TWiV 953 Clinical Update

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 12 November 2022

pdf of this transcript available (link)

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


VR: From MicrobeTV, this is TWiV, This Week in Virology, Episode 953, recorded on November 9, 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: Well, we’re all back home now, right, Daniel?

DG: Well, you’re back from your global tromp. I’m back from just Seattle. [laughs]

VR: Where I also picked up a little bit of SARS-CoV-2.

DG: Just a little bit. [laughs]

VR: Well, you know there’s nothing like Paxlovid to interrupt its work.

DG: All right, we’ll be talking about that today, but let’s get right into it. I don’t know if you know but it is our 140th clinical update.

VR: Wow.

DG: Really amazing. Let us start with the quotation, “Learn from yesterday, live for today, hope for tomorrow. The important thing is not to stop questioning.” That’s Albert Einstein. It’s really important for us, and I was reading another article today that I’ll talk about next time. We think we’ve got things figured out and then another study comes along and it allows us to ask, “Is that really true?” I definitely am learning a lot when do the ID Puscast with Sara Dong and we go through so many of these papers that challenge the dogma.

Everything that I was taught with such opprobrium, I’m definitely much more humble now as the years go by, but let’s get right into it with polio. This was raised in the context of polio when the CDC was requesting more flexibility in its ability to hire experts to help when there’s a problem. Despite having a multi-billion dollar budget, the agency doesn’t have authority from Congress to hire consultants in a timely way when an urgent situation arises. Walensky plans to appeal to Congress to allow for flexibility to do this kind of hiring in a crisis, similar to the authority vested in some other federal agencies.

Let’s say, for instance, there’s a problem with polio. It would be nice to take a little bit of those multi-billion dollars and maybe call up Vincent and ask for a little bit of input from an expert, and be able to offer some compensation as opposed to just requesting he do it from the kindness of his heart. Vincent, what do you think?

VR: I think that would be a good idea. I’d be happy to donate it to MicrobeTV.

DG: OK, yes, maybe they can hire you, and the caveat is and we will give the money to your favorite charity. MicrobeTV is one of mine. Influenza, just to mention, we are rising rapidly. I don’t know if you know but the CDC had to add a new color above high, this very, very high purplish color, for just how much influenza we’re seeing, and actually, we’re now at the highest level of hospitalization we’ve seen in a decade. Boy, this is quite early because we haven’t seen the post-Thanksgiving or the post-December, New Year’s surge, so get your flu shots if you haven’t already.

RSV. The article, “High Demand for Amoxicillin is Causing Shortages Amid Child RSV Surge,” was published, the article, in The Washington Post. So many problems here on so many levels. This is a virus. Maybe people have learned what a virus is. Maybe they have also come away with the lesson that viruses don’t get better with antibiotics. You got a virus, you’re not doing well, it’s not a great time to wipe out your microbiome with an antibiotic. So save those antibiotics for when they’re appropriate. That should be easy. [chuckles]

Ebola. Vince and I were chatting right before we started.

Three weeks from when this drops I will be in Uganda, sorting out how we continue to keep our clinical updates with the bandwidth challenges but also dealing with the Ebola outbreak in Uganda. The outbreak is continuing and news this week is we heard that the Ugandan Education Minister announced that the cabinet has decided to shut preschools, primary schools, and secondary schools from November 25 after 23 cases diagnosed in children and eight deaths from Ebola in children in Uganda. I just will mention the vaccines, will mRNA vaccine save us from Ebola?

I was taken by that because there actually are some vaccines for Ebola Zaire. We’re going to see if these work for Ebola Sudan that we’re seeing currently in Uganda. But there are two vaccines that are already proven to protect against Ebola Zaire. The Ervebo or ERVEBO sold by Merck, New Jersey there, and the Zabdeno or Mvabea sold by J&J also out in New Jersey. There’s a couple of vaccines, they’re the adenovira, pretty similar to that J&J vaccine that is out there for SARS-CoV-2 for COVID. I’m not sure we need the mRNA vaccines to save the day at this point. Makes a lot more sense to test these out there, hundreds of thousands of doses. Hopefully, those trials will be starting soon.

Monkeypox update. Monkeypox is not a gay disease or an African disease. Monkeypox is an infectious disease. We’re down to about 30 diagnosed new cases per day. I was hoping that we would be even lower than that, but the article, “Epidemiologic and Clinical Features of Children and Adolescents Aged Less Than 18 Years with Monkeypox, United States, May 17 – September 24, 2022.” This is CDC MMWR. Take this a couple different ways, but let me just stick to the data. Here we get data on monkeypox in children and adolescents aged less than 18 years United States. As of September 24, 2022, we were up to 25,000 monkeypox cases.

During this period the CDC and the health departments identified monkeypox virus infections in 83 persons aged less than 18. There are 28 in children aged zero to 12, 55 in adolescents 13 to 17. In most cases, there was direct skin-to-skin contact with an adult with monkeypox who was caring for the child in a household setting. A few other interesting situations such as towels shared with a caregiver with monkeypox as a suspected route of exposure. One non-household exposure occurred when an adult with monkeypox held the child outside the household setting.

There were 10 instances investigated in which a child or adolescent with monkeypox attended a childcare facility or school while symptomatic. No instance of secondary transmission in these settings was identified. I think this does continue to feed into the wisdom that this is not as contagious as a lot of other infections. Remember, this is predominantly through contact. No sex required. The only way you’re going to diagnose it is by going ahead and sending those swabs, so continue to test.

COVID update. I don’t know if you know, Vincent, but I got a lot of emails and a lot of comments after a recent TWiV. An infectious disease physician Dr. Jake Scott who practices out in the Palo Alto area of Northern California, was recently a guest on TWiV 952. This certainly generated as I mentioned, lots of comments and emails. So as I go through the different parts of the COVID section, I will try to put this in context.

Dr. Scott describes his personal experience of COVID. A bit about Palo Alto where this gentleman hails from, not exactly where I hail from, in this area, the median home price is $3.3 million. Median. The average household income is close to $200,000 per year. Population’s 90% White and Asian so very few Black or Native Americans. This shocked me. The COVID vaccination rate is 95%. Paxlovid is so often used that Dr. Scott is concerned that Paxlovid is being overprescribed. This really contrasts with parts of our country with vaccination rates down at 50%. National data that, Vincent, you and I have talked about, where less than 2% of eligible people get antiviral treatment in the first week.

Dr. Scott also does not see the terrible suffering of Long COVID as he explained from early on when people would refer Long COVID folks his way, he would refer them to the CFS/ME clinic. I was told that there were about a thousand people in the Stanford Long COVID recovery cohort, but he’s not participating in the care of these patients. He shared that no one calls him to consult on COVID cases anymore, so he’s back to seeing mostly HIV and recurrent urinary tract infections. He mentioned seeing only two COVID cases in the last few months.

I saw more just at the ASTMH conference, [laughs] just pointing that out. Despite currently having the highest level of flu hospitalizations in over a decade and RSV cases spiking so fast, the hospitals are overwhelmed, he’s not seeing this. This sounds really nice in the Palo Alto area, but things are different here and in much of the country. When I returned to work from our trip out to Seattle, our COVID unit was full at the hospital. I saw several outpatients with Long COVID. Two brand new, three brand new, actually, after an infection with Omicron three months before.

To put it also into context, on Monday, 11/7 people may have heard that a group of medical organizations warned the president that hospital emergency departments were reaching a breaking point as they deal with influxes of patients seeking beds that are not available. The medical groups which included the AMA and the American Psychiatric Association cautioned that the issue of boarding, ER boarding, basically keeping admitted patients in the emergency departments due to a lack of space, had been brought to a crisis point by staffing shortages.

Things are actually so bad in our region with RSV that the University of Pittsburgh Medical Center had to set up a tent and in Rhode Island every single pediatric hospital bed is full. I’ll leave links to all these comments in our notes. Children, COVID, and other vulnerable populations. Children are at risk from COVID. Let us start here with Omicron and children. Just because one does not take care of children or see this firsthand, does not mean that they don’t get sick, that they don’t get hospitalized, that they don’t die, and they don’t suffer from Long COVID. We’ve talked about these numbers before, but it’s estimated that around 1,000 children have died of COVID.

Some say that’s an overestimate. It’s as low as 800. Some say it might be as high as 1,200. I will point out that the majority of these deaths and the majority of pediatric hospitalizations occurred during the period of Omicron dominance. I will be positive here. I do think the worst is behind us. As we’ve discussed before, between infection and vaccination, we are likely down to less than 10% of our children not having some form of immunity to COVID.

All right, pre-exposure period, transmission, and testing. Transmission by fomites. The article, “Low Risk of Severe Acute Respiratory Syndrome Coronavirus 2 Transmission by Fomites: A Clinical Observational Study in Highly Infectious Coronavirus Disease 2019 Patients,”was published in JID. I wonder how they get this title, highly infectious. [laughs] These are the results of a single-center observational study, including COVID-19 patients with a high baseline viral load, so they say cycle threshold less than or equal to 25. I’ll say high RNA copy number. They documented clinical and laboratory parameters and used patient samples to perform virus culture, quantitative PCR virus sequencing.

Nasopharyngeal and oropharyngeal swabs of all patients were positive for viral ribonucleic acid on the day of the study. Infectious SARS-CoV-2 could be isolated from 46% of the patients. After coughing, no infectious virus could be recovered. However, intensive moistening with saliva resulted in successful viral recovery from steel carriers of 38.5% of the patients. They concluded that transmission of infectious SARS-CoV-2 via fomites is possible upon extensive moistening, but it is unlikely to occur in real-life scenarios and from droplet-contaminated fomites. I found this very entertaining. What did you think of this, Vincent?

VR: You shouldn’t lick your blankets, basically.

DG: Don’t go around licking stuff. Don’t go around licking surfaces. [laughs]

VR: My dogs do that all the time. [laughs]

DG: Yes, and cats. Cats are usually licking themselves. Dogs are licking everything. My dog, Hattie, whenever she drinks water, she looks around for someone to lick to get all that wetness off her face, so maybe I’m worried about her. At some point, we should probably do a real focus on all these ideas about contact transmission. I think that’s pretty straightforward and we’re reminding people with a lot of the respiratory, particularly RSV, influenza, contact’s big, wash those hands. Really SARS-CoV-2, this is a respiratory pathogen. At some point, it will be interesting to talk about the whole history of dividing respiratory transmission into different categories instead of just looking at it as a whole.

Also mention many of the rapid test manufacturers are being told to update their labeling really in line with the guidance, which is if you get a negative on a rapid test, 48 hours later, check it again. Don’t just count that first one as negative and then go about your day. Really great though in the acute setting. Start off with that rapid test. If it’s positive, we can jump in because treatment is time sensitive. If you have a high clinical suspicion, you want to either repeat that or add a molecular test to the mix.

All right. Perhaps our listeners remember that we are having challenges with so many re-infections that we cannot always tell when the last one ends and a new one begins. The article,Nucleocapsid Antigenemia Is a Marker of Acute SARS-CoV-2 Infection,” published in JID. Here the authors had this idea of using nucleocapsid antigenemia to determine if a person was having acute COVID. They performed a retrospective serosurvey of inpatient and outpatient encounters and categorized samples along an infection timeline using timing of SARS-CoV-2 testing and symptomology. Among 1,860 specimens from 1,607 patients, the highest levels and frequency of antigenemia was observed in samples from acute SARS-CoV-2 infection. Antigenemia was higher in seronegative individuals and in those with severe disease.

In this analysis, antigenemia exhibited 85.8% sensitivity and 98.6% specificity as a biomarker for acute COVID-19. Interesting. We’ll see if this ever ends up introducing itself into clinical practice. Probably would have been more important a little while ago, but maybe we wouldn’t have realized it at that time.

Non-pharmaceutical interventions. Remember masks? Lots of concerns with the quality of the study is risk for bias, but in general, the science favors mask use and suggests a hierarchy for protection with the N95 mask providing the most ventilation, most protection. Now, ventilation. I don’t think many of us have spent enough time talking about all the benefits of improved ventilation.

There’s a CDC page that is periodically updated. One, improving ventilation in your home. Many things seem simple like opening doors or windows, changing your HVAC setting for the fan to on instead of auto. My wife, we had a discussion. She’s concerned that that’s going to burn out the fan. I can replace the fan, it’s a lot cheaper, but I don’t think that happens. Maybe some HVAC expert can write in and tell us if the off and on or just leaving the fan running all the time is going to cause you trouble. Remember, change those air filters. Every three months I set a little alarm calendar thing on my iPhone in my Apple calendar. Every three months it reminds me, and then I forget. There’s also a CDC update page “Ventilation in Buildings.” I’ll leave links to those here.

VR: Daniel, you can replace the fan, but you can’t replace you.

DG: [laughs] That’s so sweet, Vincent. [laughs] COVID active vaccination. Never miss an opportunity to vaccinate. Vaccinated people still get infected. They are just less likely to die or have severe disease. I like this article. We’ll spend a little time, you and I, Vincent, going through the figure, but the article is, “Protection against Omicron from Vaccination and Previous Infection in a Prison System.” This was published in The New England Journal of Medicine. People, particularly lately, are very interested in getting information regarding the protection conferred by vaccination and previous infection, against infection.

As our listeners may know, I’m much more interested in protection against disease. I just don’t mean acute disease. I mean acute and I mean post-acute. These investigators evaluated the protection conferred by mRNA vaccines and previous infection against infection with the Omicron variant in two high-risk populations: residents and staff in the California state prison system. They used a retrospective cohort design and 59,794 residents, 16,572 staff. I will mention I used to be the medical director of a jail, so I have some great stories. At some point, I will share, but figure four I think puts this all together.

We’ll walk through people that are listening or people that don’t get this out in front of you, but if you can get it out in front of you, it’s worth looking at. The baseline reference are unvaccinated residents and staff with no prior infections and they’re going to look at that as the baseline and then compare different folks. I’m going to jump around a little bit. The first thing I think that people want to know, what if I didn’t get vaccinated but I had COVID early on. I had it before the period of Delta predominance so prior to July 1, 2022.

In those individuals, they just asked the simple question in residents and staff, how much protection, what was the effectiveness of that prior infection at protecting me from another infection? It was 27.5% and 16.3%. Not really so good. What, however, if you got infected during the period of Delta, how well did Delta protect you going forward? 38.3, 48.9. Now let’s ask the other question. What if you were never infected and you just got, we’ll say, three doses of vaccine? The recommended upfront and then the next one for the residents vaccine alone was 40.9, for the staff it was 72.

Now, let’s go ahead, and I think this is really the question if you’ve had COVID before, let’s say you had COVID before the period of Delta predominance, and you go ahead and get three doses of vaccine, where do you go? For the residents, they went from 27.5% up to 58% protection effectiveness, the staff went from 16.3% up to 78% protection. What if you were infected during the Delta and then got those three vaccines? The residents went from 38% up to 85%, the staff went from 49% up to 88%.

VR: This is against an infection, right?

DG: That’s what bothers me, right? I hope that bothers you too. Yes, it’s protection against Omicron infection and it doesn’t tell us about severe disease, hospitalization, post-acute COVID.

VR: That’s what matters.

DG: Don’t worry, most of the people asking these questions, that’s the level of sophistication there.

VR: Why is there a difference between residents and staff, for example?

DG: Yes, one might say there’s a different exposure. I don’t know how much time you’ve spent in prison or in jail, Vincent, but we’ll save that for another discussion but [laughter] it’s interesting, the resident you would think of them as higher risk but then again the staff is going to have the risk of being in the prison with whatever ventilation system is there. Then they’re also going to be having other exposures in their personal life, maybe going to parties and restaurants and other things. Having that Thanksgiving dinner with all the relatives including Uncle Jimmy from Boston. There’s going to be, I think, different exposures. Not picking on Boston or Uncle Jimmy.

COVID passive vaccination, so Evusheld, that’s the pre-exposure, not treatment. That’s what the approval is here. I’m very worried that this is soon going to become obsolete, so I’m going to talk about this in a little bit in the context of an article in the bebtelovimab section, but we’re going to need a replacement in this space with the variants that we’re currently seeing. Let us move right into COVID, early viral, upper respiratory non-hypoxic phase, and I will start right off with Paxlovid. Posted as a pre-print, “Nirmatrelvir and the Risk of Post-Acute Sequelae of COVID-19.” This is the hot paper this week. It’s been a lightning rod.

There actually are a lot of anti-Paxlovid people out there. I’m don’t quite understand. But here the investigators are asking if Paxlovid given in the acute phase might reduce a person’s risk of going on to develop Long COVID. The authors use the healthcare databases of the U.S. Department of Veteran Affairs to identify users of the health system who had a SARS-CoV-2 positive test between March 1, 2022 and June 30, 2022, were not hospitalized on the day of the positive test, had at least one risk factor for progression to severe COVID-19 illness and survived the first 30 days after SARS-CoV-2 diagnosis.

I have to say that’s an interesting qualifier and that actually came up in our paper that we’re trying to get published, looking at the post-acute sequelae of COVID in people that got monoclonal versus not. They did comment that, is it really OK to exclude the people that died because if you died that seems like a worse outcome. It’s suggesting we should somehow have death or Long COVID as a bad outcome. In this study, they identified those who were treated with oral nirmatrelvir, so Paxlovid, within five days after the positive test, and those who received no COVID-19 antiviral or antibody treatment during the acute phase of the SARS-CoV-2 infection.

We’ve got 9,217 in the treatment, we’ve got 47,123 in the control group. What did they suggest? Compared to the control group treatment with Paxlovid was associated with a reduced risk of PASC hazard ratio 0.74 adjusted relative risk 2.32. They’re going to suggest a 36% reduction including reduced risk of post-acute sequelae in the cardiovascular system, so dysrhythmia, ischemic heart disease, coagulation, hematological disorders, DBT and pulmonary embolism, fatigue, liver disease, acute kidney disease, muscle pain, neurocognitive impairment, and shortness of breath. Paxlovid was also associated with reduced risk of post-acute death.

We’ll talk a little bit about this as we walk through the figures but the reduced risk of post-acute death hazard ratio 0.52, so almost a 50% reduction and post-acute hospitalization about a 30% reduction. Nirmatrelvir was associated with reduced risk of PASC in people who were, this is important, unvaccinated, vaccinated and vaccinated with booster and in people with primary infection as well as folks that were experiencing reinfection. Let’s go through the figures a little and then I’m going to make sure we put in a number of the qualifiers. Go right to Figure 2B. This is, I think, worth enough to read through this because this is certainly a hot button on social media.

Figure 2B, they looked at post-acute death, and this is a little bit of a pet peeve of mine. This idea that COVID only lasts for five days, or once you get clapped out of the hospital, you’re on your own, but as we can see over time you actually can die past that 30 days. They actually start at 30 days where a lot of people stop looking and you actually go out to 90 days. That’s going to be when we actually hit our current definition of Long COVID, and you can actually see a really nice separation that your probability of surviving is significantly better if you got nirmatrelvir or Paxlovid. Now, as exciting as all this data seems, a couple of caveats, and I think this is important.

It’s a pre-print. It hasn’t gone through peer review which is an important process. Gives our peers a chance to ask a lot of questions, go through the data. It’s also retrospective.

There is the concern for selection bias. Was there something different about these two groups? If it had gone the other way, wow, the physicians are giving the sicker people Paxlovid because they’re more worried about them and if anything, I think we see this this bias all the time. You’re probably going to be fine. I’m not going to do the heavy lift of getting Paxlovid. The other side is some people at highest risk might not get Paxlovid because of drug-drug interactions.

What we really need is a prospective double blinded random control trial. We need to see the prospective data going forward on some of the trials that have already been done, so EPIC-HR, let’s see the data for those people 90 days out. Interesting data important data, but this should not encourage people to start using Paxlovid in low risk populations. We do not know what it does in that population. This is looking at a specific population and in a retrospective approach. Vincent, any thoughts?

VR: You would like to have a RCT to look at this, right?

DG: Not only an RCT to look at this, but an RCT to look at this in that broader population because I know what’s going to happen is you’re going to see a lot of people say, well, I’m in my thirties, I want Paxlovid because it might reduce my risk of Long COVID. We really need to know before this medicine gets licensed and starts being used willy-nilly.

VR: Sure. You think that’ll be done?

DG: I don’t know. Every time I talk to Pfizer, every time I’ve got their ear, I do mention that this is something I would like to know about. It’s interesting. Do they want to do that study or would they rather just prescribe the way they might prescribe. I much prefer having the evidence to guide my prescribing.

COVID rebound, I like to mention, that we’ve been hearing about. That’s week two. That’s the early inflammatory phase. That’s the cytokine storm phase. As we’ve mentioned before, good science really pointing out this represents an immune response. We will say, again, the science will let us know if there’s any benefit to Paxlovid given for an extended duration or given during that second week.

VR: Daniel, just to clarify, this rebound occurs also in the absence of Paxlovid. It’s a natural feature of the pathogenesis of COVID-19.

DG: Exactly. It is COVID rebound, it’s not Paxlovid rebound.

VR: This warm weather we’ve been having, it’s called Paxlovid summer.

DG: I know. I was listening to you and Nels. [laughs]

VR: [laughs] Really? That’s funny.

DG: Just a little call-out to This Week in Evolution, I really enjoyed that. It was the genetic stamp of the Black Death, so of plague.

VR: Nels is a very smart guy. I enjoyed doing that with him.

DG: That’s a podcast I never miss. I never do it live, but I always – Because you guys talk too slow, and I need to listen at 2x. [laughs]

VR: [laughs] Good.

DG: It’s funny, actually, at the meeting, someone said, “Oh, Vincent, he talks really fast.” I’m like, “No, not fast enough.”

VR: Not fast enough, yes. I don’t talk that fast, no. [chuckles]

DG: Every so often, I’ll hit a YouTube, and I’ll have it at 1x, and I’ll be like, “Why is he talking so slowly?”  [chuckles] Number two. Number one, recommended by the ID Society of America, the NIH, those of us up with the data and science-driven, not recommended by some other folks. We won’t mention them here. Number two, remdesivir. Remember that 87% reduction in progression in the PINETREE Study. A number of other studies have piled on, so that’s really number two. Listen, hundreds of people are still dying of COVID. We really could get that number down a lot farther.

Number three. Now, this is a challenge. Is it still number three? We’re going to talk about bebtelovimab monoclonal antibody therapy. The article, “Bebtelovimab for High-Risk Outpatients with Early COVID-19 in a Large U.S. Health System,” was recently published in Open Forum Infectious Diseases. This retrospective match study, the investigators looked at 377 patients who received bebtelovimab because they were unable to be treated with Paxlovid, data from the Mass General Brigham hospitals and associated ambulatory care centers.

It is interesting that in their introduction, they report that treatment with remdesivir became impractical, so instead, they were using bebtelovimab.

Maybe became impractical because they weren’t doing it, and they had so many people in the hospital that they weren’t keeping out. Anyway, they reported a 43% observed risk reduction for the combined endpoint of hospitalization or death for those treated with bebtelovimab versus those not treated. This suggested benefit was not statistically significant. It’s our trying to actually get some data on bebtelovimab. The other way is to say they looked at treatment with bebtelovimab and did not find a statistically significant benefit. While not a specified endpoint, no one who got bebtelovimab died. There were three deaths in the untreated group. Again, not statistically significant.

This, again, after that head-to-head comparison retrospective cohort of the 3,600, which showed that bebtelovimab was inferior to Paxlovid. These numbers certainly look inferior to remdesivir as well. Is it still practical to use bebtelovimab? As we go into this next article, I’m going to mention that, here in the immediate tri-state area, we’re actually stopping using bebtelovimab. Let me go through the science behind why we’re doing that.

With the preprint, “Imprinted SARS-CoV-2 Humoral Immunity Induces Convergent Omicron RBD Evolution,” receptor-binding domain evolution, we are seeing that both Evusheld and bebtelovimab are losing their neutralizing capacity against the newest variants, rendering these therapies relatively obsolete. I do look in certain regional areas and see what’s going on in the regions when I talk to folks about this. You do want to look at your variant tracker in your region when you’re advising people. I actually pasted in the figure here. I also wrote in which is Evusheld, which is bebtelovimab because it helps go through.

As you look through, you start getting into BQ.1 and BQ.1.1, you’re really seeing that bebtelovimab and Evusheld are losing efficacy. Not great efficacy to begin with, and now when you face the majority of variants being resistant, it just doesn’t make sense. I popped in the variant tracker for region two, and you could see, BA.5, where these therapies might work, is now down to only about 25% of the cases that we’re currently seeing. Really, we’ve lost monoclonals in most parts of the country, and we’re going to need a replacement here. Then, molnupiravir last and least, maybe a 30% reduction, but, again, no renal issues, no drug-drug interactions. Depressing, I have to say, Vincent.

VR: It rather is. It’s surprising to me that these variants are doing this, but we can make variant-specific monoclonals. The big companies hopefully are doing that.

DG: I think that has to be a push. I know there’s a lot of people out there, “COVID’s over, nothing to see here,” but no, we still have hundreds of people dying. There certainly are people that have a bias towards monoclonals, I think our guest actually was saying that he prefers them, but not when they’re obsolete, not when they’re ineffective. If you’re going to be using monoclonals, it’s a little bit more of a lift because it’s not just checking drug-drug interactions. You got to keep up with the variants, you got to keep up with the potency, what’s going on in my region. That’s a constantly moving target.

VR: I’m concerned that people will not look at what’s circulating in their region and just give monoclonals reflexively and lose their patients as a consequence.

DG: Well, I think we talked about that before when we got to the point where the Regeneron cocktail and the original bamlanivimab, etesevimab were no longer effective, people just kept giving them. They were like, “Well, what are we going to do, throw them out?” I was like, “Yes.” [chuckles] It’s like treating a urinary tract infection with an antibiotic that doesn’t work just to give you something to do. The something to do is use something that’s effective. As we heard about, “Oh, it’s too difficult to mobilize remdesivir,” it’s a lot cheaper to give a bunch of people remdesivir than to take care of the folks that progress and end up in the hospital.

Remember, don’t do those harmful things during that first-week viral replication, not a good time to turn off the immune system with steroids, why bother vaccinating? Remember, this is a viral disease just like RSV, not a good time to be using those antibiotics. Getting into the COVID early inflammatory, lower respiratory, hypoxic phase, the cytokine storm, the rebound summer phase, steroids at the right time in the right patient at the right dose, but we’re only getting about a 17% mortality reduction here. You don’t wait to see how they do, you jump in when you can do a 90% reduction as opposed to 17%, and you really don’t want them in the hospital. You don’t want them requiring oxygen.

Anticoagulation guidelines, pulmonary support, maybe remdesivir if we’re still in the first 10 days, immune modulation, avoid those unnecessary antibiotics and unproven therapies. I will move right into the late phase. For those with Long COVID, my biggest apology here, I know many people were upset, but the “I don’t see Long COVID, so it’s not a problem” comments. Also, a little hard that those people asking for help may have been sent away to the CFS clinic, so I apologize for that. Just to give a little bit of my experience. I came back on Monday, three new Long COVID patients plus two return cases.

Just to – these are human beings. One was a man in his early 20s, unvaccinated, this was his first infection with COVID, struggling to hold down a job and go to school. We spent a bunch of time talking and also developing a relationship because, as you can all imagine, vaccination will be one of the things that we talk about in two weeks when we check back in. Now, there was a woman in her 60s. Remember, these are just over three months ago that’s putting them into the Long COVID category, so this is Omicron. Another woman was in her 50s having numbers of problems.

Then a couple return visits, just to put this in context. One, it’s really devastating, it’s a young lady in her early 20s, had to drop out of school, is living in her parents’ home, really had a horrible crisis over the weekend, actually. This was actually right after I had called in the Paxlovid for Dixon. I was then taking this call and arranging for her care. She has POTS, with one T, so that’s that postural orthostatic tachycardia syndrome, and it had just gotten to the breaking point where she was going to head to the ER. I was like, “Let’s not do that. Let’s arrange to get you IV fluids, maybe those nine grams and that one liter of normal saline will avoid that ER visit.”

Well, not only did I call ahead, but she went to one of our urgent cares. I was a little embarrassed because when she told the ER-boarded doctor that she was referred there by her ID doc because she had POTS and IV fluids was recommended, he was very upset. “We don’t treat POTS here. You’re going to give everyone COVID, you’ll give everyone tuberculosis.” I was like, “Oh, one T, not two Ts.” She, fortunately, went to another urgent care. She got that liter of normal saline. She actually did better. I actually saw her at telehealth visit again today. People are suffering. I think what happens is there are physicians out there that are willing to see these people willing to work with them.

It’s hard. It’s not easy. We don’t have the amount of evidence we would like. I do always put a link into the BMG paper, “Long COVID an Update for Primary Care,” which I think can be a nice primer or primer depending on how you pronounce that, for folks that are seeing these patients, but I also want to mention another article, the article, “Can SARS-CoV-2 Trigger New Onset of Autoimmune Disease in Adults? A Case-Based Review,” published in the Cell Press open access journal, Heliyon.

This is a review and based on a literature search that suggested based on this review that the new onset of autoimmune disease in adults could be triggered by SARS-CoV-2, including Guillain-Barre syndrome, Miller Fisher Syndrome, lupus, immune thrombocytopenia, autoimmune hemolytic anemia, latent autoimmune diabetes. Actually saw a case of this, which was pretty interesting. Myositis, acute encephalomyelitis, autoimmune encephalitis, central nervous system vasculitis, and autoimmune thyroid diseases.

I think I’m very interested in the mechanism here, to see what happens with that. I’m also going to counter that we have no Long COVID in Palo Alto with the research of Gopi Shah Goda of Stanford University in Palo Alto, and Evan J. Soltas at MIT, estimating that at least half a million workers have dropped out of the workforce due to post-COVID issues. In their article, “The Impacts of COVID-19 Illnesses on Workers,” published in National Bureau of Economic Research.

Closing it out with low- and middle-income countries, no one is safe until everyone is safe. The article, “Retrospective Modeling the Effects of Increased Global Vaccine Sharing on the COVID-19 Pandemic,” was recently published in Nature Medicine and the news article followed, “COVID-19 Vaccine Hoarding Might Have Cost More Than a Million Lives,” published in Nature. This is all based on modeling, but the model suggests as many as 3.8 million lives could have been saved if the distribution of more vaccines to, let’s say, poor countries had happened alongside wealthier countries keeping other mitigation measures such as limiting gatherings and wearing masks in place for longer.

The news piece, I have to say, is very accessible. There’s a figure in the news piece that’s worth closely examining. They look at the current scenario compared to full sharing. It is interesting. There would’ve been a cost to the high-income countries, but there would’ve been a significant benefit for the rest of the world. Let me conclude with a few more reflections on the parts of the experience Dr. Scott was describing with which I do actually agree. Things are different in terms of COVID and better in many ways. I do not see days ahead with 17,000 COVID deaths per day like we saw prior to the introduction of vaccines or even the 12,000 deaths per day we saw last winter. Those are global numbers.

Here in the U.S., we are past the days of 3,000 to 5,000 deaths per day and the regional spikes where people died because they stayed home too long and then were emergently intubated and died in the ER. We’ve learned a lot in the last three years and now the management of COVID is much calmer, more early admissions during that viral phase, escalation to types of pulmonary support that allow us to keep people off ventilators. We already experienced that horrible process of a new pathogen entering our population. Most children were already infected, most adults already infected, and the most vulnerable have already died.

That cost was over a million Americans, hundreds of American children, and at least 6 or 7 million around the world. These people can’t die a second time. Palliative care has really moved forward and many who would never survive being on a ventilator and who are maybe rushed onto them in the early days, are quietly put on morphine drips and can die with family, not alone on a ventilator. For many parts of the country, we’re in a new stage with regard to COVID, with the combination of high vaccination coverage, the protection against severe disease, that prior infection does provide, avoiding harmful interventions, and early use of appropriate antiviral therapy in high-risk individuals.

We can all be living in a world much like that described in the Palo Alto area. Perhaps not in one of those $3 million homes and perhaps with not such a high household income. All right here, I want people to pause go to, especially those of you with high household incomes, even those without. Every little bit helps. We invite you to be part of our movement and part of our efforts. Go to, click on that ‘Donate’ button, and it’s Vincent’s favorite time of the year. We are now having our MicrobeTV fundraiser.

During the months of November, December, and January, donations made to Parasites Without Borders will be matched and doubled by PWB up to a potential maximum donation of $40,000 from PWB to MicrobeTV.

VR: Best time of the year. Looking forward to it. Show your support for MicrobeTV. We do enjoy that. It’s time for your questions for Daniel. You can send them to Paul writes, “Question on Long COVID. There’s been a lot of discussion how with multiple infections of SARS-CoV-2, your chances of developing Long COVID either increase with each subsequent infection or that each infection is a roll of the dice where you might not get Long COVID on infection one, two, three, but on the fourth: boom, you have long COVID. Is there any evidence that backs up this claim?”

DG: Let me put this in context. Early on when people had not been vaccinated, when people had never been infected with SARS-CoV-2 before, so first time COVID-19, we actually saw pretty high rates of people having COVID that affected them for more than 90 days, developed post-acute sequelae of COVID. Some of the higher numbers we heard early on have been reined in in part by the change in the definition. A lot of people are better by three months if you give it that three months, that so-called middle COVID, we have a lower estimate, but then a couple things have happened.

We did see that people who are vaccinated before and even people who are vaccinated afterward have a lower risk of PASC. We have also seen, and I don’t know how much of this to attribute to prior immunity, but we are seeing a lower percent single digit after Omicron infections. Now, what I will share is that people that got COVID a first time, got COVID a second time, got COVID a third time, never had Long COVID, they may get it after that fourth time. It is a roll of the dice, but the odds keep getting better and better in your favor.

Part of that is there probably is a genetic propensity of people who are higher risk of a bad roll, so to speak, but also the vaccinations and maybe there is a change in the virus itself. I don’t know if that’s true, but each roll of the dice, we are seeing less, but we still are seeing, as I mentioned, Long COVID after Omicron and one of the cases I saw, this was the first infection and unvaccinated, two of the cases, these were vaccinated people with prior infections and boom, now this time they get Long COVID.

VR: Rachel writes, “My friend, 54, male, never had chicken pox. Should he get SHINGRIX or is he safe from shingles without the shots?”

DG: It’s interesting, this is an individual who should get the chicken pox series. It hits close to home. I actually had, it was three years ago now, and I remember because it was right before the pandemic, and this was an elderly gentleman, elderly-elderly, over 75 from India, grew up in India. He had never had chickenpox in his entire life. Just really bad rolls of the dice here. His daughter is engaged, the fiancé, the fiancé gave the dad chicken pox, the gentleman died from fulminant chicken pox. Chickenpox can be incredibly dangerous in the young, in the elderly. Well, it can be dangerous in a lot of different populations. If you’ve never had chickenpox, you’re not going to get shingles, but if you’ve never had chickenpox, you could get chickenpox and you could get quite ill.

VR: An adult can get the pediatric or is there an adult chickenpox vaccine?

DG: They actually can go through the chickenpox series.

VR: It’s OK?

DG: Yes.

VR: I heard that there’s a small fraction of inapparent chickenpox infections, where you actually were infected and it’s latent in you, but in that case, you should get a shingles. Would a shingles vaccine confer any protection to someone who has never had chicken pox?

DG: It probably would. An interesting thing that they do, when we healthcare workers, I’m not sure if I had chicken pox or not. They’ll do a titer and a titer isn’t telling you if you’re protected. It’s basically telling you, have you had chicken pox? Then you’re going to say, Oh, or if you have titers or you must have had chickenpox, and if you have no titers, then you would actually go through a chicken pox vaccination series.

VR: Katherine writes, “A young adult who’s close to me was recently hospitalized for a week with acute psychosis coincident with COVID. No history of mental illness. Symptoms include fever, headache, severe paranoia, dangerous agitation, alternating with catatonia, some hallucination, refusal of food drink oral medication or IV related to paranoid fear of poisoning. I believe he was vaccinated, but this was his first encounter with the virus.

“Hospital physician suggested COVID may have caused the psychosis. His friends and family, hopefully, that this is the case rather than a life-changing diagnosis of schizophrenia. Well, can you tell me about COVID induced psychosis or viral-induced psychosis in general? I’ve not found many papers online. What I’ve found is a little on viral encephalitis and bold statements that COVID can be associated with symptoms of psychosis in rare cases.”

DG: Yes. It’s really tough. How rare is this versus how rare is it that it makes it in the literature? We certainly saw a lot of individuals during the acute COVID have significant, let’s say psychiatric impacts, which would then resolve. Some of them would resolve quite quickly. I just don’t know how much is published on this, but certainly, in the hundreds, hundreds, and hundreds of cases we’ve seen, there certainly were a number of individuals that had this acute psychosis, which would then resolve.

VR: Claire writes, “My husband is a family physician. Asked me about the vaccine site reaction to monkeypox vaccine. He says he knows it’s common to have a mild reaction at the site that looks like a pox lesion, but he couldn’t find clear guidance from CDC or any other body indicating whether that reaction involves active virus had any chance of being contagious. He was asked by one of his patients who had recently gotten the vaccine, had a pox lesion-like reaction, was invited to visit his three-day-old nephew. My husband didn’t think there was cause for concern but also didn’t want to take any chances with a newborn infant, so just told the patient to keep the site well covered. Didn’t seem like a common enough issue that he’s likely to be asked again, but would still like to know what the answer is.”

DG: Yes. If you’ve seen some of these sites. Some of the sites can get such a significant take or reaction that I’ve actually had physicians that then end up giving the antibiotics because it just looks so angry and red. Sometimes they come back in this, particularly with the intradermal, they come back for that four-week later injection and it really looks terrible. Yes, it is actually common to have some of these local site reactions. As far as the ability to spread it to another person, so we’re talking about the Jynneos, so the Bavarian Nordic, I’m going to think that risk is going to be pretty, pretty darn low. Keep it covered of course but yes, just common sense things.

VR: Finally, Suzanne writes, After watching Episode 951 and listening to you on how masks work, why do I see doctors such as yourself in many other pictures and videos not wearing a mask? Most of the recent medical conventions are showing doctors with no masks. It’s confusing to us wondering how you can go back and see patients who are immunocompromised as well. It doesn’t relay a good rapport with anti-maskers. It’s so confusing.”

DG It really is. This is getting challenging. COVID’s here to stay. People have to start making decisions. Today, first I did several telehealth visits, which is great because my mask can be off safely. The other person’s mask can be off. But then I was in the hospital for about eight hours. From the time I entered the door to the time I leave, I have a tightly fitting N-95 mask on. Whenever I’m in direct patient care, I’m always wearing a mask.

Personal decisions, I like to think I’m young and healthy. I’m vaccinated. I have access to early treatment with antiviral. My personal risk is very low, but I am sensitive. If I’m going to be around other individuals that are at higher risk, then I am going to be thinking about wearing a mask. There was an off-and-on at the recent ASTMH meeting. Whenever I was going into a crowded lecture hall, I would have that mask on, but there’s certain other times when we were manning the booth and interacting with folks when I was taking risks that I felt were reasonable and acceptable.

VR: 951 was recorded at ASTMH?

DG: Yes, with masks off.

VR: Yes, you’re sitting next to me with mask, but it was just me and you. We were well isolated from most other people. I will say that I saw Daniel wearing a mask most of the other times. [laughs] What he’s saying is actually correct. That’s TWiV clinical update with Dr. Daniel Griffin. Thank you, Daniel.

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


[00:55:34] [END OF AUDIO]

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