TWiV 938 Clinical Update

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 24 September 2022

PDF of this transcript available (link)

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

[music]

VR: From MicrobeTV, this is TWiV; This Week in Virology, Episode 938, recorded on September 22, 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: We almost recorded at The Incubator but we didn’t quite, right?

[laughter]

DG: It’s true. I was there, we were both there today, but I think we figured out this was a way for us to actually be home before midnight.

VR: We have a TWiV coming up and it would have been just too late. If you would like to celebrate the molecule of the year, the spike protein of SARS-CoV-2, and support science education by purchasing a Spike t-shirt from vaccinated.us, if you do that, profits will go to MicrobeTV. It’s a really nice arrangement they’re making with us, Matt, over at ‘Vaccinated,’ vaccinated.us, they have some cool Spike t-shirts. Pick your T-shirt, put it in the cart. When you check out, use the promo code ‘MicrobeTV’ and it will go towards supporting our science education. Thanks, Matt, and thanks vaccinated.us.

DG: I’m excited. Hopefully, we’ll have a link in the show notes. I think I heard about that on Immune and I’m excited to order my own Spike shirts.

VR: You should get a Spike shirt. I told someone today and they said, “I don’t like Spike.” I said, “Yes, you like it in the vaccine. You might not like it in the virus.”

DG: Exactly. We have a lot to cover today, I apologize ahead of time. I’m trying to keep this short, but part of this is we got a bit of a request for a recap of where do things stand with polio. Perhaps some people haven’t been listening for a few weeks, but I’ll start off with the quotation, “You don’t have to burn books to destroy a culture, just get people to stop reading them.” That’s from Ray Bradbury. Let’s start off with the recap of what’s going on with polio. This July, we heard that there was a case of paralytic poliomyelitis identified in an individual from Rockland County, New York.

The CDC at that point was consulting with the New York State Department of Health, this had been confirmed by the CDC to show that this was revertant polio Sabin type 2 virus. We then heard that this case in New York was genetically linked to two Sabin-like 2 isolates collected from the early June samples from Rockland County, and samples from greater Jerusalem, Israel. As well as to the recently detected vaccine-derived polio vaccine type 2 from environmental samples in London, UK. What does all that mean?

Someone was vaccinated outside the U.S., because we don’t vaccinate with oral poliovirus here. They were vaccinated outside the U.S. with oral poliovirus vaccine that contained the attenuated type 2 poliovirus. This reverted to neurovirulent, which it does in everyone who gets this, and then that virus is now here in the U.S., is infecting and in this case, paralyzed this man. We, in August, got the full case report and this was in the MMWR, “Public Health Response to a Case of Paralytic Poliomyelitis in an Unvaccinated Person and Detection of Poliovirus in Wastewater, New York, June-August 2022.”

We hear that this was a young adult. I think that’s important this is a young adult. This is not under 18, this is not a 4-year-old, this is actually a young adult with a five-day history of low-grade fever, neck stiffness, back, abdominal pain, constipation, and two days of bilateral lower extremity weakness. Visits an ER, is subsequently hospitalized with at that point suspected acute flaccid myelitis. The patient, as mentioned, unvaccinated against polio.

As part of the National AFM Surveillance, the New York State Department of Health, the CDC get involved, sequencing of the stool specimen identifies the poliovirus type 2. If it’s not interesting enough, I’ll say this is when it gets more interesting. Based on the typical incubation period for paralytic polio, the presumed period of exposure occurred seven to 21 days before the onset of paralysis. It appears that this patient attended a large gathering eight days before symptom onset, had not traveled internationally during the presumed exposure period.

It looks like he got polio at this large gathering. We have polio virus here in the U.S. and you can get polio the disease, right here in the U.S. Paralytic polio and other forms. If unvaccinated, this might involve getting paralyzed for the rest of your days. This led Governor Hochul to declare a polio state of emergency in New York after the virus was detected in Orange County, Rockland County, New York City, and Nassau County wastewater samples. I’ll throw Sullivan has now been identified as well.

On the next comment, this is fresh off the press this last week, so an update. We heard that, “Community Spread of Polio Prompt CDC Wastewater Surveillance.” Apparently, the CDC, the Centers for Disease Control and Prevention, is planning to test wastewater to detect the poliovirus in communities at highest risk for the life-threatening and potentially disabling illness. I have an issue with this, Vincent. They are going to what, look at counties where vaccination rates are low. They seem to be suffering from the same concept that vaccination prevents infection, prevents transmission.

I think we need CDC wastewater surveillance everywhere so we can continue to reinforce this message. Let’s go through it. Again, we’re going to jump you in here, Vincent. First, is this really a problem? That answer really depends on your vaccination status. I’m going to say there are likely hundreds if not thousands of cases of non-paralytic polio right now in our region. Why do I say thousands? We talked about this before, there are three polio types and each one of them has subtypes.

In general, to keep it simple, type 1 and type 3 lead to about 1:300 infected unvaccinated persons will end up with paralytic polio. Type two, that’s what we’re talking about here, vaccine reverting, about 1:2,000 poliovirus type 2 infections among unvaccinated persons is expected to result in paralysis. I hope people are shaking their heads and saying, “Dr. Griffin, what are you talking about? Where are all these people that you’re talking about?” My answer to you is, you are seeing these people, you’re just not recognizing it.

You’re not diagnosing it. What do I mean by that? It’s currently suggested that over 90% of poliovirus infections in unvaccinated persons are asymptomatic and this may be even higher in vaccinated. In the less than 10% of individuals that do have symptoms, the symptoms develop following an incubation period of we say four to 10 days, and resemble those of common viral infections. Maybe they have a headache, maybe a sore throat, maybe fever, malaise, vomiting, nausea, fatigue. Has anyone experienced any of those symptoms?

Has any physicians, clinicians seen anyone with those symptoms? Unless we actually test, which we do only with acute flaccid myelitis, these fly under the radar. I will comment, the majority of those that get acute flaccid myelitis never regain their strength. So what do we do? As mentioned, get vaccinated. “Dr. Griffin I’m so tired of all these shots. Can I just get my serology checked? I know you keep saying negative things about serology but enough is enough.” The answer is, get vaccinated. We’ve talked about this before.

The CDC says that in the absence of the availability of testing for antibodies to all three serotypes, serological testing is no longer recommended to assess immunity. We no longer test for type 2. Type 2 is what’s circulating. We have no ability to test for type 2. By the way, even if you test for type 1 and type 3, we’re not sure how reliable those are because of cross-reactivity with other enteroviruses. The other I will say, there’s no free lunch here and this is really an important lesson.

We currently use IPV, this Inactivated Injectable Poliovirus vaccine which offers zero protection against infection but greater than 99% protection against paralytic disease. Living in a highly vaccinated community does not protect the unvaccinated as we have seen with poliovirus now present not just in regions with low vaccination rates, but in highly vaccinated communities like Nassau County.

VR: Daniel, the CDC has made the decision that if you’re in a highly vaccinated community whether or not poliovirus is circulating there, they’re not interested in finding out because they’re assuming you’re protected. They only are interested in communities where coverage is low. They look for poliovirus, they find it then what do they do? They tell people to get vaccinated, but they don’t want to get vaccinated. I’m not sure what the outcome of that strategy is.

I think we need to know where poliovirus is circulating in most of the country because even if a community has high vaccination rates, there might be one person whose vaccine didn’t take and they’re susceptible to poliomyelitis. I think it’s an error not to do broader wastewater sampling for poliovirus. I learned from Laurie Garrett today, we have 1,000 wastewater sampling centers across the U.S. A lot of them in New York and California, and many states don’t have any, unfortunately. This is a real problem, but they could easily start checking for poliovirus and see just what’s out there.

It’s the same problem we had with SARS-CoV-2. It’s the same problem we have with monkeypox. If you don’t know where it is, it’s more of a threat.

DG: Yes. It’s also a backup on us as clinicians we miss stuff and when, for instance, we’ll get to monkeypox so we say, “Oh, the numbers are going down.” The number of diagnoses we are making might be going down, the wastewater will tell us, are we missing more? Is the virus really going down? I think that’s really critical and I’ll just close out the polio section by saying there are a couple updates as far as vaccine recommendations. I don’t know if I really get the science on this, but they are recommending that all healthcare providers working in any of these counties get a one-time booster.

I will move on to influenza. We got an interesting call today where someone was suggesting that the current virus was going to be a mismatch for this year. I pointed out that we don’t really know that until after the fact. Hard to predict the future as Yogi Berra points out but I thought this was interesting. The article. “Impact of Mandatory Vaccination on Healthcare Personnel, on Rates of Influenza and Other Viral Respiratory Pathogens,” published in Infection Control and Hospital Epidemiology.

I think it’s helpful with regard to some rather heated debates about mandatory vaccination policies for healthcare personnel. Lots of limitations, and unfortunately they put this behind a paywall. These investigators analyzed rates of influenza and other viral causes of respiratory infections among healthcare providers working in outpatient sites at four VA health systems without mandatory influenza vaccinations and three non-VA health systems with mandatory influenza vaccination policies.

In this analysis, they reported influenza vaccination was associated with a decreased risk of influenza, interesting, decreased risk of influenza odds ratio 0.17 so 83% reduction. They did see an increased risk of other respiratory viral infections.

VR: So they mean influenza the disease, correct?

DG: That’s what they mean here. They mean influenza disease, not running around sticking Q-tips up people’s noses trying to get positive PCR. This is decreased risk of influenza, the disease.

VR: It’s impressive.

DG: Get your flu vaccines. Actually, timing matters, right, as we keep talking we’re starting to make this recommendation that October is probably a good time, probably good timing for the influenza vaccines. Interesting I was listening to Paul Offit the other day and he said some vaccine experts actually get two flu shots. I always get two flu shots. Maybe we’ll talk about that later. Monkeypox update. Monkeypox is not a gay disease or an African disease, monkeypox is an infectious disease. I want to comment here.

It’s really interesting how the goalposts have moved. We now have as mentioned confirmed cases on college campuses across the country, such as, and I’m going to list them Georgetown, George Washington, University of Texas in Austin, Bucknell, West Chester University in Pennsylvania. The CDC, it’s actually The Centers for Disease Control and Prevention, so the CDCP is currently projecting that the outbreak will most likely continue to grow very slowly over the next few weeks. Health officials say it’s a cause for cautious optimism, but not complacency.

I don’t know, it’s interesting. We were talking about how we were going to get on top of this and I put up here the daily monkeypox cases reported the seven-day daily average. Which looks like we’re getting into this plateau about 200 new cases a day. We’ll see where that ends. I really had a lot more optimism here with the concept of interrupting chains of transmission. We’ve got vaccines that we think that work we’ve got therapies that we think work. I was mentioning, Vincent, I just saw a woman this morning in the hospital, really severe case horrible monkeypox so really a horrible disease.

One case is too many, 200 new cases a day is 200 too many, but as I have mentioned, the monkeypox situation has shifted. We have the MMWR early release “Monkeypox in a Young Infant, Florida, 2022.” This is a report of a case of monkeypox in an infant aged less than 2 months, who was admitted to a Florida hospital with rash and cellulitis. The infant was initially evaluated in the ED department so emergency department for a raised erythematous rash on the arms, legs, and trunk, which had been present for five days.

A rash swab was collected for bacterial culture, yielded a negative result. Varicella, HSV, HIV testing were also negative. The patient returns to the ED two days later, what’s going on? At which time the rash has progressed to include numerous diffusely, scattered papulovesicular lesions over the body, many with central umbilication. I think we know where we’re headed. The infant was admitted to the hospital and the diagnosis was made of molluscum contagiosum. I don’t know how many times I’ve heard that story.

The lesion subsequently spread to the back, soles of feet, face, eyelid became pustular over the first few days of admission. Finally, swabs were sent 10 days after rash onset. The infant goes ahead and is treated. I will just point out today 27 confirmed cases of monkeypox in pediatric patients aged zero to 15 have been reported confirmed in the outbreak so far.

VR: Daniel, is it because the child was so young that the clinicians didn’t suspect it would be monkeypox?

DG: I have to say Vincent, the woman that I just saw this morning, severe enough to hospitalize, horrible oral lesions, same story. They thought it was molluscum. Actually was admitted for molluscum just like this. Durham got involved and then suddenly it spread. Durham said, “We’re signing off,” then it was diagnosed as monkeypox. Outside of the MSM population, it’s as we’ve discussed characterized by delayed diagnosis and while you’re delaying that diagnosis, how many people are you exposing?

VR: Isn’t this a place where the CDC should say, calling all physicians, look at any rationale as potentially monkeypox and test for it?

DG: I think it would make sense. There’s this interesting culture, you don’t want to be the boy who cried wolf. You don’t want to be swabbing everyone. I’m on service at Columbia right now. I was talking to house staff. I was like, you should have a 90% negative swab rate. If 50% of the time you swab, you’ve got monkeypox, you are not testing enough. We don’t know enough to say it doesn’t look like monkeypox. Right now, we’re in the midst of this outbreak we’re pretty confident we’re underdiagnosing so if you see a rash, you got to test it at this point.

I think it would make a lot of sense for the CDC to step up and say, you got to start swabbing more, really encourage us to stop missing so many cases. Stop people waiting as long as it takes for them to finally get the diagnosis. Not so much molluscum contagiosum out there as people seem to think. Monkeypox transmission, this is predominantly through contact, no sex required, but as mentioned, we’re going into that room today. All these oral lesions we’re using N95 eye covering, the whole nine yards, as they say.

An interesting MMWR early release, “Healthcare Personnel Exposures to Subsequently Laboratory-Confirmed Monkeypox Patients, Colorado 2022.” Because we’re not making that diagnosis right off. The authors start by stating that the risk for monkeypox transmission to healthcare personnel caring for symptomatic patients is thought to be low, but has not been thoroughly assessed in the context of the current global outbreak. Monkeypox typically spreads through close physical often skin-to-skin contact with lesions, scabs, body fluids, respiratory secretions of a person with active monkeypox infection, so we think.

Then they go on to state that the CDC currently recommends that healthcare personnel wear a gown, gloves, eye protection, and an N95 or higher-level respirator while caring for patients with suspected or confirmed monkeypox to protect themselves from infection. Everyone else is being reassured that you don’t need to worry about us healthcare personnel are wearing our hazmat gear. Every time apparently we evaluate a patient with rash. That’s not true. During May 1 through July 31, 2022, a total of 313 healthcare providers interacted with patients who were subsequently diagnosed with monkeypox infections.

Only 23% wore all the recommended PPE during their exposures. I have to say that actually seems high. Then we read healthcare personnel with intermediate and high-risk exposures were eligible to receive PEP with JYNNEOS vaccine. Among eligible healthcare personnel, only 43% went ahead and received post-exposure prophylaxis. No confirmed monkeypox cases in this healthcare personnel. Shall I muse a little bit about infection transmission concepts in COVID-19 but let’s move on.

Monkeypox testing. Remember we should be over-testing and catching these diagnoses. You’re going to swab two of those non-cotton swabs. You’re going to try to open one of those vesicles, pustules get those into liquid. Then you’re going to either refrigerate or freeze those, send those off. As we talked about this morning with the crew the house staff, you want to be looking for VZV, HSV. You may even consider MRSA swabs because sometimes this can look like a pustular folliculitis.

The article, “Monkeypox Testing Delays: The Need for Drastic Expansion of Education and Testing for Monkeypox Virus.” This is like right down your line, Vince, and you were you’re efficient for this. This was published in Infection Control & Hospital Epidemiology. The authors retrospectively analyzed all monkeypox cases diagnosed with Atrium Health, a large healthcare system in the greater Charlotte region offering monkeypox testing across a broad geographic footprint at 32 urgent care centers, 20 ERs, one infectious disease clinic as of August 8, 2022. They specifically examined potential delays in diagnosis, given clinician unfamiliarity with monkeypox.

They found an average of a six-day delay range of two to 14 days in testing after symptom onset. Of those who had multiple visits, the mean number of visits prior to monkeypox recognition was 1.6 ranging up to five visits. The visits during which monkeypox could have been diagnosed and recognized earlier occurred most frequently in the ER about half of the time followed by urgent care clinics, hopefully none of ours, 17%, primary care offices, 13% and other outpatient clinics, 17%. The delays resulted in 222 potential healthcare worker exposures.

Forget about all the exposures at home and outside, a median of five exposures per encounter. Test more, stop delaying.

VR: No wonder it’s spreading, right?

[laughter]

DG: Yes, I can do nothing other than laugh. I thought we had learned something, but OK. Monkeypox vaccines. We’ve got them but do they work? The research letter, “Monkeypox In Patient Immunized with ACAM2000 Smallpox Vaccine During 2022 Outbreak,” was published in Emerging Infectious Diseases. Now, this is a case report so a single patient, Washington who contracted monkeypox despite being successfully immunized against smallpox with the ACAM2000 smallpox vaccine eight years earlier.

The authors state, this poses major questions regarding the efficacy of ACAM2000 vaccine amidst ongoing shortages of JYNNEOS two-dose monkeypox vaccine. I do think there’s an educational aspect to this case I’ll walk through it. This patient was a previously healthy 34-year-old man who had sex with men then came to a walk-in sexually transmitted infections clinic because of a four-day history of malaise fatigue, headache, and a two-day history of four painless penile lesions. The patient had sought evaluation at a local ED two days before he visited the clinic.

Results from testing performed in the ED were negative for gonorrhea, chlamydia, and HSV. Wait, where’s the monkeypox test? His constitutional symptoms improved over the next two days. However, his penile ulcers progressed, seeking him to get reevaluated. Why was he not already tested? In the previous 90 days, he reported penetrative, anal, and receptive oral sexual intercourse with 13 to 14 new partners denying any condom use. Why has he not been tested? Because of his military service, he had been vaccinated against smallpox with ACAM2000.

Oh, so I guess he was protected. On examination, the patient had four ulcerated penile lesions that had consolidated into a three-sonometer patch present on the foreskin two days after constitutional symptoms developed. Actually, I have a picture of this. The lesions were non-tender to palpation. Hopefully, you’re wearing gloves, no discharge, a tender three-sonometer right inguinal lymph node was present, so little thing we’re noticing. A vaccination scar was noticed on the right deltoid. Given the condition of the patient, his sexual history, guess what, they actually tested him and the test was positive.

Non-variola orthopoxvirus PCR was conducted and positive. Subsequent confirmatory testing identified the infection as Clade II strain, formally the West African, so finally make the diagnosis. They do reference the 1988 study that reported that smallpox vaccination might offer about 85% protection against monkeypox. I’m going to leave a link to this Zaire study.

VR: We’re thinking Daniel, that this is that 15% that’s not protected, right?

DG: Yes, I’m not sure this is the sky falling. You say 85%, that means people are going to get, and maybe there’s an impact on severity. I think we need to do the science, but I don’t think this is as troubling as it was portrayed. Monkeypox clinical course and treatment. That efficacy study, the STOMP trial, so go to www.stomptpoxx.org. My buddy Jason Zucker is helping to enroll patients up at Columbia, a lot of other sites as well. Just want to point out that not just severe, the severe people are all going to get treatment; the non-severe, we’re going to have a placebo control group.

 Should we study this or should we just give it to everyone? Well, let me introduce our listeners to the concept of barrier to resistance. This is how easy or likely it is for a pathogen to become resistant to therapy. High barrier resistance is good for us bad for the virus, low barrier for us, great for the virus. The FDA expanded their information page to point out that it does look like TPOXX may have a low barrier to resistance. Thus, it may be easy and likely that excessive TPOXX use will result in TPOXX-resistant MPOX.

I quote, “TPOXX works by inhibiting a viral protein called VP37, that all orthopoxviruses, so smallpox virus, monkeypox, vaccinia virus share. However, it’s noted in the drug label TPOXX has a low barrier to viral resistance. This means that small changes to the VP37 protein could have a large impact on the antiviral activity. Really a bit of a warning, don’t just be using this willy-nilly. Fortunately, the current situation prevents that. We really need to understand how well this works, for whom it works, timing, other considerations. Remember the STOMP trial.

COVID. People are likely aware that here in the U.S. with the death toll down to just over to 400-500 per day, up from a lull of about 168 in July, a prominent individual announced that the pandemic was over. As Paul Offit likes to say the pandemic is over when we decided it’s over, but remember this is a pandemic. One country doesn’t get to decide. We can’t just say here in the U.S. that the pandemic is over for the entire world, for the billions who still are without access to vaccines, testing, effective treatment, this shift in perspective seems premature.

It’s too U.S.-centric and I think too privileged U.S.-centric to me. I also have to say that even focusing on the U.S., the idea that 400-500 individuals dying per day is acceptable. The thousands dying throughout the world for all their loved ones for them, this horrible situation is not over. Just a little bit of a comment there because I know a lot of people were asking me how I felt about that pronouncement. Children COVID and other vulnerable populations. Children are at risk of COVID. The vaccines, as we mentioned can get a little complicated for the kids.

You want to have that reference chart and we’re also hearing that mid-October, there might be an approval for bivalent boosters in younger individuals. So we’ll have to discuss that when we get more information. Post-exposure period, transmission testing. Remember this is where I say have a plan, part of that plan critical to that plan is getting vaccinated. The article, “Detection and Kinetics of Subgenomic Severe Acute Respiratory Syndrome Coronavirus 2 RNA Viral Load in Longitudinal Diagnostic RNA–Positive Samples,” was published in JID.

I think this is a fairly sophisticated idea that one could use detection of subgenomic RNAs to detect active viral replication versus standard RT-PCR, which might just pick up residual genomic material. Here’s the idea? What is this? Coronaviruses such as SARS-CoV-2 are large positive-sense, single-stranded RNA virus that generate structural and accessory proteins through a process of discontinuous transcription with the resulting subgenomic RNAs encoding the leader transcription regulatory sequence in close proximity to the target gene.

Now that’s complicated. There’s actually a nice review. I’m going to put a link for those that want to dig deep, continuous and discontinuous RNA synthesis in coronaviruses. There are some nice figures that explain how this RNA synthesis is continuous and transcription is discontinuous. This is still a type of PCR, but here one is using a different set of primers targeting these subgenomic RNAs. Still, there might be some over-calling using this technology of replicating virus compared to virus cultures, as they say in their discussion.

One caveat of this study is that detection of subgenomic RNAs is not identical to the detection of infectious virions, particularly at later time points after infection and when neutralizing antibodies are present. What did they find? They looked at nearly 2,000 nasal swab samples with SARS-CoV-2 detected by real-time RT-PCR collected from 1,060 outpatients participating in a PEP and treatment clinical trials. In this study, the trajectories of the diagnostic RNA and the subgenomic RNA– They say viral load I’m going to say copy numbers, over time differed, with sgRNA peaking slightly sooner. So, 1.2 versus 1.8 days, and a faster clearance at 6.7 from peak compared with greater than 12 for diagnostic PCR. They state in their discussion that assuming individuals test soon after the onset of symptoms, the current CDCP recommendation for a five-day isolation period approach the duration of detectable subgenomic RNAs in this study. Thoughts, Vincent? Do you think this is a reasonable bit of science?

VR: Yes, I think so because without mRNAs the virus can’t reproduce, right? It’s a good indication of reproduction, as opposed to just the total RNA, the genomic RNA, which can just be pieces. I think the curve you show here is quite interesting how much sooner the shedding of mRNA stops. I think it would really be nice to correlate that with infectivity. Don’t you think though, Daniel?

DG:  And really good case-control studies, because I think this is critical. The CDC’s getting really beat up over some of their recommendations. On a call earlier today with a woman who’s like 16 days out and she did a rapid test because she has the Jewish holidays coming up. She says, “Oh my God, it’s positive. I need to cancel Rosh Hashanah.” We had a long discussion about what to do. Let me jump into the next one while everyone’s up to speed on subgenomic RNA.

The article, “Qualitative Subgenomic RNA to Monitor the Response to Remdesivir in Hospitalized Patients with COVID-19: Impact on the Length of Hospital Stay and Mortality,” was published in CID. Here the investigators looked at 117 patients that were treated with remdesivir that had a nasopharyngeal swab collected at baseline, then after three and five days of treatment with remdesivir, then looked at early discharge – less than or equal to 10 days. They looked at 30-day mortality. Of the 24 with a negative subgenomic RNA at baseline with a 62.5% had early discharge in less than 10 days.

There were zero deaths in the group. Based upon what we said, they didn’t actually have replicating virus at that point. I’m not sure what the remdesivir is doing. A second group of patients with a negative subgenomic RNA at day five, 59.6 had an early discharge. The mortality here was 4.8%. In the patients with a positive subgenomic RNA after five days of remdesivir, their early discharge rate was 29%. The mortality was 16.1%. Small study currently not something that we have easy access to clinically, but it is interesting.

Based on the study, they actually suggested that low CT values might correlate fairly well and be poor man’s proxy for subgenomic RNA checking. COVID vaccination, never miss an opportunity to vaccinate. Vaccinated people still get infected. They are just less likely to die or have severe disease. Right on. Q Anonymous last week, the day was recorded. The correspondence, “Anti-Spike Mucosal IgA Protection against SARS-CoV-2 Omicron Infection,” was published in The New England Journal of Medicine.

Here the investigators evaluated SARS-CoV-2 specific mucosal antibody responses in 338 triple vaccinated healthcare workers over time. Participants who had high levels of wild-type spike-specific mucosal, IgA, defined as those in the greater than equal to 75th percentile at enrollment, had a significantly lower risk of subsequent Omicron breakthrough infection than did those with lower levels relative risk 0.35. An interesting correlation here between really high mucosal IgA levels. I guess I should make a comment. Is that really an attainable goal? Can we keep people at that level?

I think Vincent and I will shake our heads and got another article next week already in the queue to discuss. The correspondence, “Effectiveness and Durability of the BNT162b2 Vaccine against Omicron Sublineages in South Africa,” was also published in The New England Journal of Medicine. Here the authors applied a test-negative design and data exclusion rules to obtain estimates of vaccine effectiveness against hospitalization during the BA.1-BA.2 wave and during the BA.4-BA.5 wave. Lots of limitations here, no mention of mortality.

No mention of whether these hospitalizations related to oxygen needs. Admissions for early respiratory hypoxic phase due to moderate or severe COVID or just people getting hospitalized due to being frail and doing poorly during the first week’s viral symptom phase. I expect this will get a lot of play, but I’m not really sure I know what to make of this data.

COVID passive vaccination. Remember EVUSHELD, don’t make this Evushelf. I was a little annoyed this morning. Had a patient, a TWiV listener who’s actually a patient of mine, long discussion, they’re immunocompromised. They’re on a number of immune suppressants. Finally, they were having discussion. The rheumatologist agreed to order the EVUSHELD. They had their appointment, they were ready to go, but they got a call this morning from the office. Their appointment had been canceled because their antibody levels were too high, apparently prohibitively high. I’m not sure what science I missed.

I think that’s in really directly counter to the FDA guidance regarding using those serology tests. Please don’t deprive people of EVUSHELD because you have some idea that you know what to do with those antibody levels.

COVID early viral, upper respiratory non-hypoxic phase. This was really painful for me to read, but the article, “Usage and Awareness of Antiviral Medications for COVID-19 Among Individuals at Risk for Severe COVID-19, March 2021 to 1 August 2022,” published in CID. This is a free-access article and these are results from 44,948 respondents.

We learn that individuals, age 65 and older, right? These are high-risk folks. 66% were aware that there was treatment for COVID-19. 36.3% actually sought treatment. Only 1.7% ended up getting antiviral therapy.

VR: That’s why people are dying, right?

DG: That’s why people are dying. People are dying, because they’re not getting vaccinated. People are dying because providers are saying, “Let’s wait and see. Let’s wait until my opportunity to reduce your risk of progression by 90% is gone.” Then, “Oh, we’ll put you in the hospital, and then we’ll start an antiviral,” when it’s too late. There’s no science that it’s going to be helpful. Please 1.7%. This does not make me optimistic for the coming months. Number one, Vincent.

VR: Monoclonal. Oh, sorry.

[laughter]

Number one is Paxlovid. Of course.

DG: Number two?

VR: Remdesivir.

DG: I’m actually going to say number three and I’m supposed say three and four, but number three, monoclonal therapy, bebtelovimab. We have a nice article, “Outcomes of Bebtelovimab Treatment is Comparable to Ritonavir-boosted Nirmatrelvir  (that’s Paxlovid treatment), among High-Risk Patients with Coronavirus Disease-2019 during SARS-CoV-2 BA.2 Omicron Epoch.” Is it epic? The commentary, “Bebtelovimab in the Real World: Promise and Fulfillment,” were both published in JID.

In this study, it’s a retrospective cohort study of over 3,600 patients treated either with the monoclonal bebtelovimab or nirmatrelvir-ritonavir, the Paxlovid under EUA criteria when BA.2 became the dominant sub-variant. In the bebtelovimab group, 1.4% progressed to severe disease versus 1.2% in the Paxlovid group. 0.2% died in the bebtelovimab, group, zero deaths in the Paxlovid group. There is some suggestion if you look through that the folks receiving bebtelovimab may have been at higher risk.

Really encouraging to finally have some actual efficacy data, and pretty impressive coming out pretty similar to what we were seeing with Paxlovid and actually pretty similar to what we had historically seen with the other monoclonal. That’s going to move, in my mind, molnupiravir down to a lonely fourth spot, last option. Only about a 30% reduction. Remember, avoid doing those harmful things. Now, this is week two. This is when your doctor told you to wait to see how things might go.

At this point, we can’t do a lot. This is the second week, the early inflammatory lower respiratory hypoxic phase. This is when the inflammation is going on. As I tell my patients, particularly when they’re out at day 16 or 17 and their nose is still running. You can spread the virus, but you can’t spread inflammation. Inflammation is not contagious, but number one steroids, anticoagulation, pulmonary support, maybe remdesivir if we’re still within the first 10 days, and they’re not on a ventilator. Immune modulation, perhaps tocilizumab.

Remember, avoid those antibiotics and unproven therapies unless you really have a suspicion for a bacterial infection. Then we’re going to move, we’re going to finish off here. Thank you for staying with us for this. COVID the late phase past, the article, “Association of COVID-19 with New-Onset Alzheimer’s Disease,” was published in the Journal of Alzheimer’s Disease. This study used de-identified electronic health records of over 95 million patients of both inpatient and outpatient visits from 68 healthcare organization representing 28% of the U.S. population from 50 states.

Huge study covering diverse geographic, age, race, ethnic, income, and insurance groups. Ultimately the study population comprised over 6 million older adults aged 65 and over, including over 400,000 in the COVID-19 cohort, almost 6 million in the non-COVID cohort. After propensity score matching, COVID-19 cohort had increased risk for a new diagnosis of Alzheimer’s disease. Has a ratio of 1.7. Almost twice the risk.

VR: You think, Daniel, that basically doesn’t mean that COVID causes Alzheimer’s, but the same patients who get severe COVID may be the ones that also get Alzheimer’s?

DG: It’s tough. They’re trying to do this propensity score matching to say that these are equivalent as far as risk factors, but that’s an issue. The people that end up getting COVID perhaps are in a nursing home where we have a higher risk. It is hard even with propensity score matching to know. I think that’s a good point. It’s interesting. I was looking at recent data from California and the pandemic is shifting over time. Early on, there was quite a bit of white privilege and the minority of deaths.

Now we’re actually seeing that the white privilege people are going back to the office, we’re seeing more exposures. There’s so much going on that even when you try to propensity score match to get rid of those confounders, it’s really hard to do. As I always like to conclude, no one is safe until everyone is safe. The most selfish thing you can do is worry about the world. I want everyone to pause the recording right here and go to parasiteswithoutborders.com and click ‘Donate.’ Every small amount helps. Also, feel free to go to microbe.tv to donate as well.

If you go to parasiteswithoutborders.com during the months of August, now September, and October, donations made to Parasites Without Borders will be matched and doubled up to a potential donation of $40,000 for Floating Doctors.

VR: Time for questions for Daniel. You can send yours to daniel@microbe.tv. Liz writes, “Rituximab kills your circulating B cells. Vaccine timing is problematic. You still have a T-cell response. Can you ask Daniel, what he advises for the number of months after infusion to get a vaccine?”

DG: This is a great question just to put all our listeners on the same page. This is an anti-CD20 monoclonal therapy that really depletes all the circulating B cells because they have this CD20 on the surface. When you go ahead and you vaccinate someone and they have no B cells, you can’t really expect much of an antibody response. This therapy is not two weeks, it’s not a month. It really has a many-month durability to it. We’re still hoping that there is a T-cell response and we still have a lot of optimism that T-cell responses can really provide protection against severe disease.

Probably what you want to do in a situation like this, you probably don’t want to wait. You want to go ahead, you want to get those vaccines, but you also want to get EVUSHELD. You want to passively get those antibodies. I’m not sure there’s a long waiting. You would be high risk in this situation. You want to actually go ahead and get those vaccines, but you also want to get EVUSHELD.

VR: Dumbfounded and Dry in Dallas writes, “Dear Dr. Griffin, This week at my rheumatology appointment, I asked my doctor about a plan and recommendations in case I’m exposed to COVID and test positive. The doctor first emphasized the importance of vaccination. I recently had my fourth dose of Pfizer in mid-August along with Fluzone HD. Primary Pfizer was February, third dose October. I’ve not had COVID. Always take extra precautions since I’m at high risk for complications: Over 65, long history of autoimmune rheumatic disease, mixed connective tissue disease, severe sicca SD.

Currently, I don’t require any treatment with DMARDs or systemic corticosteroids, cardiac renal, and hepatic function all good. I then asked the doctor specifically about treatment with Paxlovid, in particular, with regard to interactions with two of my medications pravastatin and Evoxac. My doctor told me in no uncertain terms that, ‘Paxlovid rebound is worse than no treatment. Symptom-directed care only with Tylenol fluids, et cetera. All my patients, every single one, 100% that were treated with Paxlovid had a rebound.’

I’ve consulted with our ID docs here and they have advised against use of Paxlovid. I’ve never seen these rebounds with other better, longer-studied antivirals like Tamiflu. Our writer said, “but doctor, rebound occurs in natural infections also.” Doctor replies, “Well, we’ll see if you’re hospitalized.” Not one word was said about the strong scientific evidence supporting the use of Paxlovid to prevent severe disease, hospitalization, death in high-risk patients, nor any suggested alternatives from the treatment summary list if Paxlovid is contraindicated. Please advise.”

DG: This is painful. I think all our TWiV listeners are well aware that this is bad advice. I hammered on this. All those folks that were so excited to get on the prime media channels to talk about their experience with rebound, this is a drug with almost 90% reduction in progression to severe disease, hospitalization, and death. Even in the vaccinated, we have evidence probably about a 75% reduction. We have 200 people dying a day who are vaccinated, who did all the right things. We can reduce that down to 20 just by making sure all these people get treated.

As we saw, what percent of people are getting treated of the over 65, less than 2%. Well, I hate to say. I’m going to say you need to get a new doctor. This person is not following the guidance, they’re not following the science. You’re not in good hands.

VR: Melissa writes. “I’m a pediatrician and my struggle right now is monkeypox. Monkeypox in the middle of hand, foot, and mouth season. Monkeypox in the middle of impetigo season. Monkeypox in a population that likes to get the umbilicated lesions of molluscum. Feels like the universe playing a cruel joke on the pediatricians of the world. I’ve listened carefully to your updates and I hear you say, clinicians need to be more suspicious and test more people with rashes because we’re surely missing a large number of cases.

I hear you saying that lesions do not need to all be in the same stage, that lesions might be papular or vesicular or postulate. That we should not fail to test because our patient is not of the right demographic, but here’s my problem. I am 100% telemedicine. I work for an awesome telemedicine company that’s all board-certified pediatricians. We strive to provide the highest quality medical care in patients’ homes, but we don’t hesitate to send them for in-person care when medically indicated. I see a plethora of weird rashes on my screen every day.

My question is this. How do you suggest we determine which of these children need to seek in-person care for testing? It doesn’t seem feasible or even necessary to send every kid with a rash in for an exam and testing. Several times I have even asked family to take their child in to be tested and the provider that sees them declines to test. They clearly aren’t TWiV listeners. I would love your input on how we can be sure the appropriate children get seen for testing without undue burden of every child being sent for in-person care.”

DG: This is a challenge. I’m sitting in a privileged position here. I do a fair amount of telehealth and when I was first starting out in Colorado I would do house calls on the way home. I really love that. In a lot of ways I consider telehealth to be similar. I could see their house, meet their dog. There’s usually a family member helping them. What we do, as I was telling Vincent, I saw this monkeypox woman in person this morning. A lot of times when I see someone that I’m worried about, monkeypox we have part of our Optum Network.

We have all these urgent care centers. Now you don’t necessarily need to have those as part of your network, but you can have a relationship. You’re not going to test every kid but a certain number of them you may want to be testing just so you can pick it up once it gets into your population. My recommendation is a bunch of urgent care centers out there. If anything, the staffing went up and now they’re getting a little bit quiet. I’m sure they would love to have a relationship where you can say, “Hey, I’m going to send so and so over.

I’m going to be sending patients periodically over so that you can do some swabbing for me.” I would have some way of actually getting those diagnostic tests done. That would be my advice.

VR: Finally, Alli writes, she has two questions, one about the pediatric hepatitis discussion we had on TWiV with Emma Thompson. This hepatitis caused by AAV2 human adenovirus or a herpes virus and kids with a unique class II HLA. She wants to know if the myocarditis that we see following COVID or vaccination might also be driven by a specific HLA type. Is anyone looking at that?

DG: That, I don’t know but it’s a great question. There recently was an article I was trying to decide to put it in or not, just at the amount of myocarditis we see particularly in younger individuals when they get a COVID infection. I see it in older individuals as well. Yes, a lot of that research is going on. If we get some interesting results, I’ll certainly share them.

VR: Other question’s about polio vaccines, so polio booster for those who received OPV as kids. She seems to have gotten three doses of OPV that made mucosal and long-term immunity but she says, “Do I need a dose of IPV to give me better systemic immunity?” She says something that I love. I’m sure we’ve been living with vaccine-derived polio in the environment for years, so I’ve probably been naturally boosted, but the scientist in me wants to know what we know.

DG: Yes, I like the way you conclude because I think Vincent, you, and I are on, I think, the same page here. They made this recommendation, oh, all the healthcare workers have to get shots. I’m not sure that’s true. I do think that this poliovirus has been here probably for quite a while. I don’t think there’s anything new here. We’re not seeing older individuals end up suddenly getting acute flaccid myelitis. That polio vaccination we got as kids is probably durable. There’s no downside to getting boosted.

I know I got boosted probably more than once because I’m always heading to these supposedly high-risk polio areas like the first time I was heading into Pakistan, some rural area of Pakistan about 30 years ago and they gave me a boost but I think you’re right. This whole recommendation of boosting all these healthcare workers, I’m not sure I know where the science is.

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

DG: Oh, thank you as always and everyone, be safe.

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