TWiV 877 COVID-19 Clinical Update #106

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 19 March 2022

pdf of this transcript available (link)

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 877, recorded on March 18th, 2022. I’m Vincent Racaniello and you’re listening to the podcast all about viruses. Joining me today from Panama, Daniel Griffin.

Daniel Griffin: Hello everyone. I apologize for my circumstances. I’m doing this from a relatively remote part of Panama. Hopefully, the audio, the sound quality, the video, and everything goes well, but let me jump right in. I will start off with a quotation, which I actually think is quite appropriate for where I am and this is a quote from Ronald Ross, who people may know who listen to This Week in Parasitism, “The Panama Canal was dug with a microscope.” I just love that. Just, how important science is in a lot of human ventures and I think, unfortunately, we forget that, but yes, I am still down in Panama but let’s jump right into it because actually, we have a lot to cover.

Case numbers and deaths continue to decrease in the US as a whole. As our listeners may have heard, the case numbers have started to rise globally again. I will say in New York, the numbers have actually plateaued, they are no longer dropping. We’re actually seeing a little more than 2,000 cases a day. We’ll see where that goes, but we did hear this week that the wastewater monitoring system is starting to see a rise in the presence of SARS-CoV-2 RNA in about a third of its samples. We’re always getting data a little bit late so March 1 through 10. This is a rise from a low number, but nonetheless, it is a rise. It is going in the wrong direction. Let’s get right into the section that will promise to give us lots of hate mail.


DG: A bit of news starting to be shared about ivermectin. Initially, I thought this was the COVID-OUT trial, but no. A little bit of press actually, Sarah Toy at The Wall Street Journal, who I’ve interacted with previously, excellent writer. She put together what I think is a pretty good article. When we get the actual data, as opposed to a Wall Street Journal article, I promise to discuss that.

We recently heard the results of a study looking at ivermectin therapy in 1,358 adults who visited one of 12 clinics in the Minas Gerais region of Brazil with COVID-19 symptoms and confirmed COVID with a positive test for SARS-CoV-2. To be enrolled, you needed to be at risk of having a severe case for reasons including history of diabetes, hypertension, cardiovascular disease, lung disease, placebo controlled randomized trial, where half the patients got placebo, half got ivermectin.

The researchers analyzed the data in three different ways. They looked at data from all patients, an analysis one. Then they analyzed the data from patients who received ivermectin or placebo 24 hours before they were hospitalized. A third review looked at data from patients who said they had adhered strictly to their dosing schedule. Really I’ll say, not just an intent to treat, but those who actually got therapy. In each scenario, they found that ivermectin did not improve patient outcomes. As mentioned, we get the actual data, I will return to this and we’ll discuss it in more detail but we have some more data on the horizon. The COVID-OUT trial that I’ve discussed previously looking at the medications, metformin, fluvoxamine, and ivermectin is completed. It is analyzed, this has been submitted for publication.

Once these results are available, I’m going to discuss those as well, and don’t forget ACTIV-6 is still enrolling. If you go to COVID-OUT, it redirects you there. We are getting very close to really putting all the nails in the lid of this so we can really have solid science. Let’s be honest, I know a lot of people are excited, but when the science is clear, we need to move in that direction. There are some things you don’t just know they’re true, you need to do the science and then you need to be honest with what the science tells us.

All right. Children, COVID and other vulnerable populations. Children are at risk of COVID. The number of COVID deaths in children is actually rather concerningly high in the US. Let me go into an MMWR Early Release: “Hospitalization of Infants and Children Aged 0-4 Years with Laboratory-Confirmed COVID-19, COVID NET, 14 States, March 2020-February 2022.”

It’s this pretty huge time period. They reported that during Omicron variant predominance beginning in late December 2021, US infants and children aged zero to 4 were hospitalized at approximately five times the rate of the previous peak during the Delta variant predominance. Infants aged less than six months had the highest rates of hospitalization. I was just talking to one of my colleagues who’s down here in Panama with me, what is going on in Hong Kong? How can all these people be dying? Because I have heard from mainstream media, that Omicron is so mild.

I think it’s really hard when you look at the data to continue to say that. What makes infection with SARS-CoV-2, what makes COVID-19 mild is immunization. Unfortunately, there are still people in our populations who do not have either the ability to be vaccinated or the ability to get that response. Moderna vaccine for children, there’s been some teasers. We’re waiting to hear. Potentially Moderna might beat Pfizer to the punch. They have been studying higher doses in younger individuals. As soon as we have that data, I will share that as well. I do also want in the same sections share the investigation, “Comparison of Seroconversion in Children and Adults with Mild COVID-19.” This was published in JAMA Network Open, and these are the results of a small cohort.

I’m not sure how much one will want to make decisions based on this on a cohort of 57 children, 51 adults. Now, the proportion of children with detectable seroconversion to SARS-CoV-2 was half that found in adults. These are confirmed infection. A lower proportion of children had seroconversion when checking IgG compared with adults, 37% versus 76%. This is worrisome on a couple of levels. If this pans out in larger investigations, one is the idea that you may be seeing more reinfections in children, some signal to support that, but it may also mean that when you do a blood test, may be more unreliable in documenting prior infection. We’ll need to follow this, but I want people to think about this. We are studying our vaccines, we’re trying to create this protection for the youngest children.

This may be a population with just serial repeat infections, even more than we’re seeing in adults, which we certainly are seeing with Omicron. Pre-exposure period testing. Here I want to point something out and this was something that was brought up well, in a few recent discussions. You cannot sequence what you do not collect. If we are not testing people, if we are looking at variants, this is going to get ahead of us. As I will point out a little bit later on, the BA.2 stealth variant when it comes to therapeutic is actually increasing quite a bit in incidents. The pre-exposure period, masks, there’s been a lot of discussions about this. I just want to point out when a politician lifts those mask mandates, that does not mean that you have to take off that mask if you want to use it to protect yourself.

The choice is there. Don’t be bullied by some politician into taking off that mask if that’s a decision that you feel is right for you. Active vaccination, it seems like we always have something to discuss here. There have been some recent concerns regarding effectiveness of vaccines in adolescence based on a pre-print. Let me mention this MMWR report. “Effectiveness of 2-dose BNT162b2” – so that’s the Pfizer-BioNTech mRNA vaccine – “in Preventing SARS-CoV-2 Infection Among Children Aged 5 to 11 Years and Adolescents Aged 12 to 15 years, the PROTECT Cohort.”

This came out as an early release, and this is worth going through in some detail. I’m trying to keep these shorter, so I apologize. At a high level, the vaccines work. Now, going through this study. These are the results of the PROTECT study. PROTECT is a prospective cohort study monitoring SARS-CoV-2 infection among participants aged 6 months to 17 years in jurisdictions in four states, Arizona, Florida, Texas, Utah. It was initiated in July 2021.

Upon enrollment, parents and legal guardians provided the participant’s demographic, health, vaccination history, prior SARS‑CoV‑2 infection information, the number of hours and percentage of time participants were masked in school, and in the community were reported monthly, vaccination was verified by vaccination cards, electronic medical records, state immunization registries. Active surveillance for SARS‑CoV‑2 infection and any COVID-19 associated symptoms within the preceding seven days occurred through weekly submission of a survey, nasal swabs.

This study reported here was based on 1,364 participants, including 77% of children aged 5 to 11, 23% of adolescents aged 12 to 15. They reported that two doses of Pfizer-BioNTech vaccine received less than five months earlier were moderately effective in preventing symptoms asymptomatic Omicron. They also found that even if there was an infection, there was a significant impact on disease severity. Just more data suggesting or supporting vaccines. I have to say even concerns about vaccine efficacy during Omicron.

High vaccine effectiveness against severe COVID-19 in the elderly in Finland before and after the emergency of Omicron was posted as a preprint. Here the author’s report and a nationwide registry-based cohort of 897,932 individuals that included all residents aged 70 years and over in Finland. Just to focus on the post-third dose data, they reported that vaccine efficacy against COVID-19 related hospitalization was 96% after the third dose. I want to say one interesting point is that Finland has been using the extended 12-week interval between the first and second doses, kudos to Finland there.

Passive vaccination, we still have Evusheld, we’ve got to do a little better job of getting it out there. I’m going to touch a little bit on why I say that. Let’s jump right into the period of detectable viral replication. The viral symptom phase, as I like to say, the time for monitoring, monoclonal, antivirals, enrollment in clinical trials, not for steroids, or antibiotics, or zinc, or aspirin, or other unproven and potentially harmful potions. I will say a little bit of an update to the IDSA, the ID Society of America, they did update their guidelines. Actually, today we’re recording this, to say not to use inhaled steroids.

To date, there’s not compelling evidence that that should be part of standard treatment. Let’s go through what should be part of standard treatment. Number one, and this is an order of efficacy and recommendation, Paxlovid. Now, I will say supply relative to demand is improving. Perhaps this is the problem, data on COVID treatment utilization shared by the US Department of Health and Human Services indicates that millions of COVID treatments are sitting on shelves unused. Just to give you a little bit, I’m going to go through what is happening.

Of the share of available supply ordered, we’ll take Paxlovid, only about 70% has been ordered. I’m going to say only about 35% has been used. I hear this all the time, “Oh, it’s so hard to get.” This drug needs to be ordered. This drug needs to be given. We finally got an effective, highly-effective oral antiviral. It is not being ordered by the states. It is not being given to the patients. We need to do a better job here. The next we’ll move on to our monoclonals, and I think there’s quite a bit going on here. BA.2, the stealth variant, the Omicron stealth variant, as we call it, now makes up about a quarter of all new cases in United States, probably about 40% in the New York Tri-state area.

Sotrovimab has less neutralizing activity. One should be looking at bebtelovimab. That’s why I care so much about the BA.2. It may have a fitness advantage. We’re seeing it outcompete the other BA.1 Omicron variant throughout the world. Remdesivir, remember the three-day outpatient IV therapy, an 85% reduction in progression if given early. I have to say considering how much of the other options are not being used, I’m not sure that we should be ending up here too much. Molnupiravir, we did hear that molnupiravir is being widely used, but again, some perspective here.

Only a little more than 60% of the available drug has been ordered by the states, and less than 10% of the available drug has been used. As we’ve discussed, there’s a lot of reasons why people might be thinking about molnupiravir including no issue with renal function, no issue with drug interactions, good availability, apparently, much better availability than people are taking advantage of. We probably shouldn’t be ending up down this far. We’ve got Paxlovid, lots of it. We’ve got monoclonal therapy, lots of it. We have remdesivir as well.

Early inflammatory phase, no big changes here. Steroids at the right time, in the right patient, anti-coagulation, pulmonary support, escalation if needed. Let’s jump right to long-COVID because I think we have a very interesting paper that just came out. The paper, “Identification of Distinct Long-COVID Clinical Phenotypes Through Cluster Analysis of Self-Reported Symptoms.” These are the results of a multi-center prospective cohort study of individuals with a confirmed diagnosis of COVID-19 and symptoms greater than four weeks.

The authors identified symptom clusters. 233 individuals were included in the analysis. The median age of the cohort was 43. 74% were women. 77.3% reported an initial mild illness. They identified three clusters. Cluster one had predominantly pain symptoms with a higher proportion of joint pain, myalgia, and headache. Myalgia being muscle pain. Cluster two had a predominance of cardiovascular symptoms with prominent chest pain, shortness of breath, palpitations. Cluster three was a milder symptom complex than the others. Clusters one and two had greater functional impairment.

I think this may be helpful for us as clinicians, just really addressing something we’ve been saying for a while. Long COVID is not just one syndrome, there can be a lot of things going on. It may be that different therapies help different groups of patients with this umbrella post-acute sequelae of COVID, another umbrella below that long COVID, and then subgroups or clusters below there. What about the rest of the world? No one is safe until everyone is safe. The study, “Estimating Excess Mortality Due to the COVID-19 Pandemic, a Systematic Analysis of COVID-19 Related Mortality 2020 Through 2021,” was published in The Lancet.

All-cause mortality reports were collected for 74 countries and territories, 266 sub-national locations. They had a lot of data here, looking at reported deaths from all causes during the pandemic in 2020 and 2021. For follow-up, for about 11 years previously. We can look at what’s going on previously and then build on top of that. Although reported COVID-19 deaths between January 1st, 2020 and December 31, 2021, totaled 5.94 million worldwide. They estimated, based on this analysis, that 18.2 million people died worldwide because of COVID-19 pandemic as measured by excess mortality over that period.

That’s an extra 18.2 million people that died, not all from a COVID infection, a SARS‑CoV‑2 viral infection, but from the impact of COVID-19. They actually break this down. I’m just going to mention a couple of the countries because they break it down by cumulative excess deaths due to COVID-19. In India, we’re looking about over 4 million deaths. The USA over 1 million deaths. Russia over 1 million deaths. It goes on. Let’s look at the excess mortality rate per 100,000. We’re going to correct for those large populations. The worst, who did the worst? Russia, 374.6 deaths per 100,000, very similar to Mexico. The USA 179.3 per 100,000.

I want to say Panama actually did reasonably well. About 131 deaths per 100,000. If anyone can say they did reasonably well. It is worth looking through this open-access paper to see the breakdown by regions, by country. Because a lot of us are starting to say, what did we do wrong? What can we learn for the next time? That brings us right into our next section; lessons learned. I want to point this out. As I said, right up front, we are already seeing a rise in cases globally. Again some suggestion that we’ve reached a plateau in the US, it is no longer dropping in terms of case numbers.

If you actually look at New York, we have not only reached a plateau, but we are maybe starting to go up a little bit there. It’s possible that we will see a small to moderate swell before summer. Most of us expect a rise in cases again in the fall that will carry into winter. Really what happens next is in our hands. It’s our option to make smart decisions for ourselves. At some point, we have to stop listening to those who are surprised after each wave that there is another that comes. I’m always shocked at the same, I will call them talking heads. This is it, this is the last one.

Next wave comes and they bring them back for some more but I do want everyone to pause the recording right here. If it isn’t paused by our trouble with electricity on my end, go to and click the Donate button and then come back. Even a small amount helps because we want to continue to do this work. I think it’s really important that we continue to be here providing honest, scientific information, helping clinicians, helping our listeners make educated decisions.

We also want to continue supporting the organizations that we partner with to spread this education and provide direct clinical care to so many in need throughout the world. This last week I’ve been down here in Panama, worked with a tremendous organization, Floating Doctors. I have to say I’m quite impressed at how well this organization is doing, really impressed at how well the Panamanian people are doing during these really difficult times. It’s very troubling. I come back here and some of my friends from years before the pandemic, they’re no longer with us anymore.

I do want to remind people that when they go there to donate throughout the months of February, March and April, donations made to Parasites Without Borders will be matched and doubled up to a potential donation of $40,000 to the American Society of Tropical Medicine and Hygiene. A portion of this money will go to provide scholarships for attendance at the annual meeting with priority given to females from low and middle-income countries who might not otherwise be able to attend.

VR: Time for some questions for Daniel, you could send yours to Darnell writes, “I was wondering if you could share your thoughts about the mRNA dose for Moderna versus Pfizer, for 5 and under. I believe Pfizer used 1 microgram for 6 months to 2 years, 3 micrograms for 2 to 5, whereas modern uses 25 micrograms for this age group.

With the Modena dosage being even stronger than what Pfizer uses for 5 to 11 and closer to Pfizer’s dosage for 12 to 17. I’m wondering if there’s a concern for safety and risk of side effects such as myocarditis. If there was a choice between a two-dose regimen of the much stronger Moderna versus three doses of Pfizer, what would be your preference?”

DG: Yes, fantastic question and actually very timely, because I think we’re about to get the data in the coming days, weeks for Moderna. One is, I’m not sure you can directly compare the dose in the Pfizer, the amount of mRNA in the Pfizer to the Moderna. How do you figure out what’s safer? You do the trials and that’s what’s going on right now.

What we’ve heard, the whispers, so to speak, is that the Moderna vaccine trials are not seeing a safety signal, but they are seeing efficacy. I think ultimately rather than thinking about what probably will happen, when we see the safety data, then we’re really going to know and be to provide that science-based guidance, but know this an excellent way you’re thinking this through.

VR: That one was from Darnell, from Ottawa, and the next one is from Sarah, from New Hampshire. “I was wondering if you had any information regarding when we might expect a third or a booster dose of Pfizer for a 5-to-11-year-old range, especially in light of news of a possible fourth dose for adults as well as the delay in the EUA for children under 5 years to study a three-dose series over only two.”

DG: No, I think, it’s really a question of when, in so many ways as far as we’re moving for boosters for everyone and actually there have been recent requests that we recommend boosters all across the board. Keep tuned but yes, that’s the direction we’re headed and we would not be surprised if boosters every fall might not become a regular thing.

VR: Gwen is from Ottawa, “I’m a family physician turned brand new medical director of a local health department. I was recently asked this question, I received two doses of COVID vaccine, and then due to complications, it was recommended I should not get a booster. Fortunately, I was eligible for Evusheld and have now received two doses of that. My question is, am I considered fully-vaccinated and boosted when looking at the COVID flow charts for exposure or do I need to follow the guidelines for unvaccinated?”

Gwen continues. “Our state guidance for quarantine has changed and it is now based on type of exposure rather than vaccination status.” The quarantine question is mostly moot at this point, but the question about how this person should view their vaccination status is a perplexing one. The person stated they even called AstraZeneca, but haven’t been able to get a good answer. How should this person view their status? What if anything, would that change in practical terms?”

DG: OK, excellent. Yes, the first, just for our listeners, when you hear about someone getting two shots of the Evusheld, it probably was that you got the 150 and then had to get the second 150 concerns with the Omicron particularly the BA.2 that we may not be getting as much protection as we initially hoped. Significant lab data suggesting a decrease in the neutralizing activity against these new variants that we’re seeing but there are a couple things that are really there.

These aren’t giving you that antibody shield, they call it Evusheld, but I call it Evushield, but that’s all they’re giving you. You’re not getting that extra T-cell boost. This is not the equivalent of being vaccinated with three doses. Just that would be the science. The vaccines are not just giving you antibodies, are also giving you that on T-cells. This will be something important going forward when we have more vaccine choices. Was there something about those issues where a protein-based vaccine or some other vaccine technology might be tolerated? Might give you that ability to get that extra T-cell protection.

VR: Our last question is from Victoria, who writes, “I’m a PA and gastroenterology prescribing both immune modulators like azathioprine and also biologic agents like infliximab. Are there any studies in how much these agents increase risk of COVID infection severity and long COVID? How about the degree of response to vaccination?”

DG: Yes. There is a lot of data on this and actually most of the data is around the vaccine response. You are not going to get as good a vaccine response when you’re on these immunosuppressive medications. The other side is yes, people who are immunosuppressed are at higher risk. That puts these people into that 10% or greater risk of progressing a hospitalization.

These are your patients who are going to be at high risk, and just remember that email right before, these might be patients that you’re thinking about giving Evusheld in addition to the vaccines and actually the current recommendations for people who are immunocompromised is a four-vaccine series, the three and then a fourth at the end. Just look that up, make sure they’ve gotten their proper recommended vaccine series and consider Evusheld as well.

VR: That’s COVID-19 clinical update number 106 with Dr. Daniel Griffin. Thank you, Daniel.

DG: All right. Thank you, everyone, and be safe out there.


[00:28:51] [END OF AUDIO]

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