TWiV 934 Clinical Update

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 10 September 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 934, recorded on September 8, 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 and joining us from the UK, Vincent. [chuckles]

VR: I am here in Manchester, UK, where sadly, the Queen has just died.

DG: Yes. I heard that today, and that is a loss. What a wonderful individual who really lived through so much of history.

VR: Yes, indeed. Everyone is out on the streets in restaurants and having a good time. It doesn’t seem to be causing a dampener on the spirits of the Brits.

DG: Oh, interesting. Well, I had heard there was supposed to be 10 days of mourning, so we’ll see what form that takes, but let’s get this running today.

VR: As long as they keep the planes running out of England, that’s fine with me.

DG: OK. [chuckles] Well, I will start with my quotation. “If one does not know to which port one is sailing, no wind is favorable,” and that’s by Seneca, the Roman philosopher. I think right now I was on The Brian Lehrer Show earlier today, and a lot of people are confused. They’re not really sure what’s the next step? Here in New York, they just remove the masking mandates on all public transportation. The new bivalent boosters have rolled out. A lot of people are left with a lot of questions like, where are we headed, what does this mean?

We’re going to continue with our commitment to give you the science to help you navigate, to help you get some sense of which port you are sailing towards, that you don’t feel just lost.

But I’m going to start off with influenza, right? I’m pushing those influenza vaccines, get your flu shots, get your flu jabs. I’m not sure if our listeners get the CDC health alerts, but the alert, “Variant Influenza Virus Infections Recommendations for Identification, Treatment and Prevention for Summer and Fall 2022.” Five cases of human infection with influenza viruses that usually spread only in pigs, also known as variant influenza virus infections, were reported to CDC in August, 2022.

Now, these cases included three infections of Influenza A, that’s the H3N2 variant, A H3N2v virus, and two infections with Influenza A H1N2. Just maybe throw people a little background here. We have our Influenza As, our influenza Bs. Those are the main ones to be thinking about in people. Influenza A tends to have a seasonal pattern, Influenza B circulates all year round, and the H and the N, we started numbering those back with the “Spanish flu”. That was the H1N1, and then the numbers go up. If you see high numbers, you’re probably talking about bird flu. Just some of our ID aficionados may enjoy that little bit of trivia.

These cases were identified in West Virginia. We got three of them there, one in Oregon, one in Ohio. Four of the five cases reported exposure to pigs or attendance at an agricultural fair prior to illness. One reported no contact with pigs or attendance at an agricultural fair prior to illness. Just keep our eye on influenza, just a way of getting people to be thinking about influenza, another respiratory pathogen, but let’s move on to monkeypox. As I had been saying, and now this is becoming evident monkeypox is not a gay disease or an African disease. Monkeypox is an infectious disease.

Across the United States, a handful of college campuses, as well as high schools and middle schools, are dealing with monkeypox cases identified in students and staff. On a bright note, the gay community, the MSM community, seems to have actually done a good job of behavioral modification. We’re actually seeing a decrease in that population of new cases. We’re not seeing that exponential rise in that group, but the demographic has shifted and we have a monkeypox demographic.

I’m going to leave a link for folks here, but when we first started to see the cases, we’ll go back to May of 2022. This was dominantly white MSM population. Now, as we get to the end of August, that is actually that population is only making up a minority. We’re starting to see it in Black, African American, Hispanic, Latino, mixed races. Also, we’re seeing, as I think I’ve discussed before, in women, in heterosexuals and in children, but just to the sky is not falling, this is a contact transmitted pathogen. This is predominantly through contact, no sex required.

We need to continue to do the testing. Always disturbed how challenging it is to get tested and the CDC actually had a report on this. If you’re outside that target population, there’s really a lot of resistance to getting tested, but we got to do that. We got to test, you should be getting a lot of negative tests. You should be testing. The way you test is by swabbing these lesions with noncotton swabs, do a couple swabs to send off for the monkeypox. You’re putting that in liquid, you’re refrigerating or freezing that.

But a case I was just consulted on today. You want to also be thinking about other things, other painful vesicular pustular rashes, could be shingles. We’ve seen an increase in shingles recently. These could be MRSA or staph, could be bacterial folliculitis, so think about that as well. If you have a concern, get to a provider, if you’re a provider, we got to be doing that: tests. Because we don’t do the tests, we’re not sure what we’re looking at. But what about vaccines? We’ve got them, but do they work? Vincent, I saw you tweeted about this article.

VR: I did, because as you will say, they measured antibodies after vaccination with JYNNEOS, and the author, one of the authors, Marion Koopmans, who I like very much, head of virology at Erasmus Medical Center in The Netherlands, she said we don’t expect these levels of antibodies to be sterilizing, which really bothered me because they don’t need to be sterilizing. All the vaccine needs to do by whatever mechanism is to prevent lesions, and that will block transmission, right?

DG: Yes. Let’s hit it. The article, “Low Levels of Monkeypox Virus Neutralizing Antibodies after MVA-BN Vaccination in Healthy Individuals,” was posted as a preprint. Now, this investigation starts with the important background that we do not have much in the way of efficacy data in humans for this vaccine. This situation, to give people some background here, people want to know what’s up with these vaccines, and I get a lot of questions. The current JYNNEOS monkeypox vaccine is really a second generation.

What are we doing with smallpox vaccines? We have this vaccinia virus where we actually use that as a way of providing protection. Then we move on to this JYNNEOS monkeypox vaccine, where this vaccinia virus is further attenuated by passage through chicken embryo fibroblast. This is the vaccine that we give. What was it licensed based upon? Interesting enough, immunobridging, checking those antibody levels, seeing if we got antibodies, but we do not have at this point, actual efficacy demonstrated in human trials.

Here in this study, the authors are reporting on immunogenicity in the form of antibody responses post-vaccination. They reported that the monkeypox virus neutralizing antibodies were detected across all cohorts and individuals with monkeypox virus exposure, as well as those who had received historic VACV vaccination. However, a modified, this is the NCAR, the JYNNEOS immunization series, in non-primed, individuals yield relatively low levels of neutralizing antibodies.

Now, they point right out in the abstract that there’s no correlate of protection. We don’t really know what this means. They’re low. Are they too low? Are they inadequate? Are they low but adequate? We just don’t know. They did see that a third vaccination boosts that antibody level again. We really need to be careful. We need actual test negative studies to assess efficacy going forward.

VR: Daniel, if we don’t know what they mean, why are they publishing them?

DG: [chuckles] Because people are reading them, they are tweeting them out there. They are sharing this information. I think it was really good that you had Andy Slavitt on the show, because unfortunately, a lot of our policy decision-makers I think are getting advised by people that are really not diving deep enough into the science and being honest with what we do know and what we do not know.

All right, so, Vincent, this reminded me of you when I read this, but what are the ongoing investigations? What are we trying to do? There’s a serosurvey study going on right now. Really trying to get a sense of what is the prevalence of monkeypox. Are we making all the diagnoses? Are we missing them? Are we only getting those really obvious ones that stare us in the face? I’ve concern that that’s the case.

There’s basically the ability to do this testing of residual nucleic acid material. There are actually bagged swabs where they can go back to these commercial labs. People were swapped for other reasons and they can look and see, so we can do serosurveys. We can actually do molecular testing. Then this is another one, which I think is something that’s come up we’ve talked about. What about the presence of the monkeypox DNA in throat, in rectal swabs, in other places, people without lesions, is there a way to make this diagnosis before that person has lesions before they spread it to others?

Number of investigations going on there, and we are hoping that here in the U.S., we can beat the Brits to some efficacy data on TPOXX, tecovirimat. Does it actually work, in the treatment? We hope it does. We think it does. Are we fooling ourselves?

VR: Here in the UK, Daniel, they’re checking the blood in blood banks to see if there’s any monkeypox DNA. Are you aware of any such studies in the U.S.?

DG: Only that it’s on the list of the CDC investigations that we want to do that we’re hoping to have move forward.

VR: OK.

DG: All right. COVID. Let me start with a quotation from a social media influencer, SMI, with over 600,000 followers on Twitter, “Except for deaths that remain at about 500 deaths per day plateau, everything all are pointing in the right direction.” Now, that reminds me of the joke, “Other than that, Mrs. Lincoln, did you enjoy the show?” Now with 500 deaths a day as we head into the fall with the start of schools, with businesses returning to in-person, all these upcoming holidays, more time indoors, the masks coming off for public transport, I feel like I’m missing something.

When did 500 deaths per day become something that we just move right past? Published a couple of articles, three articles, this last week, actually, but the new article, “COVID-19: Using the Right Tools at the Right Time,” was just published in Medical Research Archives. This is really an update to those stages. This is a little bit more simplified. Hopefully, helping people get a sense of the critical times when they need to be jumping in, but we’ll leave a link in our show notes so people can read the COVID-19 using the right tools at the right time.

Timing is so critical with COVID, but let’s start off with that pre-exposure period. We’ve talked a lot about vaccines and we’re going to get back into those again. We’ve got exciting stuff there, but the big thing that I’ve been telling my patients that I’ve been trying to tell everyone who will listen is, have a plan. This pre-exposure period is when you get vaccinated, boosted, and importantly perhaps tied in here, have a conversation with your primary care provider about what you will do if you test positive. People really need a primary care provider that they can trust and access in an emergency.

If that provider is an Ivermectin guy, then get a new provider. If they get their COVID updates from the mainstream media and not the scientific journals or the professional societies, again, get a new provider. If they cannot do telehealth and get on the phone and address urgent issues in a timely manner, then again, you need a new provider. If in an emergency, you need someone that knows you, knows your medications, knows your risk factors, knows your kidney function, and knows what pharmacy or hospital is best for you. Have a plan and also have someone to talk to. We’re going to be talking a little bit about these bivalent boosters.

Don’t make your decision sitting there on the toilet, on your phone, make it having a conversation with a trusted health professional. All right. The article, “Onset and Window of SARS CoV-2 Infectiousness and Temporal Correlation with Symptom Onset: A Prospective Longitudinal Community Cohort Study,” was published in El Lancet Respiratory Medicine.

Just for some background, we have a growing body of evidence that most transmission with all the different variants has been in the day or two prior to symptom onset and in the five days after symptom onset, and then some transmission out to day 10. In severe disease, immunocompromised individuals, this period of being contagious can extend out past 10 days.

Although lots of people have been confident that they know the answers here. This is the first study to serial, as they say, serial quantify both viral RNA and culturable virus from the start of naturally acquired SARS CoV-2 infection. Now, they say infectious cultural virus, but we’ll get back to that. They did RT-PCR in vitro cell culture-based quantitative plaque assays to enumerate infectious virus, lateral flow antigen tests from the upper respiratory tract of 57 recently exposed cases in a real-world community setting, capturing the early viral growth phase during which most transmission occurs.

Now, they suggest that this enabled them to define the window of infectiousness, mean duration of infectiousness, an interquartile of three to seven days, so mean duration of five. Its temporal relationship to symptom onset and suggested that one-third of cases may still be infectious seven days post-symptom onset. Now, they quantified the level of infectiousness in those who still shed infectious virus at days five and seven, and they give us a mean log infectious viral load relative to a peak viral load decreased by 43% on day five, by 83% on day seven.

They found no significant difference in the proportion of cases that would be released from the first day of symptom onset between vaccinated and unvaccinated cases. They also report that the lateral flow detection, those Lik-a-Stix, performance in detecting infectious virus prevalence as defined by PFUs, Platform Units, sensitivity 79%, specificity 81%. They report then that the LFD sensitivity had a high negative predictive value during the viral decline phase.

Now, interesting enough, because I know this is being tweeted out there for certain reasons, certain confirmation bias. They conclude, “our findings provide a rationale for using lateral flow detection to safely accelerate the isolation,” not extend as most of the people sharing this article are suggesting, but actually to shorten isolation. I don’t know, Vincent, if you had a chance to look at this article.

VR: We know, Daniel, from what you have said before that sometimes these lateral flow assays remain positive for a very long time. Maybe this is an ideal study, but I don’t think it captures all the variation that happens out there, but more importantly, maybe we don’t know how much infectious virus is needed to transmit. They do some nice infectivity assays, but it could very well be that the numbers they see later past five days are not sufficient to transmit. Without knowing that number, I don’t think we can make any conclusion from this.

DG: I’m thinking, Vincent, you’re in the UK, you’re in the perfect place where what they can do is they can expose people at different levels and then see if they get other people sick, because they do those studies there in the UK. That’s really the way to do this science.

VR: I’m not participating because I’m too old and I could – who knows what could happen to me, but I don’t condone those kinds of experiments, but if they want to do it, that’s what they should be doing and measuring PFU after inoculation, but then, Daniel, they should put people in a room with an uninfected person and see how many PFU you need to transmit to them.

DG: That’s really the study and really taking this work now and then somehow connecting it with contact tracing, these different people. I think it’s interesting if you go back to, I’m going to talk about another study right here, “The Transmission of SARS CoV-2: A Review of Viral Host and Environmental Factors.” This was actually published January of 2021 in Annals of Internal Medicine, great paper with about 144 references. and they actually quote a Taiwanese study where there was a huge amount of contact tracing where they were actually not able to define any transmission after day seven, zero.

Straight from the abstract, respiratory transmission is dominant with proximity and ventilation being key determinants of transmission risk in the few cases where direct contact or fomite transmission is presumed, respiratory transmission has not been completely excluded. This is respiratory spread. Distance makes an issue. A large part of this spread is actually the large droplet, but we do see this is respiratory. Particularly in those poorly ventilated areas, we’re seeing transmission, even if you’re six feet away, even if you’re farther away. Now, in here, they suggest, as I mentioned, infectiousness peaks around a day before symptom onset and declines within a week of symptom onset.

I’ll just add that with Omicron, and in certain individuals, there may be slight differences here. One of the things I really like about this article and I think it’s worth the time to read is the authors really suggest that the dichotomization, or as I like to say, the binary between droplets and aerosol transmission is really an oversimplification. It’s a much better way to talk about this as a respiratory transmission, and move away from this confusing history of contact and droplets, and this idea that there might be a strict binary.

All right, active vaccination, never miss an opportunity to vaccinate. Vaccinated people still get infected, they are just less likely to die or have severe disease. As we heard, right after we recorded last week, the CDC director, it seems so long ago, but Dr. Walensky endorsed the CDC Advisory Committee on immunization practices, recommendations for use of updated COVID-19 boosters for Pfizer, BioNTech, for people ages 12 years and older, and for Moderna for people aged 8 years and older. Let’s have a little discussion here, Vincent. There’s been a lot of people and they’re already predicting the future. This is the beginning of yearly boosters, we already know how this will go. Any comments?

VR: It’s very interesting. Last week, Paul Offit emailed me, and he wants to come back on TWiV to explain why he thinks we should not be getting these bivalent boosters for most people in the fall. I think that’s very unusual because he must feel strongly about it, and I have a lot of respect for what he thinks. I also want to point out that we do know that giving an influenza booster every year is good, because we have many years of experience correlating, neutralizing antibody levels with severity of disease. We don’t have that kind of information for SARS-CoV-2 and COVID. I think it’s a bit premature to suggest that we’re going to be doing yearly boosters until we get some data.

DG: I think the last sets is what I sort of pick the most upon is that we are going into this with a lot of optimism, with a lot of hope, but we’re going to need to learn, we’re going to need to see. Before we commit, before we announce to the world that this is the beginning of yearly COVID boosters, we’re going to have to see how this goes, we’re going to have to see what the impact.

As I think we try to remind people over and over, getting those three shots continues to do a really great job of protecting people against death, severe disease. Vaccines don’t keep you from getting infected. I think that a lot of this push is this idea that people are going to get this booster, and then we’re going to see a big social impact, a big public health impact reducing infections, but at the same time, we’re sending people back into these situations.

I think we have to be realistic because we’re actually, if anything, we’re eroding competence in vaccines if we’re not careful. We have to be really careful here not to overpromise. As I’ve been recommending to a lot of people, it goes right back to that have a plan. Discuss with your provider, what’s right for you. If you’re an older individual at high risk, well, for me, that’s a straightforward recommendation. If you’re an individual in your 30s and you had a COVID infection in June, I think there’s a different dynamic. This is not something that you really should be just getting a straight recommendation from social media or any other media source, you probably need to start having a little bit more of a conversation.

All right, but what about those mucosal vaccines? I was really impressed by how quickly this was tweeted out there, wondering how could anyone have actually read this article before they tweeted it out. What about those mucosal vaccines? This is like the oral poliovirus for vaccine, but here it’s for a respiratory contagion, the RCV, the Respiratory COVID Vaccine. The preprint, “Antibody Persistence and Safety through Six Months after Heterologous Orally Aerosolized Ad5-nCoV-2 in Individuals Primed with Two-Dose CoronaVac Previously.”

Now getting lots of attention and these are the results of a randomized open-label single center trial on safety and immunogenicity of heterologous boost immunization with an orally administered aerosolized Ad5-nCoV-2 versus homologous boost immunization with CoronaVac after two dose primary with CoronaVac in Chinese adults aged 18 years and older. I want people to pay attention, because what are we looking for and what are we not going to get?

These investigators followed the participants in this trial, including 140 in the low dose group, 139 in the high dose aerosolize group, 140 in the CoronaVac group out for six months neutralizing antibodies against live, these viruses are now live wild-type SARS-CoV-2 virus and Omicron variant and receptor binding domain specific IgG antibodies were measured in serum samples collected at 28 days, three months and six- months after the booster dose. The serious adverse events were documented till month six.

The low dose and high dose heterologous boost groups had neutralizing antibody geometric mean titers against live wild-type SARS-CoV-2, which were 26.4- and 18.4-fold higher than the CoronaVac group at 28 days. The low dose and high dose had GMTs that were 26-fold and 22.4 higher at three months respectively, and at six months, the low dose and high dose had GMTs which were 30- and 24-fold higher than the CoronaVac group did respectively.

Now, additionally, I think this is we’re getting into the low dose and high dose heterologous boosts had GMTs against live Omicron variant of 52 and 23 at 28 days, 23 and 16 and 12 at six months respectively. Are those high enough, Vincent? Do we know? [chuckles]

VR: Who knows.

DG: However, nearly all participants had no detectable neutralizing antibodies for Omicron in the CoronaVac group at 28, three months or six months. Now, I suspect our TWiV listeners are waiting patiently for the data on actual mucosal immunity, things like IgA, and the people who do not listen to TWiV and are just retweeting this are not disturbed by not seeing this. Also, not compelling anything I’m seeing in here for protection against Omicron, so who really wants this vaccine? Is this just a way to avoid needles? Is this really a vaccine that protects us against infection with mucosal immunity?

To be clear, the authors suggest that this is a way to get those serum antibodies, not necessarily those mucosal antibodies boosted, and a way to avoid sharp disposal issues, and that maybe there are economic advantages here. I think people should look closely, because everyone’s talking about those mucosal vaccines. This is mucosal delivery, not necessarily mucosal of vaccination.

VR: Daniel, can you go over the data on protection against severe disease and death, please?

DG: Oh, that wasn’t here. There was none of that?

VR: Isn’t that what matters?

DG: Yes, that is really what matters. We really do, as much as people keep measuring those antibody levels, we really need to establish some correlation. Is there a correlation there? I think we need to stop for a moment, stop publishing those studies until we actually establish some correlation. Do we know what this means? All right.

VR: I think it’s quite clear that these serum antibody levels will eventually contract. It’s interesting that they’re still pretty high at six months, but not against Omicron, but they’ll eventually contract which leads you to saying what’s so different? Maybe, Daniel, it’s really just throwing the needle away.

DG: Yes, I mean, I think that might be true. There’s a bunch of people that don’t like getting shots. Is this another way of delivering vaccines and you spray it in the room? You breathe this in? I think it’s great to have other options for delivery. I think we need to be realistic about what do these antibodies mean? Do they correlate? Are they actually causal?

There’s really, I mean, we’re two years in, we need answers to these questions. Speaking of those antibodies, just giving them to folks, passive vaccination with Evusheld, I always like to keep bringing this up, and as a little bit of a teaser, next week, I’m going to be talking about a new variant, which is now up to about 10% of what we’re seeing here in New York, and a little bit of disturbing data about whether or not Evusheld is going to be protective as this grows.

All right, so now you’ve been exposed. You’re careful, you’re waiting, you’re getting ready with your plan. What if you test positive? Number one, it’s still Paxlovid, stop worrying about that rebound. I’m seeing a lot of the worried folks, can I have my second course of Paxlovid? Can I have monoclonal? I got Paxlovid, but it’s day 11, and I still feel crummy. My goal, our goal with Paxlovid, the science is not that Paxlovid makes you feel better sooner. It’s just like the vaccines, it’s going to reduce your chance of progressing to severe disease, to hospitalization, and to death. Paxlovid continues to do that.

Number two, remdesivir. Poorly operationalized, and I think we need to start putting a little bit more pressure. This is that drug that we can do down to day 28, so what about those high-risk children? We really need to do a better job at all our healthcare systems of providing access for option number two.

Number three and four, bebtelovimab and molnupiravir. I’m a little bit disturbed, so I’m going to read the research letter, “Administration of Anti-SARS-CoV-2 Monoclonal Antibodies after U.S. FDA Administration Deauthorization,” published in JAMA Network Open. People probably remember the good old days when we had the e-way for those monoclonal cocktails, the Eli Lily, bamalanivimab, etesevimab, the Regeneron, the casirivimab, imdevimab, but those were revoked because when Omicron started circulating, we became aware that these antibodies were not effective. If anything, they were damaging opportunity costs.

People were coming in, getting this, getting reassured that they had done the right thing when we actually had effective alternatives. Well, apparently there were a bunch of people that are not willing to let science stand in the way of doing something unhelpful. I am shocked at this, 158,395 monoclonal antibody doses were administered after deauthorization, and who were the guilty culprits? Can you guess? Can you guess, Vincent, what two states did the worst? Well, Florida, I knew that.

VR: Florida. Florida, for sure.

DG: Florida was number one, 24% of these, but who was number two? New York at 20%, ouch.

VR: Oh, oh, that’s terrible.

DG: Well, no, I actually knew a bunch of facilities and physicians that kept doing this despite the lack of efficacy, lots of arguments. Well, what are we supposed to do? Are we supposed to just throw these in the trash? Yes. Put them in the deep freeze. Maybe there’ll be a time in the future where they’re helpful again, but-

VR: Oh, God.

DG: -don’t just give them to people when you know they don’t work. Ouch. OK. All right. We also, as I’ve mentioned before, we’ve got some in-vitro stuff. We think bebtelovimab works, but it certainly doesn’t work if you wait till about day nine or 10 to give it, so if you’re going to do bebtelovimab, time matters. Molnupiravir, number four in the list, about a 30% reduction in the early studies, but as we shared, maybe some better efficacy in the real world.

I do keep, every time, reminding people, let’s avoid doing things that are harmful. Remember, steroids in that first week, a several-fold increase in the risk of bad outcomes. Antibiotics, 95% of the time you’re doing the wrong thing. No Ivermectin, it is not helpful, we have studied it. Fluvoxamine, not helpful. Colchicine, not helpful. Zinc, not helpful. High-dose vitamin C, not helpful, but what about anticoagulation? Should we be recommending aspirin? Blood thinners?

Well, we do not have great guidance here on what to do in the first week as we do during that second weeks. We’ve looked at a lot of different agents, we’ve looked at aspirin, agents that block platelets, we’ve looked at agents that block clotting, we have not been able to demonstrate that that is helpful, but the article, “Clinical and Genetic Risk Factors for Acute Incident Venous Thromboembolism in Ambulatory Patients with COVID-19 ,” was published in JAMA Internal Medicine.

Now, these results are going to reinforce what we know and they’re potentially going to tell us something that actually can reduce that clotting risk, so these are the results of a population-based cohort study of patients with COVID-19 from UK Biobank, which included participants with SARS-CoV-2 infection that was confirmed by a positive PCR test between March 1, 2020 and September 3, 2021.

They’re then propensity score matched to COVID-19 naive people during the same period. They found, and these are those folks that did not require hospitalization. Those folks with COVID-19 infection that did not require hospitalization did have an increased risk of venous thromboembolism in the first 30 days. This was an incident rate of 50.99. This is respectively a hazard ratio of 21.4. These individuals are more than 21 times as likely to have a clot because they got infected with COVID. However, how do we reduce that risk? The risk was substantially attenuated among the fully vaccinated a hazard ratio reduction. This is 5.95, so about a six-fold reduction.

Not only do those vaccines keep you from dying, not only do they keep you out of the hospital, but they significantly reduce your risk of ending up with a clotting complication. Now, in the early inflammatory, right? We keep talking about this, we’ve been talking about it for two years. This is that “rebound”, that first week, that’s that viral phase, you’re feeling crummy. Some folks get hospitalized because they’re frail, they’re having trouble, they end up in the hospital, but this is really the major time. This is when people get hospitalized for moderate to severe COVID.

This is the early inflammatory, lower respiratory hypoxic phase, that pulmonary or cytokine storm phase. This is where the virus is on the way down, but the inflammation is ramping up. Steroids at the right time, in the right patient, at the right dose, anticoagulation, and we have some guidelines, American Society of Hematology, living guidelines on the use of anticoagulation for thromboprophylaxis for patients with COVID-19, the March 2022 is now updated on the use of anti-coagulants in critically ill patients.

Also, the living guidelines on anticoagulation for acutely ill. We’ve got our ICU level and our acutely ill. Just to put this into perspective, we have a conditional recommendation in favor of therapeutic intensity in those with acute illness. We have a conditional recommendation in favor of prophylactic intensity, so a lower dose intensity, in patients with critical illness, those folks in the ICU. Now, the panel emphasize the need for an individualized assessment of thrombotic and bleeding risk. I’m one of the authors on that, so you might recognize that second sentence.

Pulmonary support, here we have an update to the WHO living guidelines. We haven’t gone too deep into the pulmonary support in a while, but the WHO had some updates, so three updates. Conditional recommendation for the use of high-flow nasal cannula. Early on, there was a lot of restrictions on the use of high-flow nasal cannula, concern that this would increase the risk to caregivers in these facilities, but now we have a recommendation to go ahead and do that. A lot of our facilities have upgraded, so this could be done safely.

We also have a conditional recommendation for using positive airway pressure. This is really another one of our ways of keeping people off those ventilators and really, third, a conditional recommendation to use noninvasive ventilation rather than standard oxygen therapy for patients with severe and critical COVID-19 not requiring emergency intubation, so all these updates trying to keep people off the ventilator, trying to provide the pulmonary support without requiring intubation, and ending up on a ventilator.

Number four. Remember, maybe remdesivir, if we’re early enough, immune modulation. It’s been a while since we talked about immune modulation with tocilizumab. Now, I have mentioned that certain institutional guidelines are limiting the use of tocilizumab, and I will say the science would suggest that they are not allowing you to use this until after it ceases to be useful. Again, tocilizumab, just like so much in COVID, timing really matters, and so the article, “Timely Administration of Tocilizumab Improves Outcomes of Hospitalized COVID-19 Patients,” published in PLoS ONE.

These are the results of an open-label, randomized Phase II clinical trial investigating tocilizumab, toci, in patients with proven COVID-19 admitted to the general ward and in need of supplemental oxygen. The primary endpoint of the study was 30-day mortality, so pretty good hard endpoint. A total of 354 patients were enrolled, almost all of them, 88% received dexamethasone. The 30-day mortality was 19% in the standard arm versus 12% in the tocilizumab arm. The folks that got toci, the hazard ratio 0.62, so about a 38% reduction there. We have a confidence interval of 0.39 to 0.98.

Now, the median stay in the ICU was 14 days for standard versus down to nine for the toci. Mechanical ventilation or death at 30 days, really that was our hard endpoint, 31% in the standard arm, 21% in the tocilizumab arm. A hazard ratio of 0.65, so 35% reduction in that, that primary endpoint of 30-day mortality. Now, another study that supports efficacy for tocilizumab when given early in disease, in hospitalized patients who need oxygen support, especially as we’ve seen repeatedly in the context of dexamethasone. All right, so remember the toci

All right, the late phase, we’re going to be getting back to anticoagulation here. Now, currently at hospital discharge, we’re often stopping the remdesivir even if they’re not completed in the course, we’re often stopping the steroids even if they’re not done with the course, but what about anticoagulation? This is a touchy subject locally. Guidelines on what to do in terms of anticoagulation at discharge for COVID patients was put forth in the article “American Society of Hematology Living Guidelines on the Use of Anticoagulation for Thromboprophylaxis in Patients with Covid-19, July 2021 Update on Post-Discharge Thromboprophylaxis.” This was published way back in January 21, 2022, Blood Advances there.

The ASH guideline panel suggests that outpatient anticoagulated thromboprophylaxis not be used for patients with COVID-19 who are being discharged from the hospital and do not have suspected or confirmed venous thromboembolism or another indication for anticoagulation. COVID alone is not enough. They need to have an indication, they need to be at high risk. Pretty straightforward. This also, of course, has that individual risk assessment because I’m on the guideline panel.

The article, “Commentary on the 2021 ASH Guidelines on Use of Anticoagulation in Patients with COVID-19 Being Discharged from Hospital,” was published in Blood Advances just recently in response to some of our prior ASH guidelines. It’s written by Alex Spyropoulos and Renato D. Lopes. I love their introduction. “The COVID 19 pandemic has fundamentally changed the way we practice medicine, conduct clinical trials, and rapidly gather, generate, and evaluate high quality evidence to guide clinical practice. This is clearly apparent in the accelerated process of assessing and formulating clinical practice guidelines so they can be me meaningful during the compressed timeframe of a pandemic.

A good example of the natural tension that exists between methodological purity and the clinical relevance of COVID-19 associated guidelines lies with the 2021 American Society of Hematology guidelines on the use of anticoagulation in patients with COVID-19 who are being discharged from the hospital.” I thought this was interesting. One is that we somehow were able to achieve high quality evidence to guide clinical practice. Not sure.

It’s also nice to be accused of methodological purity, but I’m not sure there’s really attention here between this commentary and the recommendations that state, “The panel acknowledge that post-discharge thromboprophylaxis may be reasonable for patients judged to be at high risk of thrombosis and low risk of bleeding.” I think as we’ve routinely recommended over time, it’s been suggested that providers actually use a risk or individually stratify your patients, don’t just check a box.

You can use the modified IMPROVE VTE scoring system. We’ll leave a link in there. Look at your patient. If this is a low risk individual with no other issues, not necessarily needing to go out on $500 a month of a blood thinner, but this is an individual with risks, maybe this is an individual with a history of cancer or some other risks, that person is better off going out. Go ahead individualize, don’t just check a box.

All right. I always like to finish with, what about the rest of the world? As I’ve been saying for a while, no one is safe until everyone is safe. The most selfish thing we can do and if we didn’t learn this with COVID, maybe we’ll learn this with monkeypox, it’s to reach out and address issue at a global level. These are viruses without borders. They don’t respect country boundaries. I want everyone to pause right here, go to parasiteswithoutborders.com. Click on that Donate button. Even a small amount helps. I actually like the small amounts, Vincent. I know you like the big amounts.

VR: [laughs]

DG: For us to continue our commitment to be here and give you the science without having any person telling us what agenda we should be serving, we’re going to need your support because you are the folks that help us do what we do. We will continue our Floating Doctors fundraiser. During the months of August, September, and October, donations made to Parasites Without Borders will be matched and doubled up to a potential donation of $40,000, but we’re going to need your help getting there.

VR: I was walking down the street earlier coming to do this recording and I heard someone yelling my name on the sidewalk, Dr. Racaniello. This fellow came up and said, “I’m a local infectious disease physician. I just wanted to thank you for everything.” I thought that was really cool. We never get tired of hearing you tell us whether you like what we do or not, mostly that you like what we do. We really appreciate it.

DG: I prefer the positive comments.

VR: All right. It’s time for questions for Daniel, you can send yours to daniel@microbe.tv. Anonymous rights. “I’m a 25-year-old queer person and qualify for the monkeypox vaccine. I just got my first dose of JYNNEOS, woohoo. When I went to get the shot, I was asked whether I developed keloids. I mentioned I get hypertrophic scars, which are basically keloids. They administered half an amount of the vaccine subcutaneously instead of 0.1 ml intradermally.

My question is, what’s the biological reason for administering JYNNEOS sub-Q per its traditional administration, rather an ID at the lower dose to stretch out the vaccine supply for patients who develop keloids? Is the concern cosmetic? Is there a reduction in efficiency of vaccination if a keloid develops? Or is the science on this unknown? Love the pod. Thank you and Dr. R for keeping us up to date on the latest science and policy.”

DG: Now, thank you, Anonymous. As I like to say, I love your poetry. There’s not a lot of science on this. We don’t have any studies where we’ve looked at keloid formers, people that form hypertrophic scars, done antibodies, done any sort of efficacy trials, effectiveness trials. It really in this case, it’s a cosmetic consideration.

VR: Ellen writes, “I have MS and I believe that with each COVID shot, my symptoms have gotten worse. I don’t know if it’s from my immune response to the injection or not. I had no reaction to the first one, but the second and the next two booster shots caused me to have a fever, which exacerbated my MS symptoms. Have you heard of any other MS patients having this problem?”

DG: Yes, and actually thanks for writing in because I think this is helpful. There are actually a number of studies, and actually the MS Society has some studies looking at this. There’s an inflammatory, a reactogenicity. This is not something specific to any COVID vaccination. We have heard over time that some individuals will have a worsening of symptoms with vaccinations, with any kind of infection, with any kind of stress like this.

There’s been a lot of discussion and a lot of sort of, “What is better to get vaccinated or get COVID?” I think you can guess what’s better. Getting COVID, the stress, the impact on MS is significant, is severe. We definitely recommend people with MS get vaccinated, but actually, MS Society has some ongoing studies looking at this. This might be something that you want to go on there, Google, check out the MS Society, and they actually have links to some of the studies looking at vaccine responses in the MS population.

VR: Suzanne writes, “I’ve been an avid TWiV listener since May 2020, unlike a certain recent guest whose name rhymes with ‘Sandy Tavitt.’ I have a question for you about COVID-19 treatment. My father and stepmother were diagnosed with COVID last month and immediately contacted me with questions because they know I’ve been listening to TWiV. Both are 70 years old, have heart problems, are on blood thinners. Both are also quadruple vaccinated. Got all those shots as soon as they were eligible.

When they tested positive, I advised them to talk to their primary care doc to try and get Paxlovid in conjunction with speaking with their cardiologists about temporarily stopping their blood thinners. They both since fully recovered, but I was surprised by what was offered by their docs. My father ended up with Paxlovid, plus also was given bebtelovimab by infusion, not injection.

My stepmother was given bebtelovimab only again by infusion. They were told that Paxlovid often doesn’t work, but they could take it if they really wanted it. I insisted that it was what they should take. My dad did take it and temporarily stopped taking a conflicting med. The doctor however, wouldn’t give him that alone, which is why he also had bebtelovimab.

Due to what the doc said, my stepmother was concerned about the supposed Paxlovid rebound. Despite what I told her about the facts, neither was offered remdesivir. Both my dad and stepmother said it was never mentioned in their consults with their doctors. The doctor in the hospital, where they went for treatment is a regional tertiary care medical center in New Jersey, in the New York City suburbs, by the way.

It’s not the same level of hospital at which I receive care here in Boston, but it’s certainly not out in the bush either. I’m confused and somewhat concerned about several parts of this. First, Paxlovid was clearly not a preferred treatment, which seemed unrelated to concerns about heart conditions and other meds. Second, no mention of remdesivir. Third, they’re given bebtelovimab by infusion. Fourth, my dad was given two different treatments. I’m glad they’re fine now, but this type of care is confusing and concerning. What do you think of this?”

DG: I’m going to start with the “this is concerning.” Let’s go through it and what’s the problem here. Very clear society recommendations, the science, the number one recommendations, the therapy with the best data as far as efficacy, both in the unvaccinated and the vaccinated, number one is Paxlovid, the nirmatrelvir. This is the number one thing people should be getting, but the problem is we have a bit of a broken system. How are physicians often educated? How they learn about these new drugs. They have these drug dinners, they have ex-cheerleaders taking them out, they have people coming through the office with these glossy pamphlets.

Unfortunately, a lot of physicians read the mass media. They’ve heard about Paxlovid rebound. They’ve gotten concerned about that, and they shouldn’t, because Paxlovid does what we want it to do. A high-risk individual gets Paxlovid, about a 90% reduction. If they’re vaccinated, I think we’ve looked at the studies, about a 75% reduction in progression to hospitalization, severe disease, or death. Paxlovid should be number one.

Number two, we should better operationalize remdesivir. I think that that’s a big problem. Again, we live in a system where there’s certain rewards for certain things. Remdesivir, Vincent and I were in a discussion one time, where only about 3% of acute COVID care is remdesivir, so it’s really not accessible. Here in our immediate area, things are a little bit different, but things should be a little bit different everywhere.

Now, monoclonals and molnupiravir, that’s three and four. Now, bebtelovimab is intravenous, so that’s fine. The administration is fine. That’s the way it’s administered, but it’s number three/four because we don’t have the efficacy data. We’re not sure how well it works. The other problem with it is there’s often delays, as you may have encountered. It’s not like you call, get the diagnosis, and start on your medication that night. It’s often in next several days.

Again, we’re fortunate. Our little local island where people can get that bebtelovimab same day. Again, this is one of those challenges. I hate to disparage the doctors, but doctors have to keep up. If you realize that your doctor is not keeping up on COVID care, what else are they not keeping up? If your parents’ physician is not keeping up on COVID care, what else are they not keeping up on? I know it’s not easy, but there are physicians out there who really are taking this responsibility seriously and staying up to date. Those are the physicians that you want to be your physicians.

VR: That’s TWiV Weekly Clinical Update with Dr. Daniel Griffin. Thank you, Daniel.

DG: Oh, thank you so much. Everyone, be safe.

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