TWiV 899 COVID-19 Clinical Update #114

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 14 May 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 Microbe TV, this is TWiV, This Week in Virology, Episode 899, recorded on May 12th, 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. We’ll be talking about COVID, one of those viruses that makes you sick.

VR: You mean SARS-CoV-2.

DG: Actually, you’re right. Can you believe that?

VR: It’s OK. That’s all right.

DG: No, I think that’s good. SARS-CoV-2, the virus that makes you sick, and when you’re sick we call it COVID.

VR: The other aspect of this is that people said, “Oh, I tested positive. I have COVID.” You don’t have COVID unless you have symptoms, right?

DG: That’s becoming like an interesting issue and I think maybe we’ll get into that today.

VR: All right.

DG: All right. Let’s start off with our quotation. “How poor are they that have not patience? What wound did ever heal but by degrees? Thou know’st we work by wit and not by witchcraft, and wit depends on dilatory time.” That’s Shakespeare.

VR: Wow, he was up in the world.

DG: Shakespeare has got another quotation about rushing, and I think that involves, if you’re going to try to assassinate someone, but I think this is more appropriate if you’re trying to gain knowledge, if you’re trying to move forward. That’ll be a theme I try to hit on a few times in today’s episode, but I think, as everyone knows, the virus is everywhere. There’s lots and lots of SARS-CoV-2, but deaths per day are still sitting at the lowest they have since the pandemic started.

We’re still sitting in that 200 or 250 deaths per day in the United States. Just keep that in mind. That’s the best we’ve ever done. I will comment for the week ending 5/5/22, eight more children died. We’re actually down to about one pediatric death per day here in the U.S. Still waiting for vaccines for those under 5, and really much in the way of therapeutics for those under 12. We do have Remdesivir, and we’ll mention that, but let’s get right into children. Children are at risk for COVID.

It does look like June, looks like next month may be the month for kids and COVID vaccines. I’m going to start off with an article. “Evaluation of mRNA-1273,” that’s Moderna, “COVID-19 Vaccine in Children 6 to 11 Years of Age,” published in The New England Journal of Medicine. These are the results now, the peer-reviewed published results of the KidCOVE study group.

I’m going to focus on Part Two of the trial where 4,016 children were randomly assigned to receive two injections of the mRNA-1273, of the Moderna, 50 micrograms each were placebo and were followed for a median of 82 days after the first injection, so do your math there. This dose level was associated with mainly low-grade transient adverse events, so injection site pain, headache, fatigue.

No vaccine-related serious adverse events in this group, no multi-system inflammatory syndrome in children, no myocarditis, no pericarditis reported in this group at this dose. Well, what about efficacy? At least per this study among children who did not have evidence of SARS-CoV-2 infection at baseline, the estimates of vaccine efficacy against symptomatic SARS-CoV-2 infection at least 14 days after the first injection were 91.8%, according to the definition used in the Phase 3 COVE trial involving adults with 0.1% in the mRNA-1273 group, and 1.7% in the placebo group.

I’ve now decided every time the word vaccine efficacy is used, every reviewer should force them to define what efficacy they’re talking about. The estimated vaccine efficacy against asymptomatic SARS-CoV-2 infection, how does that work in the same sense? Do they have an infection if they’re asymptomatic? I’m going to get to that. Efficacy against, really, a positive PCR positive test was 62.5%.

That was basically 2.5% in the mRNA vaccinated group, 1% in the placebo group. One caveat there is this trial is really telling us about efficacy of the vaccine when Delta was the predominant circulating variant. We’re always a variant or so behind, but I think this is an interesting concept that maybe, Vincent, maybe you and I can talk about the concept of we used to always, before we had such sensitive testing techniques, always associate infection with symptoms.

Now what we’re having here, and I know we talked about on the Puscast about influenza infections, those that were asymptomatic versus symptomatic. It’s almost like the language is evolving with our technology. Vincent.

VR: Well, there was a period when we did serological assays. Before we had PCR, you could do serological surveys, and for some viruses, you always found a higher number of people who apparently were infected, but they don’t recall ever having symptoms. Now, that’s an imprecise kind of study, but that led to this initial idea that for some viruses, and poliovirus was one of the first, 99% of infections are either asymptomatic or largely asymptomatic and only 1% are paralytic.

I think we could do it with less precision when we did serology, but now with PCR we really know you’re infected but you don’t have any symptoms. A symptom is, of course, what you only can feel. A sign is what can be measured. All infections have a sign because one sign would be RNA viral load, but the symptom is what you feel. The other aspect of it, Daniel, is that for some people they have a low barrier to symptoms. “My head is killing me,” and for others, “I’m fine.”

[laughter]

DG: Always when we talk about symptoms stories I still remember the guy I treated in the ICU as a resident who was sitting there with a sweat on his brow, focused, looked like he was in a bad way. He rated his pain 4 out of 10 and said it was not quite as bad as when he was gut shot in Nam. [laughs] Yes, that’s a different threshold. All right, the next question. Does COVID present the same in kids as it does in adults?

One big feature we often see in adults is loss of smell. We’ve talked a little bit about how that’s different with different variants. The paper, “Prevalence of Anosmia in 10,157 Pediatric COVID-19 Cases: Multicenter Study from Turkey,” was published in the Pediatric Infectious Disease Journal. This multicenter prospective cohort study was conducted with pediatric infection clinics, kind of an interesting, 37 centers in 19 different cities of Turkey between October 2020 and March 2021.

Here anosmia was present in only 12.5% of the cases in the 10-to-18-year-olds. It’s really interesting. Because I keep getting back to what I harp on is the only way you know what virus a person has is by going ahead and doing that test. You can’t just guess on symptoms. You can’t just say, “Oh, well, you still have intact.” I hear this all the time from the patients, don’t be this clinician that I’m getting called about when they say, “I told the clinician and he said, ‘It doesn’t sound like COVID.’ “

[laughter]

DG: It all sounds like COVID. During a pandemic, if you’ve got a viral illness, it is that viral illness until proven otherwise. All right.

VR: This study, Daniel, from Turkey though, they say it’s lower than in adults, but they really should have done the adults at the same time because it may be different, right?

DG: You are correct, and I think that’s one of the big things we talk about. Even when we compare efficacy of different therapeutics, you really need to do it all in the same study, because there’s so many variables. During this period of time with this type of questioning, would the adults have been at 12.5%? You can’t just look at another study in a different population. I think that’s correct. All right.

Now the pre-exposure period, when we talk about transmission and testing, never miss an opportunity to test.  Occam was not a physician, John Hickam was. A patient going to have two things at the same time. Actually, I have several patients in the hospital now with flu and COVID. It was actually interesting.

One man was quite ill, and we were a couple of doors down in the ICU discussing the case with the ICU team, and the patient right behind us, who was obviously listening in, we need to be more careful about this, he said, “I have flu and COVID too.” This is not uncommon. Now what I mentioned last time is that we have really dropped the number of tests that are being done in a manner where they end up getting reported. There surely are a bunch of those home tests going on. The CDC is expanding their national wastewater surveillance and it will be challenging as we learn about this new approach to coordinate this. There’s a lot of challenges getting it done, there’s also going to be challenges understanding what these results actually mean.

Hopefully, we’ll go forward, but as we stop getting case numbers and other information, this may be a resource that we have to start looking at. Just heads up on that. All right. I have some really fun papers today. The first fun paper, “Detection of SARS-CoV-2 by Canine Olfaction, a Pilot Study,” published in Open Forum Infectious Diseases.

In this double-blinded, case-control, validation study, sweat samples from inpatients and outpatients were obtained and tested for SARS-CoV-2 by PCR. Interesting. They’re actually getting SARS-CoV-2 PCR positivity from sweat samples. Now medical detection dogs were trained to distinguish SARS-CoV-2 positive samples from SARS-CoV-2 negative samples using reward-based reinforcement. You give them food, treats, kibble. It’s just a little bit of kibble.

They don’t get a big dog bone by the way. Samples were obtained from 584 individuals, 6 to 97 years of age, 24% positive SARS-CoV-2 samples, 76% negative SARS-CoV-2 samples. In the testing phase, all dogs performed with high accuracy in detecting SARS-CoV-2. Overall diagnostic sensitivity was 98%, specificity 92%. This is where it gets exciting. In a follow-up phase, one dog, that was Tess, a 2-year-old Labrador, we’re going to get back to her, she screened 153 patients for SARS-CoV-2 in a hospital setting with 96% sensitivity and 100% specificity.

Just for our dog lovers, and I am one of those, four dogs were involved in this training. We had three Labs, we had one golden retriever ranging from 1 to 5. The dogs were Yuki, who was 1 year old, Tess, the star of the show who was 2, Sadie who was 5, and then Sampson was the golden retriever. They were trained for six weeks for a total training time of 20 hours over these six weeks, so about 30 minutes per day. This training was done in Maui. If we have any dogs listening, they may want to sign up for six weeks in Maui to develop this wonderful skill.

VR: Daniel, what are they going to do with this? Are they going to put them in airports and sniff people to see if they’re positive?

DG: There’s been a bunch of ideas about how to potentially do. That’s one. You could use them at airports, you could use them outside of an event. You could maybe even use them in schools. You could have the kids moving past, the dog sniffs each person before they go in. There’s a lot of ideas. There are some challenges. A dog can only work for about 45 minutes, and then they need a break. If you’ve got too many people, you’re going to need a few dogs.

Along this line, we have another in the canine arena. The paper, “Screening for SARS-CoV-2 Persistence in Long COVID Patients Using Sniffer Dogs and Scents from Axillary Sweat Samples,” published in the Journal of Clinical Trials. Can our dogs now tell who has Long COVID and who might be malingering? Here the researchers, again, took auxiliary sweat samples from Long COVID patients and healthy controls, and then had two trained dogs to see if they could tell them apart.

Now, the dogs identified half of the patients who reported they had Long COVID and they did not flag any of the normal sweat samples. As I say here, I now understand what people mean when they say something passes the sniff test. I think this would be great for me to use in my clinic when they’re trying to deny disability and be like, “I’m sorry, but the dog has confirmed the Long COVID in this individual.”

VR: What is it that they’re smelling in Long COVID patients, Daniel?

DG: I don’t know. I think that’s really apparently these volatile organic compounds. That’s the theory, but we really don’t know. We really don’t know. Ideally, we will identify what are the potential volatile organic compounds, that’s like hand waving, and then know that that’s what they’re picking up because, of course, as much as we all love dogs, the idea of being able to have something objective that you can show maybe on some machine or scan or something.

VR: I just don’t want people to think that this means that there’s virus present. It could be volatiles produced by immune responses.

DG: That would be my main suspicion. There’s nowhere in here that they’re saying that these people with Long COVID with the axillary sweat samples have viable infectious virus in their sweat. Yes, I think that’s actually a really important point for people to be thinking about. All right. I will say, hopefully, we’re going to keep training these dogs, training them up for the fall and the winter surge.

Globally, testing is plunging about 70% to 90% drop from the first to the second quarter here. As I keep telling providers, I’m hoping that we’re just putting things in storage getting ready for the next surge that we’re not going to just say, “It’s over because we keep doing that.” Let’s not go into the fall or next winter without being ready. We’re still in that section of transmission. Just to reinforce, one-way masking is something that we’re now talking about, reducing those exposures, outdoors versus indoors, better ventilation.

I really enjoyed reading COVID-19 risk assessment for public events that was created by the University of Texas COVID-19 Modeling Consortium. This is 17 pages, so a quick read. I did not read all of it. It is not as quick a read. Has a lot of tables and things in there. A few highlights, and Vincent, I’m going to pull you in here. I’m working you hard today. This report considered two case studies in Travis County, that’s down in Austin, Texas. I think we have a buddy who lives down there.

VR: Yes. That’d be Rich Condit.

DG: Yes. I don’t know if Rich went to any of these high-risk venues, but we’ll have to ask him next week. One was a business conference with 3,000 attendees, two was an outdoor festival with 50,000 attendees. Remember this is modeling. I just want to point that out as we go through this. What were the highlights, the bullet points that they presented? They were suggesting that testing requirements before the event were more effective at preventing attendees from arriving infected than vaccine requirements.

That may vary actually with different variants, I will say. For the business conference case study, this is the slightly smaller indoor event. This is about 3,000 attendees indoor. They compared entry testing a negative test within 48 hours prior to the event to a vaccine requirement. That results in 95% of attendees vaccinated.

Their modeling suggested that the testing policy would result in an estimated 20 attendees arriving infected, the vaccination would result in an estimated 30. Big overlap on the confidence intervals here. They were also commenting that if you shortened that testing window to 24 hours prior to the event, that would perhaps reduce the risks further, and then, and I think this is combining multiple integration strategies, could effectively prevent transmission at events, putting things together.

Now, what about the outdoor event? Remember this is going to be 50,000 people at an outdoor festival. Here they say a combination of vaccination, entry testing, and face mask requirements was estimated to reduce the number of infections stemming from the event in the subsequent 4 weeks from 895, which would be predicted, down to 120. I did the math on this. We’re looking at a little less than 2% down to 0.2%. This idea, as we’re looking here, outdoor events are safer than indoor events.

They say, although the hypothetical outdoor festival would be over 10 times the size of the hypothetical business conference, they estimated that it would produce only double the number of infections within the community during and following the event. A bunch of things to say here. One is, this is a modeling study. These did not occur. This is not actual data. This is modeling. As we start having these events, I will suggest that all we’ve learned really supports the idea that you can do these in a safer way, and I am going to also say in a more cost-effective manner, if you start moving things to outdoor venues.

Let’s say, for instance, theoretically, there was a large mandatory event for hundreds of healthcare providers and administrators with short talks that none of us could hear because of the bad acoustics, then following there was some food, drinks, socializing. This was all done inside, mostly without people wearing masks, without testing, we would anticipate, we would not be surprised if dozens of people were then out of work for a minimum of five days each, all that human suffering that goes with having asymptomatic case of this virus, a nice cost to the bottom line with all those providers not being able to take care of their patients and all those patients being frustrated that they can’t be taken care of.

You could move that socializing part to a beautiful outdoor area that was maybe adjacent to this huge conference room. Maybe there’d even be better acoustics out there, so people could stand that three to six feet apart, outdoors and converse, potentially fewer infections, fewer dollars lost in revenue, less impact on patient care, et cetera, et cetera. People are starting to do these events. This is probably that time to co-op your friendly ID doc and ask for a little guidance so that you’re not having this impact after the fact. Vincent, comments.

VR: Well, my first thought is we don’t do this for influenza, do we?

DG: True.

VR: I would submit that COVID is becoming another influenza. There are clearly some differences still, but just not clear to me why we would do this. Two issues. If you want to wear a mask at a conference, it really impairs communication. I think if you really think we’re in a phase where it’s not a good idea to be infected, then you should do your conferences online still and wait for the time when – I don’t know, when there’s less circulation.

There’s always going to be high circulation in the winter. I’m not sure what’s going to attenuate disease. I think the idea that you have to have masks and be vaccinated in distance, it’s all great, but I’m not sure we need it.

DG: I think this is a good conversation for us to have because is this sustainable? Is it sustainable every time a person gets SARS-CoV-2-infected that they spend five days isolated, unable to work. I think that becomes an issue.

VR: No, I don’t think that’s realistic at all going forward, especially as this approaches influenza where we don’t do those things, we do not test. We only test for influenza to know if it’s flu so we can give Tamiflu.

DG: Yes, and then we don’t say, “Now you have to stay home for five days. When you come back, you have to wear a tight-fitting mask for the next five.” I worry about the impact. Summer is coming up. We’re going to have summer camps. What are we going to do with the amount of virus we have circulating? Are we going to have all these kids locked in isolation cabins five days here, five days there? I think that it’s not going to get much better.

I was having a conversation with my parents because I may encourage them to attend an indoor event upcoming, just by the way. This is how they find out. They listen to Brian Lehrer or they’re listening to TWIV and they’re like, “Whoa, what are we going to?” How much better is it going to get? We have highly-effective vaccines. For the immunocompromised, we’ve actually gone a little bit farther. We now have Evusheld passive vaccination.

We have really good access to Paxlovid and some other therapeutics that we’ll talk about. I’m not sure how much better it gets. I think at some point we’ve got to start asking ourselves about what should the consequence be, because for a lot of these people, they actually did not get that sick. The big consequence was you’re out of work for five days and all the disruption that creates.

VR: Well, that’s because we make them be out of work because they test positive, but we don’t have to do that. I think, Daniel, there are two issues that are driving this. First is the under-5 not being able to be vaccinated. I know they’re not going to be at these conferences, but the people may go home to kids, and that’s a risk for them. The other one is really the elephant in the room. It’s Long COVID. People are really afraid of Long COVID; getting a mild infection post-vaccination and still getting Long COVID.

I think we need to sort that out and know what the risk really is. I don’t think we do yet.

DG: I think that’s relevant. We keep talking about data where post-vaccination, it seems to be reduced as far as risk and severity, but it’s not zero. Also, we don’t have great treatments. We have, well, really no evidence-based treatment other than saying, “Hey, go get vaccinated. That might help.”

Maybe there is still a little bit that will get better, but yes, for a lot of people that is the elephant in the room, the Long COVID. The other is, “Hey, what about these kids under 5 who are almost there?” We hope next month we’re going to be able to start getting those kids vaccinated. All right, but I think it’s important we keep having these conversations. Where are we? What are we doing? I think we can have them civilly. It doesn’t have to be partisan, one person screaming at the other with and without a mask.

VR: Oh, yes. I agree.

DG: All right. Active vaccination, never miss an opportunity to vaccinate. R-1 and done, maybe done, limited at least. The FDA released the update on May 5th, 2022. Actually, that was right when we were recording last time. I think they did it as we were recording. “Coronavirus COVID-19 Update: FDA Limits Use of Janssen COVID-19 Vaccine to Certain Individuals.”

I’m going to read this and then really point out it’s pretty targeted what they’re saying here. The U.S. FDA has limited the authorized use of the Janssen COVID-19 vaccine to individuals 18 years of age and older for whom other authorized or approved COVID vaccines are not accessible or clinically appropriate.

This isn’t just, “Oh, by the way, you still have a choice. We prefer others.” This is actually saying the authorization, the EUA, your access to this vaccine is only limited to situations where a person cannot get another vaccine. That’s a pretty big restriction. The focus of the release is the rare but clearly identified association with the risk of thrombosis with thrombocytopenia syndrome vaccine-induced. I also have to say there’s growing evidence that the mRNA vaccines are just more effective.

VR: Daniel, is there a patient population where TTS is a real potential issue?

DG: It is very rare and initially we had ideas that we could say, “Oh, it was a certain sex, a certain age.” By the time all the numbers came in, it was all over there. There isn’t a really good way to know ahead of time who would be the person at risk. That presents the challenge. Another fun paper, the article, “Recall of B cell Memory Depends on Relative Locations of Prime and Boost Immunization,” published in Science Immunology. I know there’s discussion.

Maybe this will come up on immune as a deep dive. I hope. Here’s the question. If I got my first COVID vaccine in my left shoulder, can I just pop the second one in my right thigh, in my right shoulder, or am I better off just putting them both in the same place? This is a mouse study. The researchers used a prime-boost immunization approach whereby mice received a homologous antigen booster on the same or the opposite leg. The magnitude and serum antibody responses were similar for same side versus opposite side boosters.

However, same side boosters elicited better quality germinal centers with higher avidity for antigen, higher immunoglobulin mutation frequencies, and an increased recall of B cells from primary germinal centers. These results indicate that the reactivation of local memory B cells generate superior secondary germinal center responses and suggest that localization of booster immunization should be considered in vaccination strategies.

VR: What do you think, Daniel? The same arm?

DG: Yes. For now, why not?

VR: What is the difference? Is it 1%? Is it 1X2? I can’t tell from this.

DG: I’m hoping there’ll be a deep dive. I think there was some interest from our immune colleagues back and forth on Twitter about this. I’m hoping we get a little bit of a deeper dive, but I never liked my left arm anyway. It’s getting all the shots. All right, passive vaccination Evusheld, and we’re doing a little better, I think, here. What about instead of pre-exposure prophylaxis, we just wait, let’s wait, let’s give Evusheld after the fact, let’s give it as treatment.

Here, the preprint, “Tixagevimab, Cilgavimab for Treatment of Hospitalized COVID-19 Patients, a Randomized, Double-Blind, Phase 3 Trial,” was posted on The Lancet preprint server. This is, as I’ve mentioned, let’s not just wait until after they get infected, but let’s actually wait and wait. Let’s wait until they end up in the hospital. Let’s wait till they’re starting to get past the viral replication phase. Let’s wait till they get into their early inflammatory phase, then let’s give them Evusheld.

I started thinking about this, “This doesn’t seem like a good idea.” These are the results of a Phase 3, blinded, randomized, placebo-controlled trial where adults hospitalized for COVID-19 at 81 sites on four continents were assigned to receive intravenous Evusheld 300 milligrams or a placebo, so this is the new higher dose, in addition to remdesivir and other standard of care. We have 1,417 in the primary modified intent-to-treat population infused with the Evusheld 710, Placebo 707.

By day, 90 sustained recovery was achieved by 87% who got the Evusheld, 84% who got placebo. Results were similar in the seronegative group. People who are still antibody-negative versus people who are antibody-positive, results were similar, but here, mortality was lower in the Evusheld, 8.6% versus placebo at 12.2%. A hazard ratio of 0.70. I was a bit surprised that they were seeing this statistically significant 30% reduction in mortality because they just kept waiting. A few details, I will say, and I think this is important, the median was eight days of symptoms.

They weren’t really waiting until completely after the viral replication. This is consistent with the concept of giving monoclonals within the first 10 days. We’re not seeing that 80% to 90% improvement that we saw, a few get it upfront in the first five or six, we’re still seeing a little bit because we’re still within the first 10 days, but I think this really builds on the idea that those antiviral therapies, you really want to try to get them started as soon as possible. I did want to point out that I know there’s a bunch of thought leaders out there.

I want to call them that, influencers, that I have been suggesting, “Why don’t we wait a little? Maybe we’re treating people too soon. Let’s give their body a chance to see that virus. Let’s let that response start, then we jump in with the antivirals, and we’ll be even better.” I’m a little concerned that this is the Dunning-Kruger effect. There’s no data to suggest that we should wait. There’s actually lots of data to suggest that the earlier we start treatment, the better impact we get.

Here I’m going to quote Shakespeare again, and in this case, the opposite message, “If it were done, when ’tis done, then ’twere well, it were done quickly.” Except here we are talking about assassinating the virus rather than King Duncan. If we do plan to kill the virus, let’s get it done quickly, but we’re trying to learn and move forward with science, then we need to take a little bit of time and not just throw darts at the board.

The post-exposure period, we don’t have much here, except for testing so that we can pick up when we have moved from that into the period of detectable viral replication phase or the viral symptom phase. Very similar here, but we have a few tools. Number one recommended thing, if someone tests positive, is Paxlovid for those at high risk of progression and 89% to 88% reduction in progression if given in the first 3 to 5 days?

What are the new tools?

The IDSA, the ID Society of America, has created a Paxlovid patient eligibility screening checklist for prescribers. Actually, they’ve linked to an fda.gov, source. This is pretty nice. I have already seen people building this into their electronic medical records where they click through and go through the checklist. Although we’re still waiting for more data, Paxlovid only has an EUA for those who are at high risk for progression to severe COVID-19, including hospitalization or death.

We still do not know if Paxlovid prevents Long COVID or even makes it worse, let’s be honest here. There’s a number of things we still don’t know about. We’re still waiting to get that knowledge. Just encouraging people instead of throwing darts at a board, we should be making evidence-based recommendations based on what we know. The second thing, which was helpful, the CDC has a list of what makes a person at risk of progression to severe COVID.

I’m actually going to click on this link and go through it a little bit because I actually have to say, the number of things on this list is actually pretty extensive. I’m moving it off to the side so I can go through it here. Just to go through a few things which I’m going to highlight: Cancer, but it’s probably active cancer, probably not prior; chronic kidney disease, liver disease, lung disease, cystic fibrosis, dementia, or neurological conditions, diabetes, that can be Type 1 or Type 2, disabilities.

This is actually pretty broad. They say people with learning disabilities, people with ADHD, it’s actually pretty extensive here, Down Syndrome, heart diseases, HIV, immunocompromised, mental health issues. They even say, and this is just what they say, overweight and obesity. They’re actually clearly saying here, BMI of 25 is in this list.

This one I thought was a little interesting: physical inactivity for those of us who aren’t exercising. Really interesting that this is in their list that they linked to. Smoking, transplants, prior stroke, substance abuse disorders. Rather extensive list. I do want to point that out that it’s actually becoming a challenge to find someone who doesn’t have a risk factor, who doesn’t qualify from that standpoint.

The other thing that is another nice tool and we’ll have links to this is the idsociety.org/paxlovid where they go through the top 100 prescribed drugs, and then guide you on what you should do. There’s only a couple of drugs that are really bright orange, don’t do this, avoid Paxlovid in these, but a lot of guidance, for instance, the statins, they say hold the statins while you’re on Paxlovid, and then for another five days and can start, and then they go through a number of others.

I’ve actually been using this quite frequently. It’s helpful because a lot of concerns about what do I do with the other medications a higher risk person might be on. Next thing I will go, Remdesivir. Remember this has moved up to Number Two, that three-day, early IB data suggesting an 87% reduction in progression if given in the first five days.

Monoclonals are down to three. Bebtelovimab, we don’t have efficacy, but we do have the extrapolation. Thor’s hammer, molnupiravir, our last option here at 30% reduction. Remember, the only one for those kids 28 days up to 12 is going to be your Remdesivir, so we need to make sure that that’s something we have available for the high-risk kids. Remember to avoid steroids given early. That can actually lead to a higher risk of progression. Zinc gives you GI distress without much help, and are you ready?

No role for ivermectin. Yes. Just filter out these hate mails for me. You don’t need to forward these to me there, Vincent. The article, “Effect of Early Treatment with Ivermectin among Patients with COVID-19,” has been peer-reviewed and now published in the New England Journal of Medicine. These are results of the double-blind, randomized, placebo-controlled adaptive platform trial involving symptomatic SARS-CoV-2 positive adults recruited from 12 public health clinics in Brazil.

Treatment with ivermectin did not result in a lower incidence of medical admission to a hospital due to progression of COVID-19 or a prolonged emergency department observation among outpatients with an early diagnosis of COVID-19. Not looking encouraging for ivermectin. Isolation and quarantine. Now, this is a question I get multiple times a day, so maybe this is another one of my attempts to save myself from the flood of emails, “Dr. Griffin, I tested positive. What do I need to do?”

When people, and they always say this, “How long does this patient need to quarantine after they test positive?” I always say, “First off, please, isolation for the infected, quarantine for the exposed.” Words matter. First off, we still do have quarantine rules for people not up to date with their vaccine. I don’t know if people listened closely, not up to date. That’s different than fully vaccinated.

This is a new term that maybe people are not familiar with, the distinction between fully vaccinated and up to date with vaccines. You are up to date with your COVID-19 vaccines when you have received all doses in the primary series and one booster when eligible. Fully vaccinated is just the primary series. Fully vaccinated people still quarantine, up to date people do not have to quarantine. I’m not sure the science is compelling on that, but them’s the rules.

Now, if you’re not up to date after an exposure, you are supposed to quarantine for at least five days and then take precautions up to date. Ten if you’re up to date, then no quarantine. I’m pretty sure that the people who are unvaccinated and not up to date are not following that rule, but anyway, them’s the rules. Now isolation for the infected, if you are infected, one stays home for five days isolated, and then if fever-free for 24 hours, you take precautions until day 10.

You can leave isolation, but the recommendation is wear a well-fitting mask until the 10 full days are done, no testing out early or even extending, if on day 10 you get that positive antigen test. I think we started to have this discussion before, but Vincent, is there a time when we’re going to stop doing this?

VR: Are these recommendations only for unvaccinated people who are not up to date or not fully vaccinated? Is that the idea?

DG: Actually, that’s interesting. The quarantine if you’re up to date with your vaccines, there is no quarantine, it’s gone. The only people that quarantine are people who are not up to date, so the unvaccinated or the just fully vaccinated, lumping them together. Now, the isolation for the infected, that’s everybody.

VR: If you test positive, you need to isolate. Here it says five days, and then if you’re fever-free for 24 hours, you’re good to go.

DG: Good to go, but if you go back to the workplace or to school or out and about, you’re supposed to be wearing a tight-fitting mask at all times when you might be exposing others.

VR: Your question, are we going to be doing this forever? No, obviously not. People are not going to stand for this. How long are we going to do it? What’s the determinant of how long we are going to do this because we do not do this with influenza, and for flu, we have less effective vaccines, right? [chuckles]

DG: Yes.

VR: These are much better vaccines. It seems to me that unless you’re thinking about the less-than-5-year-olds, this isn’t necessary any longer.

DG: I think this is something that – and both sides. I think that we do have a lot of division in our country, but I think that this should be a sober conversation about as we move forward, particularly as we get past June, when do we start changing the rules on this because this is a big deal. It discourages people from testing, it discourages people from, honestly – All right, so that’s a big thing. I think we can have a science-based discussion that hopefully informs policy as opposed to the other way where policy just gets dropped down.

All right, early inflammatory phase, so this is where some people progress. They start to get that early inflammatory phase. Perhaps they start to get hypoxemia, so their oxygen saturation drops below 94%. That’s when some of these individuals may end up in the hospital, started on steroids, 6 milligrams per day times 10 days. Those individuals whose oxygen saturation does not drop, we are not seeing a benefit here. Not recommending it. Only in the select group that it’s appropriate.

Anticoagulation, just to keep this very simple, those who are admitted to hospital with critical illness, those ICU patients, prophylactic intensity anticoagulation, so that’s the low dose. If you are using low molecular weight heparin, that’s 40 milligrams subcutaneous once per day, weight-based, adjusted as needed, renal with pharmacy involved. What about those individuals who are less ill, who are up on the floor, who are not critically ill and in the ICU or requiring ICU level care?

The recommendation is actually higher level, one milligram per kilogram, subcutaneous twice a day of the low molecular weight heparin, the enoxaparin, for instance, because these people, you can get away with reducing the risk of clotting without having that excess bleeding risk of those in the ICU. These are update, these are changes.

I know some systems are using D-dimers to inform and make these decisions. Number three, this is important, the national guidelines are no anticoagulation outpatient thromboprophylaxis, so you send them home not on anticoagulants unless they have a high-risk feature, and of course, use your judgment. I had a woman today in her 90s, really has a horrible opened breast cancer area, concerns about bleeding, so we did not put her on full dose.

You really you got to see the patient, you’ve got to weigh the risks because we can provide some benefit, but also, these are medicines that can have associated risks. Pulmonary support, maybe Remdesivir if we’re early enough, tocilizumab, in some cases, baricitinib, and things to avoid, no ivermectin, no zinc, no antibiotics unless it’s appropriate.

One of the big things, and we’re going to go right into this, is what about bacterial coinfection, how do we determine who might need those antibiotics? The paper, “Procalcitonin Is Not a Reliable Biomarker of Bacterial Coinfection in People with Coronavirus Disease 2019 Undergoing Microbiological Investigation at the Time of Hospital Admission,” was published in Open Forum Infectious Disease. That’s the open-access journal of the IDSA.

The authors start by pointing out that only about 5% of people with COVID-19 present with bacterial coinfection, yet 75% receive antibiotics. They found that, among hospitalized patients with COVID-19, procalcitonin did not reliably identify people with positive microbiological findings. Low concentrations were observed in some with coinfection and high concentrations in some without.

I just want to remind people of that ferritin-procalcitonin ratio. Don’t just look at procalcitonin in isolation. That was the paper my friend Leland Shapiro published, Open Forum Infectious Disease, “Diagnostic Utility of a Ferritin-to-Procalcitonin Ratio to Differentiate Patients With COVID-19 From Those with Bacterial Pneumonia: A Multicenter Study.” In this analysis, they use this ferritin-procalcitonin cutoff of 877, suggesting that a ratio of over 877 was more predictive that all this inflammation was coming from COVID.

We are getting near the end and we are to the tail phase, Long COVID, post-COVID. COVID for, unfortunately, a large number of people, is not just a two-week viral illness. The article, “Health Outcomes in People Two Years After Surviving Hospitalization with COVID-19, a Longitudinal Cohort Study,” was published in The Lancet Respiratory Medicine. This was an ambidirectional, longitudinal cohort study of individuals who survived hospitalization with COVID-19 and who had been discharged from Jin Yin-tan Hospital in Wuhan, China.

I think I’ve heard of Wuhan before, between January 7 and May 29, 2020. They measured health outcomes at six months, at 12 months, and then two years after hospital discharge. Just to bring it all to the final conclusion, the proportion of the COVID-19 survivors that still had one symptom at six months was 68%. It was still 55% at two years. The majority of these people still had at least one symptom at that point. This is maybe the good news, but we’re going to qualify, the paper, “The Protective Effect of COVID-19 Vaccination on Post-acute Sequelae of COVID-19 (PASC): A Multicenter Study from a Large National Health Research Network,” was also published in Open Forum Infectious Disease.

They started off with an n of 25,225 that had been infected and had completed vaccination, and then match these two unvaccinated controls. After matching, there were no significant differences in demographics or pre-existing comorbidities, so seemingly a good match, but we’ll talk about that. At 90 days, following COVID diagnosis, the relative risk of hypertension was 0.33, diabetes 0.28, heart disease 0.35, and death 0.21. Differences in both 28 and 90-day risk between the vaccine and no vaccine cohorts were observed for each outcome.

Interesting enough, what is this paper trying to say? It’s trying to say people who are vaccinated and then get COVID are about 80% less likely to die than those who get COVID without the benefit of vaccine, 67% less likely to get hypertension, 72% less likely to develop diabetes, 65% less likely to develop heart disease. As excited as I would like to get about these results, I think there are several limitations. One, this is a retrospective study. I think we all know at this point in the pandemic that vaccinated and unvaccinated people are different.

There’s difference as far as their behavior, they’re different as far as many other things, so not clear to me is vaccination a marker or a cause? What about the rest of the world? No one is safe until everyone is safe. We are not doing well when it comes to vaccinations throughout much of the world. A lot of ways you can think about, a lot of these countries weathered the first two years, and now the vaccine shows up, and it’s a hard sell at this point. There’s also been a lot of vaccine misinformation in a lot of these areas, as I think I shared from firsthand experience while I was there.

I do want people to pause what they’re doing right now, pause the recording, go to parasiteswithoutborders.com and click Donate. Every little bit helps. We are now in our Foundation for International Medical Relief of Children fundraiser. During the months of May, June, and July, donations made to Parasites Without Borders will be matched and doubled up to a potential donation of $40,000. We’re really focused on trying to support our clinic in Bududa in eastern Uganda, really struggling to keep this clinic open, really takes care of over 100 children and family members per day, so really critical that we get your support.

VR: Time for your questions for Daniel. You can send them to daniel@microbe.tv. John writes, “If I heard it right, Dr. Griffin said that Paxlovid can or should be given for asymptomatic infection. I’m confused. I thought the EUA was for use on patients with a positive test, mild to moderate COVID, and high risk for progression. You don’t have COVID unless you have an illness, which means at least symptoms.” I think he meant to make the point that once there are symptoms if the patient is otherwise eligible, you don’t wait to see if they worsen. I wouldn’t fault the doctor for prescribing Paxlovid to a very high risk asymptomatic patient, say an unvaccinated organ transplant patient, when you know the time of exposure or conversion of the test. As I understand it, that would be going outside the directives of the EUA.

DG: Yes. I think this is actually helpful because we’re going to talk about a couple of things here. One, it’s going to come up to the issue of what are we allowed as physicians, as providers to do under an EUA versus full licensure. Full licensure, we have a lot of rope to hang ourselves on.

We can do a lot of off-label, but EUA, and I don’t think a lot of us have grown up with a lot of experience about an EUA, but the Emergency Use Authorization is supposed to be, “Here is the authorization. The authorization is just limited to what we’re giving you here.”

If you read the fact sheet, which is required when something gets an EUA, it says for individuals at high risk of progression who have mild or moderate illness. Mild illness would be, doesn’t take a lot, but fever, cough, sore throat, malaise, headache, muscle pains. Really has a long list, but it’s really, you’re not 100%. I think a lot of the push in this direction came from direction at the White House level. I’ll use Kamala Harris, who we were told was completely asymptomatic but had risk factors that prompted her to get treated.

You are right. This is right at that edge. We’re being pushed to expand to assess the EUA. This is strictly right at the edge of the EUA. I think what we’ve said before is, that previously we’ve always gone through, there’s got to be something. Usually, you find something. The whole idea that a high-risk individual is 100% asymptomatic, I think a lot of us are questioning, but, no, right on. Strictly this is for illness, not just asymptomatic

VR: The next one is from Clark. It’s not a question, but it’s a little bit of praise for Daniel. It’s important to read it. “Dear Dr. Griffin, I’d like to say thank you for all the time and energy you’ve put into educating us about SARS-CoV-2. I first heard you speak towards the beginning of the pandemic on a conference call with Kentucky providers when I was in the U.S.

“However, I spend most of my time in Western Kenya at a relatively large referral hospital where I run the pediatrics department and for the last few years, the respiratory isolation unit. Your weekly updates have been invaluable for me, keeping up with the literature, updating our protocols and practices. It has been, in many ways, a heartbreaking few years.

“Last year, we had 183 mortalities from COVID in our unit, as we are the only ones for about a four-hour radius doing critical care. I think it would’ve been worse without you taking the time to distill and propagate the current literature. I also really appreciate your gentle and humble demeanor in approaching what has unfortunately become a very polarizing disease.”

DG: Oh, well. Thank you. It’s also nice to hear that in Kenya all throughout the world, folks are listening. Thank you.

VR: Our last one is from Deidra who writes, “I wanted to thank you for your clinical updates which have been invaluable over the past few years. I’m a physician who has been asked to prescribe Paxlovid to a patient who’s traveling to Europe, specifically Italy, for several weeks for the patient to have on hand and take if she were to test positive while overseas as it’s not exactly clear what her access to such treatment would be if she were to get ill while there.

The patient is vaccinated and 70 years of age with hypertension and obesity. From a creatinine and drug interaction standpoint, it would be appropriate. If she were to test positive in the U.S., I would prescribe Paxlovid. I know the med is not approved for post-exposure prophylaxis, but it’s not exactly this scenario. If there were significant shortages, it wouldn’t be appropriate. I’m wondering if you think this is possible or if you know what the access to antiviral drugs is in Europe.”

DG: This is actually a great question. It’s going to allow me to touch on a number of issues. One, what about this? This comes up personally for me. My parents are excited now that maybe they’re going to start traveling overseas and wouldn’t it be great if they just each had a prescription for Paxlovid sitting with them just so that should they test positive, maybe they have some home tests with them.

They can immediately get started in the Paxlovid. Again, this gets into that EUA. Often when people go on a trip, travel medicine, we say, “All right, I’m going to set you up with what you’re going to do if you get diarrhea.” Maybe it’s antimotility agents, so they don’t make a mess on the bus.

We’ve gone back and forth about whether or not they get antibiotics to have on hand, but this is a tough situation with it being under EUA because this is really moving outside the EUA.

You haven’t even tested positive yet. You might test positive in the future, prescribing it ahead of the fact. That becomes really an issue. I know that’s going on. I know physicians are doing that. Actually, I got an email yesterday from a physician who is being pressured because all her colleagues in Connecticut are doing it to their patients, and why isn’t she? That’s a little bit of an issue. The other thing that comes up is we know that Paxlovid, we have the EUA, we have the data supporting a person tests positive and then gets treated.

We looked at that post-exposure prophylaxis getting started 72 hours after exposure. The data did not support that as an indication. Also, the others keeps coming up. “Well, boy, I’ve got this trip and then I’ve got an event when I come back, I’d rather just start taking the Paxlovid during my trip so that I don’t end up testing positive and missing that event. What if I test positive and can’t get on the plane?”

We certainly don’t have any data for pre-exposure. I think those are all the relevant issues. Oh, they’re not all the relevant issues. Depending on the country they go to, you can actually – For instance, France, they have Paxlovid. For instance, I had a patient on one of the islands in the Mediterranean. I had a patient in Greece, molnupiravir was the option there.

It was really getting on the phone, having a conversation with them, then them accessing it locally. There are ways for you to find out where are they going and what are the potential therapeutics available, and then also, a travel medicine specialist may actually be able to help direct you to how they access the local systems.

VR: That’s COVID-19 clinical update, Number 114 with Dr. Daniel Griffin. Thank you, Daniel.

DG: Oh, thank you and everyone be safe.

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