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This Week in Virology
Host: Vincent Racaniello
Guest: Daniel Griffin
Aired 15 October 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 945, recorded October 13, 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: Before I hand it over to you, Daniel, two quick announcements. First, the laboratory of Amy Rosenfeld, which is at CBER in the FDA, is looking for a research assistant. Now, Amy was my last trainee. She moved the entire project set of the lab down to the FDA and she’s working on it there, including the unexpected observation that there are antibodies that can cross-react among enteroviruses.
The research assistant will help figure out what that means, both in cell culture and in animal models, which you’ll help to develop, and all the work will be done at BSL-2 levels. If you want more information, you can send Amy an email, [email protected], or in the show notes, we’ll have a link to a PDF document with more details. Also, show your support for what we do here at MicrobeTV by buying a Spike t-shirt from Vaccinated.US. Go over there and pick your t-shirt, put it in the cart. When you check out, use the promo code ‘MicrobeTV’ and they will send their profits to us to help support our work in science communication. Thanks to Matt and Vaccinated.US for their support.
DG: Vincent, they need to make collared shirts so I can wear the Spike shirt with my bow tie.
VR: It’s a great idea.
[laughter]
DG: By the way, I know someone who will buy Spike bow ties if you make them. Let’s get right into it. “Anyone who stops learning is old, whether at 20 or 80. Anyone who keeps learning stays young.” That’s by Henry Ford. Hopefully, everyone, we have all these incredibly young listeners. I know we’ve been using the terminology of elderly and elderly elderly, I’m just trying to figure out if you continue to learn, what does that do to your risk of a bad outcome from COVID?
Polio, as you just heard, don’t check your serology, just get your vaccines if you have not done so already. Influenza, actually, next time I’m going to talk a little bit about why am I predicting, why are many of us predicting a bad winter ahead, but by the way, with that foreshadowing, go ahead, get those flu shots.
Monkeypox. As I’ve been saying for a while, monkeypox, it’s not a gay disease, it’s not an African disease, it’s an infectious disease. We are actually doing much better. Current seven-day average is now less than 100 cases per day being diagnosed. I know that WHO is a bit concerned that maybe that number has dropped because of underdiagnosis. We’ll see what time has to show with regard to that, but we’ll keep track of that. Let’s get right into monkeypox transmission. As I’ve been saying, this is predominantly through contact.
We have another case report of a healthcare worker getting monkeypox reported in the article “A Healthcare-associated Infection with Monkeypox Virus of a Healthcare Worker during the 2022 Outbreak,” published in Open Forum Infectious Diseases. Here, a female medical resident pricked herself with a soiled subcutaneous needle from a patient, and four days later had the monkeypox. The story is that she is using this needle to puncture, to unroof to harvest a vesicle that she thinks is a monkeypox vesicle. She then goes ahead and pricks her thumb with that same needle.
She’s wearing gloves, so she pokes herself through those gloves, starts to bleed. She takes that thumb and she actually immerses it in sodium hypochlorite for 15 minutes. She asks the infectious disease physician what to do, and she ends up getting a smallpox vaccine within three hours. Good call there. She develops a single lesion at that site. That reminds some of the really old doctors in the room of Jenerian pustules from primary vaccinations back in the 1970s. That’s it, that’s the end of it.
VR: Daniel, should she just have been using a swab to sample the vesicle?
DG: Actually, one of the things they do recommend is actually using a beveled needle to harvest so you get that top as well. We’re doing DNA, in all honesty, so you really can, and what I do, maybe I’m a bit of a coward because I don’t want a Jenerian pustule on my thumb, is you just vigorously rub with those swabs, a couple of them, and get that fluid for DNA. Actually, I will say, some of these vesicles have a pretty thick roof so it requires a little bit of vigor, so I understand what was happening here.
VR: Daniel, we did a TWiV a long time ago about how the scarification process in smallpox vaccination amplifies the immune response because you’re inducing physical inflammation. The title of that episode was, “By the Pricking of My Thumbs, Something Wicked This Way Comes.”
DG: [laughs] That was the days of the bifurcated needle, where I don’t even think you cleaned the skin, it was actually a controversy. Maybe it was better not to clean the skin so you get a little bit of local bacterial introduction that’s part of the take.
VR: That’s actually part of it because in a subsequent study, which we also did, they showed that the skin bacteria actually multiply and contribute to the inflammation.
DG: Your own adjuvant, why add anyone, got it all right there. [laughs] The article, “Air and Surface Sampling for Monkeypox Virus in a UK Hospital: An Observational Study.” I have to say, this was published in the Lancet Microbe and it’s giving me daymares. I think about this as an infection-controlled nightmare. I’m going to bring it back down to earth, but here, let me describe.
They investigated environmental contamination with monkeypox virus from infected patients admitted to isolation rooms at the Royal Free Hospital, London, UK. They identified widespread surface contamination: 93% of the 60 samples that they collected were positive in the occupied patient rooms. They’re giving us DNA cycle threshold values of 24.7 to 37.4 on healthcare worker PPE, personal protective equipment, after use, and this is the one that gives me the nightmares, in the PPE doffing areas.
Just thinking about this, you go into the room, you’ve got all your gear on, you’re wearing your gloves before you go in, because we learned about that. Of 20 air samples taken, 25% were positive, 75% of four air samples collected before and during a bedding change in one patient’s room were positive. They mentioned that replication-competent virus was identified in 50% of four samples selected for viral isolation, including from air samples collected during that bedding change.
I’m just thinking about, we’re super careful, we go in that room, we now move back into that anteroom where we don and doff our PPE. The whole idea is that we think now we’re safe, now we’re going to take that off in a careful way, put it in the bin, and now we’re going to take off that mask, but what if we’re breathing in monkeypox? I think I want to point out, as we’ve been saying for a while, this is a contact pathogen. This is not measles, this is not tuberculosis.
VR: I also think it’s a good reason for healthcare workers to get vaccinated, right?
DG: Yes. I actually think it would be nice to see that move as our next step because I don’t want people to just fall into this – I don’t know. What is it when you’re not worried about something, that state of being not familiar with it?
VR: Complacency.
DG: Yes.
VR: I also don’t know, Daniel, that you should be so worried because we don’t know if the amount of virus here is sufficient to infect. It might not be.
DG: I think that’s a point, hopefully, that we’ve hit several times, is just because you can grow the virus, is that enough to infect? Enough to detect is not necessarily enough to infect, as we’re seeing repeatedly. As we mentioned, the monkeypox testing, that is the concern of the WHO right now, is that we may be underdiagnosing and that could lead to a surge again in the future.
Keep sending off those tests. You want to have a high negative rate. If the majority of your tests are positive, you’re not testing enough. The vaccines, we’ve got those. Remember the stomptpoxx.org, the study of tecovirimat, because it does look, and we’ve talked a little bit about the fact that monkeypox is here to stay, so let’s understand the tools that we have, how best to use those.
COVID. Now, people can jump ahead if they’ve timestamped. Children, COVID, and vulnerable populations. Breaking news, the FDA authorized Pfizer’s boosters for children ages 5 to 11 and the Moderna’s shots for kids age 6 through 17, and that was done on Wednesday, the 12th of October. Let’s talk a little bit about vaccines and boosters. I’m going to put on my glasses here because I have some statistics that I’m going to share.
The one thing I’m going to start out with right up front, which I think is really relevant, particularly in this population, is that we do have growing evidence that prior infection seems to provide some degree of protection against severe disease, and just like vaccines, a temporary fleeting protection against infection. The data is certainly not as robust as we have for vaccines. Certainly, the Hobbesian approach, the Hobbesian natural infection is a higher-risk approach to getting that immunity, but what I want to throw in this context is that we just got data from the CDC on pediatric seroprevalence with an estimate of 86.3%.
These seroprevalence estimates are from a survey estimating the proportion of the population with evidence of previous infection with SARS-CoV-2. It’s been suggested that 86.3% seroprevalence in the pediatric population. As we know, vaccination rates are pretty low in this population, this is almost all prior infection.
I’m going to throw this in just now, maybe it’s becoming a pet peeve of mine. Vincent, I think you may have a comment on this. I’ve been seeing these recent calculations about, if everyone gets their booster, we’re going to prevent 100,000 deaths this winter. If we don’t, and I feel like this is being scolded, it’ll all be our fault and we’re going to have over a million deaths a day. It’s an interesting comment, I’m not sure how the math works. A bit of the math that we’ve talked about is the biggest bang for your buck is getting those first two shots. That’s where we see, actually, and I’m going to go and say fairly durable protection against severe disease.
I’m not sure that we really want a public health message that continues to be divisive in this way. As we’ve talked about, for certain individuals, particularly the elderly elderly, boy, those boosters really are a very clear approach to going forward, but as we just have talked about in that pediatric population with such a high seroprevalence, particularly a lot of people who just had a recent infection in the last couple of months, I think the metric is a little bit different. Just going to put my opinion out there. Vincent, if you had any comments.
VR: What do you think, Daniel?
[laughter]
DG: I think I know what you’re going to say. All right, moving on. [laughs]
VR: Just to say a million a day is irresponsible because there’s no reason to think that would happen. It didn’t happen before. There’s no reason, as you say, to think that the old two vaccines and a booster or two of the original virus is not sufficient. I just think this is by people who are trying to stir up excitement, and we can almost guess who some of them are, sadly.
DG: Yes, no, I think we are routinely encouraging vaccination across the board, but let’s do it in a way that’s not so divisive. Let us move into the pre-exposure period. I think people will be shocked by the results of this study, but the article, “Misrepresentation and Non-adherence Regarding COVID-19 Public Health Measures,” was published in JAMA Network Open. I like to say this is the true battleground of public health. As the authors point out, the effectiveness of public health measures implemented to mitigate the spread and impact of SARS-CoV-2 relies heavily on honesty and adherence from the general public.
They did a survey here, and based on this survey that included 1,733 participants, 41.6% reported misrepresentation and/or non-adherence in least one of the nine items. Telling someone that they were with or about to be with in person, that they were taking more COVID-19 preventive measures than they actually were was reported by 24%. Come on, 24% were honest that they had lied, not sure about the other 76%. [chuckles] Quite apparently, only 22% of people admitted to breaking quarantine rules.
The most commonly endorsed reasons for lying to your friends, loved ones, and acquaintances was wanting life to feel normal and wanting to exercise the personal freedom to lie. [laughs] I think this is one of those challenges. Everyone’s beating up the CDC all the time, why did they say this? Why did they say that? As we knew from the early days, when there was these 14 days in place, when we actually looked at it as opposed to ask people to tell us the truth or not or here is the study about lying, it was 1% or 2% we’re really doing that 14 days. What is that? A public health recommendation with 99% non-compliance. I don’t know, Vincent. I thought this was a rosier picture than I actually think is reality.
VR: Yes, I think most people, they lied to the survey. [chuckles]
DG: Yes. I recently had to attend an event. Certain times I go outside my comfort zone because there are certain things I need to do. It involved afterwards going to a large, crowded restaurant. Oh my gosh, I was PTSD in the moment. I guess that’s stress disorder while in the moment, but one of the individuals there was explaining to me how they were just incredibly careful, they didn’t understand how they could have gotten COVID two weeks before because they never, ever go out to restaurants. Now, they told this to me, of course, in a crowded restaurant. There was some disconnect that was I missing there.
COVID, active vaccination. Never miss an opportunity to vaccinate. I’m going to say this right this time, vaccinated people still get infected, they are just less likely to die or have severe disease. I know people are rightly excited about the holy grail of vaccines, where we create such a mucosal antibody barrier that you cannot get infected and we actually remove people from the chain of transmission like those old epidemiology equations that we all hate. I don’t think anyone loved those.
Well, the article, “Tolerability and Immunogenicity of an Intranasally-administered Adenovirus-vectored COVID-19 Vaccine: An Open-label Partially-randomised Ascending Dose Phase I Trial,” was recently published in The Lancet journal, eBioMedicine. I feel like we’ve had people write in, “We’ve got these vaccines, we know they work, why not just spray them up people’s noses?” Well, the authors lead it in their introduction. The hope is that intranasal vaccination may induce protective local and systemic immune responses against respiratory pathogens.
These are the results of a single-center, open-label Phase I clinical trial of intranasal vaccination with ChAdOX1. Basically, they’re taking the AstraZeneca vaccine and they are squirting it up the noses in healthy adults using the existing formulation produced for intra-muscular administration. Thirty SARS-CoV-2 vaccine-naive participants were allocated to receive 5 x 109 viral particles, 2 x 1010 viral particles, or 5 x 1010. That’s a lot.
Fourteen just went ahead and received a second intranasal dose 28 days later, a further 12 received non-study intramuscular mRNA SARS-CoV-2 vaccination between study days 22 and 46. Drumroll. We need Dixon to do the drumroll for us here. What did they find? They found this formulation of intranasal ChAdOX1 and COVID-19 showed an acceptable tolerability profile, but induced neither a consistent mucosal antibody response nor a strong systemic response.
For all those people out there saying, “We got these vaccines, we know they work,” a little bit of humility here, no, we don’t. We don’t know that if you spray one of these vaccines up your nose that it’s going to give us what we would like it to give us.
VR: I’m very suspicious that you could make such an intranasal vaccine that would block infection forever, but nevertheless, if you’re going to try it, don’t just spray some that’s made for intramuscular. Why don’t you just work on it a bit and understand what you need for mucosal immunization, right?
DG: I think it would be tremendous if there was some way of actually achieving this holy grail, this sterilizing immunity, which I think people thought vaccines did. I think, particularly with polio, it was a reminder, “Wait, wait, we don’t really understand what vaccines actually do.” By we, I mean a lot of the medical profession, a lot of the public. Yes, we do not have vaccines that create this wall, this barrier around you.
Could we do that? The amount of energy required to maintain that amount of antibodies, produce all those proteins on a regular – maybe this will be the new weight loss approach of the future. You’ll get your nasal vaccine and you’ll just use so much energy doing that you won’t have to go out for your daily run. No. This would be a brand new horizon. I encourage people to keep working on it, but time will tell.
COVID, passive vaccination, that’s our Evusheld, our tixagevimab co-package with cilgavimab. We have talked a little bit about some increasing variants that are immune- evasive for this product. They seem to be sitting at a steady state. We’re still using it. Now, though, we’re couching in about an 80% reduction in infection as opposed to that 94%. Remember, interesting, that was symptomatic infection.
We will move on to what really is the meat of today’s discussion. COVID, the early viral upper respiratory non-hypoxic phase. I always keep pinned in my Twitter tweet the links to our discussion about the different phases of COVID-19. That first week, the early viral upper respiratory non-hypoxic phase, that second week, which is the early inflammatory lower respiratory potentially hypoxic phase. We’ve been talking about that bimodal two-week presentation, well, for over two years now. Let’s get into it. Number one, Paxlovid. Suggested an 89% to 88% reduction in progression in the unvaccinated if given in the first five days, maybe a 75% reduction in vaccinated individuals.
“Dr. Griffin, what about the rebound? It is now October and there was a deadline for getting something straight on. What is going on? How can this drug work so well if there’s all these interesting controversies?” The article, “Clinical, Virologic, and Immunologic Evaluation of Symptomatic Coronavirus Disease 2019 Rebound Following Nirmatrelvir/Ritonavir Treatment.” This is looking at Paxlovid. This was published in CID.
I feel like I do not need to give too much background here. I think this is all out there in the media, but I will say some patients who have received Paxlovid demonstrated a rise in RNA copy number between day 10 and day 14 and clinical rebound after completing Paxlovid. As we’ve discussed, we have an equal number of folks who never got Paxlovid having the same phenomena. Somehow what we have been calling the early inflammatory phase for the last two years has now been renamed the rebound phase. The authors appropriately note that the etiology of this phenomenon remains a matter of debate. Hopefully, we’re going to get some clarity here.
There are also now many questions about the impact of this rebound on the risk of severe disease, viral transmissibility, and the potential for Paxlovid resistance. To address these questions, as required, the authors performed detailed virologic and immunologic evaluations of eight patients with rebound COVID-19, which is what we should be calling it. This is going to help with that critical question about five days versus 10 days of Paxlovid, that many people out there seem to know the answer to, and really get at what is happening during that second week of COVID.
Lots of data here. Serological assays, T cells, cytokines, inflammatory biomarkers, RNA copy numbers. Most people appreciate that the first week of COVID is this viral symptom, viral kinetic phase, but is that second week now a second viral replication phase or is it some kind of immune cytokine storm that is driving the symptoms? Is that second week a time to focus on giving more antivirals or is the second week when we think about immune modulation?
Well, a nice part of this detailed study is they have both people that got Paxlovid and then had second-week rebound and people that did not get Paxlovid and had second-week rebound. I will call it COVID rebound. I’m hoping, at the end, we just call it the early inflammatory phase, but I will call it COVID rebound after Paxlovid and COVID rebound never having received Paxlovid. All the rebound patients experienced significant symptomatic improvement prior to worsening, five rebound patients repeated rapid antigen tests after initial symptom resolution, four became negative and the fifth weakly positive.
The median C-reactive protein level was lower at the time of rebound than during acute COVID-19, whereas neutrophil and lymphocyte counts and SARS-CoV-2 PCR CT values were similar across groups. Infectious replication-competent SARS-CoV-2 was isolated from the nasal swabs of six of seven acute controls. Comparatively, only one of eight rebound patients was culture positive. Positive culture was not always associated with low cycle threshold or high serum nuclear capsid antigen.
Then they use Polybrene, which increases the sensitivity of viral culture by an estimated tenfold, and repeated viral cultures using Polybrene identified positive cultures in five of eight rebound patients, including four of six who had rebound after Paxlovid. Data on this issue of viral resistance. Viral resistance, no mutations associated with Paxlovid resistance were detected. We can just put a lid on that.
More rebound patients had detectable neutralizing antibodies against Omicron spike that inversely correlated with serum antigen. CD4 and CDA T-cell counts increased in rebound cases compared with acute disease. T-cell stimulation assay showed robust T-cell responses against the wild-type spike protein with higher levels of antigen-specific cytokine-producing CD4 T-cells in those with rebound symptoms.
SARS-CoV-2-specific CD4 T-cells showed greater proliferation activation at rebound compared with acute presentation. They also assessed the spectrum of innate and adaptive immune markers a lot in here. Innate markers such as IL-6, IL-8, and CXCL10 that are known to be associated with severe COVID were down trending at rebound, where markers of adaptive immunity and T-cell activation such as interferon-gamma and soluble CD 25 were stable or increasing.
They then go on to do some unsupervised hierarchical clustering. I know everyone was ready for that. They found that these clustered separately. The difference being driven by the lower acute inflammatory markers and increased adaptive immune responses in the rebound cohort. People, if we’ve not lost you by now, let me bring you back. I’m going to agree with the authors that this case series provides important insights into the pathophysiology of rebound COVID-19, or I’m going to hope we get back to calling it early inflammatory week two phase of COVID-19.
None of our patients develop severe disease at rebound and adaptive immunity against SARS-CoV-2 appeared intact. The findings suggest that a more robust immune response rather than uncontrolled viral replication characterizes these clinical rebounds. It just surprises me that more than two years in, we are back to this timing discussion, where, again, people are suggesting using antivirals during the second week when we have moved from the viral replication phase to the inflammatory phase. How many failed trials abusing antivirals too late will it take? [laughs]
VR: Basically, Daniel, on your graph, first week, peak of viral loads. Second week it’s declining. This second week is what we’re seeing. We’re seeing the immune response kick in, right?
DG: Yes. It is crazy, because early on, and actually this was critical and I think we talked about this, in the beginning of April, Steve Catani, I’ll give him a shout-out here, he and I had a call with one of the folks at Regeneron and we asked them, “Why are you guys doing your studies in week two, week three? Why are you looking at monoclonals?” The same could be said about all the other antivirals. The response was, “Well, we really think it makes sense to do it in the first week, but we don’t know how to do those trials.”
Fortunately, people were able to step back really quickly with the monoclonals. We were able to help them get those urgent care trials up showing in the first week. It makes a difference. Boy, it took a long time before we got the remdesivir first-week therapy. Fortunately, with Paxlovid, boom, first week was where it was tried. How many times did people throw antivirals at patients during week two, week three, when they had this cytokine storm, this inflammatory phase? What happened? It did not help.
Number two, remdesivir. We have another study here on remdesivir. “Early Outpatient Treatment with Remdesivir in Patients at High Risk for Severe COVID-19: A Prospective Cohort Study,” published in the august journal, Open Forum Infectious Diseases. That title has everything we want. Early outpatient treatment with an antiviral in high-risk folks. I say the august journal, Open Forum Infectious Diseases, because I really like this journal, people may remember many times I’ve quoted it, but the first time I published in this, Steve Gough gave me a hard time. Apparently, he’d never heard of this journal. I remember him asking me, “Is that a real journal?” [chuckles] I was like, “Yes, Steve, it’s right between Nature and Science. It’s the O.” [laughs]
These are the results of a prospective cohort comparative study conducted in a tertiary referral center in Mexico City. Patients with mild to moderate COVID-19 at high risk for progression were treated with an ambulatory three-day course of remdesivir, and the primary efficacy composite endpoint outcome was hospitalization or death at 28 days after symptom onset. A total of 196 high-risk patients were diagnosed with COVID-19, 126 were included in this study, 43% got remdesivir, 57% did not receive remdesivir. Treatment with remdesivir significantly reduced the odds of hospitalization or death, adjusted hazard ratio of 0.16, p-value of less than 0.01.
Early outpatient treatment with that three-day course of remdesivir significantly reduced hospitalization or death by 84% in high-risk patients with COVID-19 Omicron variant if given early in that first week from symptom onset. Continued to be very compelling data for Paxlovid and early remdesivir. Bebtelovimab is number three. We’ve talked about it before. A little bit inferior if you’ve got a choice between Paxlovid or remdesivir and the monoclonal. Monoclonal is number three. Last and least, Thor’s hammer molnupiravir.
I keep saying last and least, and I know I’ve gotten a bit of criticism, “Dr. Griffin, is that really in line with the ID Society recommendations?” Well, I think it’s in line with the science, and I will share the article, “Molnupiravir Plus Usual Care versus Usual Care Alone as Early Treatment for Adults with COVID-19 at Increased Risk of Adverse Outcomes,” the PANORAMIC trial, “A Preliminary Analysis from the UK Randomized, Controlled Open-Label Platform Adaptive Trial.”
This was recently posted. This is a UK multi-center, open-label, adaptive, multi-arm platform, randomized controlled trial. It is a huge trial looking at molnupiravir 800 milligrams twice daily for five days. For starters, it was done right, the median duration of symptoms prior to randomization was two days. The median number of days from symptom onset to taking the medication was three days. This is early appropriate treatment.
Eighty-seven percent received their medication within the five days of symptom onset, and 95.4%, so an n of 11,857 of the participants randomized to molnupiravir avoided taking the molnupiravir for the five days. We’re looking at over 11,000, so we have 12,821 in the molnupiravir plus usual care, 95% of them are taking it. That drops us to 11,857. The usual care arm not getting the molnupiravir, it’s 12,962. What did we find in short? The investigators found that molnupiravir did not reduce an already low hospitalization death rate among higher-risk vaccinated adults with COVID-19 in the community, so last and still least in my list.
That second week, COVID early inflammatory lower respiratory hypoxic rebound phase. This is where we think about steroids, anticoagulation, pulmonary support, maybe remdesivir if we’re still on the early side, immunomodulation, avoiding those unnecessary and unproven therapies. Then we will move, for most people, into the late phase. As of October 11, 2022, the RECOVER studies have enrolled 9,277 participants. Still seems like a little bit of a low number. We need a lot more data in this space.
The article which has been making its rounds through the media, the social and mainstream, “Outcomes Among Confirmed Cases and a Matched Comparison Group in the Long-COVID in Scotland Study,”was published in Nature Communications. A Scottish population cohort of 33,281 lab-confirmed SARS-CoV-2 infections and 62,957 never-infected individuals. Where do they find these people? Were followed for six, 12, and 18-month questionnaires and linkage to hospitalization and death records. Of the 31,486 symptomatic infections, 6% had not recovered, 42% only partially.
Previous symptomatic infection was associated with poor quality of life, impairment across daily activities, persistent symptoms, including breathlessness, palpitations, chest pain, confusion. I will comment because I think we’re always looking for that number, “What’s the number? What percent?” I think one thing I can take away from this study is asymptomatic infections, were not associated with adverse outcomes, and vaccination, again, was associated with a reduced risk of seven of the symptoms.
Medium COVID, this is according to the best of my knowledge in an Atlantic article, “Medium COVID Could Be the Most Dangerous COVID,” by Benjamin Mazer. He’s referring to this 12-week period after acute COVID before things improve or a person moves into Long COVID. We’ve talked a little bit about this. This is one of those articles which I think is scarier than need be. What people are starting to recognize is, for a lot of folks, COVID is not just a five-day disease, it’s not just a two-week disease, it may take several weeks for a person to really recover. That’s why we move the goal post, so to speak, to this 12-week period, where for most people, we can be encouraging. We can talk about the fact that most people will improve by 12 weeks, and then the remaining people, to be honest, 95% of those are going to resolve within a year, leaving us with, unfortunately, a small percentage, but ultimately, a large number of individuals that continue to struggle with Long COVID.
On that note, I will move to low- and middle-income countries. Let’s not just think about ourselves. This is an infection without borders. No one is safe until everyone is safe. I’d like people to pause the recording right here. We are in October. This is the final month of our Parasites Without Borders fundraiser for Floating Doctors. We are not at our goal yet, so we need everyone to jump in. We want to get up to that donation of $40,000 to Floating Doctors, so go to parasiteswithoutborders.com. Click on that ‘Donate’ button. Every little bit counts, every big bit also counts.
VR: Time for your questions for Daniel. You can send yours to [email protected]. This one comes from last night’s live stream. Someone wants to know if Paxlovid reduces the frequency of Long COVID?
DG: We don’t know, Vincent. I think that’s really important for us to just say outright, we don’t know. Without that knowledge, that’s not really an indication for Paxlovid. It’s an important question to know, and I think those studies need to be done. I think two sides of this need to be, one, is we need to look at if people get treated with Paxlovid versus not, what’s the incidence of Long COVID?
The other, which I know a lot of people are interested in, is does Paxlovid have any impact on Long COVID? I know there are prescriptions out there that are being given to patients for that purpose. I saw an individual just yesterday, and going through the list of what he had tried, ivermectin, no benefit, Paxlovid, no benefit, et cetera. I think we really need answers to that.
VR: Jill writes, “Can symptoms of rheumatoid arthritis appear to be caused by vaccinations, specifically COVID vaccines?” Jill writes she’s had four COVID vaccines, but ever since the first one, she’s had increasing joint pain in the knee and never had that before. Then it’s continued to spread to hands and elbows and hips, and most recently, shoulders. She has an elevated RA factor of 20.
“Are there any studies that link vaccination COVID or not, where the autoimmune system gets out of whack? I found studies that integrate that RA flare-ups can occur from getting COVID and COVID vaccines, and also that Long COVID could impact or cause RA. I have had mild COVID-like symptoms three times, but never tested positive. No family history of RA. Any thoughts that can point me into some direction that I could bring to my doctor would be greatly appreciated.”
DG: These are important questions, and this is why we monitor vaccines so closely. We have an incredibly low threshold as far as safety and adverse events with vaccines, so there’s really this robust system, as people know about, the various reporting. Also, we as physicians report anytime we see something that has a temporal association with a vaccine. One of the big challenges is that people get diseases. People get cancer, people get autoimmune disease, people get into motor vehicle accidents. Lots of things happen and we’re always trying to figure out is there any rise above background, or are the vaccines in any way causally related?
We’re monitoring that. At this point, very safe vaccines, incredibly safe vaccines. Are there some people that have adverse events out there? Certainly. Is this low level and balanced very strongly with the protection? Yes, and as I keep pointing out to people, and I think this is just very straightforward, it is so much safer to get a vaccine than to get this horrible infection.
VR: A loyal listener writes, “I’m 65. I have antiphospholipid disorder. I had a TIA in 2009. Take Plavix daily.” He has been working remotely, but now his company wants him to go back to work and there are no cubicles, everybody just sits all together and the ventilation isn’t good. He says, “I’ve read several research papers that say COVID can cause clotting similar to my disorder. My son thinks I’m being paranoid, but can you tell me if I’m right or not? Am I at greater risk because of my condition?”
DG: Yes. That’s one of the big parts, as people probably have been listening for a while, when I go through that early inflammatory phase, what’s now being called the rebound phase, that second week when people might end up in the hospital, there certainly are impacts on the clotting system. Routine across the board we’re recommending different levels of anticoagulation for people that have a significant enough early inflammatory phase that they end up in the hospital. If you’re high-risk, that is potentially something that’s going to happen. COVID itself puts people at increased risk of strokes, of pulmonary emboli, of deep vein thromboses, even of bleeding issues.
This is why the vaccines are such a better choice. Now, some of the vaccines. That was the issue with the J&J, were associated with certain rare but devastating clotting complications. The mRNA vaccines are not. They are considered safe in this context.
VR: Sharon wants to know when will Evusheld be retooled for future variants?
DG: [laughs] I am waiting for that. It makes a lot of sense. Right now that we’re seeing this B.4.6, it’s time to retool our passive vaccination. There’s a lot of folks out there who are compromised, who really can’t produce the protection that we would ideally like them to be able to produce. A lot of this, I have to say, is probably market-driven. Is there an opportunity, are physicians going to start using these products to the point that the demand is going to drive an upgrade, so to speak? At this point, I haven’t heard, but certainly, there are products out there that could slide into this space with the appropriate science.
VR: Another Sharon wants to know, well, she has a 27-year-old nephew who had COVID in July 2022, got bebtelovimab because he has type-1 diabetes, is overweight, takes a biologic for psoriasis. He’s had three Pfizer shots, recent infection, and treatment monoclonal. Should he get bivalent vaccine now or wait a longer period of time?
DG: When was that COVID there, Vincent?
VR: July 2022.
DG: OK. July. To do the maths, we’ll count from July to August, September, October. We’re about three months now. We’re starting to move into that range. The recommendation is for people that have had COVID, particularly people that have had monoclonals now, as we see variants change, this guidance has changed over time, so I don’t want people to be like, “But it’s changed,” it has changed, yes. Now, about three months out is a reasonable time. It’s where we are now to be thinking about this.
VR: Finally, from Sandra writes, “It sounds like all the available treatment options are either hard to access, like IV remdesivir, or have unfavorable safety profiles, such as molnupiravir, or can’t be co-administered with many commonly prescribed meds like Paxlovid. Aside from monoclonals, which are not for everyone, are there any options coming down the pike or is the recommendation to just ride out the virus when current treatments are not appropriate?”
DG: Now, I think you’ve clearly outlined why there’s a space for a new product here. Paxlovid, as well as it works, it’s not always an easy lift. There’s a lot of drug-drug interaction. Whenever I’m doing Paxlovid, I’m always sitting in front of a computer. I go through what medicines are you on. I plug each one of them in to see if I need to make any changes. A lot of docs find that a little bit too much, a little too daunting, apparently, such a lift that they’ll actually not prescribe Paxlovid, but boy, if there was a drug that was as effective as Paxlovid without renal adjustment, without drug-drug interactions, that would be tremendous.
VR: That’s TWiV weekly clinical update with Dr. Daniel Griffin. Thank you, Daniel.
DG: Oh, thank you, and everyone, be safe.
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