TWiV 880 COVID-19 Clinical Update #107

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 26 March 2022

pdf of this transcript available (link)

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 Number 880, recorded on March 24^th, 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: For update Number 107, what are we up to Daniel?

DG: Well, I’m hoping this goes more smoothly Vincent, and if our listeners know but we had to piece together multiple cuts as I was losing electricity– what about very eight or nine minutes?

VR: It was very interesting, yes

DG: No, but I looked, you couldn’t even tell.

VR: David does a good job.

DG: Good job, thank you David. All right so let’s get right into it, I’ll start with my quotation, we actually have a lot to cover. “Politics is good when it works properly, disagreements get solved without people beating each other up, but when a regime knows its days are numbered there’s always the chance it may use its position to change the rules and make the debate it is losing irrelevant.” This is from Vernor Vinge. I actually got the opportunity to do some sci-fi fiction reading, this is from his book The Children of the Sky nice to take a little bit of a break.

I try not to be political so that’s as political as I will get, just throwing that out there, and then people can interpret am I talking about the Ukraine or Ukraine not the Ukraine, am I talking about Kiev, am I talking about Russia, or am I talking about something closer to home, so I will leave that. I am back from Panama, here in the US, and actually it was a great trip. It’s always nice to get back with Floating Doctors down there, really some tremendous people, great to get out to the villages, great to feel like you’re making a difference.

Actually maybe I’ll mention this a little bit later, but our itinerary was a little shifted, because the original we were going to go to a rather remote village, but the first lady of Panama was down there doing a vaccine booster drive, so really great to see that that’s going on down there. Let’s get right into it, I’m sure our listeners, well I don’t know if I’m so sure, but our listeners may have heard about Moderna’s announcement seeking authorization of its vaccine for children under 6.

We have a press release on March 23rd, the press release, “Moderna Announces its COVID-19 Vaccine Phase 2/3 Study in Children 6 Months to Under 6 Years Has Successfully Met its Primary Endpoint.” This was posted and this is the interim data from the KidCOVE study. For this study the company enrolled approximately 11,700 pediatric participants in the US and Canada, approximately 4,000 children ages 2 to under 6, approximately 2,000 children six months to under 2.

The interim analysis, trying to figure out those all add up, the interim analysis shows a neutralizing antibody response in both age groups after a 25 microgram two dose primary series of mRNA 1273, that’s the Moderna, along with a favorable safety profile. They reported this two-dose primary series provided similar immunogenicity, to the hundred-microgram two-dose primary series in adults ages 18 to 25, meeting the non-inferiority criteria and immunobridging goals.

As far as safety, no deaths, no myocarditis, no pericarditis, no multisystem inflammatory syndrome, yes raise your hand there Vincent. What have you got?

VR: What is immunobridging?

[laughter]

DG: OK, I have this in my notes, first, what is immunobridging?

VR: Sorry, I didn’t see that.

DG: No this is perfect, this is the first thing, you don’t have to admit your read ahead. This is actually tricky with COVID, because this is this concept is you’re going to look at a correlate of protection, so we don’t need to do these large numbers, and time required to do actual efficacy trials. Now are levels of neutralizing antibodies correlates of protection?

VR: Well they correlates of protection against infection, but that doesn’t last right?

DG: Yes and even if you thought they were against what variant? What about the T cell data? I’d love to see the T cell data, I would love to have a little bit more confidence in the correlates here. It is a little tough to actually be immunobridging without confidence that we have those correlates of protection.

VR: Immunobridging is saying, “We got this antibody level, and we think that’s good enough to protect you,” right?

DG: That’s exactly what it is here, that’s the immunobridging they’re talking about, talking about levels of neutralizing antibodies against well which variant they don’t tell us, I assume it’s not Omicron. A little bit of a problem there. Then they say, “You know what? We’ve got some efficacy data. It wasn’t our primary endpoint but after this discussion of immunobridging, you’re probably going to want to know so by the way, did you get any efficacy signal?” They note that the Omicron SARS-COVID-2 variant predominated in the US during the KidCOVE study, so we’re looking at potential efficacy in that context.

The vaccine efficacy for preventing symptomatic infection in children, six months to two years was 43.7 and then vaccine efficacy was 37.5 in the two to under six years age group, they comment that the majority cases were mild, no severe COVID-19, no hospitalizations, no deaths.

VR: Daniel, so I interrupted you before you gave the safety data, so that’s important.

DG: I think that’s interesting and I think that’s really important, because that’s always when parents come to me and say, “I don’t know, I’m worried about myocarditis, I’m worried about the heart issues.” A couple things here, and that is really, they’re not seeing that, thousands of kids, but we want to see more, and even outside this age group. Now that we’re recommending the timing between the first dose and the second dose being 12 weeks, really have significantly decreased that risk of cardiac issues.

I always like to remind people when we do see those after vaccination, very very rare tends to last a day or less, 99% of the time that’s the end of it, but we are certainly seeing a lot of cardiac issues with infection. What is the FDA going to do with this? Oh Vincent’s got his hand up again, go for it.

VR: What do you think about these efficacy numbers 43 and 37, and that’s against all symptomatic COVID, so what’s the story? It’s rather low, don’t you think?

DG: It’s interesting, so it’s rather low, it’s perfect that you asked this, because what’s the bar for kids? We were told for adults, it had to be greater than 50%, we were told there needed to be a certain efficacy, and we met that, actually quite a bit more than met that. This is below that, we don’t have a prescribed efficacy requirement, so it is interesting. There’s a couple other interesting things here, OK, this is two doses, what about a third, do people want to start going down this road now? Is this going to probably require a third also?

How does this compare to what we’re seeing adults, and the other is the amount. I think I’ve talked about this before. I’m not sure that 25 micrograms of RNA in Moderna translates into 25 micrograms in Pfizer. Pfizer is using a much lower amount of RNA, so the system’s a little bit different too. There’s a lot here for the FDA to look at, this is not a slam dunk, this is not that 94% efficacy that we saw for the adults early stage.

VR: The Pfizer efficacy wasn’t that great either right?

DG: Yes. All right so not a slam dunk, but this is out there, we will hear there’s got to be at least 15 days after the formal filing, we’ll hear what the FDA wants to do there. All right, CDC MMWR early release, “COVID-19 Associated Hospitalizations Among Adults During SAR-CoV-2 Delta and Omicron Variant Predominance, by Race/Ethnicity and Vaccination Status, COVID NET, 14 States, July 2021 Through January 2022,” so people can look at those dates and realize what we’re talking about.

This is data from the COVID-19 associated hospitalization surveillance network so COVID NET, and they’re going to be comparing COVID-19 associated hospitalization rates among adults greater than or equal 18 years of age, during the Delta period to the Omicron period. A couple things I want to point out, during the Omicron predominant period, weekly COVID-19 -associated hospitalization rates, per 100,000 adults peaked at 38.4 compared to 15.5 during Delta predominance, so more than twice as many hospitalizations per 100,000 during Omicron compared to Delta.

Also I will say hospitalization rates during peak Omicron circulation among unvaccinated adults remained 12 times the rate among vaccinated adults who received the booster or additional doses four times the rates among adults who received a primary series, but no booster or additional dose. This is actually the meat of the study here. People will say, “Oh, but you just had so many more Omicron infections, and no wonder you had so many more during the Omicron predominant period.” Peak hospitalization rates among non-Hispanic blacks, black adults were nearly four times the rate of non-Hispanic white, so white adults, and was the highest rate observed among any racial and ethnic group during the pandemic.

I think when we we’re talking about mild and the impact of this disease you have to be really asking the question who are you talking about? Are you talking about vaccinated white people? Are you talking about vaccinated black individuals? Are you talking about unvaccinated individuals? Later I’ll be asking the question are you talking about children? Particularly those who are too young to get vaccinated? Right to children. I like this. This just came out, just got posted as a pre-print, or I should say, just came to my attention.

“Intrinsic Severity of SARS COVID-2, Omicron BA2, the Stealth Variant in Uninfected Unvaccinated Children, a Population Based Case Control Study on Hospital Complications”. This was a population based study where they retrieved data from the HK, Hong Kong territory wide CDARS database of hospitalizations in all public hospitals and compare severe outcomes of the Omicron BA2 dominant fifth wave, so N of 1147 prior SARS COVID-2 variance 1st of January, 2020, to 1st of November, 2021 N equals 737.

They’re also looking at influenza. I’m going to not focus much on that. I’m going to focus on comparing the COVID variants. They reported a higher in-hospital case fatality rate for Omicron than other SARS COVID-2 variants. The pediatric ICU admission was higher for Omicron than other SARS COVID-2 variants with an odds ratio of 18.5 so almost 20 times more likely to end up in the PICU and the proportion of neurological complications was at almost 15% for Omicron.

At least in the data we’re seeing here, the intrinsic severity of the Omicron stealth variant, it is not mild as evident by the fatality and severe complications in uninfected unvaccinated children.

VR: I think that’s very important to point out because I can point to you a number of papers where they say Omicron is mild, and I think as you said earlier, it depends who you’re looking at, right?

DG: What makes Omicron mild is being vaccinated.

VR: Yes, absolutely.

DG: I think this is tough. I know here in the United States, the number of children dying per day has finally started to decrease, so that’s encouraging, but I’m going to be doing a call– It’s actually later tonight when we’re recording, but it’ll be early in the morning in Hong Kong. It’s with some of my colleagues there in Hong Kong, taking care of these children really upsetting what is going on there. One of the issues that hopefully I’ll be talking to them about is one of their policies is when parents come to the hospital with their children, there’s a separation of the child from the parent.

A lot of parents do not want that, so they’re staying home, and unfortunately the stories they’re sharing is parents showing up a little too late when the child has already died. I think when people are looking at vaccination in young people, this is my opinion, I’m making an opinion. I try not to make opinions, but maybe I’m saying the science would suggest that you don’t just look at-one time risk. What’s the risk of a child getting infected once and the complications? Hopefully this is a lifetime risk.

This child is going to grow up, potentially have repeated infections, so you want to say is the one-off risk associated that you see with the vaccine series, versus the multiple risks every time a child might get infected. The science really suggests vaccine is always the safest choice. I also like to talk in this section about women who are, or might become pregnant, and the paper, “SARS CoV-2 Placentitis and Intraparenchymal Thrombohematomas Among COVID 19 Infections in Pregnancy.”

There’s a paper published in JAMA Network Open. The introduction of this paper was interesting. They point out some of the things we’ve discussed before. Increased for still birth in individuals, and here we’re actually looking at placental pathology. This study comes out of MGH, where all the SARS COVID-2 exposed placenta, so these are women who were infected during pregnancy. The placentas were pathologic examined.

They identified 47 cases of SARS COVID-2 placentitis in all the cases, the placentitis the inflammation of the placenta, the ITIS of the placenta was diffuse, so greater than 50% involvement. 62% had multiple intraparenchymal thrombohematomas, so these thrombohematomas in the body of the placenta of these 72% resulted in stillbirths, 17 of the placentas without thrombohematomas did result in live births. They went through and looked at different viral variants, but I will say all the patients they were looking at except for one were unvaccinated.

There was one individual who was vaccinated. The vaccinated patient had a PCR-confirmed infection, seven weeks prior to delivery. Went ahead, got vaccinated, and her term live birth was without any thrombohematomas. Concerning study, and I think just more to reinforce the importance of getting vaccinated.

VR: Daniel, do we understand the basis for the placentitis? Is it just inflammation or is there actual virus reproduction in the placenta?

DG: I don’t think they did the rigorous virus isolation to convince me that this was viral replication, so I’m not sure I know from this study, if it’s inflammatory process, or a direct viral invasion. PCR is not viral isolation, just like to point that out. I think our listeners know that, Vincent.

VR: Well, that’s the good thing about repeating something over and over again. Daniel, years ago when I was a graduate student, my advisor said, “Vincent, it’s never a problem to repeat things, especially with medical students.”

DG: Yes. I think we teach dogs and so I think a dog takes five times. A medical student, it’s seven, sorry. One big challenge in medicine is making a diagnosis without diagnostic support, and so that was something we experienced quite a bit recently down in Panama, we’re in the testing section. As I like to say, never missed that opportunity to test. You cannot sequence what you do not collect, but there were strict rules early in the pandemic about who we could get tested for, a lot of discussion about, well, maybe we could do this test.

Maybe we could do that test. I still remember a discussion in the early days here in March and I was like, “You know what the best test to tell whether or not someone has COVID 19? It’s this SARS, COVID-2 PCR test. It’s actually a COVID test.” Well, the paper predictive value of isolated symptoms for diagnosis of SARS COVID-2 infection in children tested during peak circulation of the Delta variant was recently published in CID.

In this study, they looked at 602 children aged less than or equal to 18 years old. Yes, symptomatic children were more likely to have a positive test, but asymptomatic children were still testing positive. Also children, one isolated symptom, were not significantly different from children with multiple symptoms in terms of testing positive. Just reinforcing, if you want to know if someone has an infection with SARS COVID-2, if you want to know if they’ve got COVID, you got to test. You can’t just ask them a whole bunch of questions.

Pre-exposure testing, we talk about masks, reducing exposures, spending time outdoors, just my comment here, the lifting of mask mandates does not mean you have to lift your mask off your face. I just was on a call earlier today with folks over at Memorial Sloan Kettering, and there are definitely certain individuals who after a discussion with their healthcare provider may want to go ahead and continue to wear a specific type of mask to protect themselves.

The choice is still there. If you’re wearing your mask and someone gives you a hard time, let them know Dr. Griffin thinks it’s okay if I want to do this. All right, never miss an opportunity to vaccinate. We have heard that the FDA’s expert panel will discuss the US boosting strategy coming up on April 6th. This has become a little bit of a hot-button topic. I will plan to discuss this when the meeting is held.

Part of this discussion will actually be around what population might benefit from a four shot series, versus a three shot series, and we already actually have some guidance on that for particular individuals who are immunocompromised. I don’t know, Vincent are you convinced at this point that a certain group of our population benefits from a third dose?

VR: A third or a fourth dose?

DG: Going after third here?

VR: Well look, I got a third dose and Columbia required it, so I didn’t have much of a choice.

DG: Did you do it under duress? Were you kicking and screaming?

VR: No, actually I had decided, because I thought the broadening of the antibody response to include Omicron by the third dose to me made sense, even though we don’t know what effect that has on disease. According to Paul Offit, as you know, he thinks in most people two shots is enough to prevent severe disease, and a third shot might be required in older people immunocompromised or immunosuppressed. That may be the case, but I haven’t seen any data saying that a fourth shot would be needed. That’s really surprising.

DG: Yes. I think the discussion is already moved right to that fourth dose. Omicron did change things, it changed some of the things, but the most compelling data is that infection, how long will that reduction last? I think we’ll talk a little bit as we go forward, but passive vaccination. What about those people that you even give them that fourth dose, because they’re immunocompromised? Some of those individuals are still not going to get the same level of protection that some folks get after even just two.

We got a press release from AstraZeneca and the data posted as a preprint. We go right to this “Resilience of S309 and AZD7442 Monoclonal Antibody Treatments Against Infection by SARS-COVID-2 Omicron Lineage Strains.” I think at this point our listeners are getting pretty used to these cell-based assays where we use pseudo type virus or maybe we use actual virus in a BSL3 to check neutralizing activity of monoclonal antibody therapies.

What about FC mediated activity? What about the all the other things that a monoclonal antibody can do? Well, I really enjoyed this preprint at this point, because here the researchers are using a human FC gamma R transgenic mouse that expresses the ACE2 receptor to test multiple monoclonal antibodies as monotherapy or combined against Omicron sub variants. Encouraging, they reported that using this system the VIR-S309-LS.

This is the parental monoclonal of sotrovimab and the AstraZeneca cocktail Evusheld that’s what we’re talking about here, against three SARS, COVID-2 Omicron lineage variant. BA1, BA 1.1, BA.2 retained potency. This is actually, I will say a rather dense and sophisticated pre-print. I’m not suggest that everyone run out and dig through the data, but what I really liked is what I pointed out.

This is really an in vivo system. Allows you to look at mechanisms beyond just the neutralization, not just the blocking of viral entry, and actually suggesting that there may be some FC effector mediated benefits makes me feel maybe a little bit better about sotrovimab also makes me feel a little bit better about Evusheld and so just a little bit, what am I talking about? Dr. Griffin what are you talking about? This is supposed to be the COVID clinical update, not the deep dive.

Just very quickly, just remember these monoclonals are basically Y shaped, and the shaft of the letter Y is what we refer to as the FC portion. When the antibody binds that FC portion actually allows other immune cells to get in the game. Natural killer cells, monocytes, other immune cells. This system rather than just looking at that blocking of entry can actually bring some of the other players into play. All right. Period of detectable viral replication.

Someone tests positive, time for monitoring, monoclonals, antivirals enrollment in clinical trials, not the time for steroids or antibiotics or other harmful potions, no aspirin, no zinc, but let’s go right up front. Now, there was a great deep dive and actually I got to listen to this today, Vincent, the discussion of the paper, “De novo Emergence of Remdesivir Resistance Mutation During Treatment of Persistence SARS COVID-2 Infection in an Immunocompromised Patient,” a case report published in Nature Communications. I’m just going to do a shallow dive here, but I do recommend to everyone listen to what number TWiV is that Vincent?

VR: TWiV 879.

DG: 879 so one right before this. Here the authors present a case of an immunocompromised patient with an acquired B cell deficiency. Those antibody producing cells are deficient and they go on to have a protracted course of SARS COVID-2 infection. They get treated with Remdesivir therapy. The symptoms get better. They defervesce, the fever goes away. They get what they describe as a transient virological response, but then the course was complicated by recrudescence and they’re not feeling like they got cured and reinfected, but the crud stayed and then came back.

They described high grade viral shedding. They go ahead and they identify this mutation. The interesting thing is I’m going to couple interesting things here. They go ahead and they throw monoclonals at this person and then they feel like they achieve success there. They also feel like they’re describing that this change has a fitness cost. We’re not seeing this sweeping the world. They did a look in all the sequences we have out there.

This looks like it confers such a fitness cost that this isn’t likely to go on. I don’t feel like the sky is falling. My perspective from the clinician is this doesn’t give me that. Oh my gosh, we’ve got to start using dual treatment and everyone it looks like to develop the Remdesivir resistance compromise the fitness of the virus. Vincent, you want to jump in on this?

VR: Yes, I think that’s the good take. This virus they show is resistant to Remdesivir but it replicates poorly compared to the ancestral virus. As you say, it’s not likely to be a population threat, but they do come include that we should make sure we monitor virus in this population of patients, because who knows they did see other mutations emerge quite a few, and we should monitor them just to be sure there’s nothing going on.

DG: I think that’s reasonable. Hopefully, during times when numbers are a little bit lower, we can start doing a bit more of that. We need to do more of that. Actually connecting with point of care and patient management, not just off at some variance surveillance level. All right, how can we have a COVID clinical update without discussing ivermectin? I did just get back on Tuesday morning from Panama, where I was using a bit of ivermectin for scabies, for its indicated treatments.

The article, “Comparison of Trials Using Ivermectin for COVID-19 Between Regions with High and Low Prevalence of Stongyloidiasis a Meta-Analysis,” was published in JAMA Network Open. Now this is a meta-analysis of 12 randomized clinical trials involving 3,901 patients. Studies were excluded in the event, publications revealed, suspected trial fraud or randomization failure. It’s painful that you actually have to look so closely in this area, but this has become a problem.

They were looking here at whether there was a relationship between ivermectin and regional strongyloides prevalence. Remember this is a disease strongyloides where there are immune issues, lots of steroids are– COVID is where we’re seeing a disease where there’s immune issues, lots of steroids are being used, and some of our This Week in Parasitism listeners are very familiar how strongyloides and strongyloides hyperinfection syndrome, can take advantage of these situations.

What is strongyloides Dr Griffin? You’ll have to listen to This Week in Parasitism. I think Dickson does an intro TWiP in This Week in Parasitism, but strongyloides is a parasite that infects humans and other hosts there’s different strongyloides subspecies. There’s this auto infection cycle. This parasite can actually stay in a human being for decades. When a person gets exposed to steroids, you can actually get an acceleration of the life cycle, allowing this to potentially become invasive.

Now the global prevalence about 8% of people in the world are infected with strongyloides. That’s quite high. I was looking through some areas have a higher, so 10 to 15%, maybe down in Brazil, maybe as high as 30% in areas like Bangladesh, so there certainly are high levels and low levels. Here in the US, we’re in that less than 8%, so less than the area. What they went ahead and did, is they looked at these studies, and they suggested that if you compared endemic regions, areas where there was greater than 8% to areas where there was more than 8%, there may be some signal. Ultimately, I will say they said that there may be some benefit in strongyloides endemic regions, but no evidence was found to suggest that ivermectin had any role in preventing mortality in patients with COVID-19 in regions where strongyloides is not endemic. I’m not sure I’m as convinced of the ivermectin benefit in the endemic areas, because like you know, this is a meta-analysis. and I love to channel Mark Crislip when you look at a meta-analysis. When you pile a whole bunch of cow pies, it suddenly turns to gold.

Each individual study has to stand on its own statistical significance. If you go ahead and look at figure two, none of these studies really are compelling for favoring Ivermectin, even in the areas with high endemicity. We’re waiting for that data out of Brazil, where they do not show a benefit. Brazil’s 10% to 15%, so it doesn’t make sense in my mind to consider Ivermectin to treat strongyloides in a person infected with COVID, who has been given steroids and immunosuppressive therapy? Strongyloides is treated with ivermectin, but is ivermectin an antiviral?

Are we treating COVID with it? I still do not think we have any compelling evidence for Ivermectin being a standard of care. All right. Don’t worry, we will get some hate mail, Vincent. I got some [laughs]. Also, another article on inhaled steroids. “Inhaled Ciclesonide for Outpatient Treatment of COVID-19 in Adults at Risk of Adverse Outcomes, a Randomized Control Trial.” This is from the COVERAGE, C-O-V-E-R-A-G-E. This is one of those repurposed drug trials where they’re trying a whole bunch of things. Here, this is an open-label randomized control trial.

Outpatients with documented COVID-19 risk factors for aggravation, symptoms less than or equal to seven days, absence of criteria for hospitalization were randomly allocated. We’re going to be discussing here the comparison between the control arm or the inhaled ciclesonide, so this is an inhaled steroid. The median time since first symptoms was four days, so the interquartile range was three to five, so they’re getting them in early when you would think that this would be the time to do it, if you’re going to do it during that first week.

The primary efficacy endpoint was COVID-19 worsening, so hospitalization, requiring oxygen therapy at home, because we’re starting to do that now, death by day 14. The analysis involved 217 participants. Intent to treat analysis really did not show benefit, so our findings are consistent with the European Medicine Agency’s COVID-19 task force statement, that there is currently insufficient evidence that inhaled corticosteroids are beneficial for people with COVID-19. All right. Telemonitoring. What about managing those people at home as was described here?

The article “Outcomes of a Home Telemonitoring Program for SARS-CoV-2 Viral Infection at a Large Academic Medical Center,” was just published. Here, the authors are really describing a telemedicine program that was established to care for patients with COVID-19. Just to cut to the chase, they were basically saying that this looked like it was an effective way of managing these patients, reducing the touch, reducing the impact on health care systems. One of the parts of this is giving patients pulse oximeters to help in the management at home, try to figure out who needs to escalate to hospitalization.

A little science to support that intervention, “Effectiveness and Safety of Pulse Oximetry in Remote Patient of Patients with COVID-19, a Systematic Review,” published in El LANCET Digital Health. As titled, this is a systematic review, not a meta-analysis. This review did suggest that the use of pulse oximetry as a monitoring tool for patients at home with COVID-19 helped to triage patients on the basis of their SpO2 concentrations, detect the risk of deterioration, and promote patient safety.

They suggested that this was potentially cost-effective. They also threw in– I think it’s a little interesting, this consideration of doing post-exertional pulse ox readings. Get the patient up, get them walking around, see if that oxygen level drops, because some folks can have a rapid decrease. Have them do this. You don’t want someone dropping down to 82 when they get up to walk to the bathroom. You want to know about that, so just the potential to keep these folks out of the hospital. Remember, these are the people who have tested positive for SARS-CoV-2.

The number one recommended thing to go for is the Paxlovid, that’s the five-day therapy. It’s oral. You need to know what makes them high risk, you need to know their kidney function, you need to know their other meds. Monoclonal therapy. We want to keep track of those variants. Bebtelovimab is preferred, but we just discussed some encouraging data on Sotrovimab, that three-day Remdesivir approach, and Molnupiravir as your other option. Do offer these people treatment. A lot of these therapies are sitting on the shelf.

Vincent, I’ll share that email you sent my way. I was able to speak to the son of the 98-year-old mother. Apparently, 98-year-old woman gets diagnosed with acute COVID, the son calls the physician, says, “Hey, I listen to this podcast. I’m interested in my mom getting access to Paxlovid or the monoclonals,” and the doctor says, “I don’t really do those, but I can call in an albuterol inhaler if you would like,” so please. Please. We got that squared away, so good, just a little bit upsetting there.

The early inflammatory change? This is where folks might get sick enough to end up in hospital. We’ve talked about steroids at the right time, in the right patient, at the right dose, anticoagulation, pulmonary support, maybe that proning, perhaps escalation to further immune modulation if required. What about antiplatelets? What about throwing these people on aspirin or one of those P2Y12 inhibitors like Plavix, clopidogrel?

Well, the study, “The Effect of Antiplatelet Therapy on Survival and Organ Support-Free Days in Critically Ill Patients With COVID-19, A Randomized Clinical Trial,” was just published in JAMA. This is more from our REM-CAP investigators. They were looking at that very question, aspirin or one of the P2Y12 inhibitors, so clopidogrel, prasugrel, or ticagrelor– No, I’m just killing these names, ticagrelor. Anyway, platelet inhibiting aspirin and these others, basically, were not able to show benefit. They suggested, based on this data, there was a low likelihood that these would provide benefits.

Still recommending heparin, primarily low molecular heparin. Not a lot of data to suggest a benefit for anti-platelet agents such as aspirin. We’ll have to get Dickson here to help me pronounce these things. The tail phase long COVID, post-COVID. COVID is not just a two-week viral illness for many people. A really difficult time for many of those individuals out there. I was subpoenaed and had the experience of asking questions about one of my patients this week. I was going through and they were asking and I was describing fevers, chills, fatigue, some of the other symptoms.

The opposing counsel, I guess, said, “Wait, that just sounds like menopause. Are you sure that’s not menopause, Dr. Griffin? Couldn’t that be menopause?” We really need a good objective test, because otherwise, this is going to be really difficult for these individuals, to have some way of really documenting that this is what’s going on. The, “In my professional opinion,” is tough in situations like this. What about the rest of the world? What about low, middle-income countries and COVID?

No one is safe until everyone is safe. We still need to do better with vaccinations around the globe. Just got back from Panama, actually two days before we were recording this. What I saw down in Panama was pretty impressive. As I mentioned in the beginning, we actually had a shift to our itinerary, because the first lady of Panama was going to one of the remote villages to do a vaccine booster drive. On a less positive note, one of the captains, this is actually the first captain that started to work for Floating Doctors in Panama, a young man in his 40s actually developed COVID prior to vaccine access, and he did not survive, so really, really upsetting.

It’s always challenging to get reliable numbers and we talked a little bit last week when we discussed the paper estimating excess mortality due to the COVID-19 pandemic. A systematic analysis of COVID-19 related mortality 2020 through 2021, concerns that we’re really not counting the deaths. People keep saying, “Boy, why is everyone doing so well in Sub-Saharan Africa?” I’m not sure that’s true, and so the preprint “Sustained High Prevalence of COVID-19 Deaths From a Systematic Postmortem Study in Lusaka Zambia, One Year Later,” was posted as a preprint.

Here the authors obtained a nasopharyngeal swab from each decedent, and tested them using PCR from the 1,118 decedents, people that had died. COVID-19 was detected among 32%, when they looked at the different waves of transmission during the peak of transmission, COVID-19 was reported in about 90% of all deaths. What they actually were concluding is only about 10% of the COVID-19 deaths were identified in life. When you see these numbers, you say, “Oh they seem so small,” add another zero to those, because a lot of COVID deaths in these areas are going uncounted.

I will ask everyone again, pause the recording right here, go to parasiteswithoutborders.com and click the donate button, even a small amount helps with our work. I also wanted to personally thank one of our donors who made a donation in support of Dr. Judy Hoffrichter, who was a local OB-GYN who was really a proponent of medical education particularly for women who might not otherwise have access.

A reminder our listeners throughout the months of February, March and April donations made to Parasites Without Borders will be doubled up to a potential donation of $40,000 for the American Society of Tropical Medicine with priority placed for scholarships for women from low and middle income countries who might want to attend the annual meeting in Seattle

VR: Time for some questions for Daniel from you. You can send yours to daniel@microbe.tv. Rebecca writes, my 78-year-old father as Crohn’s was switched from Remicade to NTO infusions two months ago, he has diabetes, kidney disease, BMI 22, looks healthier in person then on paper, he’s vaccinated times three and boosted with Moderna.

I suggested that he’s an excellent candidate for PrEP with Evusheld, but his nephrologist at Kaiser says his biologics do not qualify him. I have two questions, is this true and if so, do we have any data regarding vaccine efficacy and individuals receiving biologics? It seems odd to me that anyone that qualifies for a third mRNA dose to be fully vaccinated due to immune suppression is not automatically a candidate for Evusheld.

DG: This sounds like a perfect candidate for Evusheld, and just you can go yourself, you can look at the EUA, what is the EUA, who has access or who should have access to Evusheld? It’s individuals who have a moderate to severe immune compromise, due to medical conditions or receipt of immunosuppressive medications. We’ve got Crohn’s here, we’ve got immunosuppressive medications, any individual for whom vaccination may not provide them the protection, so may not amount to an adequate immune response to COVID-19. I would go ahead get a second opinion, because Evusheld in this context, to me sounds like it makes sense.

VR: Charlotte writes, I’ve been listening to your wonderful podcast updates every week for the last two years. I think it’s important your input about antiviral medications that are available now for doctors to prescribe. Is there somewhere we can see these exact spelling in order of treatment? You’re so kind to give to us verbally, so type it up so we could have Step One. If that’s not available Step Two and Three and so forth, this would be helpful. Maybe you could put it on the MicrobeTV website.

DG: That sounds good. Let’s make that happen.

VR: We’ll do that, that’s no problem. I have the notes from Daniel and I can put them right up there. Julia writes, if someone has a positive antigen test, what are the chances that they aren’t contagious? If yes, how long might someone test positive for antigen after a contagious period? Is it safest to wait for a negative result before seeing one another indoors without masks? The background, mother-in-law had COVID and tested positive, two weeks ago we have plans to see her.

I would feel more comfortable if she took an antigen test beforehand. My brother-in-law believes that someone may test positive for months after their first positive test, making an antigen test unreliable. My understanding was a positive antigen test meant the person was currently shedding virus, and may be contagious.

DG: This is great. I’ll just go through the details of this. The antigen test will usually turn positive, right about when a person becomes contagious. It will continue to be positive after a person ceases to be contagious. You’d say, if I want to be super safe, I’m going to wait until that antigen test turns negative, which is usually going to be about day 11. A vaccinated person particularly is not going to be contagious at day 10 day, day 9, day 8, all the way really not much probably after day 5.

The antigen test stays positive longer than a person is contagious. Again, if you’re going to be exposed to someone who’s very high risk, there definitely are people out there who want to wait until that 10 days has passed. If they’re going to be out and about in less than 10 days, they might throw an antigen to shorten that. PCRs those will stay positive for months in some individuals, but those antigen tests, it’s very uncommon for them to stay positive past day 11.

VR: One more from Kim. My three-year-old was exposed in daycare last week, tested positive on an at home rapid test, is cold like symptoms and is his energetic-self. So far, his younger brother, two years old, is not showing symptoms. With the encouraging data from Moderna being released today, and the potential of an EUA in the coming weeks. Are there considerations for vaccinating young kids after recent infection?

Should we wait a certain period of time after infection? Would vaccination within a certain number of weeks potentially reduce risks of developing MIS-C? Is there an ideal time frame to vaccinate them to support the strongest immune response possible?

DG: These are all great questions, and we’re going to have to wait to actually see the data. We’re going to have to wait to see the full briefing that goes to the FDA. We’re going to have to listen to that discussion before that goes forward. I will just say, anticipating it’ll be very similar to how we approach adults who have been infected. We don’t recommend waiting at this point in adults.

Even after they get monoclonal antibodies, so a person gets infected whether they get monoclonal antibodies or not, we wait until they’re past that to 10 days, isolation for the infected, go ahead and vaccinate them. We’ll have to see what the recommendations are for children, but that’s where they currently stand for the adults.

VR: That’s COVID-19 clinical update, number 107 with Dr. Daniel Griffin. Thank you, Daniel.

DG: Thank you, and everyone be safe.

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