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This Week in Virology
Host: Vincent Racaniello
Guest: Daniel Griffin
Aired 19 November 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 955, recorded on November 17, 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: Daniel, is this time of year busy as usual or more so than usual?
DG: It’s busier than usual, actually. I have to say, we’ve been having issues and people are probably aware of this, that not only are the children’s hospitals, overloaded but even some of our adult ERs where there isn’t even enough room in the waiting room where we have instances where they’ve said, “You know what? Why don’t you just give us your phone number and go wait in your car?”
Which is really shocking. People boarding in the emergency rooms. We’ll get into it, but we are seeing a really massive early up-spike in a lot of our respiratory pathogens. Let’s get right into our quotation, “Better a cruel truth than a comfortable delusion.” That’s by Edward Abbey. I was earlier today on The Brian Lehrer Show, National Public Radio.
Apparently, we’re still friends, despite my mispronunciation of the fancy French store Target, my comments about his goatee, and my other reference to his social media referencing of information, but I think we’re still good friends, so at least he invited me back. Maybe they couldn’t fill the spot, but he asked me this question, “What should we do going forward?”
This will be the last episode that drops right before Thanksgiving here in the United States and my advice was don’t put your head in the sand. Don’t just decide that you’re done with what’s going on and ignore the truth, use the truth, use the science, use the facts. That’s going to allow you to have a better, safer, holiday coming up. Let us jump right into influenza.
We are not doing great when it comes to vaccinations and we’re not doing great when it comes to the numbers. Those numbers are really skyrocketing. We’re also seeing, issues with RSV. I’m going to go right into RSV and that was mainly what I was talking about earlier today, the day we’re recording this, when I was on National Public Radio talking about, respiratory syncytial virus, RSV, and I actually was thanking people in the media for drawing some attention to RSV. I’m glad RSV is on people’s radar.
I think this is a chance to provide education and I think education is one of the best ways that people can make smart, intelligent, decisions that are in their and their family’s best interests. I will say, RSV is an underappreciated disease and fortunately there don’t seem to be many RSV deniers out there, no one having their minions write about how much worse flu is than RSV like we had in the early days of COVID.
People can tell that that still bothers me but there was a very accessible piece by Keith Klugman, the director, Pneumonia, Bill & Melinda Gates Foundation, recently published, “Explainer: Four Things to Know about RSV.” I will put in a link for that in our show notes or someone else will do that for me, thank you, but just to give –
[chuckles]
As Vincent laughs because he’ll be part of doing that work so just to give people a little bit of background, this is not a new virus. This is not a novel respiratory virus. This is a virus that has been with us and actually continues to be a huge challenge. It’s estimated that a hundred thousand deaths in children under age 5 occur each year throughout the world due to RSV. Here in the United States where we have a bit more resources, maybe better nutrition and other things, 100 to 300 deaths in children younger than 5 years every winter here in the U.S., that’s the children, and 6,000 to 10,000 deaths among adults 65 years and older here in the U.S. Huge drive for hospitalizations. We have numbers from 2019, just right before we got hit. RSV sent 3.6 million people to hospitals worldwide and RSV is the most common cause of bronchitis and pneumonia among infants, the leading cause of pneumonia deaths for babies in the first six months of life.
Just a little bit of sobering, no drugs to treat RSV that are evidence-based, no vaccines that we have out there. We do have that IVIG out there, but as we’ve talked about, there’s a lot of movement to change this. There was an article, “The Burden of Respiratory Syncytial Virus in Healthy Term-Born Infants in Europe: A Prospective Birth Cohort Study,” published in The Lancet Respiratory Medicine, and here the investigators performed a multi-center prospective observational birth cohort study in healthy term-born infants.
That’s greater than equal to 37 weeks of gestation in five sites located in different European countries to determine the healthcare burden of RSV. And their findings are really, I’m going to say, really shocking and this actually made its way into mention in a lot of the popular media. RSV-associated acute respiratory infection was found to lead to the hospitalization of one in every 56 healthy term-born infants in high-income settings. This leads them to suggest that immunization of pregnant individuals or healthy term-born infants during their first winter season, could have a major effect on the healthcare burden caused by RSV infections.
Those are the vaccines that we’ve been discussing and I think if you start talking to people, I was talking to one of my college roommates earlier today, Greg Johnson, and one of his sons actually spent a frightening week in the hospital with RSV, has done well but no, this is really a significant challenge and I’m glad that people are getting educated. I’m glad that people’s interest and curiosity has been piqued.
Another one of your viruses causing trouble, Vincent. Ebola, continuing to keep track of Ebola as I ready myself to head to Uganda in a couple of weeks. A little bit of movement on the Ebola testing front. As we continue to have this issue with Ebola in Uganda, we have the article, “The Diagnostic Accuracy of Rapid Diagnostic Tests for Ebola Virus Disease: A Systematic Review,” published in Clinical Microbiology and Infection. This is a review of tests for Ebola and the summary estimate of sensitivity for lateral flow assays was, 86% for sensitivity, specificity, 97%, and the summary estimate for the rapid PCR sensitivity 96% and specificities about 97%.
Monkeypox, we continue to do well. The numbers are going down and I actually think the numbers are going down. I don’t think we’re just missing all the cases but this was a nice development. The article, “Evaluating the Accuracy of Self-collected Swabs for the Diagnosis of Monkeypox.” This was published in CID. Maybe this reminds people of, there was one point in time, you used to go to the gas station and someone else pumped the gas for you. Now you have to do it yourself.
Well, here the investigators found that the performance of self-collected samples was similar to that of physician-collected samples, suggesting that self-sampling is a reliable strategy for diagnosing monkeypox and no one poked themselves with any sharp needles. Maybe this is the future, you’ll show up at the urgent care and they’ll just pass the supplies and you’ll be swabbing your throat, you’ll be swabbing your lesions, and then maybe you’ll get a telehealth visit later on telling you what is going on.
Right to COVID. This week we have the article, “Acute and Post-Acute Sequelae Associated with SARS CoV-2 Reinfection,” published in Nature Medicine. A lot of different takes on this article but this is more data from the U.S. Department of Veterans Affairs National Healthcare Database and appropriate, I read this article on Veteran’s Day, so I thought that was very nice, but they reported that compared to no reinfection, reinfection contributed additional risks of death, additional risks of hospitalization and sequelae included pulmonary, cardiovascular, hematological, diabetes, et cetera, et cetera. The risks were evident regardless of vaccination status. The risks were most pronounced in the acute phase but persisted in the post-acute phase of six months. Lots of limitations here. I will not hang my hat on the specific numbers in this retrospective analysis, but it does reinforce that repeat infections are not innocuous. Hundreds of people are still dying per day, and in many cases, this is not the first infection. Many people are still being hospitalized and getting Long COVID. Again, for most, this is not the first infection. People may have survived that first one and now they’re in the hospital or not surviving this reinfection. I should confess at one point I was listening to a Joe Rogan podcast and there was a guest on, it was very entertaining. It was actually one of Dickson’s relatives sent me the link to listen to this.
The guest was like, “No, no Joe, you can only get COVID once. He’s like, but I have a lot of – “No, no, Joe, you’re misunderstanding. COVID is a one-and-done. You can’t get it twice.”
VR: Who’s this guy?
DG: We won’t mention the guest, but it was fun to listen to the back and forth. Joe was pretty convinced he was being misled by the guest. Unfortunately, I don’t think it was during sober October. Not sure Joe responded as well as he could have, but let’s move on to children COVID and other vulnerable populations. Dr. Walensky, the CDC director, noted that COVID hospitalizations are again rising in children under 6 months of age. This is going to be an interesting challenge going forward. The suggestion is back to what we’ve discussed about pregnant persons getting boosted in that last trimester to protect the newborns.
Maybe those boosters aren’t just for in the cards once they’re born. Maybe those boosters are going to be brought in before they’re even born. We’ve shared a bit of the data on that. Let me go straight to the MMWR, “COVID-19-Associated Hospitalizations among U.S. Infants Aged Less Than 6 – COVID-NET, 13 States, June 2021 – August 2022.” I actually pasted a few of the figures in here cause I’m going to walk through these with Vincent here, but really striking. I do encourage people to pause and look at these figures, but really striking is looking at the figure where other than the elderly-elderly, those 75 years of age older, the less than 6 months have the highest rate of hospitalizations per 100,000 during the Omicron waves.
VR: What’s the explanation for that, Daniel? Do you have any idea?
DG: I think it’s a combination of things because it is interesting if you go back over time. During the early waves, you were not seeing this. It was really during Omicron that it really spiked up. A couple of ideas. One is that, as we know outside of this age group because these folks didn’t really have the opportunity to get infected before, this looks like this is a first infection experience probably over 90% of these other age groups have either been vaccinated or infected in the past. That’s what I would suggest as a possible explanation. Vincent, thoughts?
VR: The fact that these infants are being hospitalized does that suggest that they have a lower respiratory tract infection.
DG: It would. Now [crosstalk] not always. I think that’s actually glad because I want to answer that a little more fully. We hospitalize patients for two types or forms or stages of COVID. We’re starting to see a lot more hospitalizations during that first week. During the acute viral respiratory phase where it’s failure to thrive, they’re vomiting but then we’re also seeing hospitalizations during that second week and we don’t have two different codes to really, sort that out.
VR: I just pointed out because there’s this idea that Omicron is an upper tract disease, but it doesn’t seem like in these infants it’s solely an upper tract disease.
DG: It is tough and I know we’ve, I think a couple of episodes back we had a guest on who was not that impressed by Omicron. There was a reference to a science publication where there was about a 50% lower risk of death or hospitalization. Our case fatality rates have gone from 2% to 1%. That’s still a pretty high case fatality rate. That is on top of previous infection, on top of vaccinations, on top of better therapeutics and science and understanding maybe a little less horse paste and steroids in that first week. Omicron is still killing hundreds of folks a day here in the U.S., thousands of people throughout the world each day.
Another vulnerable population is addressed in the article, “Clinical Course of SARS-CoV-2 Infection and Recovery in Lung Transplant Recipients,” published in Transplant Infectious Disease.
These are the results of a single-center observational study of outcomes in over 100 lung transplant recipients diagnosed with SARS-CoV-2, between 5-1-2020 and 3-15-2022. This is going to cover that broad period of time including Omicron. They were followed for a median of 123 days. There actually is a really nice graphical that gives us the results from this. About a quarter of these individuals were hospitalized, 10% died, 31% developed acute lung allograft dysfunction so really seeing a pretty significant impact on this population. Just pointing out, as we mentioned Omicron earlier, 27 were pre-Delta, 20 were Delta, 56, about half of these, actually the majority of these folks, this was Omicron that was killing these individuals. I like this next one. Again, I’m starting to paste in the figures to pull Vincent into it. That’s how you tell if someone has a PhD or not. You hand them an article and if they go right to the figures, that means they suffered through.
VR: That’s it. [crosstalk]
DG: If they just read the abstract, then they’re a physician. If they just read the title, probably a surgeon. The article –
[laughter]
VR: Oh boy, I like that.
DG: The article, “Effectiveness of a Third BNT162b2 mRNA COVID-19 Vaccination During Pregnancy: A National Observational Study in Israel,” was published in Nature Communications. David, just make sure you filter out all the hate mail that I just generated. The investigators compared the third and second doses vaccine effectiveness in preventing COVID-19-related hospitalizations during pregnancy during two COVID-19 waves. Delta variant in the summer of 2021 and Omicron BA.1 in the winter of 2022. It’s really interesting, they reported that compared with the second dose, the third dose effectively prevented overall hospitalizations during Delta and during Omicron. It’s actually really interesting. We were doing really quite well. If you look at the data here, if you go to the figures like the PhDs are doing, we were doing great during Delta, but if you then look at during Omicron, unless you got that third dose, you really weren’t seeing that separation. Also, you were not seeing quite the benefit that we were seeing early on.
VR: It’s very interesting because people, when Delta emerged, people were crying, “Oh, this is horrible, it’s more virulent, it’s going to kill.” The vaccines work very well against Delta.
DG: They really did. Now let us compare this to the article, “Maternal Antibody Response and Transplacental Transfer Following Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection or Vaccination in Pregnancy.” Here we’re looking at the antibody response, to a pregnant individual, either being infected or vaccinated, and we’re also looking at the transfer of those antibodies to those newborns. A theme we’ve been talking quite a bit about, not just in the context of SARS-CoV-2, but also RSV. This is a prospective observational cohort study that included 351 pregnant people who had SARS-CoV-2 infection or COVID-19 vaccination during pregnancy. They looked at the (Ig)G and the IgM, to the SARS-CoV-2 receptor binding domain. Measured that in maternal and cord blood, antibody levels and trans-placental transfer ratios were compared.
Interesting and people can say, but Dr. Griffin, what does this mean? I will say the data showed maternal and cord blood (Ig)G were higher after vaccination than infection, got a P value there of .001, transfer ratio was higher after 90 days in the vaccinated people. Modeling showed higher amplitude and half-life of maternal (Ig)G following vaccination. Let us move right into the pre-exposure period. Perhaps helpful at some point to talk a little bit about the categories of transmission. I think that this is a good reminder as everyone gets together for the holidays here in the States and in other parts of the world.
SARS-CoV-2 is mainly a respiratory pathogen, but RSV and some of these other pathogens can have a pretty significant contact component. When you get together at the holidays, wash those hands, use those alcohol cleansers. We’ve talked a lot about masks over time. Lots of concerns with the quality of the studies. Boy, I will tell you, this last article that I’m about to talk about has gotten a lot of excitement. Read the article. Think about what it has to say. Listen to what I have to say. Don’t just decide that the title has fired you up. The article, “Lifting Universal Masking in Schools – COVID-19 Incidence among Students and Staff” was recently published in the august journal, New England Journal of Medicine.
To start with the background the authors provide. In February 2022, Massachusetts rescinded a state-wide universal masking policy in public schools, and many Massachusetts school districts lifted masking requirements during the subsequent weeks, but not all at the same time. In the greater Boston area, only two school districts, the Boston and neighboring Chelsea districts, sustained masking requirements through June 2022.
The staggered lifting, this is something we see in global health efforts, provided an opportunity to examine the effect of universal masking policies on the incidence of COVID-19 in schools. They found that before the state-wide masking policy was rescinded, trends in the incidence of COVID-19 were similar across school districts. During the 15 weeks after the state-wide masking policy was rescinded, the lifting of masking requirements was associated with an additional 45 cases per 1,000 students and staff, which corresponded to an estimated 11,901 cases and to about 30% of cases in all the districts during that time.
Now, then it gets more interesting. They reported that districts that chose to sustain masking requirements longer tended to have school buildings that were older, in worse condition, and to have more students per classroom than districts that chose to lift masking requirements earlier. So you almost would’ve expected a little bit of bias in the other direction. In addition, these districts had higher percentages of low-income students, students with disabilities, and students who are English language learners, as well as higher percentages of Black and Latinx students and staff. Again, I paste in Figure One where if one takes a look at this, they can see the differences here.
I’m going to interpret this a little, and maybe Vince I’m going to ask you to step in this as well. This is not a paper that’s saying, all the kids need to start wearing masks and we need to shut the schools. I thought that was interesting that I seem to be characterized. I always try to remind people. I was the one who said open the schools, close the bars. Vincent, what are your thoughts on this?
VR: Very, very difficult to know. These curves are – First of all, they’re very similar. As you said, districts that chose to sustain the masking, they tended to have buildings that were older and in worse conditions, more students per classroom. It’s hard to compare at that point right because now you’ve got different conditions, and the nice classrooms they’re taking the masks off. I don’t think that wearing masks should be a function of what kind of classroom you have. You’re either wearing them or not, right?
DG: Yes. I think it’s interesting. This came up when I was asked about this on National Public Radio earlier. Nobody’s going back. I do not see a world where we start returning to the mask mandates in the past. There’s an interesting feature that I want to talk about. I think it’s important, is that, one of the challenges, one of the biggest challenges with COVID was this issue of transmission in the presymptomatic and in the asymptomatic periods. RSV, a lot of our respiratory viruses, our influenza. Almost all of the transmission is occurring from people who are sick, people who don’t feel well. If you’re not feeling well, you really should just stay home. There was a recent article about a 100,000 workdays lost. People have started to do this. When they’re sick, they’re not going to work. When their kids are sick, they’re taking care of them. I think we need to think about it isn’t just a binary regarding the mask. There’s a lot of complexity here.
VR: I think it’s clear from this study, though, when they lifted masks, the cases went up substantially, so that’s a good indicator for the effectiveness of masking. Whether you need it going forward with vaccines is questionable. But I do think people can make their own decisions at this point whether to mask or not, and that’s fine.
DG: Yes, and I put this in here as evidence. People ask, “Do masks even work?” They work.
VR: Yes, they do.
DG: Yes. The second question is, when and where do we consider using them? Ventilation, I always like to put a plug for that. Crack those windows even if it’s a little bit chillier. Apparently, I got some feedback on it’s better to just leave that fan on at all times for the HVAC system because that will less wear and tear than the off and on. I tried that, but my wife now her– She has another excuse that it creates noise. [chuckles]. There’s always some reason why that fan can’t be running.
All right, COVID active vaccination. Remember, vaccinated people still get infected, but they are just less likely to die or have severe disease. Never miss an opportunity to vaccinate.
Some complicated stuff here when it comes to the passive vaccination, Evusheld. We did get some interesting information on the effectiveness of this previous to now. I’m going to mention why I talk about previous to now, but the article, “Systematic Review of the Clinical Effectiveness of Tixagevimab/cilgavimab for the Prophylaxis of COVID-19 in Immunocompromised Patients.” So, that’s Evusheld, it’s posted as a preprint. This was a systematic review that identified 17 studies. About 25,000 immunocompromised patients, assessing the efficacy of Evusheld prophylaxis. Most studies reported clinical outcomes during Omicron. They found that for immunocompromised patients, prophylactic Evusheld was effective at reducing COVID-19 infection by 40%. Hospitalization, 70%. ICU admission, 88%. All-cause mortality, 81%. COVID-19 mortality, 86%, and they didn’t give us any data on PASC or Long COVID.
We also have the article, “Comparative Effectiveness of Sotrovimab” – I’m going to throw this in here while we’re talking about – “and Molnupiravir for the Prevention of Severe COVID-19 Outcomes in Patients in the Community: Observational Cohort Study with the OpenSAFELY Platform,” published in BMJ. Here they were comparing sotrovimab, so this is treatment as opposed to pre-exposure. Comparing monoclonal antibody therapy to molnupiravir, and found that sotrovimab was associated with a substantially lower risk than treatment with molnupiravir.
We’ll get back into this a little bit later. Unfortunately, the thing we’re seeing here in our area and much of the country is with the new variants, monoclonal treatment and prophylaxis is moving towards obsolescence. Here in the tri-state area, I just got the email, I think it was yesterday. Columbia University, bebtelovimab for treatment and Evusheld pre-exposure prophylaxis can no longer be relied on for clinical efficacy because the proportion of circulating variants with resistance to these agents exceeds 50% in the New York region.
All right, so we will jump right into the early viral upper respiratory non-hypoxic phase. Very happy this week. Right up front for the anti-anti-viral people out there. It’s a double negative, I guess. Shall I call them the bold optimists who tell high-risk people with COVID that things will probably be just fine and do not offer treatment. For those that are concerned that Big Pharma is making too much money and there’s overprescribing of COVID therapies. The article, “Early Adoption of Anti–SARS-CoV-2 Pharmacotherapies among U.S. Veterans with Mild to Moderate COVID-19, January and February 2022.” Here we see in a cohort study of 111,717 outpatient U.S veterans with clinical risk factors for severe COVID-19 who tested positive for SARS-CoV-2 during January and February 2022. Only 3.8% received outpatient pharmacotherapy. Black veterans and Hispanic veterans were even less likely to receive treatment.
Now, I do think this is interesting. I was musing on this today. Let’s say your child got strep throat and the physician told you, “I looked at the numbers. Your chance of rheumatic heart disease, it’s only about one in a thousand. That’s just a fraction of a percent. Your child’s probably going to be fine. I don’t think we should treat the strep throat. I won’t be prescribing antibiotics for strep throat anymore.” I think we need to look at this. These individuals that are high risk.
These people not one in a thousand, we’re talking 1, 2, 3, 4, or more per 100. A much higher risk, bad outcome ending up in the hospital, potentially dying, ending up filling that hospital bed so someone else doesn’t have access to it. I think that it’s all probably going to be just fine. May need to reevaluate their concept of what probably really means.
Paxlovid, still recommended, number one. We have a nice little preprint. I have to say, you got to read the pre-print and hopefully, people will listen to this review of it. Because the headlines, the way this is being spun is really whatever you want this study to say, it says.
Let’s go through what the study actually shows. The preprint, “The Paxlovid Rebound Study: A Prospective Cohort Study to Evaluate Viral and Symptom Rebound Differences Between Paxlovid and Untreated COVID-19 Participants.” This was posted by our friend Michael Mina. Is he still our friend? I don’t know. If people remember he had that desk with all those $1 rapid COVID tests. Whatever happened to all those cheap tests? Why am I still paying so much?
Anyway, these investigators designed a digital prospective observational study, which included participants who tested positive for COVID-19 and were clinically eligible for Paxlovid. Participants were assigned to a Paxlovid or control group based on their decision to take the medication. Both groups were provided 12 rapid antigen tests and asked to test and answer symptom surveys on a regular frequent schedule for 16 days.
They ultimately ended up with 127 participants in the Paxlovid treatment arm, 43 in the control arm, for the analysis of viral rebound based on test results and COVID-19 symptom rebound based on patient symptoms. Drum roll, please, please. What did they find? They observed a similar rate of rebound in both the Paxlovid and the control groups.
VR: It’s not Paxlovid rebound.
DG: They were clever because they call it the Paxlovid rebound study. You get a lot of clicks, when people Google, they’re going to come onto it. I will say, with all respect, this paper will probably end up in quite a different form by the time it makes it through peer review. There’s a little bit of CDC bashing and a little bit of agenda-pushing in the discussion but just my opinion there. Now finally, we have test and treat at your local CVS. People may have heard CVS pharmacists can now prescribe Paxlovid to treat COVID-19. I’ll leave a link.
I do want all those physicians out there that just thought this was too complicated and too challenging for them to think about the fact that now the pharmacists are able to do it. When you start worrying that, “Oh, I don’t know if we should let the pharmacists have the ability to prescribe.” Really. I know some of the pharmacists are a little annoyed, but –
VR: How does this work? You go to the pharmacy, you get a test, if you’re positive, they can prescribe Paxlovid, or do you have to have it done there? That’s the question.
DG: Yes. Some people have asked this, “Well, what if I do a home test and I just show up at CVS?” I imagine they’re going to repeat the test, “confirm” your test.
VR: Got it.
DG: Where potentially a physician, if you tell the right story, I believe you. I’m very comfortable over telehealth. One of the challenges, and this was brought up and I’ll just sort of comment on this and maybe this’ll come up later, but you do have this issue about kidney function. How is that going to work in this scenario? Because we do want to know that. It’s estimated about 15% to 20% of high-risk individuals will have some reason they can’t be on Paxlovid. We also have drug-drug interactions with, boy, the pharmacists are great at that.
After Paxlovid, remdesivir, I do want to point out for those listening in positions of power, remdesivir is not being well operationalized, and it is much cheaper to give folks remdesivir than to have them end up in the hospital and then have to take care of them in that context. Maybe people should be looking at how there’s ways to make this work in a capitalist society in which we live. Then number three, monoclonal therapy, now just bebtelovimab.
Well, this is a challenge as I started to talk about with all the variants. Maybe what we’re saying about the monoclonals is quickly becoming historical but historically they did find their place less effective than Paxlovid, less effective than remdesivir, but maybe somewhat superior to molnupiravir.
What about pregnancy? I’ve been talking about this quite a bit. I know there were a lot of physicians, over the last little bit, and I’m hoping we’re going to get a new monoclonal, so we’ll be able to put something else in this space. A lot of times there was this question of, well, this individual may be high risk, they may be pregnant, but I feel more comfortable using monoclonals than, let us say, Paxlovid. Was that a good choice? Was that giving this patient the most effective therapy?
We have the article, “Monoclonal Antibodies for Treatment of SARS-CoV-2 Infection During Pregnancy,” published in Annals of Internal Medicine. These are the results of a prospective propensity score-matched cohort study. They found, unfortunately, that there was no statistically significant differences in the composite outcome of COVID-related hospitalizations, emergency department visits, or mortality at 28 days, between pregnant patients who did and did not receive monoclonal antibody therapy. Number four, molnupiravir, last and least.
Now I am going to move into the COVID early inflammatory lower respiratory hypoxic phase. This is where we look at steroids in the right patient at the right dose, pulmonary support, anticoagulation, maybe remdesivir if we’re early. There was an interesting study, and I will be remiss if I did not mention this. I’m still trying to come to terms with the results but this was the article, “Twice-Daily Oral Zinc in the Treatment of Patients With Coronavirus Disease 2019: A Randomized Double-Blind Controlled Trial,” published in CID.
These are the results of a prospective randomized double-blind, placebo-controlled multicenter trial out of Tunisia. I’m going to mention that that matters. The patients tested positive for COVID-19 without end organ failure. randomized to oral zinc 231 or placebo 239 for 15 days of treatment. The primary outcome was death due to COVID-19 or ICU admission within 30 days after randomization. Secondary outcomes included length of hospital stay for inpatients and duration of COVID-19 symptoms with COVID-19-related hospitalization for outpatients.
I do suggest that if people are going to look at this, read carefully because there was no statistically significant impact on 30-day mortality but for the combined outcome of death or ICU admission, this was lower in the zinc group compared to placebo. Barely made statistical significance there. An odds ratio of 0.62. and that’s 0.38 to 0.99. They also comment in their discussion that they did not assess serum zinc levels so not clear if this is a factor but I will comment, it’s worth noting that there are a number of studies suggesting a very high incidence of zinc deficiency in Tunisia. Not in line with our other zinc study results, but interesting and just the zinc dose was 25 milligrams of elemental zinc BID for those 15 days.
Moving onto the late phase PASC. I actually thought some interesting stuff came out this week and so, I’m going to ask Vincent to, as I characterize and think through this, I’ll have him see if I’m getting this in line. A while ago I was perhaps optimistic in thinking that this would be the meat of our weekly updates. We’d be focusing on all the Long COVID knowledge and treatments but we do have the paper, “Cognitive Deficits in Long COVID,” published in The New England Journal of Medicine.
The authors start by commenting on the fact that reported deficits in attention, executive functioning, language processing, speed, and memory are a number of symptoms collectively referred to as brain fog. Together with increased incidence of anxiety, depression, sleep disorder, and fatigue, the syndrome of cognitive impairment contributes substantially to the morbidity of Long COVID. In this bit of basic science, the investigators used a mouse model to explore how mild respiratory infections of SARS-CoV-2 could lead to neuroinflammation and subsequent brain damage through multi-lineage neural cell dysregulation.
They used that mouse model perhaps we’re familiar with expressing the viral entry receptive for SARS-CoV-2, the angiotensin-converting enzyme 2 in humans. In the trachea and lung, they delivered SARS-CoV-2 intranasally. They detected no SARS-CoV-2 in the brain but found signs of neuroinflammation, elevated levels of chemokines in cerebral spinal fluid and serum, each with a distinct time course. They reported that these changes led to activation of microglia in subcortical and hippocampal white-matter regions, but not in gray matter, with distinct effects on specific neural cell populations. In the subcortical white matter, microglial activation was associated with loss of both oligodendrocyte precursors and mature oligodendrocytes. Consistent with this loss, there was also loss of myelin and myelinated axons for at least seven weeks after the infection began in these mice. They then found that in the hippocampus, the activation of microglia was associated with inhibited neurogenesis.
The activation of microglia, they suggested, was mediated by persistently elevated levels of CCL-11. They then reported that persons with Long COVID and cognitive deficits had higher levels of serum CCL-11 than those with Long COVID that lacked cognitive symptoms. I will throw another article, but just really just mentioned it, “Severe Neuro-COVID is Associated with Peripheral Immune Signatures, Autoimmunity and Neurodegeneration: A Prospective Cross-sectional Study,” published in Nature Communications, also seemingly to have similar findings. The way I’m putting this is it looks like COVID leads to a triggering of these microglia. Think of them as small macrophages of the brain, which are basically eating the person’s brain. Is that a good characterization?
[chuckles]
VR: Sure.
DG: Going to start creating these little infographics. I want to get that natural immunity from COVID. It ate a little bit of my brain, but maybe it will eat that part of the brain that reminds me of something bad I experienced. All right. We’ll close out with the article, “Long-lasting Symptoms After an Acute COVID-19 Infection and Factors Associated with Their Resolution,” published in JAMA Network Open. In this study, they looked at three French population-based cohorts, found 10% of individuals with acute COVID-19 still had symptoms one year in follow-up.
Couple things they found, we’re looking at what were the factors, older ages, greater than 60 years, female, history of cancer, history of tobacco consumption, high body mass index, and high number of symptoms during the acute phase were associated with slower resolution of symptoms. All right. I will wrap it up there and as I like to finish off, no one is safe until everyone is safe. I know Vincent will like this. I want everyone to pause right here go to parasiteswithoutborders.com and click the ‘Donate’ button. We are at our year-end MicrobeTV fundraiser. We are hoping to send a total donation of $40,000 to MicrobeTV to help them continue to do the excellent work that they do.
VR: Thank you very much for that. We appreciate it. Now it’s time for your questions for Daniel, you can send them to daniel@microbe.tv. Christiane writes, “My question is about a friend and 84-year-old female last year diagnosed with polymyalgia rheumatica. She has been treated with corticosteroids. Since, her doctor is now decreasing the doses gradually to get her off this medicine. Never had COVID, fully-vaccinated, and boosts. Last September, she went for a Moderna bivalent booster shot, never had an allergic reaction before but this time she had a huge and painful skin rash, led her to the ER, treatment with steroids.
“Public Health Department referred her to an allergy specialist, but she can’t see him till January. In the meantime, she’s decided not to take the flu vaccine. I’m not sure if she had any recommendation about that by the Public Health Department. Considering she’s 84, immunosuppressed, do you think it’s a wise decision not to take the flu shot?”
DG: I’m going to say in a situation like this, I would routinely encourage the flu shot. The reaction you’re describing does not make me suspect that there would be a problem with the flu shot. Also remember, as we’ve talked about, we can reduce that risk of ending up in the hospital and ending up dying by flu, probably at least by 50%, at least by half. It’s something I would encourage.
VR: Susan writes, “I’m a primary care nurse practitioner working in the London, Ontario, area in a family physician office, our local tertiary hospital is London Health Sciences Center, the medical chief of one department, not to be named, is advising staff to get the Pfizer bivalent vaccine over the Moderna bivalent due to its target against BA.4, BA.5. I’ve always heard you say Moderna provides better immune protection over Pfizer. I believe Dr. Griffin, you’ve had Moderna vaccines yourself. I had Moderna bivalent. Would you please clarify this chief of medicine statement? I have colleagues that are now reaching out to me asking to explain this physician’s thinking. My hunch is that the Moderna is still the vaccine to get.
DG: Both the Moderna and the Pfizer bivalent boosters target BA.4, BA.5 right there. They’re basically very similar. Is there a slightly different level of antibodies over time? This is a discussion we had earlier. This was actually something Paul Offit weighed in on. He said, “The difference we’re seeing between just getting the original vaccine as a booster this fall versus getting this new is about a 1.4-fold difference in antibody levels,” which is less than the difference in antibody levels that we saw with Moderna versus Pfizer.
I’m getting a sense that maybe this individual is misunderstanding, both the Pfizer and the Moderna are a combination of the original and the BA.4, BA.5, targeting mRNA sequence. There’s going to be very, very similar responses. I’m not sure there’s any science out there that would suggest that the Pfizer is a better choice.
VR: Nikki writes, “Can you please discuss the discontinuation of statins prior to Paxlovid? Are lovastatin and simvastatin the only statins that are contraindicated and why? How concerned should I be about my elderly parents having an adverse reaction if they were prescribed Paxlovid along with a statin?
DG: It is interesting, and you bring up some interesting points. Just statins, these are cholesterol medicines. It’s amazing how many folks are on these. They’re not all the same. They’re not all metabolized exactly the same through the cytochrome system. Something we learned quite a bit about in the management of HIV patients with the protease inhibitors over the years, certain statins, like pravastatin, rosuvastatin, to some degree atorvastatin, have less drug interactions than simvastatin, for instance. But what a lot of us have done and I have to say the ID society, basically said, “Let’s keep this simple,” being off the statins for 10 days is a low-risk thing.
If you’re putting someone on Paxlovid and you find out that they’re on a statin, you don’t need to keep everyone waiting, you just say stop that statin for 10 days and move forward. A few of us early on in the pandemic were actually having patients change over to the lower-risk statins, just to avoid a potential problem.
VR: David writes, “Here’s a mnemonic for the ER folk: A one-T PoTS should drink some soup. A two-T Pott’s may start to stoop, but I will bet my silk culottes that there isn’t any three-T POTTTS.” [laughs]
DG: I think that was a reference to that young lady who went to the urgent care reporting she had Pott’s and was kicked out because they thought she was talking about tuberculosis of the spine. Thank you for that.
VR: That’s TWiV weekly clinical update with Dr. Daniel Griffin. Thank you, Daniel.
DG: Oh, thank you so much and everyone be safe.
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