TWiV 916 COVID-19 Clinical Update #122

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 9 July 2022

Pdf of this transcript available (link)

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

[music]

From MicrobeTV, this is TWiV, This Week in Virology, Episode 916, recorded on July 6, 2022. I’m Vincent Racaniello. You’re listening to the podcast all about viruses. Joining me today from New York, Daniel Griffin.

Daniel Griffin: Hello, everyone.

VR: Actually, you’re not joining me from New York. You’re joining me from Islarosa.

DG: This is true. Join you from a small island off the Atlantic coast of Spain.

VR: Very nice. I hope–

DG: If you hear the sound of ocean in the background, or the wind, that’s what it is. Let me jump in. We always have a lot, but let me start with my quotation. This is from Ray Bradbury, Fahrenheit 451: “But you can’t make people listen. They have to come round in their own time wondering what happened and why the world blew up around them.” I am busy reading Fahrenheit 451.

I will maybe have some quotations from it in the future. I’m going to jump in, and actually, this is going to be this question. Really, did we learn during this pandemic? Did we make changes based on the lessons learned that improve how we will respond to the next infectious disease challenge? I think you may have actually picked this as one of your TWiV picks, Vincent.

VR: That’s correct. I did. Yes.

DG: I was listening to the TWiV episode. Lo and behold, this opinion piece that was in STAT, “The Next Epidemic May Be Here. The U.S. Isn’t Ready for it.” I’m going to recommend people for a deeper dive. I don’t know how much of a deep dive. I really thought that this was a wake-up message here. A bunch of the same things that we should have learned from, we’re seeing issues with now. One of the ones, I’m going to say, lack of accessible testing. I was delighted to hear today there’s now a Laborp code. A private physician without jumping through any hoops can actually just go ahead and order a monkeypox test and send off the swab.

Making some progress there, but boy, that took a while. Dedicated funding, so that we actually have a readiness group for this. Then as we’re seeing, the really slow rollout vaccine access. I just feel like this is really a good piece for people to read and think about it. Here in the United States, we have midterms coming up in the fall, and we really need to make some changes. Let’s not do with monkeypox what we did with COVID.

Let’s get right into it. COVID children and other vulnerable populations. I’d like to remind our listeners, and I’m not going to just remind our listeners, but I’m going to ask for your help, I want you to go and have conversations with a lot of folks out there. I know these are difficult. I’m going to talk a little bit about how we educate people and I’m going to ask our listeners to help us. I’m going to start off with an MMWR this is a Morbidity and Mortality Weekly Report. “COVID-19 Vaccine Provider Availability and Vaccination Coverage Among Children Aged 5 to 11 Years – United States, November 1, 2021 – April 25, 2022.”

Now in this report, among 2,586 U.S. counties included in the analysis, 87.5 had at least one active COVID-19 vaccine provider serving children, aged 5 to 11. Among the five assessed active provider types, I want people to listen to who these are, most counties had at least, one, a pharmacy, that was 69.1%; a public health clinic, that was 61.3%. Whereas fewer counties had at least one pediatric clinic, that was only 29.7; a family medicine clinic, 29%; or a federally qualified health center, that was 22.8%.

I appreciate the concept of a pharmacy or a public health clinic as a vaccine provider, but a lot of the conversations we’ve been talking about have really been pediatricians, family medicine providers. The median county-level vaccination coverage was not great. It was 14.5. After adjusting for social vulnerability urbanicity, the analysis found that vaccination coverage among children aged 5 to 11, was higher in counties with at least one active COVID-19 vaccine provider than in counties with no active providers. We’re really talking about a 15% versus about an 8% for no pediatric vaccine provider.

I just want to point out, here in the U.S. more than half, 51.1% of counties, have no pediatric clinic, family medicine clinic, or federally qualified health center. Amazing. I think this next article is relevant as many people have minimized the risk of COVID-19 in the pediatric population. I find this all the time. I’m not going to point fingers, but I am hoping the mainstream media can help to educate parents about the real risks. The paper, “Health Impairments in Children and Adolescents After Hospitalization for Acute COVID-19 or MIS-C,” was published in Pediatrics.

Now, as we’ve discussed, over 40,000 children have been hospitalized due to COVID-19, and most of these were due to Omicron. Remember that when you use the word “mild” in any sentence involving Omicron. We also mentioned that one-third of these children that ended up in the hospital had no underlying health issues that would’ve predicted this risk. Most of these kids survived with, I’m going to say, about a little more than 1,000 dying. Over 1,000 children have died of COVID. Again, most of those deaths due to Omicron.

I know when I talk to people, there’s been a challenge, “I don’t know. The CDC, can I trust them?” Go ahead. Challenge those numbers, say that those people are really just there for some other reason, like visiting the shop in the lobby, and they happen to have COVID. Then we get to this paper. These are the results of a multicenter prospective observational cohort study conducted in 25 U.S. pediatric hospitals, patients less than 21 years old hospitalized between May 2020 and May 2021 for acute COVID-19 or MIS-C, with follow-up two to four months after admission. I want all those listeners who are pediatric COVID-minimizes to listen to these results. These are people that a lot of folks are saying, “It’s incidental. They don’t really have COVID.”

How did these kids do? 11% with acute COVID and 8% with MIS-C had a readmission, 27% of the patients with acute COVID had persistent symptoms or activity impairment, and 30% with MIS-C had persistent symptoms or activity impairment when they looked at these kids two months later. Over one in four children hospitalized with acute COVID-19 or MIS-C experienced persistent symptoms or activity impairment for at least two months. Remember, we’re talking about over 40,000 children in hospital. We’re not even touching all those kids who had it in the community who didn’t require hospitalization.

I just hope when people say, “COVID’s not a big thing for children,” it was a big thing for these tens of thousands of children, for these over 10,000 children who continue to have persistent symptoms, activity impairment for at least two months.

Now let’s move into use test intelligently. Remember, there’s more out there than just COVID, but we’re going to be talking about COVID testing today. I’m not sure where this is coming from, but lots of questions lately about saliva versus nares testing. A lot of people out there, it’s interesting they would much prefer to give a sample of saliva than have someone take cells by shoving a Q-tip into them. That incredibly invasive test.

The article, “Analytic Survey in Persons With Mild to Moderate Respiratory Symptoms. Saliva and Nasopharyngeal Samples Were Compared for Detecting COVID-19 Using RTPCR.” Rather long title. It’s published in the Journal of Medical Virology. In this study of 190 patients, there was a 99% match in the COVID-19 positivity between those nasopharyngeal swabs and saliva when using RTPCR. Really pretty impressive. I actually have got a few graphs here where you can see different ways of doing this. There’s some neat approaches, some use a heat-release method.

Another kit, which is actually interesting, they use magnetic beads to actually pull the cells, so they’re really only looking for RNA that is intracellular. Theoretically doing something to not pick up the scrap RNA that might be floating around. I’m hoping we see a little more access to saliva testing because not everyone is so psyched about having a Q-tip shoved up their nose. Maybe we’re going to have a little more acceptance of testing if we give the option of letting people give saliva instead of having us take stuff. All right.

VR: Daniel, is there any significance to this being mild to moderate? Would it make any difference if they did it in more severe patients?

DG: Actually, this particular study doesn’t address that. The saliva actually looks to be very sensitive, very specific, independent of severity. Couple issues, I guess that are interesting there is we’ve been using this in sports. The NBA was using this for a while. The other thing, and it’s just really want to remind everyone, it has to be a test that is validated for saliva. You can’t just take those nasal pharyngeal antigen tests, we’ve talked about this, and then be like, “I just keep testing negative.” Then rub it in the back of your throat, you get a positive test you celebrate. Those tests are not validated.

As we’ve talked about some of those tests will give you a false positive, because maybe you had some juice or a soda, or something before you did the swab. Use the kits. Use the test for how they were designed. There are tests that are specifically validated for saliva samples.

Now this next one, I want to say I feel like this is very encouraging. “Comparative Effectiveness of the SARS-CoV-2 Vaccines During Delta Dominance,” was posted on The Lancet preprint server. It’s currently submitted, and we are waiting to hear. I say we because I’m actually one of the first authors.

In this study, we use de-identified claims in a research database that included vaccination status and COVID positivity status. Individuals greater than 18 years old, fully vaccinated with the J&J vaccine or the Moderna, or the Pfizer by Sept. 30, 2021 were included. Outcome were SARS-CoV-2 infection emergency department visits, outpatient visits, inpatient hospitalizations, ICU transfers, death, hospice transfers to Sept. 30, 2021. Robust data set we’re looking at, about 6.5 million fully vaccinated individuals.

We will say mRNA-1273 performed slightly better than the Pfizer for infection, composite hospitalization, composite ICU transfer, caused by the Delta variant. The J&J vaccine did not perform as well. It actually performed worse than the Pfizer for infection, composite hospitalization, composite ICU transfers. Just to give some perspective here, the number needed to vaccinate with the Moderna to prevent one hospitalization at 90 days was 3,000 compared to the J&J, and 15,472 compared to Pfizer. It’s really a lot of people to vaccinate. It’s actually making all the vaccines look pretty good in comparison.

The number needed to vaccinate with the Moderna to prevent one ICU transfer at 90 days was 6,358 compared to J&J, 34,279 compared to Pfizer. For every 1 million individuals vaccinated with Pfizer and compared to Moderna, the approximate incremental inpatient costs would be over $400,000, and the approximate incremental ICU costs would be over $660,000. Just to bring it full circle, I always talk about my having a little bit of favoritism towards Moderna. The two-dose MRA vaccine’s effectiveness was better than the single-dose J&J, and the Moderna was only slightly more effective than the Pfizer vaccine. Continue to have some really excellent vaccines out there.

What about this other correspondence? Vincent, you’re going to like this. I don’t know if you caught this one. This was published in The Lancet Respiratory Medicine, “Immunocompromised and Durability of the BNT162b2 Vaccine Against Severe Outcomes Due to Omicron and Delta Variants.” I just wanted to briefly mention as it’s very relevant with all the negative comments, I shall say, about the “waning” of current vaccines.

This is, and I’ll just quote, “After extending the analysis period, waning of effectiveness against Omicron-related outcomes was no longer apparent, particularly in the immunocompetent population. Among immunocompetent individuals effectiveness at three months or longer after a third dose of Pfizer against Omicron-related hospitalization was 86%.” That’s pretty darn good.

VR: Daniel, that’s interesting, because in the VRBPAC meeting last week, the advisory committee, one of the presenters showed data, and it’s a different study obviously, indicating that vaccine efficacy against hospitalization, the same metric you’re talking about here, went down depending on the age group. It went down the most in the 18 to 49-year-olds. It went down to 54%. It was 73% and 79% of the older age groups. I’m wondering why we get these diverse outcomes in these, VE against hospitalization studies. Is it that poor metric?

DG: It is tough. One of the things that I think people should go ahead and read this is some of the early, worrisome data, they had immunocompromised individuals thrown into the mix, so as in the title, immunocompromised and durability. That’s an issue. If you’re immunocompromised, you’re going to respond differently. Also, as you and I have talked about, and people will notice as we go throughout, I’ve changed my categories a little bit. Sometimes, people get hospitalized for the mild, moderate non-hypoxic viral symptom phase of COVID and that’s very different.

That’s a very different metric than people getting hospitalized during the early inflammatory hypoxic pulmonary phase. It is interesting. I’m going to even talk to ID docs like, “Wow, boy, Omicron is becoming much more of an upper respiratory illness.” I’m like, “You don’t do outpatient medicine, do you?” Because COVID has always started as an upper respiratory viral replication and viral syndrome, but those people didn’t get hospitalized early on.

Now that we have a little bit more hospital capacity, a lot of times those folks end up in the hospital, not because they need pulmonary support, not because they have severe or critical hypoxic pulmonary phase, but because they have a tough time with that first week. Actually this is going to be relevant because I am going to get people prepped with mention of an opinion piece. I know there was a little bit of a deep dive on this. I will mention TWiV 915. The opinion piece, “FDA, Don’t Rush a Move to Change the COVID-19 Vaccine Composition,” published in STAT John P. Moore and Paul A. Offit.

I think it’s a well-written article. There’s a number of good points. There is a great deep dive into this on TWiV 915. We’re going to suggest people spend some time. Also, understand Paul Offit is going to be on the show. You’ll hear it directly from Paul, who I have a tremendous amount of respect for. I will suggest that there are a few issues they do not necessarily discuss but I hope will be addressed. We are now entering more and more into an arena where people will have preferences of which vaccine they want to get, and even if they choose to get a booster.

I’ll circle back to the importance of having choices when it comes to vaccine uptake. Let me just start with a couple of excellent points that are made in this piece. I’m going to go right here to, well, vaccines made from the original SARS-CoV-2 strain produced strong protection against SARS-CoV-2 circulating in 2020 and 2021. The Omicron variants have been more problematic. They are highly resistant to neutralizing antibodies, which the human immune system uses to prevent infections. As a result, the Omicron viruses find it easier to break through this protective barrier causing what are mostly mild infections.

Interesting way of wording it. A couple things now, a little bit of anthropomorphism maybe. Let’s go into this next one, which I think is interesting and it’s going to reflect back on some of the discussion I just had about a comparison between Moderna and Pfizer. With the new updated shots two to four weeks after the booster shots, notice that two to four weeks, neutralizing antibody levels against Omicron BA1 we’re about twofold higher with the Omicron-based vaccine than with the original vaccine. What do an approximately twofold higher level of neutralizing antibodies mean in practice?

The analysis that I discussed up above in preprint form, Moderna and Pfizer that’s about the difference between the levels of neutralizing antibodies between Omicron and Pfizer. Should we just say, “Let’s just forget about Pfizer. Who needs Moderna? Because we can get that same level.” I think that’s an important. That kind of twofold difference, as I point out, is similar to the modestly greater peak in neutralizing antibodies triggered by the first two doses, the Moderna vaccine compared with the Pfizer vaccine.

Some experts have suggested that a booster should be based not on the BA1 but on the BA4, the BA5 sequences. This is the last one, I think. If an Omicron-based booster provides little advantage over the vaccine stocks that already exist, is it worth the switch? I know it’s interesting. I was listening to Dixon, I always like to listen to Dixon because I think he gives us that perspective. He was, “Oh, you can just roll out a new mRNA vaccine in six weeks,” little bit more than six weeks. There’s developing the new vaccine, there’s testing the new vaccine. Then we live in a world with 7 or 8 billion people rolling out billions of doses.

Manufacturing billions of doses is really a huge undertaking, think of just the number of doses that we’ll want here in the U.S. alone. Making and rolling out an entire new supply of COVID-19 vaccines on a nationwide basis is no trivial matter, particularly when Congress seems reluctant to provide the funds. This last part I think is critical. One, are they really that much better? If so, for a week, a month? Are they already a day late and a dollar short as they update to raise antibodies against a variant that’s already been displaced by new variants? As mentioned, what about timing, logistics, manufacturing? What about the current supplies?

We do have all these questions about putting resources into the development of vaccines that, are you ready for this, the superpower that everyone seems excited about, are there actually the ability to produce vaccines that can prevent infections? There really maybe a little bit of optimism, and maybe don’t take all the money away from science yet.

With cars, we didn’t stop at seatbelts, we didn’t stop at airbags. We now have auto-braking, we have accident avoidance systems. We even have some cars that drive themselves. Maybe we should be talking not just about what shots we’re going to do next fall, but about what funding we need to improve and create next-generation vaccines. Vincent, I figured you’d have a comment here.

VR: I think that these are all very good points that they make. The key is, we really do not have any evidence that this updated vaccine will be any better. It’s already behind because the variant against which it’s directed has been displaced by others, so that’s a problem. There’s no data saying it’ll be better, and so often, and more argue that is this really worth it? It could be that within a few months you have another variant that makes it moot. You’re right, you have to develop a different strategy rather than coming out with a new booster every six months. That’s just not going to work.

DG: All right, let’s move to passive vaccination EvuSheld. Remember, this is for those individuals that either have been vaccinated, and we just don’t think they’re going to get those protective antibodies we want, so these high-risk individuals, or for those individuals who for some reason cannot get vaccinated, cannot get fully up to date with their vaccines. We’ve been talking for a while about the thought that at some point EvuSheld may be something that is every six months, and we now have it.

Updated EUA for EvuSheld repeat dose, every six months, repeat dosing should be timed from date of the most recent of EvuSheld dose. That’s for those folks that came in right at the time when we gave 150, and then we realized we want to do 300, so we give an extra shot of 150. That’s when the clock starts people who started off with 300, six months later. We actually have a bunch of folks who will be getting ready for their six months and time for their next EvuSheld. Keep this in mind, who’s dying right now? We still have over 2,000 people a week dying in the U.S.. It’s folks that didn’t get those four doses of vaccine plus EvuSheld, it’s folks that are unvaccinated.

The article, “The Latent Period of Coronavirus Disease 2019 with SARS-COV-2 B.1.617.2 Delta Variant of Concern in the Post-Vaccination Era,” was published in Immunity, Inflammation and Disease. I thought this was helpful because we need to keep reinforcing. Despite a shorter period of time from exposure to symptom onset and positive tests with the current circulating variants, we still talk about a two-to-14-day incubation period.

This is a retrospective study where the dates of exposure and the dates of the first positive PCR test of 40 patients were collected to estimate the distribution of the latent, or this period of time from when you’re exposed to when you end up sick and positive. Of the 40 patients, 40% were male. The median age was 47.5. The median latent period, so the median incubation period, was six days. The interquartile range was four to nine days. The longest period was 13 days after exposure. The latent periods, I thought this was interesting, were a little longer in male compared to female so 8.5 versus 5. It actually has a p-value of less than 0.05.

That was interesting, that there’s a difference there. The median latent period was comparable among fully vaccinated, that was 6.5; not vaccinated, 7.5; and partially vaccinated, 5.5, so very similar there. I want to just repeat that. The median latent period for Delta was six days, we think that shorter with Omicron. The latent period between vaccinated and non-vaccinated was not significantly different. The authors conclude that the 14-day quarantine period is sufficient to prevent the transmission of COVID-19 by Delta variant of concern in the post-vaccination era. What do we need more, we need an Omicron study.

VR: Daniel, one of the problems I have with these kinds of studies is the date of exposure. I think it’s not easy to figure out the date of exposure. I think there’s a lot of guessing there. You have to be careful, because they don’t even tell you how they do it. “When do you think you got exposed?” “I think it was on Tuesday.” “OK.” That’s not good enough, I think.

DG: Actually, I think that’s a huge thing. Two parts is really important. This has been a part of infectious disease forever. People come in, they’re sick, and then they tell you, “I went out to this restaurant last night.” I’m like, “What did you do three or four days ago?” Once we know the pathogen and we have some sense, we know when to look, but it’s a guessing game. I had a lady in the hospital recently, who probably got sick from some bad oysters, probably. Again, a lot of this is a guessing game. We’re not doing controlled experiments in the UK where they expose the kids to the virus and then count the days.

Now we move into, and you’ll notice I have slightly modified these, I’m actually writing an update to my stages paper, we’re now in the early viral upper respiratory non-hypoxic phase. If people look at the WHO stages, you’ll notice there’s arrows the idea that the mild or moderate, it’s not like you get to choose whether or not your COVID is going to be mild or moderate necessarily. The mild or moderate is the first week. The severe and critical is that second week. We’re going to be just reinforcing that. Number one is still Paxlovid. Let’s talk about Paxlovid.

We have a preprint. “COVID-19 Rebound after Paxlovid and Molnupiravir During January through June 2022.” This is posted as a preprint. The authors noted that some patients who are treated with Paxlovid reported rebound COVID-19, I’m going to say infections, symptoms two to eight days after completing an eight-day course of Paxlovid. The CDC has issued a health alert to update the public on the potential for this.

Here they’re going to look at this. This is a retrospective cohort study of electronic health records of 92 million patients from a multicenter and nationwide database in the U.S. The study was comprised of 13,644 patients aged 18 or older who contracted COVID-19 between January 1, 2020, and 6/8/2022, June 8, 2022. 11,270 were treated with Paxlovid. 2,374 with molnupiravir. All started within five days of their COVID infection. What did they find? The seven- and 30-day COVID-19 rebound rates after Paxlovid treatment and molnupiravir were 3.5 and 5.4 for COVID infection. It’s a little higher from molnupiravir. 5.86 and 8.59; 2.31 and 5.87 for COVID-19 symptoms, versus 3.75 and 8.21.

I think this is where it gets critical, 0.44 and 0.77 for hospitalizations, versus 0.84 and 1.39. The hospitalization, really pretty low. These are high-risk people who qualify for treatment with Paxlovid or molnupiravir, expecting probably 20% to 40% ending up in the hospital without vaccines, without treatments. We’re looking at less than 1% and about 1.4% ending up in hospital. Pretty impressive.

What did they say? After propensity score matching, and I think this is important because different people ended up with different medicines, sometimes we won’t give molnupiravir to someone, sometimes we won’t give Paxlovid to someone because we’re worried about a number of drug/drug interactions, the rebound risks between Paxlovid and molnupiravir COVID-19 symptoms or hospitalization, no significant differences. These COVID-19 rebound occurred both after Paxlovid and molnupiravir. They say especially in patients with underlying medical condition.

This indicates that this COVID-19 rebound people are talking about is not unique to Paxlovid. What I wish they had was that third untreated group so we could actually just see the comparison between treated and the natural history of disease. After Paxlovid, number two, remember remdesivir. We have the three-day early IV data suggesting an 87% reduction in progression. We still have monoclonal therapy, bebtelovimab. Then at the end of our list, last and least, molnupiravir. As I like to say, not only do we want to do things that are helpful, we want to avoid doing harmful things.

Yes, we did get an updated Cochrane review, “In Outpatients with COVID-19, Adding Ivermectin to Standard Care Does Not Improve Outcomes.” Insufficient evidence exists for effects in inpatient. It’s all right there in the title. I don’t want this to be a partisan sharing topic, but do want to keep everyone up to date with this science here. I’m not a believer in the idea that some things you just know are true and do not need to study them. The authors have a few key messages. I’m just going to read those here. Key message one. “We found no evidence to support the use of ivermectin for treating COVID-19 or preventing SARS-CoV-2 infection.”

The evidence base improves slightly in this update, but is still limited. I do want to let people know evaluation of ivermectin is continuing in 31 ongoing trials, and we will update this review again when their results become available. There are still a number of ongoing trials as mentioned. One of them, the one that UHG was involved with, is still under embargo, but I will discuss as soon as the embargo is lifted, and we’ll talk about ivermectin in COVID-19 again. Remember isolation for the infected. I need to just keep repeating to people, it’s not just five days.

I am going to go right into the letter to the editor, “Duration of Shedding of Culturable Virus in SARS-CoV-2 Omicron BA1 Infection,” published in The New England Journal of Medicine. I’m going to start off straight away with all the caveats we’ve talked about. It is very challenging to do those transmission studies, those tracing studies. It’s very difficult to know at what level of cultural virus translates into someone being contagious or transmissible. With all those qualifications, we’ll go forward.

As we have discussed, the CDC prevented shortening the strict isolation period for infected persons in non-healthcare settings, I want to point that out, non-healthcare settings, from 10 days to five days after symptom onset or after the first initial positive test, followed by five days of masking. Here, the authors use longitudinal sampling of nasal swabs for determination of viral load – they really mean RNA copy number – sequencing and viral culture options in outpatients with newly diagnosed COVID-19 from July 2021 through January 2022. They enrolled 66 participants, include 32 with samples that were sequenced and identified as Delta, 34 samples that were Omicron or Omicron sub-lineages.

Participants who received specific therapies were excluded. All of these but one were symptomatic in this longitudinal cohort of participants, most of whom had symptomatic, non-severe COVID-19 infection. The viral decay kinetics were similar with Omicron and Delta. Although vaccination has been shown to reduce the incidence of infection and the severity of disease, these researchers did not find significant large differences in the median duration of viral shedding among participants who are unvaccinated, those who are vaccinated but not boosted, and those who are vaccinated and boosted. I’ve got some –

VR: Daniel, could I just quickly interject that if you may remember, there was a study out of the University of Geneva where they looked at a similar problem. They used plaque assay to titrate infectivity. They concluded that virus isolation, single, you take swabs and you throw it in cell culture, and you ask, is there any virus there, they’re not really useful for determining how much is being shed, and nor is PCR. These results are in contrast to the Geneva findings. I think you have to be careful. One study is never conclusive.

DG: Yes. Let’s go ahead. Let’s actually put a link to the Geneva study right with this one. We’ve got that in our notes. It is a challenge. This is critical. We have a population out there that is really done with isolating. That five days is already asking too much from a lot of people. We need really good data. We can keep moving forward with this science. COVID is here to stay, and these are critical questions to ask.

Now, renamed the early inflammatory lower respiratory hypoxic phase. As we’ve talked about, this is driven mainly by inflammation. It’s not like suddenly the virus has gotten down into the lower airways and started replicating at high level. We believe this is the cytokine storm inflammatory phase. We actually have the article. I will just walk us to it. Steroids, right time and the right patients, anticoagulation. Now, the “Review: In Adults Hospitalized With COVID-19,  High- vs Low-Dose Venous Thromboprophylaxis Reduces Venous Thromboembolism, but Increases Major Bleeding.”

This is a nice review. It was published in the journal, Internal and Emergency Medicine. Here they looked at 5,470 patients from nine randomized control trials. Basically I’m going to sum it up. In hospital patients with COVID-19, the high dose thromboprophylaxis was more effective than low dose prevention of those venous thromboemboloc complications, but it increased the major bleeding risk.

I think this just goes in line with the current recommendations from the American Society of Hematology, which are qualified with an individualized assessment of the patient’s risk of thrombosis, and bleeding is important when deciding on anticoagulation. I’m also going to throw in an assessment of a facility’s ability to handle those complications, should probably also be factored in as well. Pulmonary support, remdesivir if early. Tocilizumab, maybe baricitinib. Remember, avoid those unnecessary and unproven therapies. Now we will move into the late phase.

Couple interesting ones here, a couple articles as we close out. The article, “Mild Respiratory COVID Can Cause Multi Lineage Neural Cell and Myelin Dysregulation,” was published in Cell. This is a very complex article. I’m only going to just touch on it, and then I’ll direct our listeners to spend more time if they wish. I’m just going to share the summary. COVID survivors frequently experience lingering neurological symptoms that resemble cancer therapy-related cognitive impairment, a syndrome for which white matter, microglial reactivity, and consequent neuro dysregulation is central.

Here, the authors explored the neurobiologic effects of respiratory SARS-CoV-2 infection, and found white matter selective microglial reactivity in mice and humans. Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes, and myelin loss were evident together with elevated CSF, cytokines, chemokines, including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concurrently, humans with long lasting cognitive symptoms, post COVID, exhibit elevated CCL11 levels.

I’m going to stop there, but just to say, really interesting where I’m getting a little bit, I feel outside of my lane as I get into what is an incredibly complex area here, but really interesting to see that we are making progress in trying to understand what may be going on as far as the neurological complications. I will say, and to close with some more good news, the research letter – I actually really like this. This is a research letter published in JAMA Network Open. “Association Between BNT162b2 Vaccination and Long COVID After Infections Not Requiring Hospitalization in Healthcare Workers.”

Here, remember we’ve talked about different definitions of Long COVID and they’ve defined Long COVID as reporting at least one SARS-CoV-2 related symptom with a duration of more than four weeks. This is going to pick up a lot. In this longitudinal observational study conducted among healthcare workers with SARS-CoV-2 infections, not requiring hospitalization. There were 2,560 participants, 739 or 29% had COVID, 1,989 were asymptomatic of whom 229, 31%, had reported Long COVID.

 Now, this is really the finding. the prevalence of Long COVID varied across the pandemic waves: 48.1% in wave one to 35.9% in wave two, to 16.5% in wave three. The number of vaccine doses was associated with lower Long COVID prevalence, 41.8% in unvaccinated patients, 30% with one dose, 17.4 with two doses, and 16% with three doses. Sort of encouraging. We’re not getting rid of Long COVID with vaccination but we may be reducing it once we get folks up to two or three doses. I will finish with, no one is safe until everyone is safe. This is where people pause their recording. Go to parasiteswithoutborders.com, click on Donate. You can also go to microbe.tv and click on Donate.

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VR: Time for some questions for Daniel. You can send yours to Daniel at microbe.tv. Chris writes, “Can you discuss the longevity of smallpox vaccination in light of monkeypox? The spread of the disease seems to be increasing rather than slowing, from my reading. As for SARS-CoV-2, the public health response is practically nil.” Chris is 68, around my age. “Is it likely that persons of my age who were vaccinated will have an immune response against monkeypox?”

DG: We’re not that optimistic that you’ll have an immune response. Part of that we base upon a small experience. One of the big things that I really think we all need to bring to monkeypox is humility. When we look at that outbreak in the middle of our country about 20 years ago, we really did not see any protection offered. We did not see any significant difference in severity of disease between those people who had reported being vaccinated many years younger and those that did not. We’re not particularly optimistic. The other side is you’ve got to ask yourself, and I think this is relevant, how is monkeypox spread?

I think we can avoid getting into the same problems with language that we got into with COVID-19. There’s a spectrum. Everything has a spectrum, nothing is black and white. COVID, SARS-CoV-2, the virus is mainly spread by breathing. There’s not much contact transmission. Really opposite end of the spectrum for monkeypox. It is mainly direct contact transmission. Even looking in households, It’s a minority of household members with significant contact that get it. We’ve even seen people on a crowded airplane active infectious, not spreading it to hundreds of people around them. I think we can put that in perspective.

VR: Harrison writes, “I read that Dr Fauci did not take Paxlovid immediately after testing positive for SARS-CoV-2 because he had mild symptoms. When his symptoms worsened, he began Paxlovid. It’s unclear exactly what day of infection this was. It would seem that he would’ve been better served by starting Paxlovid immediately, being a high-risk individual, to maximize the effect on viral replication?”

DG: I remember reading that. I don’t know how true it was, was my reaction. I was like, “I wonder if that’s true.” Because it’d say his symptoms were mild, but when they progressed, I’m like, “I don’t think a clinician who’s up to date, I can’t imagine Anthony Fauci not getting it or having a physician that takes care of him that doesn’t get it.” I assume that that was just the way the media portrayed it, but that’s not the way. You don’t wait. It’s not a wait-and-see. If someone’s high risk, you go ahead. The earlier start, the better.

VR: Jeff writes, “I’m a Canadian physician with an undergrad background in virology, immunology, and molecular biology. A big fan of TWiV. I do a combination of emergency medicine and family practice. I love the way you break down timing and treatments of COVID. In general, I completely agree with you in regards to not starting corticosteroids until the patient starts dropping their SpO2, and not throwing around antibiotics. In general, I don’t prescribe antibiotics without a valid indication. I have to wonder about whether this may result in a shift in how we approach COPD.

Historically, the group I was with, relatively liberal with antibiotics with those with COPD. We tend to have patient self-directed action plans where patients start their own antibiotic for COPD exacerbations. Historically, we have been moderately liberal with corticosteroids in this population as well. I’ve even seen some COPD patients with action plans with prednisone for them to start when their COPD is exacerbated. Do we need to reassess these action plans in our approach for the patient who diagnoses themselves at home with a false-negative RAT (rapid antigen test)?

Could a patient with COPD harm themselves by starting their prednisone too early if the virus triggering their COPD was COVID-19? Likewise working in the ER, if I see a COPD patient who has a false negative rapid antigen test, have I potentially harmed them if I start them on prednisone for their exacerbation, particularly if their PCR is positive a few days later or if PCR is not done. We’re often doing serial RATs, and admittedly not every patient is doing enough RATs that I would be confident to say they’ve ruled out COVID. Do we have to be more diligent in ruling out SARS-CoV-2 present when seeing patients with acute exacerbations of COPD?”

DG: [chuckles] These are really excellent points. I think it’s just hammers home it’s not easy being a physician. You need to take that responsibility seriously. You need to start thinking. I applaud the way this physician is approaching these patients. We do know that getting steroids in that first week during that viral replication phase when you really need your immune system to work for you, can increase your risk of mortality. It can increase your risk of progression probably three to sixfold. These are huge. It does become really critical.

I actually think we’re in really good stead now that we have the rapid antigen test. Maybe people want to add to that plan when you have what you perceive to be COPD as exacerbation. Maybe you want to start doing a rapid antigen test immediately, one the next day, maybe even a third. If those remain negative, that’s reasonable to have that as part of the action plan. If one of those turns positive, then you’ve got to start rethinking.

It is tough, on the other point, when people have these COPD exacerbations. Sometimes you’re going to have to actually go ahead. Hopefully, these folks are going to jump in with an antiviral. There are going to be high-risk individuals at least for this COPD or so. I think you’re thinking this all through correctly, and actually applaud the level of thought you’re bringing to this.

VR: Finally, anonymous writes, “I’ve been wondering for a while. We know that most people are most contagious in the one to two days before symptoms start, so presumably before a positive antigen test. We have also been using antigen tests as a marker for infectiousness, not clearing precautions until the test is negative. How is it that we are most infectious before that test turns positive?”

DG: For starters, anonymous, I love your poetry. A couple of comments on some of the things here. That was a joke, by the way. A couple of things have changed here over time, and this is with the different variants. I’m not going to say we have the data to be able to draw a cartoon and necessarily claim that it has to do with vaccination or previous infection. In the early days of the ancestral virus, we were seeing really good documentation of transmission in the two days before someone had symptom onset and a test positivity.

Things seem to be different with the current variants. People have an exposure, they start to have symptom onset. They may not have a positive molecular or antigen test until the next day. We’re actually not necessarily seeing those two days ahead of time. We’ve also talked about the other end is we still are seeing transmission at day six through day 10 in people with more severe COVID-19 or immunocompromised.

We’re seeing it even past 10. For some folk, we talk about isolation out to 20 days. We are seeing intermittent antigen negativity, antigen positivity. We’re seeing that people can transmit even when they’ve had a negative and then a positive test. I don’t think that these original things that you’re thinking about from a year plus ago still are relevant today, so slightly different.

VR: That’s COVID-19 clinical update number 122 with Dr. Daniel Griffin. Thank you, Daniel.

DG: All right. Thank you. Everyone, be safe.

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