TWiV 903 COVID-19 Clinical Update #116

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired  28 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 MicrobeTV, this is TWiV, This Week in Virology, Episode 903, recorded on May 26th, 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 understand you don’t want to do another hour update, Daniel.

DG: Well actually, maybe that’s what my quotation this week is about, maybe that was a little too much. The quotation, we’ll get right into it: “The best doctor gives the least medicine,” and that’s by Ben Franklin. I’m going to start right ahead, Vincent, by mentioning your pick from TWiV 902, the article, “Physicians Spreading Misinformation on Social Media, Do Right and Wrong Answers Still Exist in Medicine?” It was published in The New England Journal of Medicine. I’m also going to lament that this is behind a paywall. Because I really think stuff like this needs to be out there for everyone, not just what academicians who are like basically just nodding their heads saying, “Yes, yes, we need this to be part of the discussion.”

I will say, the first sentence I thought was golden, “Medicine has a truth problem.” In the era of social media, and heavily politicized science, truth is increasingly crowdsourced. If enough people like, share, or choose to believe something, others will accept it as true.

VR: That’s beautiful, that’s absolutely the problem we have, right Daniel? It’s so true.

DG: I will say that I’m thinking a lot of physicians and scientists should clarify when they say something. They should say this is evidence-based, this is what the science shows, instead of just giving an opinion, and then hoping that when they’re right they can then retweet that back out there and say, “See, I knew.” Because you’ll be right just like a broken clock at least two times a day, but that’s not what science is about. Science is saying, “I don’t know,” and then finding out the answer. If you go into science anytime you say, “Oh, I knew.” You basically, maybe science isn’t the right place for you, who thinks that they know things before the science is done, before the experiments are finished.

I am going to go ahead and actually also agree with the closing sentence of this, one of the closing sentences, but it is a little bit U.S.-centric. They are talking, I think, about U.S. physicians and scientists here when they say this, “With nearly 1 million Americans dead from COVID, and deaths some of them clearly preventable continuing at a rate of more than 200,000 per year, it has become imperative for our profession to empower our institutions, to signal clearly who is and who is not providing evidence-based information.”

VR: Daniel, this is a real problem with social media as you know, and that’s why I complain about the cardiologists, but it’s really a mantra for anyone going outside of their lane, making proclamations that are clearly wrong because they don’t know better. This is not good because a lot of people are hanging on their word and they need to be right.

DG: I think this, and we will spend a little bit time here, I was going to move on but no this is, I think, important. In like, let’s say the Twitter format, the 250 characters, it’s really not enough to really express scientific truth. It might be enough to steer someone towards an article, where they can then read through. That’s about as many characters are allowed in a title, before you even get to the abstract. We now know 90% of people only read the title, then a few more percent of people read the abstract, and then there’s a couple of us that actually read the whole article.

I think it is tough because there are, “Thought opinion leaders,” out there. They say things and I think we really have to be careful because in those 250 characters, what’s actually being said in this sound bite can easily be taken by someone as confirmation bias of whatever they’re thinking as opposed to really getting into the actual evidence. I would almost like as we’ve talked about with vaccine efficacy, we say against what? When you say something, I think it should be like, “Hey this is my opinion, I’m throwing darts, I hope I’m right, please forget if I said this if I was wrong.” As opposed to, “this is the science, this is evidence-based comment.”

VR: That’s why we do these one- and two-hour podcasts, because that’s what it takes to discuss a paper properly. If you don’t know how to read a paper, you don’t understand it, listen to our podcasts and we go through it for you. I think that is what you should– When I use Twitter I use it to say, “Hey I just released a new podcast with Daniel on Monkeypox go listen to it.” I’m not going to give you the bottom line on Twitter. It doesn’t help.

DG: It’s interesting, I’m usually one-way directional on Twitter, I think much like you, Vincent, where, I put stuff out there. I think it was a week or two ago someone was like, “Oh I understand you’re having this Twitter feud.” I was like, “What?” Because I don’t really and they showed me I was like, “Oh interesting.” One of the things they showed me is someone made a comment, “Well, he’s been wrong about other things.” The interesting thing, and hopefully I’ve tried to do this, is as I share what the science is. I’ve never been wrong about that, I show you what the science is, I discuss the articles, that’s what we know. I try not to then say, because of this I’m going to make this proclamation of truth.

VR: I’ll give you an example, Daniel. The other day on Twitter, the cardiologist tweeted about a paper testing a mucosal COVID vaccine in mice. The cardiologist tweeted, this is a variant-proof vaccine, which is as wrong as you can be because it’s not even in people.

DG:  Yeah. It is challenging. Maybe for our listeners, just, I know it’s a little harder to actually get through these longer venues, but if you really want truth. I do think maybe we’ve learned in the last two years that it is important to be educated about these topics, about virology and other scientific topics, this is the format it takes.

VR: Learning is not a crowd-based thing, you don’t learn when everybody on Twitter says this is so; you have to read and watch and listen and think take tests on your own, that’s, how you listen. They got it right on in this article, this whole idea that this truth problem. I think the answer is yes there are still right and wrong answers in medicine, though, right Daniel?

DG: I think that’s key. As a physician your responsibility is not to sleep well at night feeling like you’ve done right by yourself, you should sleep well at night feeling you’ve done right by your patient. Ninety percent of our good ideas are non-evidence-based ideas, turn out not to be helpful. Practice evidence-based medicine. I know 30 years ago when this was first being introduced to medicine, if you can believe that, it was controversial, but I think it’s very clear now that evidence-based medicine is what is expected from people in our profession.

All right, and along these lines, the article, “Excess Mortality in Massachusetts During the Delta and Omicron Waves of COVID-19,” was published in JAMA. Just will briefly mention it in this study that they found that more all-cause-excess-mortality occurred in Massachusetts during the first eight weeks of the Omicron period than during the entire 23-week Delta period. There was excess mortality in all adult age groups including in younger age groups. I don’t know if we keep saying that enough people, will appreciate that it is not innocuous to get infected.

VR: You remember the tweets early in the Omicron about how it was mild and everyone was going to get naturally immunized with no disease, that’s an example of what we’re talking about.

DG: People were actually encouraged, people went out based on that, I will say bad advice, this is that vaccine that the pharmaceutical companies couldn’t produce, go out there and get it while you can. I think that’s responsibility that comes with people saying things like that. All right children COVID, other vulnerable populations. I was recently asked by a friend of mine, ICU physician, if I have noticed if there’s any evidence out there that there might be more bronchospasm with Omicron. That’s that wheezing, that’s that closing of the upper airways.

I kept my eyes open, and a couple papers the first paper, “Croup Associated with SARS-CoV-2, Pediatric Laryngotracheitis During the Omicron Surge,” was just published in JPIDS. You’ll hear much about that journal on the Puscast. It’s a favorite of Sarah Dong’s. This was a small, retrospective analysis, describing weekly croup and corresponding viral prevalence patterns in a pediatric quaternary care system in metropolitan Atlanta, and they characterize this series of 24 patients with croup associated with SARS COVID-2 infection and suggested that this clinical presentation increased substantially in frequency during the period of high Omicron versus Delta transmission. The other article, “Rhinovirus as the Main Co-Circulating Virus During the COVID 19 Pandemic in Children,” was published in Jornal De Pediatria. These investigators were looking at the prevalence of a large array of respiratory pathogens in symptomatic children and adolescents during the pandemic in Southern Brazil, 436 participants included, 45 hospitalized. Rhinovirus was the most prevalent pathogen followed by RSV, with a co-infection occurring in 31 of the 436. We are seeing maybe a little bit more of this bronchospasm, but it’s not clear to me if this is a change in the virus, if part of this is being driven by co-infections.

VR: That’s not surprising because rhinoviruses are the most common causes of respiratory infections. It’s not surprising you would see it, along with SARS COVID-2.

DG: Yes, now that things have changed, right? We’re seeing a lot of these viral infections out of season. A lot of these other viral infections are associated with that bronchospasm.

VR: Also, the levels of rhinovirus during lockdown masking and so forth, didn’t change as did some of the other respiratory viruses like influenza. That is probably also playing into it. Why it didn’t change is a good question. It may be that it’s not so much transmitted by droplets, but more touching and contact.

DG: Maybe more of a contact issue. Hopefully, we’re going to learn a lot when we bring all that data together. All right. Now I have updated, we are now in a different stage of the pandemic. Let me change this to use tests intelligently. Now, Vince and I are on the same page here. Last time we talked a little bit about the guidance and the rules around isolation of the infected and quarantine. Let’s go a little bit deeper into the science here. This is not, I don’t want people to feel like, “Oh, you’ve just thrown up your hands. Dr. Griffin,” things have changed and as things have changed as we have different tools, the calculus, the risk calculus has changed as well. I want to talk about the article, “Infectious Viral Shedding of SARS COVID-2 Delta Following Vaccination, a Longitudinal Cohort Study,” posted as a preprint.

I really liked this preprint, I’ll say that upfront. In this study, the investigators compared longitudinal viral shedding dynamics in unvaccinated and fully vaccinated adults. SARS COVID-2 infected adults were enrolled within five days of symptom onset and nasal specimens were self-collected daily for two weeks and then intermittently for an additional two weeks. SARS COVID-2 RNA load and infectious virus were analyzed relative to symptom onset stratified by vaccination status. They tested 1,080 nasal specimens from 52 unvaccinated adults, and 32 fully vaccinated adults. I will mention those 52 unvaccinated were enrolled in the pre-Delta, the 32 fully vaccinated that were predominantly during Delta. They found no differences by vaccination status in the maximum RNA levels, the maximum infectious titers, and the median duration of viral RNA shedding.

The rate of decay from the maximum RNA load was faster among vaccinated, and maximum infectious titers and maximum RNA levels were highly correlated. This is where I think we get the most important and interesting results. Drum roll, please? Amongst participants with an infectious virus, the median duration of infectious virus detection was reduced from 7.5 days in unvaccinated participants to six days in those vaccinated. Accordingly, the odds of shedding infectious virus from days 6-12 post-onset were lower among vaccinated participants than unvaccinated with an odds ratio of 0.42. This is about a 60% reduction in the odds of shedding infectious virus in vaccinated people after day five. These results suggest that vaccination had reduced the probability of shedding infectious virus after five days from symptom onset. I’m going to pull you in here in a second Vincent, but a couple of things I want to reinforce here.

I want to point out that we’re again, seeing a disconnect here between viral RNA and infectious virus as time passes from symptom onset. I think time is critical when you’re doing this calculation. I do want to say we’re also seeing confirmation of something that I feel like a lot of people are missing. We are still seeing infectious people after day five, and we’re going to run into a little new twist coming up.

VR: A couple of points here, first of all, I’m a little surprised that the duration of infectious detection is only reduced a day and a half basically. I’m more surprised that the maximum levels are not changed at all. This tells me that these individuals are probably at least six months out from their vaccine when they are depending on a memory response to kick in with antibodies. The virus is getting in and reproducing, and so they’re protected against severe disease, but not against shedding. Then, the real key though, is how much virus do you have to shed to infect someone else? There, you said, we are still seeing people infectious after day five, but how do you know they’re transmitting? Because we don’t know how much virus you need the shed to transmit, right?

DG: Yes, actually I think that’s perfect. To change the wording of the authors into what I think is more honest is saying, shedding infectious virus, not necessarily infectious to others because, again, there’s a threshold there. It is interesting when you think about kinetics. Is that for those T-cells to kick in its three to four days for those memory-B cells to kick in, again, it’s going to be four to seven days. It takes a little bit. If we use that fire extinguisher analogy, you got to go grab the fire extinguisher by the time you come back, there’s time passes.

VR: If you did this study with any other virus for which we vaccinate, you’d probably find similar results.

DG: Yes, it is interesting and a little bit humbling, the idea that we get back to what do vaccines actually do. They keep people out of the hospital, they keep you from dying, but all these other things we’re so focused on, keeping you from getting infected, stopping the transmission cycle. That’s not really what they do super well.

VR: When the polio vaccines were developed, they were developed to prevent paralytic disease. We didn’t have PCR, but it would be interesting, but we can’t do it anymore. Because there’s not much polio to do this study and you would see poliovirus shedding in vaccinated people. I don’t think this is a condemnation of the vaccine in any way. I think this is the way they work.

DG: I think it just is an appreciation of how they work, particularly think about the injectable Salk. I don’t think we’re going to see much impact there. All right. Active vaccination, never miss an opportunity to vaccinate. Now a press release from Pfizer, “Pfizer BioNTech COVID 19 Vaccine Demonstrates Strong Immune Response, High Vaccine Efficacy, and Favorable Safety in Children 6 Months to Under 5 Years of Age Following the Third Dose.” As we’ve discussed before, this is really an immuno-bridging study where they were demonstrating antibody levels, but I’m going to actually focus on a secondary endpoint, which is vaccine efficacy, which was a secondary endpoint in this trial. It is tough, right? Because we keep talking about infection versus severe disease. Severe disease is not very common in children 6 months to 5 years of age. The vaccine efficacy here is going to be symptomatic COVID; I was looking for them to spell that out, but they don’t, so you have to go back to prior.

They were reporting an 80.3% reduction in vaccine efficacy, at preventing symptomatic COVID, and we’ll leave some links. You can actually look at the press release. There’s also another secondary document where you get a little more information. This is along the lines of the optimistic, going into June that we’re going to see vaccines available for the down to 6 months of age. This is, I’m going to say, the glass is 90% full article, “Protection of mRNA Vaccines Against Hospitalized COVID 19 in Adults Over the First Year Following Authorization in the United States,” published in CID. Case-control analysis of adults greater than or equal to 18 years hospitalized at 21 hospitals, 18 states, March 11 through December 15th, 2021.

This was including COVID 19, case-patients, and RT-PCR negative controls. They looked at unvaccinated, vaccinated – and by vaccinated here, we’re looking at two doses of the mRNA vaccine before the date of illness onset. Among immunocompetent adults, vaccine efficacy for preventing hospitalization in the first 180 days was 90%. After that, it was still 82%. They break it down looking at a couple of different vaccines, the Pfizer BioNTech, the Moderna, they look at younger adults. They look at older adults. I’m actually just going to focus on the Moderna vaccine. That’s my favorite by the way, with just two doses demonstrated a vaccine efficacy against hospitalization of 93% and 87% looking at the first 180 days, and then out past the 180 days. I want to point out that’s just two doses.

That is actually still pretty impressive. Now I will say the data is largely pre-Omicron variant circulation, but as the authors conclude, and I will agree, effectiveness of two mRNA doses against COVID 19-associated hospitalization was largely sustained through nine months. This is my 90% full comment. Now with Omicron, I think it’s reasonable to say that this is a three-dose series, but this is pretty reassuring.

VR: You mean it’s not waning, Daniel?

DG: [laughs] Oh, no.

VR: I used the wrong word, I know, but I did it on purpose.

DG: No, you did on purpose. No, and I’m sorry to be so positive, but no, this is very impressive and then you give that third shot. I think the mRNA vaccines continue to be very impressive. All right, passive vaccination, Evusheld, so remember that for your individuals at high risk, I had another consultation today where this individual was not being offered Evusheld. It was a difficult story.

This is a woman who got the first vaccine and actually had one of those rare complications. She developed a rash, the level of her platelets dropped. It was decided not to give her any more vaccines. She ended up with COVID she’s recovered. Now she was interested in Evusheld, but her oncologist, she has an issue there, actually was telling her that her antibodies were so good that he really didn’t think that she should risk Evusheld.

Please don’t do that. The FDA has made it really clear. There’s no serology test out there that can tell you whether or not this person has adequate protection against the current circulating variants. Go ahead, let’s make sure we get those higher-risk people this extra benefit. I thought this was an interesting idea. This article, “Transfusing Convalescent Plasma as Post-Exposure Prophylaxis Against SARS-CoV-2 Infection, a Double-Blinded Phase-2 Randomized Control Trial,” published in CID.

Here was that idea. Let’s use that high-titer convalescent plasma as prophylaxis. We’re comparing this to Evusheld, right, where there’s an 83% reduction in symptomatic COVID, pretty impressive. Well, I have to say, while appearing safe, convalescent plasma did not prevent infection.

VR: Daniel, what is the length of time Evusheld will sustain that 87%.

DG: We don’t know, the current recommendation is that this may be every six months. As we go forward, we’ll have to see if that gets adjusted. All right, post-exposure period. This is when we think about testing, remember quarantine for those not up to date with vaccines. Really, I have to say if you are up to date with your vaccines. This is now an issue with kids who now can get that third shot down to age 6, the only thing that you have to do after exposure is maybe do a test five days after the exposure, but you can go about your day.

You don’t have to be isolated, quarantined, et cetera. There is a big social benefit to having that third shot in those situations. We will get ahead because we’re going to have some new issues coming up. Now we move into the period of detectable viral replication. You’ve got that positive test, real-world data on Molnupiravir and Paxlovid.

We have two preprints the first preprint, “Real-World Effectiveness of Molnupiravir and Nirmatrelvir/Ritonavir Paxlovid Among COVID-19 Inpatients During Hong Kong’s Omicron BA.2 Wave: An Observational Study,” was posted. Now, this is a retrospective cohort study evaluating the clinical and virological outcomes associated with using Molnupiravir and Paxlovid during a pandemic wave dominated by Omicron BA.2 in Hong Kong.

It’s a composite outcome. We’re going to be looking at all-cause mortality, ending up on a ventilator, ending up in the ICU and then there’s a few other individual outcomes, lower viral load. Well, they say viral load, but I’m going to make that RNA copy number and what did they find? They found that oral antiviral use was associated with a significant lower risk of this composite outcome, Molnupiravir has a ratio 0.53, so about a 50% reduction, Paxlovid, 0.33 so about a 70% reduction, when they looked at all-cause mortality, very similar about a 45% reduction, about a 70% reduction.

I do want to point out this is looking at hospitalized patients. These are patients who ended up in the hospital early, so they’re still in that first week. They’re not hypoxic. They start it within the first couple of days and they still get this benefit.

VR: The implication, Daniel, is that even when you’re hospitalized, there is some benefit to an antiviral?

DG: Yes, and actually today I got a message from Dr. Fatima Johari, one of my colleagues at Northwell, that now they’re going to actually have availability because just the fact that you end up in the hospital, right? Some people end up in the hospital because they’re dehydrated, they’re having trouble at home. They’re still in that window of opportunity.

I’m not sure that window really needs to only be three to five days. We’re seeing here, you can end up in the hospital even a couple more days go by. We’re still talking about timing, but ending up in the hospital during that first week for a viral issue should not make you ineligible.

VR: If you end up in the ICU, then it’s probably too late.

DG: Then it’s probably too late. By the time you get past the viral replication phase doesn’t really make much sense. All right, how about use in outpatients? This is what we’re supposed to be doing. Get it in there early before you end up in the hospital. Another pre-print, “Impact of the Use of Oral Antiviral Agents on the Risk of Hospitalization in Community COVID-19 Patients, a Retrospective Cohort Study,” from Hong Kong.

They’re looking at Molnupiravir and Paxlovid on reducing hospitalization and deaths in a real-world cohort, nonhospitalized COVID-19 patients. Now, they reported that Paxlovid use was associated with a reduction, but they did not see that with Molnupiravir in this study. All right. Dr. Griffin, this is all so exciting, but I’ve been hearing all this bad stuff about Paxlovid out there.

Apparently, I did an interview on NBC News and millions of views. Let’s go ahead. What was this CDC alert COVID-19 rebound after Paxlovid treatment? First off, can we please change the title to COVID-19 rebound now identified as part of the natural history of COVID-19 in some individuals, but no one’s going to read it unless it’s got Paxlovid in the title.

It starts in a really positive way with this statement: A brief return of symptoms may be part of the natural history of SARS-CoV-2, the virus that causes COVID-19 infection in some persons independent of treatment with Paxlovid and regardless of vaccination status and I know we discussed last time, that this was actually seen in the Paxlovid trials in the placebo group, actually we’re seeing roughly the same frequency in that population.

They then go on to say, limited information currently available from case reports suggest that persons treated with Paxlovid who experience COVID-19 rebound have had mild illness. There are no reports of severe disease. There is currently no evidence that additional treatment is needed with Paxlovid or other anti-SARS-CoV therapies in cases where COVID-19 rebound is suspected.

Also, as the FDA has pointed out, that is not in the E-way to go ahead and give these people more drugs, no science. That is not an evidence-based recommendation by the way, to treat them again. Now, regardless of whether the patient has been treated with an antiviral agent, risk of transmission during COVID-19 rebound can be managed by following CDC’s guidance on isolation.

This gets a little confusing. It was very vague. What is this guidance? Well, here’s where and I will point out if you keep reading and you’ve got to keep reading, possible transmission of infection during COVID-19 rebound has been described, and there’s a reference that we will discuss. However, it remains unknown whether the likelihood of transmission during rebound differs from the likelihood of transmission during initial infection.

This is the new guidance that’s buried in here. People with recurrence of COVID-19 symptoms or a new positive viral test after having tested negative should restart isolation and isolate again for at least five days. All right, so let’s discuss what is this reference that is changing CDC guidance, because this is new. This is, you’ve isolated. You’ve used extra precautions for 10 days, you’re feeling all better, you’re out there in the world, and then you have this relapse. Then maybe you test positive. The CDC new guidance is, should that happen, you again are going to restart that isolation. Another five days of isolation, another five days of precautions. This is based on a pre-print case report, “Rapid Relapse of Symptomatic Omicron, SARS-CoV-2 Infection Following Early Suppression with Nirmatrelvir/Ritonavir.”

I’m going to spend a little time, and Vincent, I’m hoping that you can weigh in on this, but the authors describe relapse of COVID-19 symptoms, and SARS-CoV-2 viral load following Paxlovid treatment in eight non-immunocompromised adults aged 31 to 71 years old. Most patients improved rapidly after treatment with Paxlovid, had negative antigen or PCR tests prior to relapse on days 9 through 12 of their illness. I’m going to sort of stop there and pause for a second.

That’s actually not what we’ve been talking about. We’ve been talking about people make it through that acute illness, they have a week of feeling better, and then it’s about day 20 to 25 when suddenly they have a recurrence. This is really an extension of that initial period, we’ll discuss more about that, because we say, if you’re not feeling great on day 10 or 11, you don’t end your isolation, you continue to stay isolated. I will make a few comments like, are we talking about apples and oranges here?

Relapse symptoms were described most frequently as cold symptoms, although some patients experiencing a relapse of fatigue and headache. All relapses resolved without additional antiviral treatment, viral load during relapse was comparable to levels during initial infection, sequencing in three patients indicated that relapse was not due to a treatment-emergent mutation or infection with a different viral strain. One patient transmitted SARS-CoV-2 to two family members during relapse, the presence of high viral load and the occurrence of one transmission event suggests that people with relapse should isolate until antigen testing is negative. I will mention, David Ho is the last author on this pre-print posting.

VR: Daniel, I do not know how they conclude that this person transmitted during relapse and not before, when they’re living with their family. I mean, it makes you think, “Oh my gosh,” but I doubt there’s very good evidence for that.

DG: Yes. That’s one thing. You’ve got this, because the incubation period could be like 14 days, it’s a pre-print, so we don’t get all the information we want. Was that it? Was that the only exposure? In a world that is full of virus, was that really the only exposure? The other, which I think is interesting is, I’m not sure this is talking about what we’re talking about. One of the things that we’ve described for a really long time. We actually discussed this in our publication back in February 2021, I’m going to quote that we say this appears to be a characteristic feature of the disease process and does not only occur in patients having undergone treatment.

Then as the CDC says, a brief return of symptoms may be part of the natural history of SARS-CoV-2, independent of treatment, independent of vaccination status. What was being described is, you go through your viral phase for the first week. You then have your second week, which is this early inflammatory, goes out to about day 14. These people are still within those 14 days. We’re not talking about I was better for eight to 12 days as the CDC is talking about, and then I had this return of two to three days of symptoms.

This reminds me, I was thinking of the people in that, in the airport, you’ve got to take your shoes off because one guy tried to sneak through with a sneaker bomb. One transmission, one person transmitting, that’s an anecdote, say the plural anecdote is not data. Well, the singular of anecdote is actually anecdote. I’m not sure that this anecdote actually, really applies to the same situation. We’re just basically saying, people continue to be potentially infectious out to day 14, which we knew. We’re not talking about someone almost a month later having that two- to three-day relapse that we described.

Yes, people often do this where they’re really strongly antigen-positive, maybe PCR of course. Then it becomes negative, and then it gets bright again before it finally goes off. I’m not really sure that this is the data, but it has actually changed CDC isolation guidance.

VR: I find that very unfortunate that it’s based on a pre-print which has a number of uncertain conclusions in one patient, as you said. This other statement here, viral load during relapse was comparable, but I’m sure that’s PCR. Who knows the relevance?

DG: Yes, that’s the challenge. It is CT numbers. I’m hoping that David Ho has the BSL-3. I’m hoping that he really means viral load. It doesn’t tell us here, I’m hoping he isn’t just saying RNA copy number, because that’s what you would want to know, are we getting the same viral load, not just RNA copy number. Yes.

VR: You want to know a kinetics. You want to know if it went up and down and then up again, or it just went up and stayed up for a while before coming down. It’s a big difference, right?

DG: Yes. I would say I do think a certain percentage of people are still contagious at day 12, 13, 14. I think we’ve known that. I guess, the real question that we’re trying to find out, which is being used, is that are people then contagious at day, do the math, it’s going to be day 25 and they have two to three days. I think that that’s important to know. I don’t think an antigen test gives us that knowledge. I think case tracing, transmission studies, viral culture, there’s a lot of other things that I would like to have here.

What I don’t like is the impact it has. I’m getting lots of questions from providers and patients saying, “Oh, I hear all this bad stuff about Paxlovid.” This is not bad stuff about Paxlovid. Paxlovid continues to be incredibly effective and is the number one recommended therapeutic option in our patients with risk factors. Number two is the IV Remdesivir. Number three is Bebtelovimab, the monoclonal is still standing, and a distant fourth is Molnupiravir.

All right. Let’s move into the early inflammatory phase, steroids at the right time in the patients, anticoagulation adjusted for the individual patient, pulmonary support, maybe Remdesivir if we’re still early, immunomodulation added on to that if needed, and remember, avoid those unnecessary antibiotics and unproven therapies. Then should we move into that secondary infection risk phase, that multi-system inflammatory phase, as we described, sometimes we’re seeing people start to have problems for two to three days. That’s when we start asking, is there a secondary bacterial, a fungal infection, a clotting issue, or is it part of this bimodal nature of the illness that we’ve been describing for two years now?

All right. The tail phase and Long COVID, the article, “A Longitudinal Study of COVID-19, Sequelae and Immunity Baseline Findings.” This was a study, and this is actually NIH. This is a study to characterize medical sequelae and persistent symptoms after recovery from COVID-19 in a cohort of disease survivors and controls, this is ACP Journals. Self-referred adults with laboratory-documented SARS-CoV-2 infection, who were at least six weeks from symptom onset were enrolled, regardless of presence of post-acute sequelae of COVID, a control group comprised patients with no history of COVID-19 or serological evidence of SARS-CoV-2 infection. Both groups were enrolled over the same period of time, and this is disappointing. Despite extensive diagnostic evaluations, they were not able to find any specific cause of the reported symptoms in most cases.

Go on to an MMWR. “Post-COVID Conditions Among Adult COVID-19 Survivors Aged 18 to 64, and Greater Than 65 Years, United States, March 2020-November 2021.” These are the results of a retrospective matched cohort design used to analyze EHRs during March 2020-November 2021 from Cerner Real World Data. We’re looking at 63.4 million unique adult records. They reported that COVID-19 survivors had twice the risk for developing pulmonary embolism or respiratory conditions, and this is the one that got all the headlines. They are saying one in five COVID-19 survivors aged 18 to 64 years and one in four survivors aged greater than 65 experienced at least one incident condition that might be attributable to previous COVID-19.

Notice all those qualifications, might be attributable, at least one incident condition. I’m not sure how much to make of this. I do want to point, whenever we talk about, oh my gosh, and this is the headline, one in five, 20% of people with COVID, now have Long COVID. I’m not sure they’re saying that. If you actually spend a little time going through this, I don’t think you’re going to see that Long COVID is a significant issue. It’s not something I want to downplay, but it’s also not something that I think we need to be dishonest about or overstate. Now my PSA for Long COVID is that recover studies are enrolling and we’re going to leave a link in our show notes, studies.recovercovid.org.

As of May 24th, Recover Studies had already enrolled over 3,000 participants. I want people to consider enrolling, consider encouraging others to enroll, but our final article, “Trajectory of Long COVID Symptoms after COVID-19 Vaccination: Community-Based Cohort Study, published in the BMJ. Another positive observational cohort finding from the UK with the author’s report that the likelihood of Long COVID symptoms was observed to decrease after COVID-19 vaccination, and evidence suggested sustained improvement after a second dose at least of the median follow up of 67 days. This may remain to date our only true evidence-based therapeutic for Long COVID.

All right, no one is safe until everyone is safe, so this is where I ask everyone to pause the recording. If you’re driving, pull off to the side of the road, well maybe that’s not such a great idea. Pause the recording and when you get to a place where you can, jump on, go to parasiteswithoutborders.com, click that Donate button. Every small amount helps with our work and also our continuing FIMRC 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. Mainly we’re going to be focusing support on the clinic in the Bududa District of Eastern Uganda.

VR: Time for some of your questions for Daniel, you can send yours to daniel@microbe.tv. Susie writes, “I’m a pediatric infectious diseases physician with five partners at a children’s hospital. We are still testing all routine admissions, but are under increasing pressure to stop. I have concern about our immunocompromised patients and our patients at risk for severe disease. If we learn they are positive on admission, we could potentially intervene. We would also have better ability to keep common areas of the hospital safe. Do you have any thoughts about routine hospital admission testing?”

DG: I do. This is a great question and I’ll bring up a scenario that I ran into a couple weeks ago as a patient came in and they had had COVID six weeks ago and their PCR was positive. Suddenly they’re locked in an isolation room, no one’s visiting them. I was asked to weigh in and so we had them run the PCR on a machine where we could actually get the CT value and the CT value came back at 42 and my first question was, how many cycles are you running this machine? Because what are we trying to do? We’re not trying to make the diagnosis, we’re trying to keep other people safe. Running that out to 45 cycles, that’s a little bit much if we’re trying to do screening to make sure we’re not bringing infectious, contagious people, we’re trying to keep other patients safe.

If you’re going to use PCR, I don’t think you need to run it 45 times. You can actually think and maybe it would be reasonable for us to start dropping that, maybe 30 or 35 is reasonable and you stop the machine. If you haven’t picked it up by then you’re not bringing a contagious person in. Consider antigen tests. It’s actually quicker, you can get people in, you can even do another antigen test the next day if you want to be safe. I think we do want to keep people safe, the hospital is a scary place and we want to really rebuild the confidence in there. We don’t want people coming into the hospital and getting COVID, but I think there’s more intelligent ways to do this. Start looking into how many cycles are you running those PCRs? What’s really the goal, and then making sure we do testing intelligently.

VR: Zach writes, “I received a booster shot and I’m on Evusheld due to an immune system suppressed by Remicade. I received my Evusheld in early April, mRNA booster in December Moderna Moderna Pfizer. I’m 41, mildly overweight, Crohn’s, otherwise in good health. My next infliximab infusion is mid-June. What will be the best time to take my second booster? I have a very forward-facing job, a lot of indoor interactions with the public. I wear an N95, but want to give myself the best chance to avoid serious complications if I am infected.”

DG: The guidance, and we actually have nice guidance from the rheumatological associations as well, is really trying to space that a two week between, so the infliximab that’s one of our TNF alpha monoclonal antibody therapies so you’re targeting the TNF alpha. In your case, what you want to do is you want to try to time it so that you’re least immune impacted so about two weeks apart is what most of us are recommending in line with the guidance.

VR: Lori writes, “I’m a pediatrician in a busy private practice in San Francisco with so many questions, but I will limit them to three. One, parents of 5- to 11-year-olds. want to know if they should get the booster now or wait until fall unless visiting grandma or other high-risk individuals over the summer.”

DG: This hits a couple things. One is, there’s a lot of virus out there right now, so now’s a reasonable time to get it. There’s also the advantage is that this removes you from all these societal restrictions associated with not being up to date with your vaccines, the quarantine and with summer camp and all these summer activities, I’m actually encouraging most parents of children this age group to go ahead now with at least a couple weeks before a lot of these summer things fire up so that they then, say June is the time for boosting so they can really enjoy the summer.

VR: Number two, everyone wants Paxlovid, you mentioned that the prescribing slope is getting slipperier and I just learned from you that LD is a risk factor. We’re trying hard to hold the line. It seems like it is not a benign drug, plus the rebound issue could complicate things. People are now asking for a 10 day course. Are we doing our patients with mild asthma and or ADHD, a disservice in saying no?

DG: I think the first part is, and we’ve tried to point this out. The FDA, the EUA approval is not for 10 days. It’s for five and it’s just for five. I don’t want people to think that the Paxlovid rebound, it’s terrible.  It shouldn’t have been termed that. This biphasic, this rebound is part of the natural history. It’s something we’ve seen for two years. We so far have no science to suggest that it’s more common with Paxlovid. We also have no science to suggest that you should wait and not give that Paxlovid till day five to somehow interfere with this. That is not evidence-based guidance out there.

You are right, it is a slippery slope, so you do want to have these conversations. It really has been made that, who doesn’t qualify for Paxlovid? It seems like almost everyone qualifies under some learning disability or something else. As physicians, as clinicians and as pharmacists, we really need to use our judgment. We need to have those difficult conversations. Your patient’s decision, end up on Paxlovid, should be evidence-based. It should be based upon that decision, not based upon what they read in the popular press or what they hear about on social media.

VR: Number three, what are your thoughts about the initial data on the Pfizer three dose immunizations for the under-5s; seems a little underwhelming to me at this juncture.

DG: It is tough and as we’ve talked about that data, we’ve so far just have the press release as we move forward as we get actually the full data, we’ll definitely revisit that.

VR: All right. One more from Morro. “When Moderna and or Pfizer get UA for kids 5 and under, do they just use the same vial for adults and prepare more syringes with less volume or do they have a special formulation? I’m asking because we’re eager to get our daughter vaccinated and we’re wondering if we’d have to wait for kids special formulations to be delivered.”

DG: One of the nice things I will say is, once this gets approved, within 24 hours, I expect those vials to be out there. I don’t think you’re going to have to go and have someone try to drop smaller doses but they already have different color caps. This is all ready to go. It’s the same formulation. It’s just a smaller dose and those are all ready to go. Come June, when we anticipate approval, I don’t think there’ll be any big waiting for the supplies to arrive.

VR: That’s COVID-19 clinical update number 116 with Daniel Griffin. Thank you, Daniel.

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

[00:49:11] [END OF AUDIO]

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