TWiV 976 Clinical Update

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 21 January 2023

pdf of this transcript available (link)

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


VR: FromMicrobeTV, this is TWiV, This Week in Virology, Episode 976, recorded on January 19, 2023. 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: How’s your ICU looking these days, Daniel?

DG: It’s depressing that you bring that up. I just had a COVID patient die this morning in the ICU. I have to say I was a little bit surprised about the discussion. I mentioned to one of my colleagues that one of my patients in the ICU who had COVID died, and the first question, and maybe you could guess, did they die with COVID or from COVID? Then I went and I was talking to the ICU physician and they were like, “Hmm.” We went through the story. I’m like, “Well, OK, let’s think about this story.” I was talking with Dr. Lee, one of my partners, about this.

This was a kidney transplant patient who was doing fine, got COVID. During the first week, was not treated, with the whole “you’ll probably be just fine.” By about day eight, they started to get hypoxic, ended up admitted to the hospital, started with low-flow oxygen, this escalated, they were on steroids, they got tocilizumab, they required intubation, they then developed a secondary bacterial and looks like it may have also been a fungal infection, and then about day 23, this morning, they died. It’s really interesting because in my mind, that’s a COVID death. That’s a death due to COVID.

Then there was this whole discussion, “Well, but they didn’t really die from the COVID. They died from that bacterial pneumonia that developed during the end of the second week.” I was like, “Well.” This is what we saw. This gentleman was fine, got COVID, 23 days later so they’re not alive. It is really an interesting and challenging. Is this a COVID death? I would say yes but not everyone. Yes, challenging we try to get these numbers. That’s a nice entry because we’re going to get into that, but let me start with a quotation.

All right, “Don’t put all your eggs in one basket is all wrong, I tell you. Put all your eggs in one basket and then watch that basket. Look around you and take notice. Men who do that do not often fail. It is easy to watch and carry the one basket. It is trying to carry too many baskets that breaks most eggs in this country. He who carries three baskets must put one on his head, which is apt to tumble and trip him up.” This is from Andrew Carnegie from June 23, 1885 when he’s addressing the students of Curry Commercial College of Pittsburgh, Pennsylvania. It just made me wonder, is he talking about Spike?


VR: Yes.

DG: All right, we’ll start with influenza and a little bit of good news here. It’s pretty large, but I’ll put on my glasses for this. We are continuing to see that flu has spiked and is dropping. It’s actually holding to that 2021-22 season where it went up and just kept dropping. We’re hoping that’s what happens. Fingers crossed that we don’t see this rise back up. RSV, more good news today. This is from Moderna, as they reported in a press release, a vaccine efficacy of about 84% against RSV lower respiratory tract disease in older adults. Think of that as severe disease from RSV.

These are the results of the ConquerRSV trial which is a randomized double-blind placebo-controlled study of approximately 37,000 adults, 60 years or older in 22 countries, including the U.S. We’ll hopefully get some peer-reviewed publication that we’ll be able to discuss in the future. COVID updates. Here in the U.S. we may have reached a plateau with about 4,000 deaths a week. One of my colleagues was a bit pessimistic reminding me that it takes time to die, so we’ll see how much above this 4,000 deaths a week we see in the coming weeks. I’m actually hoping it’s not a plateau. That it’s more of a peak and we just drop right off the other side of this.

One of the challenges, and I think a couple challenges here, I’ll start with the first one, is this is really turned into a pandemic of the elderly. That is really the population that is being most impacted. If you follow some of the charts and they can break these down into the different ages, it’s really the 70-plus. I don’t know if anyone on this show is 70-plus, but anyone on the show or listening to the show, it’s really the 70-plus that we’re seeing this rise. Prior spikes, you saw a rise across all the different populations, but it was really just a little bit of a rise in the under 70, but it was really the 70-plus that we saw another peak here.

The other thing that I think is really a challenge, accurate and granular data is critical for understanding where we are with COVID-19. People ask, and I think they ask for many reasons. They might be a COVID denier and they say, “Oh, I’m sure those people aren’t really being admitted for COVID. Maybe it’s with COVID. Are they dying with COVID?” The other, which I think is the honest reason that people ask this question, is we want to know. Because we talk about vaccine efficacy. We talk about efficacy of different things we do.

I’m going to leave in a link to the Massachusetts Department of Public Health, and this page is updated every Thursday by 5:00 PM and probably could have updated this four minutes ago. This is data that I pulled off where here they actually break it down into cases, which I’m not sure I trust anymore, hospitalizations. Here they say on January 10th, there were 1,250 total patients hospitalized with COVID-19. There were 409 patients primarily hospitalized for COVID-19. I think that is helpful. Then gets a little bit disturbing when they mention that there were 119 patients in the ICU with 46 patients intubated.

Then they talked about confirmed deaths, probable deaths, average age of the deaths. More granular data helps us because there’s two sides to look at this. One of the sides that I am a bit concerned about is this, “I got my vaccine. How come we’re still seeing hospitalizations for COVID-19 with such a high immunity rate?” It really is a distinction. That person who shows up for a knee replacement and ends up with a positive PCR, that’s quite a bit different than the individual I described at the beginning of the show, renal transplant, gets COVID, develops that hypoxemia, ends up on a ventilator. Very, very different animals.

VR: Daniel, do you ever see kidney transplant show up with positive for flu and develop severe disease as well?

DG: Yes, we certainly do. I think that’s one of the interesting things. We’ve talked about the fact that if you’re fully vaccinated, I’m not sure what that means at this point but we’ll say three doses or more, you get early treatment in the first week. Those people are rather comparable to our flu cases at this point. Now that I have shared all this optimism, let’s get into the thick of it. The article, “The Missing Workers Who Are Never Coming Back,” in Axios by Emily Peck. According to Federal Reserve Chair Jerome Powell, one reason the labor market is so tight right now is that many workers died from COVID-19. He goes on to say that close to half a million people who would have been working have died from COVID.

Compared to pre-pandemic projections, there are about 3.5 million people effectively missing from the American workforce. This number includes older workers who left the labor force earlier than expected, and a lot of us are probably familiar with people that just said, “I just don’t feel like it’s worth it,” and have stepped out a little bit earlier than they would have. He suggests that these excess retirements might now account for more than 2 million of the shortfall. Then he says 1.5 million comes from a decline in immigration and a surge in deaths. Now, I suggested last week that if things do not add up, one needs to start asking a few more questions.

The morning our last episode dropped the South China Morning Post published the article, “China Records Almost 60,000 COVID-related Deaths after Abrupt Shift in Policy.” This is unfortunately behind a paywall, so people need to subscribe to read the full article. I’m not convinced this is accurate and all indications suggest that the death toll is much higher. I’ll leave a link into a Washington Post article where they actually show satellite footage which really suggests that a lot more folks are dying than just that 60,000 reported.

All right, right into COVID. Children, COVID and other vulnerable populations. The article, “Detection of SARS-CoV-2 IgA and IgG in Human Milk and Breastfeeding Infant Stool Six Months after Maternal COVID-19 Vaccination,” published in Journal of Perinatology. Really interesting. We have a lot of questions that come up about individuals getting vaccinated to protect them against the sevenfold higher risk of death or hospitalization during pregnancy but also, do these antibodies somehow protect the newborns, particularly that first six months of age. In this study, 37 mothers and 25 infants were enrolled between December 2020 and November 2021. For this, it is a prospective observational study.

All mothers were vaccinated during lactation except three, which were vaccinated during pregnancy. Milk, maternal plasma, and infant stool was collected pre-vaccination, and at periods up to six months following COVID-19 vaccine series initiation completion. SARS-Cov-2 antibody levels and their neutralization capacities were assessed. We’ve got a couple of figures here. I say not unexpected with what we’re seeing. Figure 2, they’re looking at SARS-Cov-2 specific IgA and milk and plasma, they say up to six months but if you really look, you’re seeing the concentration significantly elevated in this 15 to 30 days post that second dose.

Statistically still up at six months, but really dropping pretty close to baseline. Looking at plasma, again, you’re seeing the bump in that 15 to 30 days. Then when you go to Figure 3, where they have the SARS-CoV-2 specific IgG and milk and plasma, again, you see the most significant concentration rise in that 15 to 30 days sustained, but really dropping by about six months.

VR: This is passively transferred antibody from the mother, correct?

DG: Yes. I think we should make a point now of, as we’ve commented before, it’s not just they’re looking at antibodies, but there’s actually transfer of some cellular immunity as well. A little bit more than even this might suggest. Maybe giving a little bit more mechanism behind some of those studies we’ve talked about where having immunity during pregnancy can actually translate into some protection for the child. All right, moving into that pre-exposure transmission testing period.

I’m going to keep reinforcing this, have a plan and get that plan in place ahead of time. Schedule a visit to talk. I know a lot of physicians, oh, we’ll just wait, and then when it happens we’ll scramble. Let’s not scramble. Let’s come up with a plan ahead of time. What can we do to stay safer? Non-pharmaceutical interventions. The science favors mask use and suggests a hierarchy with N95s offering the highest level of protection and ventilation transmission.

There’s an interesting tweet I saw recently where we have all these rules about the water has to be clean, the food has to be safe to eat. It would be nice if we had even better, the air has to be safe to breathe in this restaurant or wherever we want to go because remember outdoors is much safer than indoors. All right, let’s move right into COVID active vaccination. People may have heard that a vaccine safety monitoring system in late November picked up a signal that the updated Pfizer vaccine booster might be linked to an increased risk of strokes in people 65 and older.

They see a signal. The signal was detected in the Vaccine Safety Data Link, a collaborative involving the CDC and about a dozen healthcare organizations with electronic health records on 12 million people. Really robust here. A deep dive into several large databases failed to confirm the preliminary information, leading federal health officials to conclude the risk is extremely low and probably non-existent. Just from the CDC site, a large study of the updated bivalent vaccines using the Centers for Medicare and Medicaid Services database revealed no increased risk of ischemic stroke.

A preliminary study using the VA database did not indicate an increased risk of ischemic stroke following an updated bivalent vaccine. Their’s managed by CDC and FDA, has not seen an increase in reporting of ischemic strokes following the updated bivalent vaccine. Pfizer BioNTech’s global safety database has not indicated a signal for extreme stroke with the updated bivalent vaccine and other countries have not observed an increased risk for ischemic stroke with the bivalent boosters.

Just a few comments here. It’s not misinformation or irresponsible to continue to monitor vaccine safety or admit that there can be rare but serious adverse events. We discussed the issues with J&J vaccine, relative risks of myocarditis with vaccination versus infection. I think if anything this should be reassuring to people that we are monitoring this and that these signals are being taken seriously. All right, I will move on to COVID early viral upper respiratory non-hypoxic phase.

The article, “Effect of Fluvoxamine versus Placebo on Time to Recovery in Outpatients with Mild to Moderate COVID-19: A Randomized Clinical Trial,” was published in JAMA. Drumroll, people are waiting. Is this the wonder drug? These are the results from the ongoing accelerating COVID-19 therapeutic interventions and vaccines active six platform randomized clinical trial that was designed to test repurposed medications in out-patients with mild to moderate COVID-19.

A total of 1,288 participants aged 30 or older with test-confirmed SARS-Cov-2 infection experiencing two or more symptoms of acute COVID-19 for seven days or less, this is that acute viral period, were enrolled between August 6, 2021 and May 27, 2022 at 91 sites in the U.S. Participants were randomized to receive 50 milligrams of fluvoxamine twice daily for 10 days or placebo. The primary outcome was time to sustained recovery defined as the third day of three consecutive days without symptoms. There were seven secondary outcomes including a composite outcome of hospitalization, urgent care visit emergency department visit, or death through day 28.

They reported that among participants who were randomized the median time to sustained recovery was 12 days in the fluvoxamine group with an interquartile range of 11 to 14; 13 days in the placebo group with an interquartile range of 12 to 13. It has a ratio of 0.96 credible interval of 0.86 to 1.06. Not seeing a significant probability of benefits. For the composite outcome 3.9% of fluvoxamine were hospitalized, had an urgent care visit, had an ER department visit or died compared with 3.8%. Not seeing much difference there.

One participant in the fluvoxamine group, two participants in the placebo group were hospitalized. No deaths occurred in either group. Adverse events were uncommon in both groups. Thus in conclusion, among outpatients with mild to moderate COVID-19 treatment with 50 milligrams of fluvoxamine twice daily for 10 days compared with placebo did not improve time to sustained recovery. These findings do not support the use of fluvoxamine at this dose and duration in patients with mild to moderate COVID-19.

VR: Do you think that seven days or less, is that too long maybe?

DG: Well, I would say particularly looking at this data there’s a couple of things and I think that’s important that you bring up, because there’s going to be a few limitations here that we’ll talk about. One is if you’re thinking of this as an antiviral, should you be getting this in within the first three to five days as we’ve seen? If you’re thinking it’s going to affect the cytokine storm, then you should be looking at that 7 to 14 days. I think that’s important. Also, there weren’t a lot of clinical events. It’s really hard to say that you reduce clinical events when you’re not seeing a lot. There is this issue, the median time from symptom onset to receipt of the drug is not within those five days, it’s really at about five days.

Not seeing a lot in this trial. All right, moving into things that are evidence-based and pretty, pretty profound evidence base. At some point, I’m just going to say early antiviral therapy, and then people will know the oral option is Paxlovid, the IV option is remdesivir. I always like to say avoid doing those harmful things. Moving into the COVID early inflammatory, lower respiratory hypoxic phase, and we just endured this with this patient who didn’t survive, starting steroids at the right time and the right patient at the right dose.

That’s that second week, anticoagulation guidelines, pulmonary support, remdesivir if early enough, immune modulation. Remember tocilizumab is now approved for this purpose, not just EUA. I’ll throw in here and this is something that you’re going to have a guest on to talk about convalescent COVID plasma at some point, Vincent.

VR: Yes, Arturo Casadevall is going to come back and talk about it.

DG: When’s he coming on? I’m going to mark that on my calendar. Well, Vincent, while you look that up I will mention the article. [crosstalk] [laughs] the article. I think that we have a new calendar. The article, “Hyperimmune Globulin for Severely Immunocompromised Patients Hospitalized with Coronavirus Disease 2019: A Randomized, Controlled Trial,” was recently published in JID. I’m going to go through this a bit. I’m going to actually say this is positive data here. As the authors point out, an unprecedented number of randomized trial demonstrated that plasma-derived antibody treatments such as convalescent plasma, or hyperimmune globulin, does not improve outcome in hospitalized COVID-19 patients.

This is missing that window, using it later on. They say, what about severely immunocompromised patients if we start that treatment early enough? The study included adult patients who are severely immunocompromised. They were infected within 72 hours after admission. Patients that had received prior treatment with convalescent plasma or intravenous immunoglobulin with neutralizing antibodies, patients with hypersensitive to IVG, patients that required respiratory support with endotracheal intubation or high-flow nasal oxygen were excluded. Make sure I just clarify that. These are individuals that we’re looking at here who are randomized within 72 hours of admission.

They have progressed to the point where they’re requiring hospitalization, but they’re not at that severe point where they’re requiring endotracheal intubation or high flow. We’re still in probably that first 10 days, but these people are immunocompromised. Different population than we’ve failed to show benefit for in the past. Patients were randomly assigned in a one-to-one ratio to receive this COVIG or an IVIG control. The COVIG is going to be this hyperimmune globulin. Anti-Severe Acute Respiratory Syndrome Coronavirus-2 hyperimmune globulin derived from a single batch containing a neutralizing titer of 900 IU per ml, so a VNT of 50, against wild-type SARS-CoV-2. The primary endpoint of this study was the occurrence of severe COVID-19 evaluated up to day 28 after treatment and defined as any of the following. This is, I should say, very severe COVID-19. One, respiratory deterioration requiring high flow nasal oxygen or mechanical ventilation. Two, ICU admission for respiratory deterioration. Three, lack of clinical improvement from day seven, so no improvement in oxygen requirement or in patients not requiring oxygen and disease burden and fever. Four, readmission for COVID-19.

A number of secondary endpoints including occurrence of severe COVID-19 in the subgroup of patients that had no SARS-CoV-2 antibodies upon inclusion, duration of hospitalization, 28-day mortality, and 4 individual endpoints that compose the primary endpoint and serious adverse events. Severe COVID-19 occurred in two, you’re going to notice small numbers here, 20% in the COVIG arm compared to seven 88% in the IVIG. That’s a placebo arm, P value of 0.015. Among all 16 seronegative patients, 13% developed severe COVID-19 in the COVIG arm compared to 88% in the IVIG arm, P value of 0.10. A couple comments here. It’s a small n with only 18 patients in this study.

A bit of challenge with only 10 in the treatment group, only eight in the control group. Also, a very special high-risk group and some treatment differences such as everyone in the COVIG arm getting steroids, one getting Toci while only 50% of the controls got steroids. No use of Toci in the controls. Also interesting that about 90% of these individuals were not infected with wild-type SARS-CoV-2. These are tested against wild-type SARS-CoV-2. Also, the trial was terminated prematurely when based on the results of the recovery trial effective monoclonal antibodies casi/imdevimab became recommended for the seronegative hospitalized COVID-19 patients by the Dutch COVID-19 treatment guidelines saying that it was felt to be unethical to withhold this therapy for patients in the trial.

VR: Arturo will be on TWiV February 24.

DG: Great. All right, now we have a lot, actually, in the COVID late phase PACS, Long COVID. First, I get comments sometimes when I speak. They’re always very kind. That’s right. I got a number of comments regarding the article,Long COVID Outcomes at One Year after Mild SARS-CoV-2 Infection: Nationwide Cohort Study” published in BMJ we discussed last week. The comments suggested that maybe I was being a little bit too rosy regarding the results. It was retrospective, was done using electronic medical records.

The comment, which I found to be unfortunately probably true but also discouraging, was that maybe people just gave up after a period of time, just stopped going to see the physicians and reporting complaints after months of not getting much help. A sad, learned helplessness which, unfortunately, is something that we are seeing too often when patients just give up after months of not being offered any solutions and experiencing some dismissiveness.

Well, let’s move on to some other articles. The review, “Long COVID: Major Findings, Mechanisms and Recommendations,” was published in Nature Reviews Microbiology. Couple things I’ll say. Mixed reactions to this paper.

Figure 3 lays out a number of hypothesized mechanisms. I think this is nice to have a conversation with your patients. What do we think might be going on? What are the different hypotheses out there? They talk about the immune dysregulation hypothesis, the microbiota dysbiosis hypothesis, the autoimmunity ideas, the endothelial abnormalities, the dysfunctional neurological signaling theories. Then we get into Table 1. I really have a lot of mixed feelings about Table 1.

For an individual, that I think all our listeners are familiar with my preference for evidence-based approaches, when I see in a table in such an august journal comments like “substantial anecdotal reports of success within the patient community,” that gets me. I always prefer, as everyone knows, evidence-based therapies and enrolling or helping patients to enroll in trials to generate that evidence to help the millions that are suffering. I was actually comparing this table to the table in the BMJ article that I’ve talked about before. I’m a little bit concerned, to be honest. What am I concerned about? I’m concerned that people will look at this table.

Maybe, for instance, the last author will tweet out just this table, and they’ll take this as a list of therapies to try without any evidence. Here we have fatigue, we have co-enzyme Q10, D-ribose, and they say ME/CFS literature. I’m not really sure what that really means. Where’s the one where they say that thing about the no active trials despite strong evidence? This is Paxlovid where there actually is a trial going on at Stanford. Just to make a suggestion there.

I’m also going to talk about the article. “A Systemic Review of Trials Currently Investigating Therapeutic Modalities for Post-acute COVID-19 Syndrome and Registered on World Health Organization International Clinical Trials Platform,” is published in Clinical Microbiology and Infection.

They start by commenting that post-acute coronavirus 2019, COVID-19, syndrome, PACS, is a well-recognized complex systemic disease that is associated with substantial morbidity. They do acknowledge the paucity of established interventions to treat patients but then they go ahead to identify 388 trials from 42 countries. Some interesting things here, I have to say. They reported that 331 trials tested mono-therapeutic strategies.

Trying one thing where 39 trials included a combination of interventions. Little challenge here I’m going to have to say, rehabilitation was the most employed class of intervention with 169 trials. I think we’ve talked a bit about the post-exertional malaise, the triggering of setbacks with overdoing exercise, and we’ll talk about pacing here in a moment. They encountered 76 trials examining pharmacological agents of various classes. Complementary and alternative medicine accomplished 64 trials looking at traditional Chinese medicine Aryuvedic, homeopathic medications, naturopathic medications, vitamins, dietary supplements and botanicals. Psychotherapeutic and educational interventions were also employed. Other interventions including transcranial current direct stimulation, transcutaneous auricular vagus nerve stimulation, general electrical stimulation, cranial electrotherapy stimulation, stem cell innovations and oxygen therapy innovations were also identified, so really trying a lot of things out there.

VR: What happened, Daniel?

DG: These are just all the ongoing trials, as soon as we get answers. I think that’s the thing. People are like, “Oh, I see they’re trying it. Let me just try it as well.” Unless you want to be a guinea pig. If you’re going to be a guinea pig, do it in a way we’re actually going to get some knowledge, a systematic investigation to generate generalizable knowledge, please. I do want to mention, and I think that this is an important article, “Effect of Using a Structured Pacing Protocol on Post-Exertional Symptom Exacerbation and Mental Health in a Longitudinal Cohort with the Post-COVID-19 Syndrome,” published in the Journal of Medical Virology.

This study suggested a benefit in a small group of 31 individuals, who’ll get a small n, that completed this six week protocol. The protocol advises the individual to stay at each phase for a minimum of seven days and the individual can use the example activities as a guide. I’ll just go through a little bit about how we’ve been using pacing in practice for folks with Long COVID. You initially start off by establishing a baseline. Is this person already exercising at some level of intensity or is this person going to start at the beginning in phase one where they’re preparing to return to exercise? You start off with, let’s say we are starting at phase one.

The example activities would be controlled breathing exercises, gentle stretching and balance exercises, gentle walking, then moving to level two, low intensity activity. This might be walking. We’ve talked a little bit about walking around the block so that a person can pause if they start to get into trouble. Moving on to moderate intensity, might involve brisk walking, jogging, and then moving on to high intensity. The big thing about each one of these phases with the pacing approach that they applied here is that when an individual starts to feel that heat, that trigger of inflammation, they stop. They try not to exceed that. This could be a long process, but here is actually, as I like, evidence to support this approach.

VR: Daniel, for years, the ME/CFS community has been up in arms over claims that this kind of exercise helps and the studies that show it are rather flawed and yet they persist even though they don’t seem to work. I’m afraid we might get into a similar situation here.

DG: I’m glad you bring that up because this is really an important distinction that I want to bring up here. This is not just “condition you back up.” This is not the idea that, oh, the reason you have fatigue and these issues is you’re just out of shape. Then they have these pretty rigorous, they call it graded exercise, where you just keep ratcheting up and this is pacing versus graded exercise. This is acknowledging that triggering of inflammation, acknowledging that post exertion malaise and being very careful not to trigger that. This is a very gradual paced approach. You have a good day, you don’t go out and overdo it because you’re going to trigger that inflammation and set yourself back.

I’m glad you bring that up because this is an important distinction between pacing and that graded exercise, which is no longer recommended for ME/CFS or hopefully for those folks with Long COVID with that post exertional malaise. Thank you. I will close out with low- and middle-income countries. No one is safe until everyone is safe. We’re getting right here to the end. I think only a couple more episodes before we finish off the MicrobeTV fundraiser until the end of January. Donations made to Parasites Without Borders will be matched and doubled by PWB up to a potential maximum donation of $40,000 from PWB to MicrobeTV.

VR: Time for your questions for Daniel. You can send them to Laura and Kip write, “We wanted to resend this document that we created a few months ago, which explains why Paxlovid tablets should not be crushed. Hope you’ll find it helpful. Thank you for your informative clinical updates.” This is from Laura and Kip who are supporters and pharm Ds out in San Francisco.

DG: Yes, I love – Are you going to post that as a PDF on the web or?

VR: Yes, I asked them if we could and they said sure and so we’ll post this PDF, which explains why you shouldn’t crush them.

DG: It’s really well written. You feel like you’re reading a novel here, the way they walk you through it. I thought it was great. They start off commenting that both components are film coated, not enteric coated. Then going through this technology that is being used, even though it seems like you should be able to, unreliable if you do that. It still leaves me with the question people ask, why don’t they formulate it so that it could be crushed, put in the apple sauce for those folks that have swallowing difficulties.

VR: Yes, how many people are in that category? Do you have any idea, Daniel?

DG: In the high-risk population, it’s a fair number. We’re talking about tens of thousands of individuals with swallowing issues who you would love to give this to, but they’re not going to swallow a tablet, so you’d love to be able to put it in the apple sauce or the pudding.

VR: Efthimis writes, “My grandfather’s 87, diabetes, high cholesterol, has issues with too high or low blood pressure leading to brain bleeds and strokes in the past, is generally a fragile and skinny individual, fully vaccinated, two boosters, taking a myriad of medicines including Eliquis, atorvastatin, metoprolol, metformin and others. I followed your advice. I contacted his doctor to set up a plan for COVID in case he gets sick. To my surprise, my doctor’s front desk told me it would be better to wait until he tests positive before deciding which therapy is best. Do you agree with this approach of waiting until symptom onset to decide which therapy to be used? If not, which therapy would you recommend? From my unprofessional investigation, Paxlovid might not be an option because of the drug-drug interactions. If this is the case is remdesivir the best option? Would an IV drug have any complications for someone like my grandfather?”

DG: Yes, as people are well aware, I always suggest you have a plan ahead of time so we’re not rushing about trying to create one at the 11th hour. I think you’re right on with your concerns about drug-drug interactions. There’s a number of medications there which would have significant drug-drug interactions. Paxlovid would be quite difficult to use without stopping actually the atorvastatin, the direct oral anticoagulant that this individual’s on some interaction with metoprolol which could be managed.

You’re probably going to move quickly past Paxlovid and then really there’s IV remdesivir. I would think that would be the most appropriate in this a context and it would be important to know is, is that something that can be accessed? If it can’t be accessed in your local area, then what is the plan? Can those other medicines be briefly stopped? I think that it would make a lot of sense to know ahead of time, so you’re not scrambling.

VR: Robert writes regarding TWiV 974 Q&A and the parent asking if a toddler should receive a second dose of MMR. Children are recommended for two doses of MMR, especially for protection against mumps and measles. Standard age for the second MMR is 4 to 6 years before starting primary school, but it instead may be administered before the fourth birthday at a minimum of four weeks after the first dose. He provides a CDC PDF for reference. Robert is in the California Department of Public Health.

DG: Oh, this is great. That I think makes a little more sense. I wasn’t sure I understood what she was asking, so I think this actually clarifies, so thank you. It’s great to have our listeners helping us with the lifting here.

VR: Our last is from Confused Pregnant Lady, “Thank you for all the information. I’m in my late 30s. I had a three-dose COVID vaccine series, got COVID four months ago, mild, almost asymptomatic. Listening to your and Paul Offit’s reasoning, I was in no hurry to get the bivalent booster and wanted to wait for more science to emerge as well as give my germinal centers time to do their thing after infection. I then got pregnant. Now at 11 weeks, the question of whether or not to boost became more urgent due to increased risk for the fetus. I’m stuck in my risk-benefit analysis. On the one hand, I can get the shot now and somewhat decrease risk of infection for most of the pregnancy. On the other hand, I would like to pass on maternal antibodies to the baby so there is rationale to wait until the third trimester at the cost of somewhat increased risk of infection earlier. I raised this question with my OB nurse and she suggested getting a booster now and another in six months seems excessive. What would your recommendation be?”

DG: This is a great question because it allows us to talk a little bit about what we know, a little bit about hybrid immunity protection, a little bit about the risk of bad outcomes for you or the unborn child when pregnant. Here’s we’ll start. You actually have that wonderful hybrid immunity, right? As I joke about, the best way to not get COVID is to get COVID, right? You’ve gotten your three vaccines, you’ve even gotten COVID, it was about four months ago. Your risk of severe disease is relatively low and then you get pregnant.

During pregnancy, we sort of ballpark the numbers that your risk of ending up in the hospital is about sevenfold increased by the pregnant status. Your risk of death is about 20-fold higher than it was not being pregnant. Those are significant. Risk of losing the child goes up if you get COVID during pregnancy. Being vaccinated and having prior infection probably reduce those. It’s been about four months, so it’s hard to know at this point how much more of a boost you’re going to get, particularly being pregnant, but the general recommendation across the board is anything you can do to reduce your risk of ending up in the hospital or not surviving.

There is probably some minimal benefit to the bivalent vaccine. I don’t want to over-promise, but there probably is some benefit. It is safe, but then what I think you’re having this discussion with the OB nurse is, what about your child? You’re going to protect them during the pregnancy, but now you’re getting to that point where you’re going to deliver. We even discussed in an article this week, in that 15 to 30 days after vaccination, there’s a significant amount of immunity that can be transferred to the child.

There is, I’ll say, science behind this actual recommendation of getting a boost in the end of the pregnancy pretty close to when you’re going to give birth. I’m giving you all the science, nothing here is as strong a push as we did early on when people were unvaccinated. You got to get those first three shots in. We still feel really strongly about that, but there is evidence that vaccination can reduce the risk of bad outcomes during pregnancy. We keep seeing growing evidence that particularly in that third trimester, you can actually transfer protection to the newborn.

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

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

[00:42:53] [END OF AUDIO]

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