty breathing. He wants to know; can she get the mRNA vaccine? Should she wait for J&J? He’s heard about people in Europe, frail seniors in Europe passing away after receiving the mRNA vaccine. In Florida, he’s worried that she’s going to get infected if she’s not vaccinated. What do you think, Daniel?

DG: No, these are excellent questions, and I think you lay it out. I’ve certainly seen some fairly frail older individuals, who I say, the difference between you and me, with reactogenicity, may be whether or not we make it to work. With some individuals, the reactogenicity may be whether or not they continue to survive. A lot of people have significant oxygen requirements. They have pretty severe disease. I’ve actually seen a few people get vaccinated actually end up in the hospital for a few days because the reactogenicity put them below that level.

This is not one of those where I just say, “Oh, go ahead and have her do it.” You want to have a conversation because this is a risk-benefit here. If she gets a second bout of COVID, and we certainly know people get reinfected, it’s a question of what percent, how is she going to do when you describe her getting a second infection? You want to balance that against the reactogenicity. The reactogenicity is a couple of days of, and in a person who’ve had prior COVID, pretty significant reactogenicity. Probably going to have fever, probably going to feel crummy, probably going to have a little bit increased breathing.

No, this is not a straightforward decision. I think this is one of those reasons why I’m not a huge fan of the convention center mass vaccination site. This is an individual, ideally as you are bringing up, who has this conversation with her physician, with her family. Then if they’re going to be a progression to get the vaccinations, this is someone you want to keep an eye on. Mather Hospital, my mother was there recently, out in Port Jefferson.

VR: Yes, Port Jeff, right.

DG: Not sure why you went to Florida.

VR: That is COVID-19 clinical update 50 with Dr. Daniel Griffin. Thank you, Daniel.

DG: Oh, thank you. Everyone, be safe. We’re almost there. Things are getting better.

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