TWiV 941 Clinical Update

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 1 October 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 941, recorded on September 29, 2022. I’m Vincent Racaniello and you’re listening to the podcast all about viruses. Joining me today here at The Incubator in New York, Daniel Griffin.

Daniel Griffin: Hello, everyone, and hello, Vincent.

VR: Hello, Daniel. How are you? Good to see you here.

DG: I am doing well.

VR: It’s been a while since you’ve been here. Let me make –

DG: Well, since I stayed. [chuckles] I’ve come by and visited.

VR: That’s right. You were here last week and then you decided to leave. Before we get going, let me make two announcements. First, a research assistant position is available at the FDA in Amy Rosenfeld’s lab. A focus of that research, which is at the Center for Biologics Evaluation, a review at the FDA, is to evaluate mechanisms by which cross-species anti-enterovirus antibodies may affect virus pathogenesis. The research assistant will support work on coronaviruses like Entero D68, which you’ve heard about from Daniel, poliovirus, which you’ve also heard about from Daniel, human rhinoviruses, genetic, biochemical, cell-based studies for understanding multiple aspects of immune dysfunction associated with virus infection.

The individual will carry out experiments in cell culture and participate in the development of small animal models for studying multiple aspects of infection, including the tissue-specific cellular immune response, where the work will be done at BSL-2 conditions, and then, of course, help celebrate the molecule of the year, which is, of course, the spike protein of SARS-CoV-2, and support our work here at MicrobeTV by going over to, buying a T-shirt, and using the promo code “MicrobeTV” on checkout. The promotion’s been extended through October. Thanks to Matt for that. They’re also now including kids’ T-shirts, so you can get your toddler a Spike T-shirt. How nerdy would that be? OK, Daniel, it’s all yours.

DG: I just wish I had a toddler so I could get them a Spike T-shirt. All right, let us start with our quotation. “‘Why is it,’ he said one time at the subway entrance, ‘I feel I’ve known you so many years?’ ‘Because I like you,’ she said, ‘and I don’t want anything from you,'” and that’s Ray Bradbury, Fahrenheit 451. Vincent, that made me think about this show and it’s a little bit sappy, so feel free to write in the emails.

No, I love getting emails from our listeners and I feel like I know you. I think a lot of you feel like you know us. Over the last two years, yes, I feel like we have this relationship. I was reminded of this. It’s a privilege for us to be able to discuss science, privilege for us, hopefully, to help you understand and get excited about science. Science has a PR problem, I hate to say, and we saw that the last two years.

Hopefully, we’re making science accessible. We’re getting you excited about science. This isn’t a news station. This is a chance for you to learn, for you to get the science, and hopefully feel good about that. All right, right up top. Another reminder with the MMWR, “Increase in Acute Respiratory Illnesses Among Children and Adolescents Associated with Rhinoviruses and Enteroviruses, Including Enterovirus D68 – United States, July-September 2022.”

In short, what are we seeing? I was just on a call with some of my colleagues earlier this week. We are seeing, and here in the MMWR, a rapid rise in the percent of emergency department visits associated with acute respiratory illness. For this time, being higher than we have seen in several years. The reported percentage that are testing positive for rhinovirus, enterovirus are rising rapidly.

I’d like to say that’s not a new creature. It’s just the primers will come up with this as either a rhino or an enterovirus, not really distinguishing it. But, this is where I think this is critical. The percentage of those that are positive for EV-D68 among children and adolescents with these acute respiratory illnesses and have a positive rhino, enterovirus PCR, this is now 56% during week 32. This is now the majority of those rhino, enteroviruses are this EV-D68.

Now, why is that a problem? Well, the problem here is that previous increases in EV-D68 respiratory illness have coincided with increases in cases of the acute flaccid myelitis that we’ve talked about. That’s this neurological disease that affects the spinal cord. Per the CDC, clinicians should consider acute flaccid myelitis in patients with acute flaccid limb weakness, especially after a respiratory illness or fever, and ensure prompt hospitalization and referral to specialty care for such cases.

Clinicians should also test for poliovirus infection in patients suspected of having AFM because of the clinical similarity to acute flaccid paralysis caused by poliovirus. Now, I should mention that acute flaccid myelitis is something we even see in adults. I had a case of a man in his 40s actually and his children, but not his wife, developed AFM after an EV-D68 infection. Something I think Vincent and Amy are quite familiar with.

VR: It’s a very interesting cohort because you would like to know why the wife didn’t have a problem, right? Studying them may provide some insight.

DG: Yes, I think that we should probably reach out to that man and connect him with Amy.

VR: Yes.

DG: [chuckles] OK.

VR: By the way, Daniel, the EV-D68, AFM, we’ve not seen it in big numbers in the U.S. since 2018. We were expecting an outbreak in 2020. Because of COVID lockdowns and so forth, we didn’t. Now, we’re worried that this increase in respiratory infections will come with some more AFM. We’re hoping that’s not the case.

DG: Yes, I was musing the other day. Remember when, “Oh, it’s just a virus,” was somehow reassuring?

VR: [laughs]

DG: Polio. An update on polio. The positive polio wastewater sample that we heard about here in Nassau County appears to have come from – and they probably know exactly where it came from – but either from Port Washington where I live, Roslyn, Manhasset, or Glenwood Landing, so really hitting close to home. The message here is very simple. The poliovirus is here.

The best way to avoid the risk of paralysis is to just get vaccinated. Living in a highly-vaccinated community does not mean you are protected if you’re unvaccinated. Children, go ahead. Pediatricians know exactly what to do. For the adult providers, there is an inactivated, injectable poliovirus vaccine. You get your first dose. You get your second dose a month later. Third dose at about six months later.

As we’ve talked about before, there are some recommendations about a one-time booster, maybe six months after that, but really straightforward for the adult docs out there that are, suddenly, now hopefully getting requests from individuals who maybe were not vaccinated as children but really want to get protected now.

Influenza. Timing matters. Most of us are suggesting that it’s time to get those flu shots scheduled. Probably October is a good time to get that. Boy, that’s right around the corner. Based on numbers out of Australia, we expect this to be the worst flu season in years. Let’s do all we can to mitigate that.

All right, monkeypox. As I’ve been saying for, actually, quite a while now, monkeypox is not a gay disease or an African disease. Monkeypox is an infectious disease. If you look at the monkeypox tracker, you can see that we’re sitting at about 200 cases a day.

I ran into my buddy, Jason Zucker, the other day and, sort of celebrating, we’re down to only seven cases the other day here in New York City. Amazing that seven cases in a day is an exciting number to be down to. Let me start with the dispatch estimates, “Early Estimates of Monkeypox Incubation Period, Generation Time, and Reproduction Number, Italy, May-June 2022.” Everyone is sharing their information, their case series, so this is great.

This was published in Emerging Infectious Diseases, one of my favorite journals, based on a total of 255 PCR-confirmed cases that had been reported in Italy. We got a preliminary estimate of a mean incubation of 9.1 days with 5th and 95th percentile distribution of between five and 23 days. Pretty long incubation period there. We also have the article, “Monkeypox Virus Infection in Humans Across 16 Countries – April-June 2022,” published in The New England Journal of Medicine.

Here’s an international case series of 528 infections at 43 sites in 16 countries. This is used to describe the presentation, the clinical course, and the outcomes of these PCR-confirmed monkeypox virus infections. As a caveat, and I think this is important, transmission was suspected to have occurred through sexual activity in 95% of the persons with infection.

This is important as we see more cases with different routes of acquisition, right? This may be a little different, depending upon the type of exposure. 95% of the persons presented with a rash with the majority, 64%, having less than 10 lesions. Seventy-three percent had anogenital lesions, 41% had mucosal lesions, with 54% having a single genital lesion. Think about this when your radar is going up.

Common systemic features preceding the rash included fever, only 62% of the time. Lethargy, about 41%. Myalgia, the muscle pains, 31%. Headache, 27%. Lymphadenopathy was also common. About 56% of the cases is what they reported. Concomitant sexually-transmitted infections were reported in 29%. That seems to be a fairly good number there. About one in three people also have something else going on. Hats off to John Hickam there.

Among the 23 persons with a clear exposure history, the mean incubation period was seven days. We get the range very similar, three to 20 days. The rest seems in keeping with what we are hearing from other smaller series. Seventy people or about 13% were hospitalized. The reasons for hospitalization were pain management, mostly for severe anorectal pain. I have to say, this can be incredibly painful. Soft-tissue superinfection, pharyngitis limiting oral intake. I discussed a woman that I’m currently taking care of who’s hospitalized for that very indication. Eye lesions. We have had some bad experience in the past in West Africa with those. Acute kidney injury, myocarditis, infection-control purposes, trying to block that chain of transmission. In this series, no deaths reported. They’ve got lots of pictures, so a good place to go and look to educate yourself. Monkeypox transmission, this is predominantly through contact as we’ve been discussing and we keep getting that supported in the literature.

No sex required. This is not a sexually-transmitted infection. There’s no sex required. That’s just going to increase the amount of contact and the risk. Monkeypox testing. Remember, do those two swabs, put them in the liquid medium, refrigerate, or freeze. If you do not test, you’re not going to get that positive test. You should have a lot of negative tests. If the majority of your tests are coming back positive, you’re not doing enough tests. Monkeypox vaccines, we got them. I will already give you a teaser for next week.

Next week, we’re going to talk about some fresh data. Do they work? As far as monkeypox clinical course and treatment, we’re mainly talking here about TPOXX, but those Viroptic eye drops, the trifluridine eye drops, if we’re worried about eye involvement, and continue a little shout-out for the A5418 study of tecovirimat for human monkeypox virus, the STOMP trial.

For more information, I have to say, if you’ve been diagnosed with monkeypox, if you’ve diagnosed someone with monkeypox, those 200 folks that are getting diagnosed per day, let’s get them all enrolled in this trial and we will share a link, Columbia is one of the sites and my friend, Jason Zucker, is helping us here enroll patients. This is not just for severe. Anyone with monkeypox can enroll in this trial.

A call-out to our listeners. We have sites in Texas. We have sites in Florida. We have sites here in New York. This is one of those, “Stop the recording right here,” if you have had the diagnosis, if you’ve made the diagnosis, and let’s get people enrolled because we really need the science here. Remember, this is a therapy with a low barrier to resistance. We really need to know who needs it, who doesn’t need it, what’s the timing, what’s the impact.

All right, COVID. I wanted to put this peer review journal article right up front, “Rapid Increase in Suspected SARS-CoV-2 Reinfections, Clark County, Nevada, USA, December 2021,” published in Emerging Infectious Diseases. I still remember a podcast. I don’t want to give too much air to the podcaster, but I still remember him with a guest and the guest kept saying, “No, no, you’re mistaken there, sir. You can only get COVID once. No, no, I understand. All your friends think they got it a second. It’s not true.” Well, I think it’s now clearly true.

I was reading a book by someone that I really respect that just came out in print. Right in the introduction was this false idea that getting COVID or getting a COVID vaccination would then remove a person from the chain of transmission and, eventually, the coronavirus would run out of people to infect. There certainly were some people that pronounced early on that reinfection with SARS-CoV-2 was just not possible.

If you thought it was, you were just mistaken. Well, this article looked at reinfections defined as a second positive PCR test collected greater than or equal to 90 days after initial positive test. They calculated the proportion of all new cases per week that were suspected reinfection and rates per 1,000 previously infected persons by demographic group. Initially, the rate of suspected reinfections remained less than 2.7% until December 2021 and then increased to about 11%.

About one in every nine infections are reinfections, a person getting infected another time. This did correspond with local Omicron variant detection. Then reinfection rates were higher in certain populations. Particularly, interesting enough, adults in the 18 to 50 years of age, women and minority groups, especially persons identifying as American-Indian, Alaska Native.

VR: Are these individuals vaccinated, Daniel?

DG: No, these are actually people who are forgoing that wonderful intervention.

VR: I see.

DG: All right, I will make sure I check on that. Children, COVID, and other vulnerable populations. Children are at risk from COVID as I’ve been stating for quite a while, but vaccines are complicated for kids. We have heard that mid-October, there might be an approval for bivalent boosters. Friday, September 23, Moderna requested emergency use authorization of its updated vaccine in two age groups. Adolescents aged 12 to 17 years and children aged 6 to 11. The application for the bivalent vaccine for children between the ages of 6 months and under 6 years is expected to be completed later this year, the company said in a tweet.


DG: OK, Pfizer asked U.S. regulators, Monday, 9/26/22, to expand use of its updated COVID-19 booster shot to children ages 5 to 11.

VR: In this paper, which you just talked about, additional data of interest, including vaccination status, were not available for this analysis.

DG: OK, excellent. Well, not really excellent, but yes.


DG: It would be nice to have that in there because I think as we keep pointing out, getting a vaccine is not going to guarantee that you’re not going to get infected or even reinfected. All right, use tests intelligently. Remember, there’s more out there than just COVID. As I like to say, have a plan. This is the time to have a plan before you end up with COVID.

We got an update from the CDC, “Interim Infection Prevention and Control Recommendations for Healthcare Personnel During the Coronavirus Disease 2019 (COVID-19) Pandemic.” This was updated on September 23, 2022. This will have some implications or it seems to be having implications for providers, facilities, and patients. It does look like it’s part of a shift that really seems to be acknowledging that zero COVID is not a goal, that COVID is really here to stay. It starts with a long bulleted list and there’s a lot of details. For those interested, I will leave the link.

COVID, active vaccination. Never miss an opportunity to vaccinate. Vaccinated people still get infected. They’re just less likely to die or have severe disease. This is where I should tell the story. My wife just recently took Barnaby for a trip. Barnaby is my son. I was going to say my youngest, oldest. He’s my only son. They were going to be gone for four days. Before she left, she leaves a couple, “By the way, make sure you feed the dogs. By the way, I’m only gone for four days. Don’t get vaccinated while I’m gone. I don’t care if there’s some new vaccine. You can wait and discuss it.”

Apparently, I’m so excited about vaccines that she needs to warn me. [chuckles] OK.

As they say, repetition is critical in teaching. I’m hoping to keep reinforcing the concept that while protection against severe disease appears to be durable, protection against infection with SARS-CoV-2 vaccination is transient and fleeting and temporary. The research paper, “SARS-CoV-2 Secondary Attack Rates in Vaccinated and Unvaccinated Household Contacts During Replacement of Delta with Omicron Variant, Spain,” was published in Emerging Infectious Diseases.

These are the results of a prospective, cross-sectional study of household contacts of symptomatic index-case patients with SARS-CoV-2 infection during the shift from Delta to Omicron-dominant variants in Spain. They included 466 household contacts from 227 index cases. The secondary attack rate was 58.2% during the Delta-dominant period and 80.9% during the Omicron-dominant period.

During the dominant-dominant period – That’s kind of a tongue twister. The Delta-dominant period, unvaccinated contacts had higher probability of infection than vaccinated contacts with an odds ratio of 5.4. Very exciting, but this effect disappeared at about 20 weeks after vaccination. This is where people keep asking, “Oh, my gosh, 20 weeks. What? Are we supposed to get vaccinated every five months?” I’m okay with that. I’m not sure everyone else is. All right, I think with the timing, this is the episode that will drop the day before Paul Offit comes on as a guest on TWiV, Vincent?

VR: That’s correct, yes.

DG All right. Tomorrow, Paul Offit will be recording. When you listen, it’ll be tomorrow that that episode drops. I’m looking forward to his appearance. I’m a bit concerned that his comments are being taken out of context. I think it’s really ideal that he’s on TWiV, where I think he’ll be given the time and the context to really communicate the science. As mentioned, I’m a bit more bullish on vaccines and boosters as our listeners probably know, as does my wife.

I just wanted to share a link to the CDC data on unvaccinated, fully-vaccinated, vaccinated with a primary series, plus two boosters with regards to deaths. Maybe we can place this in our show notes along with the link. It really points out that, wow, those first two shots is where we see this dramatic reduction, this 90% reduction in the risk of severe disease, hospitalization, death.

We do get a little bit of further benefit when we start throwing boosters on there. As I always point out to people, if your risk of ending up in the hospital and dying is zero, well, 50% reduction is still zero. I think there is an important discussion here. If you’re an older individual, if even that 90% reduction is still giving you a 5%, 6%, 10% risk of ending up in the hospital, if you can get another reduction, that becomes much more meaningful.

I do think that it is reasonable to have this discussion. I don’t think we need to be tribal about this. I think it’s reasonable to have a discussion. We’re going to even discuss, coming up, when should you get that booster if you should be getting it? All right, so the publications, there’s going to be two here. The first is, “Breakthrough Infection by SARS-CoV-2 Delta and Omicron Variants Elicited Immune Response Comparable to mRNA Booster Vaccination,” published in JID.

I think this makes for a good discussion. The data here is supporting the idea that an infection might be the immune equivalent of a booster shot. Here is data presented as well as a reference to other published data suggesting that both Delta and Omicron infection after vaccination elicited markedly high levels of serum total RBD, so receptor-binding domain, immunoglobulins and neutralizing antibody, as well as T-cell responses in individuals who previously completed two-dose vaccination.

The levels of immune response were comparable to those receiving the heterologous mRNA booster vaccination. I’m always hesitant when I share data like this. I never like the description of natural infection in the Hobbesian sense like a natural shark bite. Getting infected has all the associated risks. It’s not a nice way to get that immunity. I think we’re starting to see the science here, so don’t go out and have an infection party. That’s not the safest way to go.

VR: Of course, Daniel, they’re looking at antibodies, neutralizing antibodies, and they’re not looking at disease in any way, T-cells. We don’t know what this actually means in terms of protection against severe disease.

DG: They did do some T-cell stuff, but I think that’s really critical. We don’t have the data the way we do with the vaccinations on protection against severe disease and death. I sometimes worry, we think we’re smarter than we are. We look at these antibodies. We think we know what to make of them. We look at T-cells again. We think we know what that means. I was having a discussion today that I entered medicine when evidence-based medicine was considered as offensive as handwashing. It was this whole idea. I think we’ve discussed that, apparently, a well-controlled trial was more persuasive than a seasoned physician in 30 years of confirmation bias, right? [chuckles]

VR: In my experience, right?

DG: “In my experience,” the three scariest words in medicine. All right. Now, I want to bring this all together with the article, “Interval Between Prior SARS-CoV-2 Infection and Booster Vaccination Impacts Magnitude and Quality of Antibody and B-Cell Responses,” recently published in Cell. All is in this graphical abstract that we’ll post in a link and we’ll discuss briefly here. Again, it goes back to this concept. Is it all about antibodies? They look here at people that were uninfected and then got their booster.

They looked at people that got infected and then they boosted them within 180 days, compared to those who had an infection more than 180 days prior. Then they looked at people who were boosted and then infected. One of the things in the center of this graphic is people that had an infection in the last 180, so the last 6 months, then got a booster. You really didn’t see much happen to the antibody levels.

VR: It’s interesting because the previous study, an infection, at least in terms of antibody responses, does appear to be the equivalent of a booster.

DG: I think what they have to do in that first study is look at the timing. When was that infection relative to the timing? If you got your boost, let’s say, or your prior vaccine and you get infected a month later, does that do much? Does that give you extra? Does it count as a booster or do you need to have a certain amount of time from your vaccine? I do think there’s a lot here more we need to learn.

VR: Also, the order is different. In the first study, it was vaccination and then infection. Here, it’s infection then boosting, so maybe that makes a difference, right?

DG: Yes. Unfortunately, most of us will, at some point, get infected. At least the growing science suggests it’s nice to have that vaccine first. If you’re still out there, if you’re unvaccinated, if you’ve never gotten COVID, now’s the time to get vaccinated. The window’s closing.

All right, COVID passive vaccination, Evusheld, right? This is that product where we give you those antibodies authorized for use in adult and pediatric individuals down to 12 years of age. I hope that pediatricians are taking note of that. Even your high-risk teenagers, those who have immunocompromised, just think about this as an option.

I do want to discuss the correspondence, “Further Humoral Immunity Evasion of Emerging SARS-CoV-2 BA.4 and BA.5 Subvariants,” was published in The Lancet. Here, the background is that multiple BA.4 and BA.5 subvariants with this arginine-346 amino acid substitution, they used a different word there, but I corrected it, in the spike glycoprotein have been identified in various countries.

What are these? There’s the BA.4.6 thrown in there among others. I previously mentioned that BA.4.6. Lots of data here using a pseudovirus neutralization assay. While bebtelovimab still appeared effective, that’s our therapeutic monoclonal antibody, there were concerns about the passive vaccination with Evusheld losing efficacy. Maybe this is time for us to revisit the variant tracker.

Is the BA.4.6 something significant? Well, it is rising in our local area. The Region 7, that’s Iowa, Kansas, Missouri, and Nebraska. Don’t worry. I don’t have those memorized. There, the BA.4.6 is actually up to between 14% to 29.5%. Really rising in that area. It’s over 10% to 15% here in the New York Tri-State area. Definitely a concern for those that we’re trying to protect with the passive vaccination.

All right. COVID, the early viral, upper respiratory, non-hypoxic phase, that first week. The order is the same. Really, I guess what I’ll say is if you’re listening, if you’re a clinician, if you treat COVID patients or you know someone who does, you pause, have them pause. Jot this down. This is my recommendation. This is the NIH recommendation. This is the recommendation from the ID Society of America. These are the professional recommendations that are data-driven.

Number one, Paxlovid. About an 89% to 88% reduction in progression to hospitalization and death. I don’t care about the rebound or anything. What we are doing is we’re trying to keep people from dying. We’re trying to keep people out of the hospital. We have 400 to 500 people still dying per day. If we give all those people Paxlovid, right now, what is it about, 1% or 2% are getting treatment? We can instantly take that 500 and drop it to about 50 or 60.

Number one, Paxlovid. Number two, remdesivir, early three-day IV. We have data demonstrating an 87% reduction in progression if given in the first five days. If your loved one, if you end up hospitalized, people do end up hospitalized in the first seven days, three days of remdesivir is a perfectly reasonable, appropriate, recommended therapy.

I will talk about the article, “Short-Course Early Outpatient Remdesivir Prevents Severe Disease due to COVID-19 in Organ Transplant Recipients During the Omicron BA.2 Wave.”  This was published in the American Journal of Transplant. These are the results of a prospective cohort study in outpatient adult solid organ transplant recipients during the Omicron BA.2 wave, so April through May of 2022, to determine the effectiveness of the three doses of remdesivir given within seven days of symptom onset. Patients were followed for at least 30 days.

The primary outcome was hospitalization of 210 solid organ transplant recipients that had COVID-19. They included 192. The most common transplant was kidney. That was 41.7%. Lung, that was 19.3%. Liver, that was 18.8%. Heart was 6.3%. Most patients, over 90% had previously received at least three, so three or more COVID-19 vaccine doses, right? A lot of clinicians I know are out there saying, “Oh, you’ve been vaccinated. I’m not worried about you.”

The adjusted number needed to treat to prevent one hospitalization was only 15. There was an 88% reduction in the hospitalization rate, so an adjusted hazard ratio of 0.12. No patient that received early remdesivir needed ICU admission or died. Just more and more evidence. I know a lot of clinicians out there, “you’re probably going to be OK.” Well, the 99% of those 500 people that died may have been given that message. For them, it was not OK.

Monoclonal therapy. Now, we have bebtelovimab and the encouraging data that this is going to continue to be effective even with BA.4.6 increasing. Some evidence that it’s only slightly inferior to Paxlovid. I do want to point that out. The data we have head-to-head suggests that it is not superior, not equivalent, but slightly inferior.

All right, molnupiravir. We talk about our last option. It’s nice in that we don’t have drug-drug interactions, no renal issues. Remember, be careful in women of childbearing age, not authorized for those under 18. You want to get that negative pregnancy test if you’re going to be using it in a childbearing age population.

The article, “Effectiveness of Molnupiravir in High-Risk Patients: A Propensity Score-Matched Analysis,” was recently published in CID. These results are based on the database of the largest healthcare provider in Israel. People may know the name of them by now. They looked at adults with first-ever positive tests for SARS-CoV-2 performed in the community during January through February 2022, who were at high risk for severe COVID-19 and had no contraindications for molnupiravir use. Patients were included regardless of SARS-CoV-2 vaccination status.

A total of 2,661 patients who received molnupiravir were propensity score-matched with 2,661 patients who had not received molnupiravir, so that’s our control group. Patients were followed through 10 March 2022 for up to 28 days from the first occurrence for the composite severe COVID-19 or COVID-19-specific mortality. Now, what did they find? Everyone’s on the edge of their seat.

The composite outcome occurred in 50 patients in the molnupiravir group and 60 patients in the control group. Molnupiravir was not associated with a significant reduced risk of the composite outcome. We have overlapping confidence intervals here. They did then go on to do subgroup analysis that suggested that molnupiravir was associated with a significant decrease in the risk of the composite outcome in older patients.

There, they’re seeing 0.54, so a 46% reduction. Interesting enough, in females, 0.41, so a 59% reduction. And I think this is interesting, in patients with inadequate COVID-19 vaccination, that was 0.45, so a 55% reduction. I will point out. What was their definition of inadequate vaccination? This included people whose last vaccination or booster dose was greater than 100 days prior. Interesting.

OK, moving on to, “Don’t do harmful things,” and I think I can leave it at that. I think we know what those harmful things are. All right, COVID early inflammatory, lower respiratory, hypoxic phase. This is when often when those folks end up in the hospital. What defines hypoxemia? It’s been shifted in a number of different studies. Is it 94%? Is it 92%? It’s always less than 90% in all the different guidance.

Number one, steroids at the right time in the right patient at the right dose. Two, anticoagulation. Again, dose-adjusted based on your specific patient. Three, pulmonary support. Four, maybe remdesivir if you’re still within the first 10 days. Not if you wait too long and they end up on a ventilator. Not as effective as we talked about in that first week. Five, immune modulation. That’s our tocilizumab, our IL-6 receptor blocker, and, in some cases, baricitinib. Then six, avoid those unnecessary antibiotics and unproven therapies.

Moving on to COVID, the late phase or PASC. Actually, I feel like this was a good week for folks here. The article, “Long COVID – An Update for Primary Care,” was recently published in BMJ. I am going to recommend that all providers, I mean all providers, not just people who take care of people with Long COVID, we all take care of people with Long COVID, take time to read this article.

It will not take a tremendous amount of time. I do think that that time will result in a benefit for patients that are under your care, may even help you to recognize that these patients are under your care. They start with an updated definition. The term “Long COVID” refers to prolonged symptoms following infection with SARS-CoV-2 that are not explained by an alternative diagnosis.

It embraces the NIH and Care Excellence (NICE) terms “ongoing symptomatic COVID-19,” so symptoms lasting four to 12 weeks, and “post-COVID-19 syndrome,” symptoms beyond 12 weeks, the US CDCP group of “post-COVID conditions, and the WHO’s “post-COVID-19 condition.” They reference the data that rates of Long COVID are lower in people who are triple vaccinated, but prevalence of Long COVID, persistent symptoms at 12 through 16 weeks after laboratory-confirmed SARS-CoV-2 infection, remains high at 5% for the Delta variant and 4.2% for Omicron BA.2.

I’ll put in a link to the UK data they reference on this. Even though the absolute percentage might only be between 1% to 4%, there are a number of studies showing a lower risk of Long COVID after one dose, lower with two, and then a little bit lower with that third dose. Percentage of study participants. We have a link that we’ll post in looking at COVID based on vaccination status, based on types of symptoms.

VR: I’m glad to see that we’ve come down from 50% incidence of Long COVID at some studies we’re reporting, right?

DG: Yes. All right, they next discussed the different symptom clusters, right? I think we’ve talked a little bit about this. All Long COVID is not the same. There tend to be different symptom clusters. That actually helps us as clinician as far as guiding what therapies we might consider. Then they actually go through a list of things that physicians can do, which include – I’m going to just mention a few of these because we can do things. Don’t just throw up your hands.

One, hearing the patient’s story and validating the experience. That is critical. Two, making the diagnosis of Long COVID, which does not have to be by exclusion. You want to make sure there’s nothing else, but then you also want to make the diagnosis. Providing holistic relationship-based care through continuity of care with a sympathetic, they say, clinician, I’m going to say “provider,” who knows the patient. Then they focus on managing specific symptoms and there’s a Table 1. Really nice table.

You can go through what symptoms, what’s bothering you, and it goes through different suggestions on what you might want to do. They also talk about detecting and acting on red flag symptoms. There’s a nice infographic there. Managing those comorbidities, diabetes, cardiovascular disease, and then, I think this is really important, helping set realistic goals for recovery.

Ninety-five percent of these folks are getting better. They have to understand. This is not going to be a, “Wake up the next morning and be better.” This is going to be gradual. There’ll be two steps forward and then two steps backward. There will be a waxing-waning. I think it’s important to be realistic. They do talk, and I think this is really critical, of referral to other members of the primary care team. Get your pharmacist, your advanced clinical practitioner, your specialist, your social support services, and then follow them over time.

Monitor the progress, assess their mental well-being, manage depression, anxiety, other things that are either driving this or resulting from this. Really practical advice here, so I do encourage everyone to take a look there.

All right. I’m also going to put in, as we wind down here, a plug for a recent episode of Febrile, Sara Dong’s podcast. The title, “A MIS-Chievous Case,” gives it away, but it’s a nice exploration of a case of multisystem inflammatory syndrome in children.

I know there’s still significant hesitancy out there regarding childhood vaccinations for COVID, but I want to say, this is very sobering. They actually quote here that 8,600 confirmed cases of this multisystem inflammatory syndrome in children have been confirmed by the CDC. Thousands of children going through this. Just compare that to the safety and efficacy of our vaccines. Remember, this is a vaccine-preventable issue.

Our final article for today, “A Distinct Symptom Pattern Emerges for COVID-19 Long-Haul: A Nationwide Study,” was published in Scientific Reports. They have a really nice graphic. It really is, I think, helpful for us as clinicians to understand the timing, what patients might be going through, when to expect that. It starts off with acute COVID, fever, chills, maybe cough, sleeping more than normal, fatigue, headache, the viral phase.

Then it moves into the difficulty breathing, that second week, but then it moves into the third week when we start to see some confusion, joint pain, dizziness, the heart palpations, tachycardia, blurry vision. Just a really nice study looking at what we’ve been seeing, this progression over time.

I close as always, “No one is safe until everyone is safe.” I want everyone to pause the recording right here. Go to and click the “Donate” button. Even a small amount helps for us to continue to do our work. We are right now in the middle of our Floating Doctors fundraiser. During August, September, which is almost over, and October, donations made to Parasites Without Borders will be matched and doubled by PWB up to a potential donation of $40,000 for the tremendous work that Floating Doctors does down there in Panama.

VR: It’s time for your questions for Daniel. You can send yours to Adrian writes, “If we decide to get the bivalent booster, how important is the timing? My wife saw an article claiming you shouldn’t get it sooner than four months after a previous COVID infection because the body won’t develop a strong immune response to the shot, but I recall guidance on TWiV that people could get the vaccine a few weeks after infection, so does timing matter?”

DG: Yes, I think as we’re learning more and as things are changing with the pandemic, and I’ll say what I mean by that, our advice, our guidance is evolving with the knowledge. Early on, when we had people completely unvaccinated and they would get an infection, we kept having this variant, this variant, that variant. People were getting infected 30, 45 days after the first infection.

We were saying, “Listen, once a couple of weeks have gone by, if you’re unvaccinated, let’s get going. Let’s start that vaccination series.” I still feel the same way about the unvaccinated. If you got your infection, maybe that’s the wake-up call. Maybe it’s time for you to jump on board. As we discussed today, if you’re an individual, you’ve gotten three shots, let’s say, two shots. You just got an infection in June. Here we are, July, August, September, I’m counting on my hands, three months out.

I’m not sure that that booster is going to do a lot for you. One month, two months, three months. Start thinking about timing. We think that our boosters are going to give us protection against infection for a limited period of time. We talked about that being 20 weeks or less, maybe diminishing a little bit over time. We don’t know yet how much that’s going to add to moderate, severe disease, hospitalization.

Again, that’s going to come down to your risk factors. If you’re a 91-year-old gentleman carrying extra weight, a number of health issues, then three months might seem reasonable. Now, we’re starting to get into areas where we know that the sooner you get that, you may not get that antibody response, which is actually what all the data was prompting us to go forward with these boosters.

VR: Anthony writes, “I just received my bivalent booster of COVID-19 vaccine, but I’m also prescribed hydroxyzine for anxiety. I was wondering if you knew anything about antihistamines reducing the efficacy of a vaccine because of reduced inflammation and thus reduced immune activation.”

DG: Yes, I would sleep well, which maybe hydroxyzine will help you do. Now, I’m not particularly concerned that that’s going to have a significant impact upon your vaccination.

VR: Bradley writes, “Love your podcast. This is my question. I was told I should wait at least 14 days after taking COVID-19 booster before taking a live vaccine. Could you explain this waiting period versus vaccines that are given simultaneously? I heard the opportunity to take my first JYNNEOS intradermal vaccination at a festival in San Francisco this last weekend, so I did even though I was only 10 days post-COVID-19 booster. It was convenient. No waiting in line. Do I have anything to worry about? I’m 63. I’m sure I had Dryvax when I was young. I had quite an injection-site reaction.”

DG: In this situation, I don’t see a problem. We’ve talked a little bit about recommendations of the timing. We’re, interesting enough, prioritizing that monkeypox vaccine. Here’s the situation you described. You got your booster and then, boom, suddenly, there’s this opportunity to get your JYNNEOS monkeypox vaccine. Fine. Go ahead. Get that monkeypox vaccine. Get another dose four weeks later. I do not think that that COVID vaccine is going to reduce the response, reduce the protection that you’re going to get.

VR: Erica writes, “I want to thank you and Dr. R for the incredible service. I teach undergraduate medical and molecular virology at Colorado State, Fort Collins, with Tony Schountz,” who’s been on TWiV, of course, and who I saw recently. By the way, Erica, Tony was saying, “I have to start working on the course with Erica,” at the time of that meeting. “I’m curious if you have any clinical experience with patients who have mast cell activation syndrome and COVID. I was originally diagnosed with mastocytosis. They later downgraded to MCAS.”

“I’m very well-controlled with lots of H1 and H2 antihistamines and Elmiron without having to take cromolyn. I have read that patients on the mast cell stabilizers are less likely to progress to hospitalization. I know that famotidine has been correlated with better outcomes among high doses of that. What I cannot find any information on is, do people with MCAS have to be more concerned about Long COVID?” She goes through some publications. “I’m just curious if you’re seeing any MCAS patients if they’re more likely to develop Long COVID.”

DG: Yes, so I see a number of patients who have this. You’re really describing the treatment paradigm that we approach. The high doses of the different antihistamines. I’m not sure how much I can add to what you brought in. There was some early excitement, I’ll say, that famotidine would be this early treatment for COVID. I’m not sure that ever really panned out. If you looked at 1,000 variables, you could find 12 that looked interesting. Data mining, in my opinion.

There also was a lot of interest in the idea that maybe a subset of people with Long COVID, of PASC, actually, have developed this mast cell activation syndrome. There is actually, as you’ll see in some of the literature, a subtype, which really looks like it’s – we call it allergic subtype, an antihistamine responsive subtype. I think there’s still quite a bit here to learn. Keep my radar up. As we learn more, I’ll definitely share information on this.

VR: William writes, “I’ve heard some talk about using high-dose influenza vaccine in immunocompromised patients under 65 years old. Is this a good idea?”

DG: Yes, this is interesting actually. As our listeners may or may not be aware, this is the first year that the CDC has come out with preferential recommendations on the vaccines basically saying, “Hey, people over 65, these are the ones that are studied. These are the ones that we recommend.” About a year ago, we had a discussion. I think we discussed the data on TWiV, where the cell base of the Flucelvax, if you look across the entire population, tended to be more effective.

What we’re doing, I know, as an organization is all the way across the board, we’re recommending the cell-based Flucelvax. Then when people get over 65, we’re recommending those high-dose, the double-dose, egg-based, and some of the others out there. They’re not approved for under 65. What I’d say for folks under 65, look for that Flucelvax.

VR: Finally, Carol says she’s making a plan as you have suggested. She wants to get Paxlovid from her primary care physician, but the physician says, “Before you can do that, you need to get a creatinine test,” which she said is very expensive and wants to know if it’s really necessary before you get Paxlovid.

DG: Yes, it is actually. It’s important to know the renal clearance, the renal function, and that creatinine test is how we know that. I do apologize for our broken healthcare system, but no, it is critical to know kidney function for your clinician to safely use Paxlovid.

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

DG: Oh, thank you, and be safe. Vincent, you be safe too.

VR: I will.


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