TWiV 924 Clinical Update #126

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 6 August 2022

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

[music]

VR: From MicrobeTV, this is TWiV, This Week in Virology, Episode 924, recorded on August 4, 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, I wanted our listeners to know that the name of this update is changing. It used to be COVID-19 Clinical Update with Dr. Daniel Griffin. Now, it’s TWiV Clinical Update with Dr. Daniel Griffin to reflect the broadening coverage that we’re doing. What do you think about that?

DG: I think it makes a lot of sense, unfortunately, shall I say. [chuckles]

VR: Yes.

[laughter]

DG: All right, let me start right with our quotation, “What was previously perceived as nerdy is now viewed as original. What I like about nerdiness, geekiness, is it doesn’t really matter what you’re into. It just means you’re not a follower.” That’s Kristen Bell and that actually builds on my quotation from last week from Mark Twain, so perhaps Kristen Bell is the modern incarnation of Mark Twain.

I’ll share what I enjoyed recently. Recently, one of my partners, Dr. Anuja Lee, and that is spelled A-N-U-J-A, L-E-E – I do that because every time we do a transcript, I have to correct that. Maybe now, I’ll stop having to do that, but she sent me a link to a podcast called Armchair Expert with Dax Shepard. Malcolm Gladwell was on as the guest in this episode. I don’t know if people know, but Dax Shepard is Kristen Bell’s husband. I did not know that prior to this.

Apparently, Dax Shepard brings up TWiV at about 54 minutes into the episode and talks about the social contract that TWiV has with the audience. Vincent, you’re going to have to now go and listen to this. We should probably find it and put a link in. It was about this social contract, how we here, all of us here at MicrobeTV, are here to learn. We’re here to move forward. Periodically, if there’s a new scientific finding, we change our minds.

We’re not stuck. [laughs] We’re not born with all knowledge. I’m also a big Veronica Mars fan, so that’s the quotation. Also, I think Malcolm Gladwell listens to TWiV as well. I have to say, this is praise to you, Vincent, because I think you help set this tone. You invite people to be part of this tribe who share a respect for knowledge and science, not just an obsession with being correct.

VR: I think this idea of a social contract is interesting. I never thought of it that way, but it’s true, isn’t it?

DG: It’s interesting when you see different guests on different shows, they’re this, like, “OK, I’m going be asking hard questions and try to catch you.” That’s the social contract of some shows. I think the social contract on TWiV is, no, we’re all here to learn. This is a safe place. Nerds and non-nerds, everyone is welcome.

VR: It’s absolutely right. It’s a safe place. People often ask me, “Why didn’t you challenge Paul Offit on this or that?” I said, “We don’t do that. We just want to get information out there. We’re not here to challenge.”

DG: Yes, don’t worry. Someone else will take care of that.

VR: I’m sure.

DG: All right, so let’s get right into monkeypox, as we’ve expanded. We’ll leave links to the monkeypox tracker. Just to give people a sense of what’s going on with monkeypox, the numbers are pretty significant. I just took a look at the tracker prior to doing this. Over 26,000 cases outside of Africa. I’m going to keep commenting about how embarrassing is that we have to keep saying that.

Here in New York, we seem to be at the epicenter. We’re approaching 2,000 diagnoses. We’re making sometimes close to 100 diagnoses a day. I like to remind people and I’m going to have to say this over and over again. I think this is going to be a lesson that in the fall, people are going to remember and hopefully have learned. Monkeypox is not a gay disease. It’s not an African disease. It’s an infectious disease.

Also, I will just mention. You don’t have to have sex to get the monkeypox. You can cuddle. You can kiss. You can have close contact even with fomites. Those are inanimate objects. We really have to broaden our net. I saw a couple of cases just earlier today. One gentleman was along in his course. The other was a fresh diagnosis where the colorectal surgeon actually sent me photos from, “I’m seeing these odd lesions.”

Yes, this was actually a case where this had already been considered. The orthopox DNA test was already positive, but just had not caught up with the patients, so we really need to keep our radar up for this one. Remember, and this is a little bit of an update, how do you make the diagnosis? If a clinician is thinking about this or if you as a patient are thinking about this, what you’re going to want to do is get swabs, noncotton swabs, of the lesions.

Remember, Occam was not a physician, John Hickam was. You can have more than one thing, so you want to be sending off a swab for the HSV, the herpes simplex virus, and the VZV, the varicella-zoster virus PCR. Those are going to go into the viral or universal transport medium. This is an update. The monkeypox, you’re going to send off another couple of swabs. Again, this requires a little bit more effort because, a lot of times, there can be a thicker roof to these lesions.

You’re also going to send those off in universal transport medium or viral transport medium. That’s an update from dry swabs, which is what we were talking about really just about a week ago. All right, New York City is the epicenter of the outbreak outside of Africa. We are starting to hear about some of the first deaths, again, outside of Africa. Interesting enough, a couple of the individuals that died were otherwise young, healthy males. No obvious immunocompromising conditions progressed to an encephalitis.

Not clear what happened there. In general, just keep this in context. We’re talking about 26,000 cases and we’ve heard about 6 deaths so far. We have vaccines, not enough. Actually, I’m going to predict that, hopefully, people are going to be creative and come up with some ideas. How do you make those vaccines go a little bit further? Maybe we can talk about intradermal injections instead of subcutaneous.

You might be able to get about five times as many doses out there if we’re a little bit creative. There’s some science on that. I think we have to come to grips with we do not have enough vaccines for the demand that we are looking at. Treatment. We think we have treatment, but does it work? I talked about the conference at Columbia where we were discussing that it seems to work, but we’ve also talked about confirmation bias. Maybe they’re showing up when they were about to get better anyway.

The article, “Tecovirimat for the Treatment of Human Monkeypox: An Initial Series from Massachusetts, United States.” This describes a small, three-person case series. The people were not small. The number of people was a small number. This was published in Open Forum Infectious Diseases. If anything, this article just reinforces how little we know about monkeypox treatment, how little we know about the role of TPOXX. I know there are a number of proper trials being launched. It’s a few months. These trials would be nice if we already had some information from them.

VR: Daniel, when someone dies of monkeypox, what is the cause of death?

DG: It’s been different in different situations. It can progress to an encephalitis. That’s an inflammation of the brain. It can progress to a pulmonary manifestation. Actually, in some of the areas, for instance, the DRC, all these open areas can actually be portals for bacterial sepsis. There’s really a number of different ways that individuals can die.

Polio update. I’m glad I’m doing this show with you, Vincent. You’re the guy.

[laughter]

DG: As we heard, as part of ongoing surveillance efforts, New York wastewater samples are shared with the Global Polio Laboratory Network, the GPLN, which includes CDC and the WHO. The GPLN confirmed that the case in New York is genetically linked to two Sabin-like type 2, SL2, isolates collected from the early June samples from Rockland County and samples from Greater Jerusalem, Israel, as well as to the recently-detected VDPV2 from environmental samples in London, UK. Vincent, can you make any sense of what that is?

VR: In the U.S., we’re using an activated polio vaccine, not oral polio vaccine, which is infectious. In the UK, they’re using inactivated polio vaccine. In many parts of the world, they’re still using OPV, Sabin vaccine. In particular, whenever there’s an outbreak of – so the problem with these OPVs is that after you ingest them, they reproduce in your gut. They revert and they can cause polio in unvaccinated people. They spread through the population. They spread silently.

In many countries in the world, particularly in Africa, you have outbreaks of vaccine-derived type 2 polio because vaccination rates drop. What do they do when there’s an outbreak? They go in with OPV to control the outbreak. That introduces even more type 2 and type 1 poliovirus. These circulate. They spread to other countries because people travel. They bring them with them in their intestines. In Israel, in the UK, and then they can spread locally. Because if not everyone is vaccinated, these type 2 strains can make their way into their intestines.

They’re also here in the U.S. We have never done environmental surveillance for polioviruses. Now, we have, and we see that they’re in our sewers. I’ll bet the more we look, the more we will find them. In most cases, it doesn’t matter. Because if you’re immunized or vaccinated with a polio vaccine, you will not get polio. As we saw in Rockland County, their rates of vaccination are low and we had a case of polio. It’s a call for people to get vaccinated.

DG: I think they always ask the question of, “If we did waste water surveillance and we found polio, what would we do?” Maybe we would let people know that you need to keep getting vaccinated for polio because it’s here.

VR: I think that is exactly the reason to do the surveillance and tell everyone. Maybe that would motivate them to get vaccinated.

DG: All right. More to come, hopefully not on polio. All right. Let’s get into COVID. Children, COVID, other vulnerable populations. Remember, for the kids, get those vaccinations in time for the start of school in the fall. It’s interesting when I see these demonstrations, we have the anti-maskers and the anti-vaccination as one group. It seems like if we can get folks vaccinated, maybe we don’t need masks. Think about that connection there.

Also, remember, if you’re up-to-date with your vaccinations, you’re exempted from all that quarantine business. Now’s the time to get those vaccines for the fall and we’re not doing great by the way. All right. Oh, and by the way, I know a lot of people are waiting. Well, you’re waiting because you didn’t want to go first. You’re not going first. Lots and lots of people have gone. Time for everyone to go forward.

Also, this, I thought, was an interesting article because this is something that comes up not a lot, but it does come up. This “Safety and Acceptance of COVID-19 Vaccination After Multisystem Inflammatory Syndrome in Children in Spain,” was published in J Peds. This is an important study even though there are only a limited number of participants, so this is really a concern. What do you do if an individual, if a child had the multi-inflammatory syndrome? Is it safe to go ahead with a vaccine? Is it wise to go ahead with a vaccine? Is it prudent to go ahead?

This was a cohort of 42 adolescents with a previous multisystem inflammatory syndrome diagnosis. Seventy-six percent were vaccinated with COVID-19 vaccines and it really was a low incidence of any relevant adverse events. More important, most importantly, this did not trigger MIS-C or myocarditis. They followed these folks at about 10 weeks. Really safe. Go ahead and get those vaccines

Another vulnerable population I like to keep reminding people about, those with organ transplants that are on immunosuppressive medications. The brief communication, “Is the Omicron Variant Truly Less Virulent in Solid Organ Transplant Recipients?” This was published in Transplant Infectious Disease. These are the results of a single-center, retrospective cohort study of solid organ transplant recipients, SOTs, diagnosed with SARS-CoV-2 infection from December 18, 2021 to January 18, 2022 when the prevalence of the Omicron variant was more than 80% to 95% in this community.

They identified 166 solid organ transplant patients: 67.5% kidney, 13.3% liver, 6% lung, 4% heart, 9% had combined transplants. Thirty-two percent of the recipients required hospital admission, 35.8% required ICU level care, and the mortality approached 4% in these patients. Remember, these are individuals that have access to vaccines. They have access to early treatments. A significant number of these individuals even got early monoclonal antibody treatment.

We still are seeing these negative consequences. Really, be careful with all these comments about how mild folks think Omicron is.

All right, testing. I like to say use those tests intelligently. I could talk for hours and hours about how testing is being used lately in this country, but one of the things that maybe I haven’t spent enough time on is, what about those nonpharmaceutical interventions?

Masking, right? In many situations, we’re talking now about one-way masking where only certain individuals who are either at high risk are doing this because they’re trying to protect themselves, or some of us are still out there wearing the masks. The article, “Update Alert 8: Masks for Prevention of Respiratory Virus Infections, Including SARS-CoV-2, in Health Care and Community Settings”, was published in the Annals of Internal Medicine.

This is the eighth update alert for a living rapid review on the use of masks for the prevention of respiratory virus infections, including SARS-CoV-2 as mentioned in the title in health care and community settings. It’s very brief, but it’s a nice resource for all the science on mask efficacy.

All right, active vaccination. A couple of exciting things here. Updated vaccines for the fall. We have heard that now September, next month, is the target date for the updated vaccines and that there are assurances from Moderna and Pfizer/BioNTech. I spoke to a German lady today who called it “buy-in tech.” I thought that was clever. These shots will be ready by September. It’ll be Pfizer here in the U.S., BioNTech there in Germany, and Moderna for lots of other folks.

My patients are starting to get their Novavax shots. Yes, you can go to vaccines.gov. There’s a vaccine finder. You put in your ZIP code. You put that you’re looking for that Novavax shot and there now are Novavax vaccines all over the place. If you were waiting for that, you can go ahead and do it. I’ve already had some patients go ahead and start to get those Novavax shots.

VR: These are first-timers who are getting those Novavaxes?

DG: That’s what it is. This is authorized as a first time. Now, I have to say, there will be some individuals that maybe had an issue with a second dose of an mRNA that may be wanting to do this as a third shot. I think that makes sense. I’ll just sort of throw that out there. Not sure that’s right in line with the EUA, but I think it’s right in line with science. Passive vaccination. Let’s keep this “Evusheld.” Let’s not turn it into “Evushelf.” [chuckles]

I’m going to talk about a couple of articles here. Remember, this is for people with moderate-to-severe immunocompromised or those folks who cannot tolerate the vaccines. The article, “Pre-exposure Prophylaxis with Tixagevimab and Cilgavimab, (that’s Evusheld,) for COVID-19 among 1,112 Severely Immunocompromised Patients,” was published in Clinical Microbiology and Infection.

These are the results of an observational, multi-center, cohort study of immunocompromised patients that received Evusheld as pre-exposure prophylaxis between December 28, 2021 and March 31, 2022. Evusheld was administered to these 1,112 immunocompromised patients. They followed them out for a median follow-up of about 63 days. COVID-19 was confirmed in 4.4%, at least five days following treatment.

During this study period, mean weekly incidence rate was 1,669 per 100,000 individuals in this area of France and 530 per 100,000 among patients who received the prophylaxis. Among infected patients, 88% had a mild-to-moderate form. Only 12% had a moderate-to-severe form. Patients with moderate-to-severe illness were less likely to have received early therapies than patients with mild forms. That was 53.5% versus 16.7% and 4% of patients died from COVID-19.

VR: Daniel, I met a local internist today, Dr. Jackie Mayo, and she said, “Tell Daniel, I use Evusheld for my patients. It’s very easy to get. It’s not sitting on the shelf.”

DG: Excellent, excellent, so thank you. [chuckles] Thank you for your service. Now, we really have to keep doing this. Also, another study, “Association Between AZD7442 (tixagevimab-cilgavimab),” so Evusheld, “Administration and SARS-CoV-2 Infection, Hospitalization and Mortality.” This was published in CID. In this study, immunocompromised individuals aged 12 and over identified in the Maccabi Healthcare systems database invited by text or email.

I like this. They sent out texts or emails to all the eligible people, “Hey, you’re eligible. Come on in and get your Evusheld.” Demographic information, comorbidities, coronavirus vaccination, and prior SARS-CoV-2 infection and COVID-19 outcome data were extracted from the database. Rates of infection and severe disease were compared between those administered the Evusheld and those who did not respond to the invitation over a three-month period.

What are the results that struck me most? Of all the 825 immunocompromised individuals that got Evusheld, only one person, 0.1%, was hospitalized for COVID-19 compared to 0.6% in the non-administered group. No mortality was recorded among those folks that got Evusheld compared to 40 deaths in the non-administered group. After adjustment, 92% less likely to be hospitalized or die than those folks that did not get the Evusheld.

VR: Good number, Daniel.

DG: Yes, 92% reduction, right? That’s huge. Come on, why is it sitting on the shelves? All right. Now, this next one, I have to say, this is a pretty interesting one. I may have actually been involved in the design of this next trial, but this was back– Remember Regeneron? Remember the Regeneron cocktail? That was all the rage, right? Everyone wanted that. Finally, we’re getting the results. “Repeat Subcutaneous Administration of Casirivimab and Imdevimab in Adults is Well-Tolerated and Prevents the Occurrence of COVID-19.”

This is an investigation looking at the Regeneron cocktail as pre-exposure. There’s results of a phase I, double-blind, placebo-controlled trial conducted to evaluate the safety, tolerability, and exploratory efficacy of repeat monthly doses of subcutaneous Regeneron cocktail. Once a month, you’re getting a dose. This is in uninfected adults. The participants were randomized 3:1, getting the monoclonals versus placebo every four weeks. They did this for six months, so six doses.

Primary and secondary endpoints looked at safety, pharmacokinetics, immunogenicity, and exploratory efficacy was evaluated by the incidence of COVID-19 or SARS-CoV-2 seroconversion. Nine hundred sixty-nine participants received the Regeneron cocktail. Repeated monthly dosing led to a 100% reduction in laboratory-confirmed COVID-19. That’s an even better number, I’m thinking.

So, 0% in the folks that got the monthly dosing versus 4% in the folks that did not get the monthly dosing. No serious adverse events. No deaths were reported, but there’s a big limitation here and this is sort of the dating issue. This study was conducted before the emergence of several of the SARS-CoV-2 variants that are basically now resistant to the Regeneron cocktail.

We do believe that the Regeneron cocktail retains its neutralizing capacity against the pre-Omicron variants, but we are not expecting this cocktail to retain activity against several of the Omicron variant lineages. This is a wonderful proof of principle concept, but we’re going to need an updated cocktail, Evusheld, for instance, dare I mention, to protect us going forward. I will mention, Evusheld has been tested against BA.4, BA.5, and it looks to continue to be effective.

All right, the early viral upper respiratory non-hypoxic phase. Number one, what do we do? What is the recommendation? Paxlovid, but what about the Paxlovid rebound, Vincent? I don’t know about this. I’m starting to get concerned because we’re seeing Paxlovid rebound everywhere. This is a preprint, “Viral and Symptom Rebound in Untreated COVID-19 Infection.” This was posted as a preprint, posted on med – How do I pronounce that? MedRxiv?

VR: Med-archive.

DG: Med-archive. OK, that works. That’s easier to say. This is information derived from the ACTIV-2 study. Here, the investigators evaluated the incidence of viral and symptom rebound in untreated outpatients with mild-to-moderate COVID-19. Here, we’re looking for Paxlovid rebound in people that never got Paxlovid. The study population included 568 participants enrolled in the ACTIV-2/A5401 platform trial who received placebo, so untreated folks.

Anterior nasal swabs were collected for SARS-CoV-2 RNA testing on days zero through 14, day 21, and day 28. Participants recorded the severity of 13 targeted symptoms daily from day zero to 28. Here, we are seeing both RNA copy numbers and symptoms during this 28-day period. In both the primary and secondary analysis, 12% of participants had, they say, viral rebound.

Viral rebounders were older than non-rebounders. Median of 54 versus 47. Not huge. Symptom rebound occurred in 27% of participants after initial symptom improvement and in 10% of participants after initial symptom resolution. The combination of high-level viral rebound and symptom rebound after initial improvement was observed in 1% to 2% of participants.

Now, I think that this is really critical information and I have a number of comments here. Now, you and I are going to talk a little bit about this. Certainly, if you want to get that mainstream TV appearance or that featured quotation, everything is Paxlovid rebound. Here, I’m looking at the study and I’m seeing 27% of people that never even got Paxlovid had Paxlovid rebound.

[laughter]

DG: Then we also saw the way the RNA copy numbers were sort of bouncing around after day four. I think that, actually, this is a study worth looking at because people have this thing where it’s day six and they get an antigen test. It’s negative and they celebrate. For some reason, they get one on eight and it’s positive. Well, apparently, that’s now Paxlovid rebound too. There’s really a lot in here. Before I pull you in, Vincent, I want to remind people of the phases of COVID that we’ve been talking about for two years.

The first week is this viral symptom phase. You start to feel better. The second week is the cytokine storm, where maybe you start to have hypoxia. You start to feel maybe worse than you did during that first week where you might end up in the hospital. I love to remind everyone of Ian Lipkin who, during that first week, just had a cold, but then the second week got the COVID. He had Paxlovid rebound before anyone even gave the thing a name. Vincent, what are your thoughts?

VR: Well, I think this is correct that this is what happens with viral infections as you well know. Dr. Mayo told me today. I asked her, “What do you think about this rebound?” She said, “I see rebound with all viral infections, metapneumovirus, et cetera. We see recovery and rebound. It’s part of the clinical process.” The unfortunate fact of the matter, Daniel, is that it got a lot of attention from Paxlovid. The press pushed it, but they ignored the fact that it happens even without it. We’ve known this for some time. I wonder, Daniel, what is causing this RNA copy to go up and down? I wonder if it has something to do with sampling. Doing a nasal swab is not like taking some blood, right? It’s very different.

DG: I was talking to a colleague of mine, Yuan-Po Tu, who’s out at The Everett Clinic in Seattle. We put the swab in there. We do it around, but we don’t really put a housekeeper in there like, “How many cells did you get?” I know that’s a little bit tougher to do. In studies like this, it would be nice to see, or is it just that we’re getting different amounts of samples or we’re getting more mucus-less cells on each day? I think that would help.

VR: You could normalize it to the housekeeper and then you could get rid of this jumping up and down, I bet, yes.

DG: Exactly.

VR: Daniel, when you take blood or you do HIV viral loads, do you see this kind of up and down?

DG: Blood is a little bit different, right? Because with blood, it’s how many RNA copies per microliter, right? Certainly, you know how much blood you drew. You know how much blood you’re putting up.

VR: Exactly.

DG: With swab, I notice, you don’t know. When we used to do the qPCR in the lab, we would always have a housekeeping gene that you threw in there. Maybe it was like actin or GAPDH or something.

All right. Remdesivir, number two theoretically, but no one can get it. It might need a new name. We need to operationalize that a little bit better. Maybe the drug company could do something. I think their sales are dropping by the way.

The case report, “Extended Remdesivir Infusion for Persistent COVID-19 Infection,” was published in Open Forum Infectious Diseases. This is a case study of a five-month persisted COVID-19 in an immunocompromised patient who was, they say, successfully treated with a 30-day course of remdesivir. They did prolonged remdesivir infusion. They followed the CT values, suggesting that might be something to consider in some of these folks who just don’t really have the immune system to help them clear the virus, so interesting.

Then three and four, a little bit of a change here, right? When this first came out, the NIH was really firm like, “These are in this order.” I think, now, it’s monoclonal or molnupiravir as the three and four. Most of us still hold bebtelovimab, the last-standing monoclonal antibody, as number three for a few reasons. One is that if we’re usually going here, it’s because we’re trying to avoid drug-drug interactions.

It’s also based upon our experience with the other monoclonals where we were seeing about an 80% reduction in progression. So, 80%, where molnupiravir, about 30%. You could imagine the preference there. Molnupiravir is a much easier lift because, remember, though it’s only a 30% reduction, we don’t have to worry about renal issues, no drug-drug interactions. You can call it into your local pharmacy, millions of doses sitting around, so just leave that as a comment there.

All right. Now, the second week, the Paxlovid rebound week, the early inflammatory lower respiratory hypoxic phase. Remember, this is the time when you consider steroids at the right time in the right patient. Anticoagulation, pulmonary support, maybe remdesivir if you’re still a little bit early, and then immune modulation on top or instead of the steroids. We’ve talked about tocilizumab, but what about baricitinib? That’s our Janus kinase inhibitor.

I’m definitely fascinated with the whole concept of immune modulation versus just shutting stuff down. The paper, “Baricitinib in Patients Admitted to Hospital with COVID-19 (RECOVERY): A Randomized, Controlled, Open-Label, Platform Trial and Updated Meta-Analysis,” was recently published in The Lancet. More data from the RECOVERY trial. Eligible and consenting patients were randomly allocated 1:1 to either usual standard of care or usual standard of care plus baricitinib.

4 milligrams once daily by mouth for 10 days or until discharge if sooner. The overall outcome was 28-day mortality assessed in the intention-to-treat population. Overall, 12%, of the 4,148 patients were allocated to baricitinib versus 14% in the usual care. Oh, sorry about that. This is how many died. 12% in baricitinib versus 14% in the usual care. We were seeing a 13% proportional reduction in mortality. Not as impressive as steroids, but definitely something to consider among your options.

All right, avoid those unnecessary antibiotics and unproven therapies and let us get to the late phase. The article, “Cognitive Impairment 13 Months After Hospitalization for COVID-19,” was published in Open Forum Infectious Diseases. This is something I’ve started trying to formally check in my patients. A lot of them are quite upset with the cognitive deficits. This study assessed cognitive function 13 months after hospital discharge for coronavirus disease, COVID-19, using computer-based cognitive tests.

I’m always interested in how to approach and document cognitive impairment in my patients with post-COVID. The patients here completed a tablet-based battery of one warm-up task and then four cognitive tests from the Cambridge Neuropsychological Test Automated Battery. The system has been validated in a variety of neurological and psychiatric conditions. The four tests were: One, delayed matching to sample, testing short-term memory, visuospatial processing, learning and attention.

Two, One Touch Stockings of Cambridge, testing executive function, including higher-level thinking and decision-making processes. Three, rapid information processing, testing sustained attention. Then, four, spatial working memory, testing working memory and strategy. This whole testing takes about 34 minutes to complete, so you could get through one of these in as long as it takes to get through one of these clinical updates. Basically, they found, compared to population norms, 14% to 25% of patients were impaired in each dimension and 53% had cognitive impairment in one or more of the four tests. There was some association they were seeing with acute COVID-19 disease severity.

VR: Daniel, I wonder what these population norms are. Are they pre-COVID population norms? In which case, I would say, “Now, get people who went through COVID without getting infected maybe and see how stressed out they are.”

DG: I think that’s a good point because COVID has been hard on everyone. I think all of us have taken a bit of a hit. If you’re doing worse than everyone else compared to post-COVID, then that’s actually saying something. All right, so as I always like to end, no one is safe until everyone is safe. This applies to what we’re seeing with polio, what we’re seeing with monkeypox, what we are seeing with COVID-19. It is amazing. We talk about vaccine scarcity here in the United States and in Europe. What about vaccine scarcity in Africa?

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VR: It’s time for your questions for Daniel. You can send them to daniel@microbe.tv. David writes, “My 97-year-old father was diagnosed with COVID May 2. He’d been taking Coumadin for years. Doctors told him to go off Coumadin while he took a course of Paxlovid five days. After finishing the Paxlovid, he started Coumadin again. Two days later, he had a blood clot in his arm, sent him to the hospital. A number of doctors since have told us there was no reason to take him off Coumadin while he took Paxlovid. Just curious if there’s some miscommunication here. He’s been in and out of the hospital since. Pneumonia, two liters of fluids in the lung, swollen legs, et cetera.”

DG: This is tough. Here’s what I’m going to say. Prescribing Paxlovid is not just a, “Oh, what problems do you have? What medicines are you on?” Click, click, “I’ll send that in.” A couple of things you need to know is, one, you need to know what the medical problems are. You need to know what the kidney function is. You need to know what the list of medications are.

You also need to know why a person is on those different medications because some of the different medications are going to have interactions, right? The person wants to take their Cialis. Well, that’s easy to say. Just don’t take your Cialis. Things like cholesterol medicines, usually very easy to stop for those 10 days. Certain medications, so our direct oral anticoagulants are, well, Coumadin. In this case, there can be interactions. Actually, it can be a little bit challenging to figure out what exactly to do.

We talk about how the ritonavir is a pharmacological enhancer. It’s going to work through the CYP3A, the cytochrome system, but there’s different cytochromes and warfarin actually has two forms. It’s actually a mix of enantiomers. There’s an R-enantiomer and there’s an S-enantiomer. The S-enantiomer is more potent, but it’s metabolized by a different CYP than the R. You can actually end up in short-term use, the short five-day course of ritonavir.

You can actually increase the amount of blood thinning or the anticoagulation you’re getting with the warfarin. What’s recommended, and, actually, there are recommendations in the package insert, is you can monitor with the INR during this period of time. You could potentially consider halving the dose of the warfarin, but you got to ask yourself, “Why is the person on warfarin?” If the person’s on warfarin for atrial fibrillation, they’ve calculated maybe a 1% stroke risk per year.

OK, that’s a situation where you may consider stopping it. This sounds like a person who’s hypercoagulable, to begin with. There’s a hypercoagulability that comes with COVID. In a situation like that, you really want to think about stopping it. Again, this is a challenge. I understand that the physician may have made a decision here to say, “Well, let’s just go ahead on the side of stopping it.” This is a challenging decision, managing some of the drug-drug interactions.

VR: Kayla writes, “I’m a clinical pharmacist currently involved with COVID treatment through the VA. My role involves assessing patients for early outpatient treatment with either Paxlovid or molnupiravir. As you might expect, I often run into issues with drug-drug interactions and Paxlovid, so I have to consider alternatives. I rarely am able to offer IV remdesivir due to logistical constraints, but can sometimes offer IV bebtelovimab if the patient is willing to come into the ER for an infusion.”

“I’m curious why you ranked molnupiravir as a last-line option when it’s my understanding, it’s a similar level of recommendation compared to IV bebtelovimab. I deal with many patients who live in rural locations are unable to come in for IV treatment. How can I talk about the effectiveness of molnupiravir compared to IV bebtelovimab to better help my patients decide between these two treatment options? Appreciate your insight.”

DG: Now, this is great. It actually dovetails really well with the last question. Paxlovid is not always the easiest lift, the best choice for every patient, right? Because as we saw, here’s an individual where there was the reason to take them off the warfarin, and then they have complications not being on this medication. That would be a situation where, boy, in retrospect, other options might have been considered.

Again, in retrospect, it’s easy to Monday night quarterback. You may be looking at this. You may be looking at a patient be saying, “You’ve got some situations here where I’m not happy with Paxlovid. I want to look at alternatives.” As we’ve mentioned repeatedly, remdesivir has not been well-operationalized, which is terrible. Then you’re back to monoclonals or molnupiravir.

Here’s a couple of ways to compare it. Probably, the most important thing we’ve seen in all our studies is the earlier you get treatment, the better, right? If it’s day two and you get them started on molnupiravir right away versus, “Oh, we’re going to schedule and you’re going to get a call. Maybe in four days, you’re going to get that monoclonal antibody,” I’m not sure that that monoclonal is going to provide you better efficacy than early start on molnupiravir.

I think it can be individualized. The age treatment guides have put these in alphabetical order as the third choice. I think you can look at it this way. If you’re a rural area, it’s going to be several-day delay in getting the monoclonals. That person then has to travel and go wherever they have to go versus being able to just call in a script for molnupiravir to a local pharmacy. It’s going to be a lot of situations where molnupiravir is fine. It’s an appropriate choice. May even be the best choice for that patient.

VR: Aaron writes, “I was thinking about monkeypox and wondered how much of a transmission risk public swimming pools represent if someone who’s infected visits one.”

DG: We think the actual swimming in the pool is low risk. Vincent, you can jump in on this. We think that the pool water itself has enveloped the virus. We think that chlorine is going to be helpful here. What’s going to get you in trouble is sharing towels at the pool, things like that, the close contact, a lot of naked people rubbing against each other, stuff like that. Yes, the actual swimming in the water if you want to jump in and do some laps, we think that that’s pretty low risk.

VR: Brian writes, “Is there a recommended amount of time to wait after recovery from COVID before getting a monkeypox vaccine?”

DG: I would just wait the two weeks. I’d wait till you get over it no longer isolating for the infected. I don’t think there’s any formal recommendations out there other than just vaccines in general. Wait for that 14 days and I’ll throw monkeypox in with vaccines in general.

VR: Our last one is from Selvi, who writes, “I’m a 34-year-old healthy woman, currently 29 weeks pregnant. Overall, uncomplicated pregnancy, fully vaccinated, two Moderna, Pfizer booster. About a week after the Fourth of July, I became symptomatic, tested positive for SARS-CoV-2, mild illness, sick about a week, not prescribed Paxlovid, just told to rest and drink lots of water.”

Everything was fine with the baby on ultrasound. A couple of nights ago, I went to a large stadium concert in Los Angeles where COVID rates are very high, not really considering the risk of getting COVID again having just had it. However, now I’m starting to worry about the possibility of reinfection. What’s the likelihood of being reinfected so soon after having just recovered?”

“Have you ever heard of such cases in people who are pregnant and, therefore, somewhat immunocompromised? Could a second SARS-CoV-2 infection at this stage in pregnancy have more severe negative consequences for the baby or perhaps less than the first? Basically, how worried should I be? Would pushing for a Paxlovid prescription if I were to be reinfected at any point during pregnancy help curtail any potential negative outcomes of a second infection?”

DG: We covered either the last or one of the recent Clinical Updates about how getting a COVID infection in the last trimester can be associated with significant increased risk of preterm birth. Getting COVID during that last trimester is not great. As far as reinfections, in a sense right now, we’re in an interesting time. Everything is BA.5, right? It’s like over 80%, so we’re not, so far, seeing BA.5 reinfections.

A lot of the reinfections with COVID over time has been you’re going through the variants. We certainly have some people who are collecting the variants like Pokémon or stickers. A couple of things that are reassuring. One is that, yes, having probably had BA.5 recently. I don’t think we’ve seen any evidence or seen any studies or heard any reports about someone then getting another BA.5 infection very shortly after that.

Again, we don’t do a great job in the States here of tracking, “Which variant do you have?” The second, I think this is really the comment that’s the most important, is getting COVID during pregnancy is not great. What we saw from that recent study is getting COVID during that last trimester is not great for you or the baby. You probably want to lay low and just make some lower-risk decisions just for that last trimester, and then you’re going to be locked away with the baby.

VR: Paxlovid is not a problem, right?

DG: It’s not a problem. There’s a whole section. I think we’ve talked about Section 8.1, where they address pregnancy. Actually, it is not contraindicated actually with pregnant women, pregnant individuals being a high-risk group. It’s actually an appropriate group to be treating with Paxlovid.

VR: That’s TWiV clinical update number 126 with Dr. Daniel Griffin. Thank you, Daniel.

DG: Oh, thank you, Vincent. Everyone, be safe.

[music]

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