TWiV 901 COVID-19 Clinical Update #115

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 21 May 2022

Pdf of this transcript available (link)

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

[music]

VR: From MicrobeTV, this is TWIV, This Week in Virology, Episode 901, recorded on May 20th, 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: I just want to say thank you, Daniel, for coming to our incubator grand opening last night. It was a lot of fun.

DG: It really was. It was a great time. I’m going to turn off something that’s making noise and be right back.

VR: OK. [laughs]

DG: There. All right. I am right back

VR: We had a number of fans who came and express their appreciation for what we do. That gives me a lot of energy going forward, Daniel.

DG: Now, I really appreciate all the– I feel like it’s a family. The people that listen to This Week in Virology, all the other MicrobeTV podcasts. That’s why we do it. We do it because people are listening.

VR: Yes.

DG: I hope we don’t just do it because we like watching and listening to ourselves.

VR: No, no, no. I just love teaching and I know you do as well.

DG: Well, I think that brings us right to my quotation, which is perfect along those lines, why do we do this? Why are we so passionate? I will quote Nelson Mandela, “Education is the most powerful weapon you can use to change the world.” That’s hopefully what we’re doing. Hopefully, we’re giving people knowledge, we’re educators, and hopefully, people can take that education and go forward and change the world. It’s exciting to hopefully be part of that.

In that theme, let me start off with our update. Where are we? Today, as I go through, I always try to follow the stages of COVID-19. What I want to do is, as we talk about each stage and some of the new information, some of the new articles, and what are we learning, I’m going to throw a few real cases in there. All the cases I share always are real cases. I don’t just make them up, but I always try to de-identify, I say, to protect both the innocent and the guilty. [laughs] At each stage, hopefully, that’s going to help people understand like, “OK, this is what we know. What would we do practically?”

Also, I think it may also help to let people in on the fact that it’s still tough. I know early on, people were banging pots, I appreciated what the healthcare workers were doing out there. I have to say, sometimes I talk to my colleagues, and it’s pretty tough. People, a lot of ways, have lost interest in following some of the advice and guidance, and I know that can be really hard on the healthcare providers. I will make sure I acknowledge that as we go forward.

I also want to acknowledge all the people again that we have lost. Over a million people here in the U.S. to COVID, millions worldwide. One of the things I want to say in the U.S., which was really tough, one of the things that we have as a resource-rich country, it’s not just our resources in terms of material objects, but it’s people, and one of the great resources is our seniors, people that have had experience, people that have lived through a lot. Three-quarters of those who died of COVID were 65 and older. We really lost a tremendous number. That’s 1% of this age group, and if you look at the over 85, 3% of the entire over 85 population in the U.S. is now dead from COVID, just in the last two years.

The other thing I want to nod to is reinfections. Oh my, who could have seen that coming? “How many times have you had COVID so far?” is now part of my history. I go through, “When did symptoms start? How many vaccines do you have under your belt? How many COVID infections have you had so far?”

Vincent, you and I were talking just a little bit before we started about Jeffrey Shaman. I’m going to just read a little bit of this excerpt from a nice New York Times article where Jeffrey was quoted.

“At the pandemic’s onset many,” and I put a line through “experts” based their expectations of the coronavirus on influenza, the viral foe most familiar to them. They predicted that, as with the flu, there might be one big outbreak each year, most likely in the fall, and the way to minimize its spread would be just to vaccinate people before its arrival. Instead, the coronavirus is behaving more like four of its closely related cousins which circulate and cause colds year-round.

“While studying common cold coronaviruses,” this is Jeffrey Shaman’s quote, “We saw people with multiple infections within the space of a year,” said Jeffrey Shaman, an epidemiologist at Columbia University in New York. Imagine that. Coronaviruses behave like coronaviruses, not like flu viruses. Who could have seen that coming?

VR: Daniel and I were complaining about this, why you would base coronas on influenza, but we talked with Jeff Shaman early in the outbreak, and he talked about this study, and nobody paid attention to it. Because now The New York Times writes about it, and oh, suddenly, it’s news, but the other thing here, Daniel, they say the way to minimize spread of influenza would be to vaccinate people. That’s incorrect.

DG: [laughs]

VR: The way to minimize disease is to vaccinate people before its arrival, and you may say, “Oh, well, that’s just a small error.” No, it’s not. It’s important, and last night, people were asking us, laypersons, not scientists, “Why is this disconnect between “experts” and in the press and everybody else? That’s because you don’t pay attention to important words like this. Vaccines are not to minimize influenza spread. It’s to minimize disease, as Daniel himself has said many times.

DG: Yes. No, I think this is key, words really matter. We need to keep reinforcing that. I’m going to get to sort of my seatbelt analogy later on, but vaccines, at least the ones that we currently have, are really good at keeping you out of the hospital. They’re really good at reducing your chance of death, but they’ve never been great at keeping you from getting infected. They’ve never been great at stopping the spread. I think we were hearing last night we should do a special on the Sabin-Salk vaccine and talk about the impact there.

Hopefully, if monkeypox becomes more significant they’re not going to just like use flu because they’re familiar with that to come up with strategic plans, but all right. [chuckles]

The article “Limited Cross-Variant Immunity from SARS-CoV-2 Omicron Without Vaccination” was recently published in Nature, the august journal Nature. These researchers used the mice overexpressing, the human H2 receptor, infected them with Omicron, and they reported that after infection alone, they could only neutralize Omicron. In contrast, Omicron infections after prior vaccination, induced overall higher neutralization titers against all variants, VOCs, variants of concern.

I’ll just quote the authors here, “Our results demonstrate that Omicron infection enhances pre-existing immunity elicited by vaccines, but on its own may not confer broad protection against non-Omicron variants in unvaccinated individuals.” If you’re going to get COVID, get vaccinated first.

All right. COVID, children, other vulnerable populations. Big news this week, booster shots of the Pfizer-BioNTech for the 5-to-11-year-old kids, May 17th the U.S. FDA amended the emergency use, the EUA for the Pfizer-BioNTech COVID-19 vaccine, authorizing the use of a single booster dose for administration to individuals 5 through 11 years of age, at least five months after completion of a primary series with the Pfizer-BioNTech COVID-19 vaccine. I will mention the CDC quickly followed with an endorsement, a recommendation for that vaccine as well.

Now, as I go through it, and we’ll put this in the show notes, I want people to be thinking about those stages that we’ve talked about before. What’s that first stage? Well, it’s the pre-exposure, the time when there might be transmission, the time when you might be thinking about testing. I say never miss an opportunity to test, but maybe we want to use a little judgment there. Maybe we’re moving into the time when perhaps maybe there’s a little too much testing, but we’ll touch on that.

I always like to say, and I think this will be relevant right here, Occam was not a physician, John Hickam was. A patient can have two things at the same time. I’m going to bring this up before I talk about the next study, but here as I mentioned, we’re going to talk about a few cases and get people to think through what you’re going to do. This is that testing moment. We have an obese man in his 80s. He’s symptomatic. He tests positive on a home test after attending a large, crowded indoor gathering. He has a large number of medical problems. He’s on a long list of medications.

Initially, the first interaction is through a telephone call. There’s lots here. There was actually maybe a little too much in my opinion for this to be managed through telehealth, a long list of medications, a large number of medical problems. One of the other things that was raised here at the same time is we are seeing a lot of influenza. At this large gathering, it makes sense that we get at least a few people tested for influenza so we know whether or not we want to be treating both things. Maybe not just the COVID. Maybe the SARS-CoV-2, the COVID-19 disease, and the influenza infection.

This gentleman shows up, he’s encouraged to go to an urgent care where he can be tested, evaluated, all the drug interactions sorted through. He shows up not wearing a mask, all right. This is not the time to be anti-mask, when you are acutely infected, wearing that mask is really great source control. You’re really doing a lot for others. This is pretty clear and black and white. I don’t think there’s controversy there.

A lot of times you’ve got to really be going through all these medicines, checking kidney function and certainly you want to make sure an individual here has good follow-up. We’ll be getting into what potential treatments and how this individual was treated.

Here’s the next thing and I’m going to pull Vincent in. I’m going to work Vincent hard tonight. I hope you’re ready there. This is the article, “High Attack Rate of SARS-CoV-2B11529 Among Two-Dose Vaccinated Populations in Two Indoor Entertainment Setting Outbreaks.” This is published in the Journal of Infectious Diseases.

In this article, the authors describe SARS-CoV-2, so this is Omicron infection, among people attending a nightclub and a graduation ball. A nightclub and a graduation ball where over 95% had at least two vaccine doses. The attack rates were 55.1% for the nightclub attendees, 54% for the graduation ball attendees. At-the-ball attack rates increase with time since vaccination: 12.5% among those vaccinated, one to two months previously; 68% among those vaccinated three-plus months previously.

We’re talking about infections here and Vince is going to get pulled in because should we even be talking about this? Such differences were not found at the nightclub. They were happy to support their idea, but then they didn’t find it in the nightclub. The authors suggested this emphasizes the importance of non-pharmaceutical public health measures, in addition to vaccine booster doses to maximize protection in high-risk contexts.

This is, I think it’d be an opportunity for me to hopefully hammer something home. I was recently on News 12 Long Island with Elizabeth, I say Hashagen, but I think it’s Hashen. I always pronounce people’s names incorrectly if I don’t have Dixon around helping me out. She reminded me when I was on this week of a seatbelt analogy, apparently that I had used about a year ago, where I was likening vaccines to seatbelts. The way the media is covering saying, “You know what, everyone started wearing seatbelts. We have less motor vehicle deaths, we have left people ending up in the hospital, but we have seen no impact on accidents, people are still crashing.”

I use this recently on a patient who was very upset again, “I got my vaccine, and I still got the COVID.” Of course, you can imagine where I go with this. What are you thinking Vincent? Here we are, we’re in Australia, we’ve got greater than 95% of people vaccinated. We’re talking about people attending a nightclub or a graduation ball. What about serious illness? What about these other things? Thoughts?

VR: Well, they don’t report the serious illness because there probably wasn’t any. This is all infections and as you intimated at the top, I’m not even sure this is worth reporting. These individuals got infected. If you did this study with a common cold corona for which we don’t have a vaccine, but we have previous infection, you’d find the same thing. At a big gathering, you’d have people getting infected, even though they were infected, say six months before.

What are we learning from this, except that vaccines do not prevent infection? Oh, but we already knew that, didn’t we? That’s the seatbelt analogy, vaccines don’t prevent car crashes. I’m mixing them all up now. I don’t think this is of any news whatsoever but it will fuel the fire of people saying, “Ah, the vaccines don’t work,” and the press will add to it as well, “Vaccines don’t work.” Well, this is how they work. They don’t prevent infection. They prevent severe disease. Not 100% of the time either. Nothing is 100% except death.

DG: Yes. I really am hoping that this carries over, not just from COVID, but across line. We just start– and I’m asking all our listeners, the scientists who, whenever you talk about efficacy, really qualified vaccine efficacy against serious disease against death. The more we talked about vaccine efficacy against infection, this fleeting thing, I think the more we mix the expectations. We have a huge education challenge going forward. It’s not the media’s fault. We have to take responsibility and make sure we continue to communicate clearly.

VR: We have been doing this for a long time, Daniel.

DG: You’ve been doing it for a long time.

VR: It’s just frustrating that people don’t pay attention, but they pay attention to The New York Times. We said that common cold corona story two years ago, and oh well.,

DG: Yes, we’ll keep. We’re not going to give up. We’re not going anywhere.

VR: No, we don’t give up. I’m just venting my frustration.

DG: [chuckles] Well, apparently, our listeners, not only do our listeners enjoy you venting your frustrations, Vincent, but they really enjoy the COVID detection dog articles. I got lots of emails, calls, and texts. Another article, don’t worry more on the scent dogs. The article, “Scent Dogs in Detection of COVID 19: Triple-Blinded Randomized Trial and Operational Real-Life Screening in Airport Settings” was published in BMJ Global Health.

Triple-blinded. Who did they blind? Did they blind the dogs?

Now, four dogs were trained to detect COVID 19 using skin swabs from individuals tested for SARS-CoV-2 by RT-PCR. This controlled, triple blinded validation trial comprised four identical sets of 420 parallel samples from 114 individuals tested positive and 306 negative by RT-PCR, randomly presented to each dog over seven trial sessions. In a real-life setting, the dog screened skin swabs from 303 incoming passengers, all concomitantly examined by nasal swab SARS-CoV-2 RT-PCR.

All right, what were the outcomes? The main outcomes were variables of diagnostic accuracy. People, our listeners should know, sensitivity, specificity, positive predictive value, negative predictive value, for scent dog identification in comparison with the RT-PCR. The validation experiments had an overall accuracy of 92%, a sensitivity of 92%, a specificity of 91% compared to RT-PCR. Across the board, all greater than 90%.

This is where it gets interesting. The dogs did great when someone was infected with wild-type virus but was less accurate for the alpha variant. Apparently, and remember Vince and you did a great job, the dogs are not smelling the virus, the dogs are smelling these volatile organic compounds. Apparently, you smell a little bit different with each different variant and you’ve got to train the dogs to recognize. You’ve got to keep retraining them as we keep getting new variants.

VR: You can have a stable of dogs each with a different training.

DG: [laughs] I’m hoping we could get– remember that dog Tess who did really well? I’m thinking like, as long as she’s not too old because old dogs can’t learn new tricks, but I’m hoping that the dogs can keep picking up each new variant. Keep training them up. People were worried about the dogs, Vincent. What about these dogs? “The dog’s going to get COVID Dr. Griffin?” Can you imagine if a dog got COVID and lost its ability to smell?

VR: Oh, it would be terrible.

DG: You cruel man.

VR: Because everything dogs do is based on smell pretty much.

DG: I know. It would be like their world would just end. Well, I want to reassure our listeners, we got some input from Dr. Sarah Hamer, who’s leading a research team in examining how COVID-19 is impacting our pets, been looking at this since the summer of 2020, and here’s a quotation.

“In our study here at Texas A&M University, we have sampled more than 580 household pets that all live where at least one person was infected with COVID 19. We confirmed infections in about 100 animals.” Hammer said, “As far as we know, pet infections result from spillover from humans. Infected people who share space with their pets can infect their pets, just as humans can infect other people, but a couple of things, most pets were not symptomatic, and if an animal was symptomatic in general, the symptoms were mild, the pets were treated with supportive care. We’re not hearing that these dogs are losing their sense of smell.”

VR: One of the emails I got about this, they asked, are the dogs triple vaccinated?

[laughter]

DG: It is interesting. There are vaccines that are used in the gorillas and some of the animals. That’s interesting. It seems to me like it would make sense for these wonderful dogs to be vaccinated. Active vaccination, never miss an opportunity to vaccinate. We covered the update there in the 5-to-11-year-olds. We will get into this a little bit more because this is going to impact quarantine and isolation rules, really more quarantine as we head into summer because, as we’ll mention, if you’re a boosted– if you’re not just fully vaccinated, but up to date, you are exempted from those quarantine rules.

I have to say, we’re getting to a point where there’s, I think, an educated, a reasonable discussion about how much harm do we do with isolation and quarantine in a low-risk population versus what good that we’re trying to do in that. Passive vaccination, I think this feeds right in for those high-risk people, those people with immunocompromise. Not only are we talking about maybe a fourth dose in them but also remember passive vaccination Evusheld authorized for adults and pediatric individuals, so 12 years of age and older, weigh at least 40 kilograms.

What are the rules? These are individuals who have moderate to severe immune compromise due to medical condition, or receipt of immunosuppressive medications or treatments and may not mount an adequate immune response to COVID-19 vaccination. We’re not checking these people. We’re not checking their antibody levels. We’re not denying them treatment because those antibody levels are above a certain amount, remember, an additional 80%-plus reduction. Actually, that was symptomatic infection in those studies.

The other qualification is for whom vaccination with any available COVID-19 vaccine, according to the approved or authorized schedule is not recommended due to a history of a severe adverse reaction to a COVID-19 vaccine, or a COVID-19 vaccine component.

Post-exposure period testing, and remember quarantine for those who are not up to date with vaccines. The CDC even has a nice calculator. You go through plugging in. Just very simply, if you are boosted, if you are up to date with your vaccines, there is no quarantine. Quarantine is only for folks that are either unvaccinated or not up to date. Should you be exposed, the current recommendation is quarantine for at least 5 days, then take precautions until day 10. That’s your post-exposure period.

Now you test positive, the period of time detectable viral replication for some, this is the viral symptom phase, for some people, they might be asymptomatic. I did want to point out some subtle differences between the detailed EUA factsheet for Paxlovid and the FDA eligibility tool. I think this is interesting. They’re both produced by the FDA but there are subtle differences.

In the EUA, it says the approval is for patients with positive results of a direct SARS-CoV-2 viral test, who are at high risk for progression to severe COVID-19, including hospitalization and death. The FDA eligibility tool basically has the box has one or more risk factors for progression to severe COVID-19. This links to the CDC, pretty extensive list.

I also will say, in this fact sheet, they also say additional risk factors such as being unvaccinated or not having received a booster. A little bit of a disconnect there. I think the message we’re getting is that we’re encouraged to err on the side of prescribing this as opposed to worrying that maybe it’s a little gray, maybe don’t quite meet criteria.

Remember that Paxlovid has an 89% to 88% reduction in progression, if given in the first three to five days. There’s a number of resources we’ll post in the show notes where you can find the medication, how you can check for drug-drug interactions. I do want to say, take the time look through those because drug-drug interactions are real and I’m going to mention the article, “Super Therapeutic Tacrolimus Concentrations with Nirmatrelvir/Ritonavir in Solid Organ Transplant Recipients Requiring Hospitalization, a Case Series Using Rifampin for Reversal.”

They say a case series, it’s two folks. This was published in Open Forum Infectious Disease. Tacrolimus is an immunosuppressive medication that we use quite widely in transplant medicine to inhibit the intracellular calcium increase associated with the T-cell activation. It’s for the aficionados a macrolide calcineurin inhibitor. Why do we care about it here? Because it’s metabolized by the liver via the P450 CYP3A. Getting Paxlovid, even for those five days, blocks metabolism, the level can become elevated. Actually, this is a description of that happening in two patients resulted in hospitalization.

We just had a case, actually just yesterday, where I was on the phone with the urgent care doc and too many drug interactions. He said, “You know what, Dr. Griffin, I’m going to send this person for IV remdesivir, bebtelovimab, the monoclonal might be a choice as well. We have other options. Boy, the difference that 88%, 89% versus 87% reduction with remdesivir, start thinking about that.

The next, and this is all over the news. We hear that the NIH is talking with Pfizer about doing more studies. Do we in some individuals do a second round of Paxlovid or maybe five days isn’t quite enough? I’m going to go into this a little bit in the context of a couple of cases here. Another one here, 16-year-old with his second case of COVID, his first was back in December, now it’s May. He’s got mild symptoms. He’s got three shots of the vaccine, but the father is concerned about Long COVID and I’m asked to weigh in on this.

I want to discuss a little bit about his concern here. He is hoping that maybe his minimally symptomatic, low-risk 16-year-old would have a reduction in his risk of developing Long COVID if he got Paxlovid. We had a pretty long discussion about the fact that we do not know. We do not know if Paxlovid decreases the risk of Long COVID. We do not know if Paxlovid increases the risk of Long COVID. We are waiting for the science to sort this out. Currently, that is not in the EUA, that is not in the authorization for use of Paxlovid.

VR: Would you treat the boy with Paxlovid anyway, because he’s mildly symptomatic?

DG: Well still, it goes back to that issue of, is there any feature that, so Paxlovid isn’t just for everyone. It’s for people who have at least one feature that would put them at risk. This boy, 16 years old, there was not a single risk factor he had. No learning disabilities, no obesity, no inactivity, nothing. In a young, healthy individual like this, currently, the EUA would not be consistent with treating him.

VR: I’ve heard, though, that people are not following that, right?

DG: There are a lot of folks who are just giving the Paxlovid out like candy. $800 of course, interesting. We need to do the science. Remdesivir, remember, the order has changed. This is now at number three. I think we need a new name because people are like, “Ah, I hear that remdesivir is not that impressive.” Well, it was not that impressive giving it to someone in the ICU during week two or three on a ventilator, but that first three to five days, 87% reduction. If you’re a doctor, is discussing remdesivir in the first three to five days, just remember timing is so critical in everything with COVID.

VR: Isn’t it called Veklury anyway, so you could just use that name.

DG: Actually, maybe that makes sense. I don’t really want you to get that remdesivir but this Veklury, I don’t know if you’ve heard of Veklury, it’s a new Viking medication, the Danes sent it over. You get to go to Veklury. Actually, this is good. This is another one of these scenarios. Actually a very similar one just recently actually, on my drive through the rain home.

Eight-year-old boy. He’s got diabetes, obesity, developmental delays, has a congenital heart condition. He’s diagnosed with acute COVID. He’s symptomatic and he has a 12-year-old asymptomatic test positive brother. What was recommended? Actually, very similar, I had a 7-year-old that I was just called about consulting, discussing with the pediatrician, Down syndrome, some other issues. In both these cases referred for the IV remdesivir, which is when you get under the age of 12-year-old asymptomatic test positive brother, no risk factors at all. No treatment was recommended for the brother. Do you want to reinforce those under 12? This is again, for those of you updating, the EUA has not been modified. When this provider looked at the EUA for remdesivir, actually, it’s licensing now. It’s not even EUA but licensing. They hadn’t updated the physician fact sheet. It still set down to 12. He was questioning. I had to actually show him where that FDA media update was so he could see that this had been updated.

All right. Monoclonals. Remember, I get a lot of questions. People are, what about those monoclonals? What’s happened there? Remember, we are down to bebtelovimab. It’s dropped down to number three. We just don’t have the efficacy data, so we’re just not sure here. Number four, Thor’s hammer, molnupiravir, right. Veklury, molnupiravir, and I guess the Nordics, the Vikings are taking over, but remember this is number four because there’s only a 30% reduction. It got to be 18 and over and you want to watch for those pregnancies. You want a negative pregnancy test, et cetera.

All right. Now the other thing is the Do No Harm. While we’re trying to do something good, Do No Harm, let’s avoid giving those steroids in the first week. Zinc, not helpful, just giving some GI distress. We have studied that. Antibiotics for a virus? Please, unproven therapies. I’m going to go right into fluvoxamine. A lot of people were really vehement out there. Why isn’t everyone getting fluvoxamine? Well, fluvoxamine was reviewed by the FDA and the FDA decided not to authorize fluvoxamine. The memorandum explaining the basis for declining requests for emergency use of fluvoxamine maleate, and this memorandum goes through the results of several trials.

Talks about other options, and I’m going to just hit a few bullet points here. They discussed the TOGETHER trial. We’ve discussed this as well. The TOGETHER trial was a randomized, double-blind, placebo-controlled platform trial in high-risk symptomatic adult outpatients in Brazil. The primary endpoint was a composite endpoint. When they looked through this, basically they felt that there was not a clinically meaningful impact here. The treatment benefit of fluvoxamine was not persuasive when they focused on what they felt were clinically meaningful outcomes, such as proportion of patients experiencing hospitalizations and deaths.

They also looked at STOP COVID, which was real-world data studies. Some issues here. They looked at a couple of additional trials the STOP COVID 2, the COVID-OUT. Both were terminated early for futility. I’ll just finish with the quotation here, “Based on the review of available scientific evidence, the FDA has determined that the data are insufficient to conclude that fluvoxamine may be effective in the treatment of nonhospitalized patients with COVID-19 to prevent progression to severe disease and/or hospitalization.”

I think a couple of things here before I mention another review article is that, we do have effective treatments. They’re actually pretty lenient as, Vincent, I think you were intimating with our ability to use Paxlovid. If you’re in that situation where you really feel compelled to do something, then fluvoxamine is not that something you should be doing. Paxlovid, IV remdesivir, maybe monoclonals. There was a really nice review published on April 6th in JAMA Network Open, “Fluvoxamine for Outpatient Management of COVID-19 to Prevent Hospitalization: A Systematic Review and Meta-Analysis.” This was just really nice if you want to go through and try to understand what was the science behind the FDA memorandum.

Well, I want to hit, and this is avoid doing harm, and this is another case. This is a woman in her 40s. I saw this woman. I’ll mention where I saw her in a moment but gathering this history. She had COVID back in 2020, went ahead, got fully vaccinated, and up to date with her vaccinations. Then her husband got infected. Then a few days later, she became symptomatic, also tested positive, but she ends up in the ICU. I’m trying to figure out. Now I’m saying that I don’t understand. You’re in your 40s, you don’t have any risk factors. You did fine the first time. You’ve been vaccinated. What was different this time? We try to go through it.

She says, “Well, symptoms started. A couple of days later, I wasn’t feeling great. Now my husband had been given a prescription for steroids by his primary care doctor. He decided not to take them, so I took them instead.” Instead of letting that prior survival immunity, instead of letting those vaccines protect her, she went ahead, took steroids, and ended up in the ICU. Maybe there was a connection there. Let’s not do steroids during that first week.

Remember, the other thing we have to talk about our patients, and this is getting harder, this is where really my heart goes out to all the docs out there trying to work with patients through this. Remember, isolation for the infected. People are done with isolation and getting infected with COVID does not make you any more excited about this virus. What is the CDC guidance? Isolate for at least 5 days and then take precautions until day 10. People seem really upset, but I just will reinforce, and this is something the CDC has acknowledged. People can still be contagious day 6 through 10 and some past this point.

There are some other subtle rules of the CDC guidance. I’ll just make some comments here. If you get very sick from COVID-19, if you have a severe case or if you have a weakened immune system, you should isolate for at least 10 days and you should consult before ending isolation. For some people, it may be longer than those 10 days. This can be challenging with regard to public health decisions going forward. Vincent, you and I have talked about this quite a bit. Some folks are talking about, and even in the CDC, is the option to add antigen testing, potentially extending that isolation.

We previously discussed the “MMWR, Antigen Test Positivity After COVID-19 Isolation, Yukon–Kuskokwim Delta Region, Alaska, January Through February 2022.” In the study, among persons with symptomatic infection, 64% received a positive antigen test result during the five to nine days after infection, after symptom onset. The authors go on to say, and I’m going to quote. “However, a positive antigen test does not necessarily mean that a person is infectious. Similarly, a negative test result does not necessarily mean that a person is not infectious.”

I just want to point out here. More than half of people continue to have positive antigen tests past day five. People can still be contagious day six through 10 and in some people, for even longer. I have not seen any published peer-reviewed data convincing me that a negative antigen test before day 10 has 100% all clear or that a positive test past the generous 14 days means a person is still infectious. I just want to repeat, and boy, Vincent, I’m going to pull you in on this one. PCR detects RNA. Rapid antigen tests detect viral proteins. Plaque assays detect viable potentially infectious virus, and contact tracing demonstrates transmission.

I do want to make a clarification here because we have some people talking about this, maybe did not listen to all the prior TWiVs but not all viruses have RNA as their genetic material. Some have DNA. Don’t say like, viruses have RNA and people have DNA. Particularly when we start talking about monkeypox, I will point out, we’ll be doing a PCR for DNA. I will share a couple of cases here. Then Vincent, I want to pull you in on this. Unless, did you have any comments about so far?

VR: Well, first of all, can everyone listening please go take my virology course. It’s free. Don’t tell me you don’t have time, you do, because you’re going to learn a lot. It’s a long time, but it’s free and you’ll understand all this stuff. Secondly, I wanted to ask you, Daniel, when is the confirmed infected quarantine going to stop? Is it going to be next week, next month, next year, or never? What is going to be different that the CDC will say an infected person no longer has to be isolated or quarantined? I don’t understand.

DG: I think this is, we were having this discussion last night, where’s the plan? Where’s the end game? Where are we headed? Until we hear that, I think people are really a little frustrated and a little bit lost. Is there any threshold? You and I talked about it. We’re like, is it once you allow vaccines for people under 5? Is it, now that we have Evusheld and Paxlovid? What is it? Was it, we were waiting for there to be enough Paxlovid out there? Were we waiting for the hospitals to have capacity? Really, who’s in charge? Who’s driving the bus?

VR: I agree, that’s putting it beautifully, or I hope they’re not thinking when the virus goes away because it’s not going away, right?

DG: Well, I think that’s one of the problems. I think that some folks are just realizing like, “Oh, this is a coronavirus, it’s going to behave like a coronavirus and it’s not going away.” Who was it early on? From the NIH. I’m trying to remember, who basically was saying, “This is probably not going to go away. This is going to become endemic. I think we need a plan.”

VR: The other point here is this statement from your Yukon paper MMWR, a positive test does not necessarily mean a person is infectious, a negative doesn’t mean it’s not infectious. We use diagnostic tests to facilitate decisions, right? I’m not sure how useful that is. It’s not a hundred percent, but nothing is a hundred percent. What is the percentage? You’ve talked about this before, positive tests are pretty close to a hundred percent and negatives are also, so they’re not a hundred, but I’m not sure that saying not necessarily is useful to most people because they’ll say, “What’s the point of a test then?”

DG: Yes. I think the thing that we’ve talked about, and I remember I got excited about the paper when it finally got peer-reviewed and published, but it had been talked on sort of a deep dive, but time matters too. Upfront, when a person starts to have symptoms, there is a nice correlation between that antigen test and the time at which they can spread to others. But as time goes out the other end, once you get past day 14, day 15, some people still stay positive.

We were actually talking about that last night and it was like, say a few cases. We were back and forth, a teenager still positive at day 17 on an antigen test. Is that child still infectious? I don’t think we have any compelling evidence at that end. Time needs to be part of this discussion too. It is tough. I think this might get back to the question of maybe I need to change my statement, never miss an opportunity to test. We need to start using those tests intelligently and asking ourself, what are we going to do with that information?

VR: A while ago when I said we need to test less people, always used to tell me, but Daniel, your colleague says you have to never miss an opportunity to test. I said, OK Daniel, the other question I have for you, as you know I just returned from Switzerland and I needed to test negative to return. There’s a lot of virus in the U.S. What’s the problem if a few people bring a few more PFU in? I don’t get it.

DG: I actually think that’s huge. That’s hurting the economy, it’s hurting travel, it’s frightening people. That’s the big thing I worry about when I travel, and actually, one of my recent trips, I limited where I went because I’m like, I got to go and I’ve got to somehow figure out how I get this test before I go back. When I was down at Panama, it limited the amount of time that I could spend helping people because I needed to devote this time to get back to a place so I could get my test, so I could return to the U.S.

We’re going from lower risk places back to here with this virus everywhere. Again, who’s driving the bus? We really need to move forward and come up with, I think, guidance that is relative to the current situation. All right. Let me use a couple of examples, which I think will hit this home because I think this point is really important. This is a recent case. This is an individual typical viral symptom. He assured me that these viral symptoms were not COVID despite that he had just attended a large indoor gathering, where we now know at least a dozen people have been infected with SARS-CoV-2.

The next day, we get a test, it’s a positive, high-risk individual. I started him on Paxlovid. Couple of days later, I get the call. “Horrible chills. I can’t taste or smell the coffee. This is going in the wrong direction.” Oxygen SATs are still in the high 90s. I reassure him. Later that day, I hear from his wife, he’s done with this COVID, he’s better. He’s done isolating. He’s going to get himself one of those negative tests, and then he’s going to stop isolating.”

What do you think, here’s this older gentleman, very upset. He’s going to get that negative test. What if it comes out? What if he does it himself and gets a negative test. This is day three. Are we good? Is he fine? Can he go back out there?

VR: This is why I’m not a clinician, Daniel, oh my gosh.

[laughter]

DG: No, I mean, this is what I run into every day is that a lot of these are self-tests and people will get the answer they want. His similarly high-risk wife is not infected. He’s ready to rip that mask off. He’s done with all this. I’m not convinced that a self-administered negative antigen test on day three is going to make me feel comfortable.

VR: If he was truly positive, before day three, he’s not going to be negative.

DG: Yes, that’s true.

VR: Unless it’s a false negative.

DG: I wouldn’t trust a negative on day three. I would just think something was fishy. The next story, this is a teenager. Actually, this is a case where it’s 15 last night, we were talking about day 17. Asymptomatic teenager, there was an exposure. Did the antigen test. I always love when people say, “Oh, Dr. Griffin, I think you’re confusing PCR and antigen.” Please. No, I can tell the difference.

[laughter]

DG: Pardon me. The mother has been recommended to keep the teenager isolated and continue to get daily tests until they get a negative test there. Day 15, the antigen test is still positive. The mother is told, very vehemently and forcefully, it would be irresponsible to let him out of isolation on day 15 with a– Yes.

VR: I think this is why we can’t keep people inside based on testing. What’s the purpose of isolating this teenager? Tell us what you’re thinking CDC. Is it because he might encounter a less than 5-year-old who has not been vaccinated? What is it? You’re ruining the kid’s life for no good reason. I think, to say it’s irresponsible is an abrogation of responsibility on the healthcare provider because that’s not fair. Obviously, day 15, Daniel, it’s not likely to be infectious any longer, right?

DG: I think this is one of these issues is that we saw all these zero COVID approaches. There’s so much SARS-CoV-2 out there. I think it is time. At least I think it’s important for the CDC. I’m going to weigh this on the CDC. Dr. Walensky, if you’re listening, at least we need to hear, what is the thinking? Why are we doing this? When will we stop? What are we worried about? Who are we protecting?

We know there’s certainly a bunch of kids in that school where this child might return, who had sniffles, probably have SARS-CoV-2, who are not testing, avoiding testing, just so they can keep. With summer coming up, five days is an eternity for a teenager. 15 days is an eternity times three.

VR: Oh, five days is the whole summer camp wiped out, right?

DG: It does. It’s going to ruin, and my gosh, 15, 17 days.

VR: In that summer camp, as you say, there are kids who are infected. It doesn’t matter, it’s ridiculous to keep him out of that. Wherever he’s going to go or she, they’re going to be infected kids. Makes no sense.

DG: Yes. Next time, I think we’ll have to talk a little bit about the mental health impact of isolation of the infected, but there’s harm associated with that and we need to start asking: Are we doing more harm in our mitigation, in our isolation measures than we’re actually benefiting society?

VR: Good point.

DG: I’ll just finish with a quotation. I’m going to read the IDSA statement. This, I think, is nice. It’s humble. It’s honest. Knowledge is evolving on the duration of infectivity of patients with COVID-19; current data suggests people begin to transmit SARS-CoV-2 a few days prior to symptom onset, that non-immune-compromised hosts with non-critical illness are unlikely to be infectious 10 days after symptom onset and that individuals with critical illness or significant immune compromise are unlikely to be infectious 15 days after symptom onset.

Peak transmission likely occurs around symptom onset, coincident when viral RNA load is at its highest. While prolonged viral RNA shedding can occur, in most cases SARS-CoV-2 cannot be cultured after 8-12 days; whether viral culture clinically correlates to a lack of infectivity is not known, but epidemiologic data suggests it may be a reasonable surrogate marker. As mentioned, you’re seeing people here, not PCR, but sometimes antigen-positive well past that 12 or even that day 14.

VR: There are some problems with this, Daniel. First of all, it’s probably in a non-vaccinated person that they’re making these numbers. It can’t be cultured after 8 to 12 days. I’ll bet it’s a lot shorter in a vaccinated person, but nobody has looked at infectivity. Secondly, the Swiss study out of Geneva showed that RNA is not an adequate surrogate for infectivity. This is not correct. Do you know if these statements are from unvaccinated people? Probably, right?

DG: They’re old, right? They’re old because the two days before, they’re prior variants, they’re unvaccinated, they’re not people that have been on antivirals, so I think all this stuff needs to be updated. Hopefully, the CDC doesn’t get so distracted by monkeypox that they can keep updating the CDC information. OK. Let’s move on. I think we’re going long tonight.

In early inflammatory phase, remember steroids at the right time in the right patient, not too soon. Anticoagulation, pulmonary support, maybe remdesivir. We’ve got tocilizumab. Avoid those unnecessary antibiotics. I’m going to avoid the whole, we’ll talk about maybe next time, the whole Paxlovid rebound and what may or may not be happening or whether or not that’s even a thing, and I’m going to finish off with a few articles on Long COVID.

Some real theories here being tested, hypotheses being tested. Is it viral persistence? Is it an ongoing inflammation? Is it a bit of both? I think maybe, again, this will be when we talk about efficacy of vaccines, maybe we should qualify, that are vehement strongly held opinions, whether they’re hypothesis or evidence-based. The article, “Inflammasome Activation in Infected Macrophages Drives COVID-19 Pathology,” now published in Nature, still that unedited version. I will encourage our listeners to listen to TWiV 900 for a really deep dive.

But a really impressive, dense article looking at how potentially the virus may end up in macrophages. This may lead to a macrophage activation, may actually even be an antibody-dependent FC entry into some of those macrophages. Really interesting knowledge here, interesting information, and quite the list of authors. I will recommend people for a deeper dive, go to TWiV 900. What a number.

We also have a couple of other articles. I’m going to be curious what your thoughts are on this, Vincent, because it hits a couple of things. The first was, “Gastrointestinal Symptoms and Fecal Shedding of SARS-CoV-2 RNA Suggests Prolonged Gastrointestinal Infection”. I was really good until that last word threw me a little. This was published in Med, a Cell Press journal. Now, the research started off with that title just well. They were analyzing the dynamics of fecal RNA shedding up to 10 months after COVID-19 diagnosis in 113 individuals with mild to moderate disease. They correlated shedding of viral RNA, not necessarily infectious variance with disease symptoms.

Fecal SARS-CoV-2 RNA was detected in 49.2% of participants within the first week of diagnosis, where there was no ongoing oropharyngeal SARS-CoV-2 RNA shedding in subjects at four months. 12.7% of the participants continued to shed SARS-CoV-2 RNA in the feces at four months after diagnosis, 3.8% at seven months. They reported that GI symptoms, abdominal pain, nausea, vomiting, were associated with fecal shedding of SARS-CoV-2. They reported that participants that shed viral RNA in their stool were more likely to report nausea just at odds ratio 1.6, vomiting 3.2, abdominal pain 2.05.

The next paper, “Post-Acute COVID-19 is Characterized by Gut Viral Antigen Persistence in Inflammatory Bowel Diseases,” better title. Published in Gastroenterology, currently available as a pre-proof. These are the results of an endoscopy site, so they pass the scope down, 46 inflammatory bowel disease patients, 219 days after a confirmed SARS-CoV-2 infection, they were able to detect viral RNA and viral antigen in gut epithelium and CD8+ T cells at about seven months, but we’re not able to culture virus. They also found a correlation between RNA with antigen detection and symptoms.

The authors argue that viral antigen-persistent may reflect, I put the “may” in there, incomplete clearance of SARS-CoV-2, rather than, and I’ll agree, subclinical latent or persistent infection as they were unable to culture virus from biopsy derived tissue. Vincent.

VR: Actually, today’s TWiV, which will drop on Sunday. Heads up folks, you can listen to that. We did a paper on a similar study from Spain, where they found a viral RNA by PCR in feces of certain fraction of COVID patients. The shedding did not correlate with any symptoms. They didn’t have shedding and correlating with gastrointestinal system, which contrasts to what’s shown here, and they could not recover infectivity. They put the fecal material into cells and culture and they could not recover infectivity.

The problem with these experiments is none of them do the spiking experiment. They take feces, normal feces, and add SARS-CoV-2 and ask, “Can it be infectious in feces?” Because, as Kathy Spindler said, there’s a lot of nasties in feces that inactivate the virus. You have to do that because it could be if you put a million PFU into feces, you get nothing out, and that would complicate what we’re trying to interpret here.

DG: Yes, I think it’s challenging because one of the potentials is that there’s some viral persistence, people, not like people, but me, some of us are looking at doing trials of antivirals in folks with Long COVID, but if there’s no replicating virus, if there’s just maybe remnant antigen, remnant material, those are not going to work. Those trials are not going to work. It would be ideal if we had some ability to somehow detect and say, “Oh, look, we are seeing replicating virus.” Maybe the sequence is changing over time. Maybe we have the ability to really culture it from the feces, that then would be quite helpful, but yes, we’re left still sorting this out.

All right. Well, let me finish here with the rest of the world. I keep trying to remind folks and maybe people will get this. No one is safe until everyone is safe. I say this slowly, the most selfish thing we can do is vaccinate the world. It is in our best interest. We live in a global world. If people aren’t seeing that with the economy and supply chains, we can’t just vaccinate in our own backyard. We need to worry about the world.

I want everyone to pause the recording here. If you’re driving, you could pause it here, and then you can go to parasiteswithoutborders.com. Click on the Donate button, and then you can come back and we’ll finish. If you’re walking the dog, pause it here. You can go home, click on Donate, and then go back and finish that dog walk, but I want to say every little bit helps. Right now, during the months of May, June, and July, we are doing our fundraiser to support Foundation International Medical Relief of Children. We have that clinic in Eastern Uganda struggling. We really need the financial support, so please help us help them.

VR: All right. It’s time for your questions for Daniel. You can send them to daniel@microbe.tv, and I’m going to try and shorten these up because we’re hitting an hour here. First one is from Amanda who is an RN and she has three questions. First, Daniel, would you encourage someone to get a second booster before international travel for the obvious reasons of preventing positivity and not being able to get back?

DG: Yes, for a temporary period of time, you’re going to a reunion, you’re going to travel, that makes a certain amount of sense, a temporary boost in your protection against infection.

VR: What about access to antivirals in other countries? Is there a good resource to see what’s available in each country?

DG: There isn’t, actually, and I’ve been looking through this, it’s piecemeal. Ideally, there should be, and ideally, I would love some direction. If I’ve got a high-risk individual who’s going to be traveling somewhere where I’m concerned they won’t have access to antivirals, I would love if there was some direction and that it was actually OK to maybe give them Paxlovid for the purse, so to speak, but the current EUA does not really support that. Again, if you’re listening out there, that would be helpful for us.

VR: Finally, I know the answer to this because I’ve asked you before, if someone were at high risk for severe COVID traveling to a country with limited health care, would you give that traveler a packet of Paxlovid to bring with them?

DG: No, unfortunately, the EUA does not really open us up to allow that. I know certain providers are doing that. I think it would make perfect sense. I don’t see a moral issue there, but I do see the EUA legal issue.

VR: All right, Noah’s wife is pregnant and just tested positive eight weeks into pregnancy, 33 years old, triple vaccinated, no complicating factors. Should she take Paxlovid? Are there any contraindications?

DG: Yes, she should. Pregnancy is a high-risk condition, so yes, we encourage Paxlovid to be used in that context. We’re doing it lots and lots of times. Yes, I would encourage it.

VR: All right, and finally, Ed wants to know if giving Paxlovid will impact any antiviral immunity that you would otherwise develop.

DG: We’re hoping actually, I have to say, we do not want your immune response to that virus. That’s what gets us in trouble, that’s what gets you into the hospital. If you want to boost your immune system, go ahead and get a vaccine. Getting an infection, letting it run its course, waiting to start those anti-virals, all bad ideas.

VR: That’s COVID-19 clinical update Number 115 with Dr. Daniel Griffin. Thank you, Daniel.

DG: Oh, thank you, and everyone be safe.

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