TWiV 970 Clinical Update

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 31 December 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 970, recorded on December 29, 2022. I’m Vincent Racaniello and you’re listening to the podcast all about viruses. Joining me today from New York, Daniel Griffin.

Daniel Griffin: Hello, everyone.

VR: Daniel, that’s the end of 2022. Our last update, it’ll drop on the 31st, right?

DG: It’s perfect timing to, end of the year, with a clinical update.

VR: It’s been quite a year. I would venture to say that next year will also be quite a year because viruses don’t go anywhere. [chuckles]

DG: They really don’t. I think we were all getting ready for a little bit of quiet. I think that was wishful thinking. As we’ll see today, a lot to share here at the end of 2022. Let’s start right off. At the last minute, I changed my quotation because of some disturbing news. My quotation, “Success is no accident. It is hard work, perseverance, learning, studying, sacrifice, and most of all, love of what you are doing or learning to do.” That’s Pelé. Unfortunately, on the day we are recording, it was announced that Pelé died at age 82. The world certainly feels diminished without him. Growing up, I loved the game of football or soccer as we call it here in the States. He was definitely a figure that I looked up to.

Not just a fantastic footballer but just an individual who really demonstrated perseverance, hard work. He made a quotation at one point about, “Soccer players are not born, soccer players are created.” Really, that’s what this quotation is about. You’ve got to really work hard to reach a level that he reached. Let’s get right into it. Measles. Perhaps people heard the report of the massive measles outbreak in India. As of November, India had recorded 12,773 cases of measles so far, according to the WHO. The revival of measles in India, mostly in four large cities, it’s felt to be happening because millions of children didn’t get vaccinated in 2020, owing to the disruptions caused by the COVID-19 pandemic.

On top of this, there have been persistently low coverage and routine immunizations of newborns for the past few years, which has contributed to the current outbreak. I’ll leave a link to the Nature article about this. As I shared when I was recently in sub-Saharan Africa, we are seeing measles cases. Just what do I see? What keeps me up at night? It’s this diminution in the public messaging and the education in really the excitement about vaccinations. Just what a wonderful tool. I hate to see us losing ground here.

Speaking of vaccinations, influenza, we did not do a great job this year. We have not done a great job of getting ourselves vaccinated here in the States. Things have actually gotten so bad here in the U.S. that the United States is releasing Tamiflu from the strategic stockpile. I like the title of the article in the Associated Press, “As Flu Rages, U.S. Releases Medicine from National Stockpile.” I wish Tamiflu was a little bit more exciting, had a little bit more of an impact. Really, vaccination is our main tool here. Also, it’s not a great tool as we know. We need better tools.

I was on the Amy and Vincent Q&A last night and just lamenting that we’ve been working with flu for so long and just really could use some advances. I put up for Vincent here and we’ll have a link to the CDC flu weekly U.S. map. Apparently, people are looking at this map and saying, “Look how much better things are getting.” I’m looking at this map and I don’t know what they’re seeing that I’m not seeing. Vincent, are you seeing this –

VR: I think last week, there was more blue or purple on the Northeast anyway-

DG: All right.

VR: – so maybe that’s – There’s still a lot of activity. It’s still in the high. It’s a very activity, so I wouldn’t say it’s all that much better for sure.

DG: It looks like New York went from the bottom of very high to the middle of high. [laughs] I’m feeling so much better. All right. Actually, one of the things that’s interesting. If people actually look at some of the national trends, often what happens is you get a surge with the flu, then it starts to drop. Then guess what happens? Everyone starts traveling after the December New Year’s holidays, and then we see things rise back up again.

Don’t take this one week and say, “I’m going to rip off that mask. I’m going to go to that crowded, packed, poorly-ventilated party this weekend.” Maybe people are going to listen to this on New Year’s Eve, make smart decisions. I’d rather have you enjoying this podcast as you’re driving to and from some enjoyable activity rather than visiting me in the hospital.

All right. Right to COVID. Let me start our COVID section with the Nature news article. I think this is something a lot of people are talking about. “China COVID Wave Could Kill One Million People, Models Predict.”

Some of our listeners, probably almost all of our listeners, are likely aware of the changes in China from a zero-COVID policy to a realization that Chinese is here to stay and a really abrupt lifting of the prior policies. The models for what is likely to come from this over the next year are not great. There’s a preprint, “Modeling the Adjustment of COVID-19 Response and Exit from Dynamic Zero COVID in China,” suggesting a million deaths in 2023 directly from COVID,” goes through different measures that could potentially reduce this number. The authors of the Nature news article comment that these estimates include only deaths directly due to COVID-19.

As I will point out, deaths are deaths and if one gets COVID and then one week later, maybe week three dies with a stroke, a pulmonary embolism, or a heart attack in their 40s, I’m not sure I get why so many people are so ready to make, “this does not count as a death related to COVID.” I remember how often Mark Crislip on the Puscast would talk about the increase in cardiovascular events after acute infections, even influenza. I know when we run the numbers on the benefit of influenza vaccine in a value-based care model, we don’t just look at people that die in the week of the acute illness, but we actually look at the 28-day mortality.

We’re going to see what happens with “the mild version” of the virus in China. COVID and children, other vulnerable populations. As everyone else is moving forward, a couple things that I think it’s important for us to just make sure we don’t move too quickly past is, every year millions of children are entering this world. That first six months of life can be quite dangerous. We’ve talked quite a bit about strategies where mom is vaccinated in that last trimester providing some protection for the newborn. We also have millions of individuals who are elderly-elderly, or otherwise immune-compromised.

As we move forward, I’m just going to acknowledge that those people are out there and we’re not just going to forget about them as we move forward. Pre-exposure period, transmission, and testing. When you’re going to those big, crowded, exciting events, which people like to attend, remember the science favors mask use and suggests a hierarchy with the N95s offering the highest level of protection. Ventilation, really this has been, I think, underappreciated during the pandemic. Leave that HVAC fan turned to “on.” My wife and I had this big discussion before I left to Africa and really committed to leaving that HVAC fan turned on despite, apparently, the annoying sound.

I will say, knock on wood, I did not get a positive COVID test, nor did any of my children. My wife has made it through her 10 days of isolation. Crack those windows [laughs], try to improve the air quality and testing. This is my favorite part this week because it involves dogs. I will start off by saying I really enjoyed the recent TWiEVO 85, “Teaching Old Dogs New Genetic Tricks,” where Vincent and Nels discuss the use of genome sequence data, over 4,000 domestic semi-feral and wild candidates to understand the genetic drivers of canine behavior. We’ll leave a link there.

I’m enjoying the holidays with our two dogs, Peregrine and Hattie, as well as fostering a service dog in training, Joy, so her trainer can have a little bit of a break for the holidays. Joy is a comfort dog for our listeners. Her job is to sit in your lap and really just get all of her weight on top of you. Even if you’re in a tiny chair she’s very excited about doing her job. You can imagine how excited I was with the article, “Canine Real-time Detection of SARS-CoV-2 Infections in the Context of a Mass Screening Event,” published in BMJ Global Health, so spend a little time going through this because I think this is an interesting article. Here, eight dogs were trained to detect SARS-CoV-2 RT–qPCR positive samples.

As we pointed out before, they’re not sniffing the virus, they’re sniffing these volatile compounds. Four concerts with a total of 2,802 participants were held to evaluate canines’ performance. I don’t think they held the concerts for the performance, but they took advantage of this. That was interesting the way they worded that. Anyway, sweat samples were taken from all participants, apparently had to be some informed consent there, and presented in a lineup setting. In addition, every participant had been tested with a SARS-CoV-2 rapid antigen test qPCR. We get information about age, sex, vaccination status, medical disease history. The participant’s infection was unknown at the time of canine testing.

Safety measures such as mask-wearing and distance-keeping were ensured and here are the results. The SARS-CoV-2 detection dogs achieved a diagnostic specificity of 99.93% and a sensitivity of 81.58%, so 99.93 and 81.58. The overall rate of concordance results was 99.68, so remember we’ve got a couple dogs here testing everyone. The majority of the study population was vaccinated with varying vaccines, vaccination schedules, some of the folks had chronic diseases, some of them were on chronic medication. This did not influence the dog’s decisions.

There’s a great figure that I recommend people take a look at. How does this work? I have this perfect world where I imagine it being like at the airport where people just walk by and the dog follows them in line, but here’s how they did it. At the venue entrance, after check-in, all participants were screened using these detection dogs. There were two lineups simultaneously. Each lineup contained 20 mountings for sample containers, therefore 40 participants could be screened at once so pretty quick. They use these disposable paper cups. The cups and the contained samples were moved after each run, handled by the same two persons wearing disposable gloves to prevent odor contamination because this is about sniffing.

The sample containers were then attached to these fence elements which served as sample presentation and there was a partition wall to separate the participants from the dogs. Every participant gets this cotton pad and they’re actually wiping their underarms, their arm crooks as they say. Really, I have to say, fascinating the way they’re doing this. I know people don’t like screening, they don’t like vaccination passports, but I like this idea about dogs making sure that people aren’t ending up in these venues. Why stop with COVID? I’m thinking about the parties coming up, you could screen for,  you could have influenza dogs, you could have COVID dogs, you could have RSV dogs. [laughs]

VR: Daniel what does it mean when a dog detects someone? What’s the dog threshold value? That’s what I want to know.

DG: [laughs] Exactly. This one, we don’t have the detail of that. Actually, I think in some of the earlier studies we actually talked about the fact that the dogs are really good even when the CT value is getting quite low. Maybe they’re over good. The issue is that, this is not detecting that acute viral replication. This is somehow detecting our response to being infected and whenever volatile compounds are [crosstalk] being exuded.

VR: I think what we should do is find out whether these people are infectious or not and correlate that with the dogs. It could be that the dogs are detecting people long after they’re infectious, in which case why exclude people from a concert in that case?

DG: Yes, actually I think that’s a good point. You could almost use this as just a screening up front and say, “OK, so the dog tagged you, you’ve had COVID in whatever period of time. Now let’s see if you’re still in this infectious period,” and then maybe we do quantitative on a smaller number. I think that’s a good point because if you pick up someone and it’s day 14, do you really need to exclude them from this exciting venue? I would say no.

VR: I think also this is probably a little bit too late for COVID because –

DG: Yes, we’re over COVID so time to start training the influenza dogs.

VR: Maybe –


VR: – polio.

DG: The polio dogs, yes. Just in time for the holiday, just in time for that party, the article, “Two Masks Can be Worse than One: N95 Respirator Failure Caused by an Overlying Face Mask.” I was harassing my buddy in the ICU today who had multiple masks stacked on top of each other, but this was published in Infection Control & Hospital Epidemiology. In this report, 100 participants successfully completed their fit testing wearing a 3M N95. You do it, “Do you smell this?” They do smoke the saccharin. Apparently, I don’t answer right. When they blow the smoke around, I’m like, “That tastes – that’s just weird.” They’re like, “No, no, you’re supposed to say sweet.” I’m like, “No, it’s weird. It’s not really sweet.”

Anyway then they go ahead and they put one of these procedural masks over and 13% of them end up failing, so putting that extra mask on can actually negatively impact the performance so just want to throw that out there.

The article and I really like this again because there’s nice pictures here, “Airflow Patterns in Double Occupancy Patient Rooms May Contribute to Roommate-to-Roommate Transmission of Severe Acute Respiratory Syndrome Coronavirus 2,” published in CID.

In this study, the investigators used a device emitting condensed moisture to identify airflow patterns in double-occupancy patient rooms. Simulations were conducted to assess transfer of fluorescent microspheres, 5% sodium chloride aerosol, aerosolized bacteriophage MS2 between patient beds. Then they say, “Three meters apart,” the beds are usually not that far apart.

Then they went ahead to assess the effectiveness of privacy curtains and portable air cleaners in reducing transfer. What did they find interesting here? Air flowed from the inlet vents in the center of the room to an outlet vent near the door resulting in air currents flowing toward the bed adjacent to the outlet vent. You don’t really want to be in that bed probably. Let’s see what they find.

The fluorescent microspheres released from the inner bed were carried on air currents toward the bed adjacent to the outlet vent. Closing the curtains reduced the transfer. Then here, this surprised me, operation of a portable air cleaner reduced aerosol transfer to the bed adjacent to the outlet vent, but did not offer a benefit over closing the curtains alone or in some situations resulted in an increase in aerosol.

I feel like I’m picturing – it’s like you’re sucking the stuff towards you and on its way then it ends up in the filter. Maybe we should start thinking about folks with transmissible respiratory pathogens, maybe not being sharing a room with someone who would not benefit from breathing that in.

VR: That’s not currently the practice, Daniel?

DG: What we’ve been doing quite a bit is testing folks and then if they have what’s considered an infectious respiratory pathogen, not putting them in a room with someone else, or trying to cohort them, keep them. The only thing that happens unfortunately is that the patients are visiting. I had this story yesterday where the patient was really cagey about not wanting to go home. I’m overhearing this conversation, I’m listening in.

Then it turns out that finally, the hospitalist is like, “So what’s going on?” They called a family member who’s at home. Turns out that the wife actually has COVID, but the wife’s been coming in and visiting the guy every day. The reason the guy doesn’t want to go home is he’s like, ”I don’t want to go home because I’m going to get COVID.” I’m like, ”I bet he’s already got COVID.” They test him, he’s already got COVID. Now he’s got COVID and what about his roommate? That’s where I think this is.

Now I thought of Rich Condit when I read the article, “Clinical Validation of a Novel T-cell Receptor Sequencing Assay for Identification of Recent or Prior SARS-CoV-2 Infection,” published in CID. Remember this is that issue: How do I find out if I’ve had COVID? I’ve had occasionally a runny nose, something like that, maybe I didn’t test. We learn that if you’re vaccinated, that nucleocapsid antibody test is not as sensitive as we might hope.

Here they’re reporting is using a T-cell assay. T-Detect a commercially available assay that uses over 4,000 SARS-CoV-2 associated T-cell receptor sequences identified by comparing 784 cases over 2,000 controls from five independent cohorts. This T-Detect COVID, it’s made by Adaptive Biotechnologies. It is commercially available. Applies this classifier to the TCR repertoires. Actually, they’re reporting pretty impressive positive percent agreement, pretty good negative percent agreement for trying to figure out if you’ve had COVID before. Raise the important question of does this matter? Just putting it out there.

VR: Daniel, is the idea here that if you’ve had an infection with SARS-CoV-2 certain T-cell receptors are going to be amplified in those patients and you should pick them up by this procedure? Correct?

DG: Yes. This actually goes back to the early days pre-vaccination when Adaptive Biotech came out with this. Then you could say, “OK, you’ve been exposed,” but the original algorithm couldn’t determine whether that exposure was a vaccination exposure or an infection exposure. Now they’ve modified the technology. I think this also feeds into your T-cells are doing quite a bit. This is over 4,000 T-cell receptors they’re looking at and looking at the number of T-cell-directed responses.

COVID active vaccination. Never miss an opportunity to vaccinate. As we’ve been talking about here in the States, we’re saying about 97% of the population has some degree of immunity, whether that was that risky acquired infection-induced immunity or vaccination or a lot of folks now it’s combination hybrid but building on a theme here. The article, “Antibody-dependent, Cellular Cytotoxicity against SARS-CoV-2 Omicron Sub-lineages is Reduced in Convalesced Sera, Regardless of the Infecting Variant,” published in Cell Reports Medicine.

Perhaps the theme is immunology, I’m trying to share that immunology is a bit more complicated than serology results and just neutralizing antibodies. As people dip their toes into the complex world of immunology, I do encourage everyone to add Immune to their subscribed podcasts. The conversations and paper discussions with Vincent, Cynthia – actually Cindy she goes by – Steph, and Brianne make for great listening. At this point, when I tell people I spent years getting my Ph.D. in immunology, they’re trying to figure out, “Well, did you just measure antibody levels for all those years?”

No. [laughs] In this investigation, the authors assess the sensitivity of BA.4 to binding neutralization and antibody-dependent cellular cytotoxicity potential addressed by the FC signaling in convalescent donors infected with four previous variants of SARS-CoV-2, as well as in post-vaccination infections caused by Delta or BA.1. Not surprising that they were able to confirm that BA.4 shows high-level neutralization resistance regardless the infecting variant.

However, BA.4 sensitivity to the antibody-dependent cellular cytotoxicity – this is the non-neutralizing antibody activity – is reduced, but with smaller fold losses compared to neutralization and similar patterns of cross-reactivity. They suggest that although the non-neutralizing activity against BA.4 is reduced, residual activity may contribute to observed protection from severe disease as we’re seeing, and we have not even gotten to the T-cells.

VR: Not just neutralizing antibodies, huh, Daniel?

DG: It’s really tough, Vincent. There are labs out there who will remain mentionless and they publish this stuff on, “Oh, the neutralizing antibodies, they’ve dropped. The world is over, the sky is falling.” There almost needs to be some, dare we call it, peer review for these preprints. Where there maybe it’s just a qualifier in the preprint saying, “This study only looks at neutralizing antibodies and does not communicate information about all the other benefits and activities of antibodies or the rest of the immune orchestra.”

VR: Let me bring something up now that we know that our monoclonals or therapeutic monoclonals do not neutralize the latest variants. Has anyone checked to see if perhaps they still maintain clinical efficacy by non-neutralizing activities?

DG: I have to say, that’s one of those things that keeps me up at night. Have we just said on the basis of the neutralization that, “Oh, they’re no longer neutralizing, get rid of them.” Now, it is challenging because that’s the way we identify which ones we want to move forward. It’s easy to do these neutralization assays, and that’s what they were designed to do and then you do that and then you lose that.

You say, “Oh, geez, that was what brought us to this point.” Yes, I actually think that that’s a reasonable thing to look at and to study. Just because they’re no longer neutralizing, do they have some other efficacy? Should we really have just tossed them all in the trash? I don’t really know.

Moving into the early viral upper respiratory non-hypoxic phase, very exciting article this week. I think it’s exciting. “VV116 versus Nirmatrelvir-Ritonavir for Oral Treatment of COVID-19.” I’m going to change the title to something understandable. Oral remdesivir is just as effective as Paxlovid. You guys could print that in the mainstream media if you want. For background, Paxlovid is highly effective for treatment of acute COVID if given in the first five days but access to Paxlovid is limited worldwide.

Its effectiveness depends on co-administration with ritonavir resulting in multiple drug-drug interactions, warranting specialized assessment before prescription. I’ll also throw in that we have issues with renal adjustments. Now, remdesivir is also recommended but the current form needs to be administered intravenously, which limits its widespread use during the pandemic. Therefore, several oral analogs of remdesivir have been developed to address this issue, including GS-621763, ATV006, and VV116. There’ll be a test afterwards.

In this multi-center observer-blinded randomized controlled trial symptomatic patients at high risk for progression to severe COVID-19 were randomly assigned in a 1:1 ratio to receive either VV116 or Paxlovid for five days. The primary efficacy endpoint was the time from randomization to sustained clinical recovery through day 28. Secondary efficacy endpoints included progression to severe or critical COVID-19 or death from any cause.

They reported non-inferiority for the primary endpoint. By the time of the final analysis, no participants in the trial had died or had progression to severe COVID-19 so again, non-inferior. It’s a nice figure, I actually pulled panel C out of this. There’s a couple things here that are really exciting. One, and we’ve been talking a bit about this and people are saying, “Where’s the data on that?” These are high-risk individuals. They’re getting either Paxlovid or this oral form of ritonavir. No one is progressing to severe COVID-19 so really –

VR: Is this a phase two trial or what?

DG: It’s efficacy. This is phase three.

VR: It’s already there.

DG: The number of participants were 303 in the VV116 group, 293 in the Paxlovid group.

VR: Looks very good. The graph is very impressive, Daniel.

DG: Yes, basically it’s like two lines following each other.

VR: A surgeon could follow this.

DG: [laughs] Well, they have to change the title for the surgeon so change the title to, “Oral Remdesivir is Just as Effective as Paxlovid.”

VR: Based on this, would you give, if it were EUA’d, would you use remdesivir then?

DG: If there was the oral remdesivir, the VV116, and give it a catchy name, please, yes. I think this is really compelling. I think that we have a lot more experience in data with Paxlovid, but there are a number of people out there with drug-drug interactions, renal issues, et cetera. This would be a great drug to get more experience with.

VR: Plus you don’t get a bad taste in your mouth with this.

DG: Yes, my wife was complaining about that.

VR: It’s not so bad, but just annoying.

Daniel: She thought it was so bad. Another article, “Nirmatrelvir Plus Ritonavir for Early COVID-19 in a Large U.S. Health System,” a population-based cohort study published in Annals of Internal Medicine. These are the results of a population-based cohort study conducted in a large healthcare system, providing care for 1.5 million patients in Massachusetts and New Hampshire.

During the Omicron wave, first of January to 17 July, 2022, 44,551, non-hospitalized patients, over 90% of them with three or more vaccine doses, aged 50 or older with COVID-19, no contraindications. The primary outcome was a composite of hospitalization within 14 days or death within 28 days. I like those endpoints. During this study period, 28.1% of patients were prescribed Paxlovid, 71.9 were not. Patients prescribed Paxlovid were more likely to be older, have more comorbidities, be vaccinated. Recipients of Paxlovid had a lower risk for hospitalization, even though they were sicker. Adjusted risk ratio of 0.60 and death adjusted risk ratio of 0.29.

In this highly vaccinated population a 40% reduction in hospitalization, a 71% reduction in dying when you took the Paxlovid. There’s a nice figure except one, by the way, might want to increase the font so you can read it without a microscope. Couple things to point out. One is that as expected, most hospitalizations are during that second week. Second is that in this high risk but vaccinated population, we’re only seeing hospitalization or death about 1% of the time. In keeping what we were talking about before, we really can reduce the number of folks that end up in the hospital or don’t survive with vaccination and early treatments.

VR: Daniel, I presume the drug is given at the appropriate time after positive test, right?

DG: Yes, and I think that’s really critical. The EUA for Paxlovid is to give this within the first five days of symptom onset. Also to give it to high-risk individuals if your risk of progression is zero. We still don’t have that compelling data that this is a Long COVID prevention drug. Number two, remdesivir, the IV stuff, remember three days, if you could get in that first week. A little mention in the monoclonals. We don’t think we have any that work at the moment, so all the EUAs have been pulled but I think an interesting point is there some non-neutralizing activity.

Last and least, molnupiravir, let’s see the paper, “Molnupiravir Plus Usual Care versus Usual Care Alone as Early Treatment for Adults with COVID-19 at Increased Risk of Adverse Outcomes (PANORAMIC): An Open – ” I love these names – “An Open-Label, Platform-Adaptive Randomized Controlled Trial,” published in The Lancet. Here the investigators are looking at the safety and efficacy of molnupiravir in about 25,000 vaccinated individuals. This is a UK-based national multi-center, open-label, multi-group prospective platform, adaptive, randomized controlled trial. Eligible participants, high risk, so aged 50 or older or 18 with relevant comorbidities.

You had to be within that first five days. One-to-one randomly assigned primary outcome all-cause hospitalization or death within 28 days, and hospitalization or death were recorded in 1% of the participants in the molnupiravir group and in 1% of the usual care group, so really not much different. Thus in this large randomized controlled trial, molnupiravir did not reduce the frequency of COVID-19-associated hospitalization or death among high-risk, but vaccinated adults in the community.

Don’t do harmful things. The next, early inflammatory, lower respiratory hypoxic phase.  Little bit more time here this week because we have some new things. One, we’ve talked about steroids for a while at the right time in the right patient at the right dose. That’s after that first week it’s in folks that are hypoxic, oxygen saturation is less than 94%. I’ve been saying for a while, steroids at the right time in the right patient at the right dose. Steroids given too early could do harm, but what about the wrong dose?

I will mention early on there were some folks from a different specialty that will remain nameless who were excited about giving a thousand milligrams of Solu-Medrol for several days to some of these folks. Was that a good or bad thing? This is a preprint so take that with an unhealthy dose of salt over the shoulder, but remember this is also out of the recovery trial, so perhaps take it a little easy on the salt. “Higher dose corticosteroids in hospitalized COVID-19 patients with hypoxia, but not requiring ventilatory support (RECOVREY): A Randomized, Controlled, Open-label, Platform Trial. This is posted on medRxiv. As a reminder, these are the results of the randomized controlled open labeled trial, RECOVERY. Eligible and consenting adult patients with clinical evidence of hypoxia, so that’s an oxygen saturation in this study of less than 92% on room air. The folks either got dexamethasone 20 milligrams once daily for five days followed by 10, or the usual, which is just the 6 milligrams. They followed primary outcome 28-day mortality. Overall, 18% of the folks allocated to high-dose versus 12% of the usual care died within 28 days.

This is a pretty high-risk group, but as you saw, excess mortality with overdoing it with the steroids. There was also an excess of pneumonia reported due to non-COVID infection, so 10% versus 6%, an increase in hyperglycemia. Just to bring this all around in patients hospitalized for COVID-19 with clinical hypoxia, but not requiring more than simple oxygen such as low flow nasal cannula, higher dose corticosteroids significantly increase the risk of death and other bad outcomes. Keep in mind though, the other literature, if you’re talking about individuals that are actually intubated, that have that tracheal inflammation, you may want to look at some subtleties here, but across the board we seem to have hit the nail in the head with the 6 milligrams. Anticoagulation guidelines, the right dose and the right patients, we have guidance there.

Pulmonary support. Remdesivir, if we’re still in the first 10 days. Immune modulation, so we have the announcement that the FDA approves Roche’s Actemra tocilizumab for the treatment of COVID-19 in hospitalized adults. Now that this is an FDA-approved indication, will all the hospital restrictions be modified to allow us to use this in the right patients at the right time? While per the approval, the U.S. FDA has approved Actemra tocilizumab intravenous IV for the treatment of COVID-19 and hospitalized adult patients or who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation or extracorporeal membrane oxygenation, ECMO. Remember the data here is you want to use this in the context of steroids. If you use this without steroids, we actually saw worse outcomes. I’m happy that we have a bunch here to throw in the Long- COVID post-acute sequelae of COVID phase.

A couple articles here and we’re seeing two different stories on what’s happening so the article – we’ll start off with the bad news. The article, “Structural Brain Changes in Post-acute COVID-19 Patients with Persistent Olfactory Dysfunction,” published in Annals of Clinical and Translational Neurology suggests that there might be some insight here into the loss of smell and taste after COVID. Here, 48 COVID-19 patients were included in the study, 23 were classified as having olfactory dysfunction, 25 normal olfaction, so able to smell, not able to smell. COVID-19 patients were evaluated using T1-weighted and diffusion tensor imaging on a 3T MRI scanner. They’re doing MRIs on these folks. They’re doing gray matter, voxel-based morphometry, voxelwise statistical analysis, and a lot of other challenging things in here. Basically, what are they showing? This study suggests that there might actually be brain abnormalities rather than just olfactory nerve issues.

With that big downer, let’s look at another article suggesting that maybe that’s not the case in everyone. The article, “Persistent Post-COVID-19 Smell Losses Associated with Immune Cell Infiltration and Altered Gene Expression in Olfactory Epithelium,” published in Science Translational Medicine. In this investigation, they analyzed olfactory epithelial samples collected from 24 biopsies, including from nine patients with objectively quantified long-term smell loss after COVID-19.

This biopsy-based approach revealed a diffuse infiltrate of T-cells expressing interferon-gamma, a shift in myeloid cell population composition, including enrichment of CD 207 positive dendritic cells, and depletion of anti-inflammatory M2 macrophages. There was an absence of detectable SARS-CoV-2 RNA or protein. Gene expression in the barrier-supporting cells of the olfactory epithelium termed sustentacular cells appeared to reflect a response to ongoing inflammatory signaling, which was accompanied by a reduction in the number of olfactory sensory neurons relative to olfactory epithelial sustentacular cells.

Here these findings suggest that T-cell-mediated inflammation persists in the olfactory epithelium long after SARS-CoV-2 has been eliminated from the tissue suggesting a mechanism for long-term post-COVID-19 smell loss. How can they both be right? I’m also a bit cautious.

VR: Maybe these people with the inflammation, maybe their brain was also altered, but they didn’t look for it, right?

DG: Yes, I hate to say that was actually my thought. I was hoping this was a little bit of good news after we told people if you can’t smell, your brain is damaged but we’re still sorting all this out. I am always a bit cautious on putting a number on. how many people here in the U.S. are suffering from Long COVID. It’s a large number. “The Epidemiology of Long COVID in U.S. Adults,” was published in CID. Here the investigators conducted a population-representative survey, June 30 through July 2, 2022, of a random sample of about 3,000 U.S. adults. They found that about 7.3% of all respondents reported Long COVID. Corresponding to, they’re going to calculate about 18 million, almost 19 million adults.

They report that one-quarter of respondents with Long COVID reported their day-to-day activities were impacted a lot. Twenty-nine percent had SARS-CoV infection over 12 months ago. The prevalence of Long COVID was higher among respondents who were female, we’ve seen that consistently, had comorbidities, were not boosted, not vaccinated. Certain things here, I think, are consistent with what we’ve seen in the predominance of female reporting issues, the impact of vaccination in reducing the incidents. Are there really 19 million individuals suffering from post-acute sequelae of COVID? Again, I always hate to put a number on things, but it is a significant number of individuals.

The Danes seem to be doing worse actually. In the article, “Persistent Symptoms and Sequelae after SARS-CoV-2 Infection Not Requiring Hospitalization: Results from Testing Denmark, a Danish Cross-sectional Survey,” published in Open Forum Infectious Diseases. They report that in Denmark non-hospitalized SARS-CoV-2-positive individuals had significantly reduced physical and mental health. They say one in four reported persistence of at least one Long COVID symptom. Again, it was the ladies that were at higher risk.

We also got more results from the COVID-OUT trial posted on the medRxiv as a preprint. I would be remiss if I did not mention this trial. Some of our colleagues, friends, compatriots were involved in this publication and in this trial, “Outpatient Treatment of COVID-19 with Metformin, Ivermectin, and Fluvoxamine and the Development of Long COVID over 10-month Follow-up.”

As a reminder, as we’ve discussed this trial before, COVID-OUT was an investigator-initiated multi-site, phase three, randomized, quadruple-blinded, placebo-controlled clinical trial. This trial simultaneously assessed three oral medications, metformin, ivermectin, fluvoxamine, using two-by-three parallel treatment factorial assignment to efficiently share placebo controls and assessed Long COVID outcomes for 10 months to understand whether early outpatient treatment with these medications would have an impact on Long COVID. We’ve talked a little bit about the impact or lack thereof on acute outcome.

In this trial, over 1,000 adults aged 30 to 85 with overweight or obesity, fewer than seven days of symptoms were enrolled within three days of a documented SARS‑CoV‑2 infection. The different arms were immediate-release metformin, titrated over six days up to 1,500 milligrams per day, 14 days total. Ivermectin for three days. Fluvoxamine with an up-titration for 14 days. Medical provider diagnosis of Long COVID, reported by participant by day 300 after randomization was a pre-specified secondary endpoint. We’ve already talked about the primary outcome of the trial being severe COVID by day 14.

Median BMI was about 30. The majority of the folks 51% had a BMI of greater than 30. Overall 8.4 reported having received a diagnosis of Long COVID from a medical provider. 6.3% in the metformin group, 8.0% in the ivermectin group, 10.1% in the fluvoxamine group. There were different control groups where the incidents range from 7.5 to 10.6. There was a reported small absolute reduction in the incidence of Long COVID in the metformin group. I have to say it will be interesting to see if this small impact remains statistically significant after peer review and an analysis of the statistical methods are applied.

Low and middle-income countries, no one is safe until everyone is safe. I did want to stop for a moment here as we wrap up 2022. Happy New Year’s to everyone and just say that we are in a much better place than we were in the early days of 2020, perhaps looking at China as a reminder of April 2020 here in New York. We’ve learned a lot. For those that are vaccinated, those that avail themselves of testing, early treatment, avoid harmful interventions, we are really in a much better place even for the elderly-elderly and immunocompromised, intelligent decisions, and our current tools really have transformed this reality. As we’ll see, in the coming weeks and months in China, the virus has not gotten weaker, but we have learned and we have gotten stronger.

I do want to encourage everyone to pause here and go right to Click on the “Donate” button. Every small amount helps, maybe make you feel better, be part of what we’re trying to do here, provide science education. We are in the midst of our MicrobeTV fundraiser. During the final day when this drops, of December and January, donations made to Parasites Without Borders will be doubled, up to a potential maximum donation of $40,000 for MicrobeTV.

VR: Time for your questions for Daniel. You can send them to Jan writes, “COVID-free until December, got infected, tested positive, took Paxlovid, finished it on December 21, went back to work, woke up today,” today being, I don’t know, a few days ago, “with sinus congestion, sore throat burning in my, chest. Tested positive, again, strongly positive on a home test. I’m so frustrated how can this be? I guess I have rebound COVID. I know from listening to Dr. Griffin that it’s not from Paxlovid. I would like to know if there are any associated risks with people who have rebound COVID?”

DG: This is one of those things like breakthrough infections, rebound COVID. I wish that we had been a little better at the terminology. This is not rebound COVID. It’s certainly not Paxlovid rebound. What this really is, is this is the natural history of the disease that we’ve been describing for years now. That first week – probably remember this, if you’re listening, you feel crummy, headache, fever, maybe sore throat, and then you start to feel a little better, and then that second week, third week is when you start to feel like, “I’m getting sick again.” That’s when your immune system is kicking in, that’s when you’re having this inflammatory, that’s what people are now calling COVID rebound.

Some people test positive. Is it that you’re shedding some of those cells that actually have antigen or if you’re doing PCR, they have genetic material in them? I’m still trying to sort out the details on what’s driving that. Stop testing and take a deep breath. If you’ve taken Paxlovid, if you’re vaccinated, as we’ve talked repeatedly, your risk of progressing to a bad outcome, of becoming hypoxic, of having issues, it’s really incredibly small.

People are still doing these repeat tests, and I discourage that. The antigen tests are great for making the diagnosis, but then just move forward. Don’t be discouraged. I expect you to do well. Maybe you should write back in a couple of weeks and then tell us how well you eventually did.

VR: That’s a great idea. OK, Jen, do that. Many people wrote about the following, including Mary. “Saw some discussion on Twitter about this immunological study showing COVID mRNA booster produces later on a certain kind of antibody response IgG4. Over my head what this means, but some see as a negative for the COVID vaccine, particularly the anti-vaxxers. Is it possible to explain, for the layperson, the significance of production of IgG4 antibodies and how it relates to the effects of the vaccine?”

DG: Sure. I don’t know if you’ve been following this space but this is making the rounds. The poor authors in the article, one of them is like, “Please stop using my publication as an anti-vaccine trope.” We have different subclasses of IgG so IgG1, 2, 3, 4 and there’s even sub between those different ones so you’ve got your 2A and et cetera. The fours in general, are felt to be less inflammatory so maybe that’s a positive thing over time to see that repeated exposures might be producing an antibody that produces less of a cytokine storm. We’re sorting this out. I don’t think this is a bad thing in any way. I understand that anti-science, anti-vaxxers are looking for anything to support their agenda, but I’m not seeing anything here that is worrisome. Actually, when I first saw it, I said, “Oh, this sounds like it might be encouraging.”

VR: Arlene writes, “I’m 80 years old. I’ve been on amoxicillin for 10 days. If I got COVID while on the antibiotic, would you recommend stopping?”

DG: No. The issue here is that antibiotics don’t treat viruses. We don’t want to lose our antibiotics. Everyone’s excited about treating viruses with antibiotics because they think there’s some magical impact. The magical impact is we’re entering the antimicrobial resistance world where we’re not going to have antibiotics that work, but no, if you’re on that amoxicillin for an appropriate indication, finish that course. I don’t think it’s going to be harmful for you with the COVID.

VR: Our last email for 2022 is from Jamie. “My daughter came home from college with an upper respiratory infection. She had COVID three months ago, vaccinated, boosted, tested negative for PCR, COVID-negative rapid flu. Within a day or two, I, her immunocompromised mom, primary immune deficiency with secondary lymphoma on Rituxan and IVIG, got the same symptoms. Tested negative day one. Three days in a row negative rapids. Just repeated PCR, but don’t have the results yet.”

“I’m assuming this is a garden variety upper respiratory infection, but given time limits on Paxlovid and how at risk I am, I wondered if you can comment on the accuracy and timing of these tests. Early in the pandemic, I know some immunocompromised patients repeatedly tested negative on swab but then positive on bronchoscopy. Are the tests better now, worse since they were designed for the original virus?

DG: This is a great question. Actually, this relates to one of the discussions we’ve had with our tristate urging care centers. In a lot of situations, someone comes in, we’re doing the rapid testing. We’ve really actually backed off on doing those point-of-care molecular Abbot ID NOW tests, but what we have thrown in is say, “Listen, if this is an individual who is high risk, who really would benefit, you want to be able to treat them if they’re positive.”

We’ll actually go in and throw in a molecular. We’ll send off a PCR test. In your situation, it sounds like with your whole scenario, all the different negative tests here, this is probably not COVID. Individuals who are higher risk should still think about going to that provider, going to that urgent care, getting that more sensitive test because as you pointed out, it’s appropriate. You don’t wait and see how people do. There’s a window that we know is related to the efficacy of these medications.

VR: That’s TWiV clinical update with Dr. Daniel Griffin. Daniel, thank you for doing another year’s worth of these. Look forward to more of them next year.

DG: Thank you and everyone be safe and have a happy and safe New Year’s.


[00:52:49] [END OF AUDIO]

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