TWiV 932 Clinical Update

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 3 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]

From MicrobeTV, this is TWiV, This Week in Virology, Episode 932, recorded on September 1, 2022. I’m Vincent Racaniello and you’re listening to the podcast all about viruses. Joining me today from New York, Daniel Griffin.

Daniel Griffin: Hello, everyone.

VR: Daniel, you’re still enjoying these updates even though it’s not just COVID anymore?

DG: [laughs] I feel like there’s a certain catharsis. I feel these updates keep me sane. I have to say today I went to the hospital after being in the office and it’s just, I feel like it’s nice for me to share what I’m learning, what I’m seeing. Because part of it, I have to say Vincent and I’m sure you experienced this as well, I read stuff in the newspaper, I’m like, “That’s just not what I’m seeing, that’s just not what the data shows, why are they saying that?” I don’t know, I feel like it’s nice for me to have this outlet [laughs]. I’m going to call it an outlet and I appreciate all the people that actually come here and spend the time for a little bit of a deeper dive than just that headline.

VR: Great. Glad to hear it.

DG: I will start with my quotation. “I started philosophy looking for answers but along the way, I came to prize exploring the questions.” That’s Kwame Anthony Appiah. People, we’ll put a little link in but this is a modern contemporary philosopher from sub-Saharan Africa, so I recommend people check that out. People may not know I was a philosophy major as an undergraduate. How did I end up here? I think that one of the big things about science is you can’t just be so anxious for those answers, you’ve got to really, I think, appreciate what are the right questions. What are the questions we can ask? What are the questions we can answer?

I will start right up front here with California’s legislature on Monday, 8/29, August 29, approved a bill that would allow regulators to punish doctors for spreading false information about COVID-19 vaccinations and treatments. Imagine that it’s actually going to be an issue if physicians want to say untrue things that put money in their pocket or give them political gain, so the law would designate spreading false or misleading medical information to patients as unprofessional conduct subject to punishment by the agency that licenses doctors, the Medical Board of California, that would include suspending or revoking a doctor’s license to practice medicine in the state. Sort of shocking to me that this isn’t already a thing, that this isn’t a thing in every state. Apparently, it’s OK to spread misinformation. It’s OK to lie to people as a physician and just keep going ahead and, yeah.

VR: I guess we’re going to have some kind of a process for saying, “OK, doc, you said you said this vaccine doesn’t work when it really does and we have 10 people who heard you and so you’re going to be punished,” something like that, right?

DG: Yes, it’s not going to be like one guy willy-nilly going out. It’s a board so the Medical Board of California will actually do their due diligence, they’ll do their investigation. As we know there are a number of prominent MDs, a number of prominent DOs, a number of individuals out there who went to medical school who refer to themselves and make other people refer to them as doctor but yet, they have no problem with saying things that are just not true.

VR: I’m glad to hear that. I think it’s great.

DG: I think we referred right, Vincent a couple of episodes back. Some gentleman, they even found he knew he was lying to people, but he knew it was making him a lot of money, and he did it anyway.

We are almost to flu shot time of year. I break up my year into different things, it used to be human metapneumovirus season which meant I should prepare my sailboat. Flu shot time of year when I should be thinking about putting that sailboat away. I know many people think they’re just too healthy to worry about some microscopic virus knocking them down but every winter, we have a number of children who die after getting influenza. We also hear the question, “Why should I get that shot because people who get the flu shot still get the flu?”

Part of my fine bedside manner is to ask my patients if they died when they got the flu after that shot. Because as we keep discussing vaccines do not completely protect you from infection, they protect you against severe disease. Vaccinated people still get infected they are just less likely to die. The article, “Vaccine Effectiveness Against Life-Threatening Influenza Illness in U.S. Children,” was published in CID. The investigators enrolled children less than 18 years of age admitted to the ICU, with acute respiratory infection across 17 hospitals. Using a test-negative design, they estimated vaccine effectiveness.

I’m just going to cut to the chase, effectiveness was 75% against life-threatening influenza, 78% against matched H1N1, dropped to 47% but still was 47% against mismatched H1N1 viruses, and was actually, a surprise, 75% against mismatched influenza B-Victoria viruses. Just I think as we keep trying to send this message, don’t think that an infection means that the vaccine failed. What the vaccines do is they keep you from dying, they keep you from ending up on a ventilator, they keep you out of the ICU.

Polio update, I just want to keep polio on everyone’s radar. I’m going to keep discussing this, hopefully, our vaccination rates are going to go up. I mean they set up these tents and everyone rushed in and a few hundred people got vaccinated that was a little disappointing. The article, “Clinical Manifestations of Infection with Poliomyelitis Virus,” was published in JAMA in 1948.

I didn’t quite get to this when it first came out, but I will say this is an open access article, it starts off with what I think is where in many ways we have returned now about 80 years later so let me just read the first sentence. “Most of the clinical observations of poliomyelitis have been limited to the relatively rare form of the disease that results in residual paralysis.” They then discuss something called subclinical poliomyelitis as cases without stiff neck, stiff back paralysis, or obvious paresis, that’s weakness, and in the survey, they identify mild fever of short duration, headache, vomiting, constipation, drowsiness as features of the non-paralytic manifestations.

Now, I will say it is currently suggested that over 90% of polio infections are asymptomatic and this may be vaccination dependent. In the less than 10% of individuals that do have symptoms, symptoms develop following an incubation period of four to 10 days, and I think this is really key, they resemble those of common viral infections, headache, sore throat, fever, nausea, vomiting, malaise, fatigue. Unless we actually test, which we only do with acute flaccid myelitis, these fly under the radar. I had a group of urgent care doctors we were talking on Wednesday, usually my Wednesday update, and I said, “Listen, who out there has seen a case of polio here in the tri-state area?”

My comment was, “You probably all have but we just don’t diagnose these.” Now if the person does go on and get the acute flaccid myelitis, the majority of these individuals never regain their strength, about two-thirds, and we certainly have a post-polio syndrome with progressive neurological deterioration.

VR: I think the problem, Daniel, is that with these symptoms you probably wouldn’t even seek medical care, right?

DG: I think that’s one of the things we’re realizing, I’ll sort of hit this with monkeypox, is a lot of people had a little sort of low-grade fever, and then went away, I felt kind of crummy for a few days. I mean that isn’t necessarily going to prompt you to go to see a physician, a clinician, and it’s also not going to trigger anyone to go test you for polio.

VR: No. I mean right now we’re starting to use wastewater as a surrogate for the presence of the virus which is a little bit too late, but at least we’re doing it, but it would be really nice to get a broader screening as you say as we should for monkeypox as well.

DG: Yes. I’m going to keep harping on that because if we don’t have better surveillance if we don’t know what’s out there, we’re not going to look for it until it’s too late, until as we have until we have a paralyzed young man. Monkeypox update, I keep repeating, and I will keep repeating, monkeypox is not a gay disease or an African disease, monkeypox is an infectious disease. We’re now up to 50,000 cases worldwide outside of Africa, over 18,000 cases here in the U.S. We now have cases being diagnosed in every state.

We have over a hundred cases in individuals under the age of 20. Some people refer to these folks as children. We even have some cases in younger children 6 to 10 as well as those 5 and under. It’s really interesting. I put up and maybe we’ll put a link to this or we will put a link to this, but I have it in front. If you look at the number of cases that were diagnosed. Just Monday we diagnosed over 600 cases. People are like, “Oh, but it’s down because in early August there was a day that we diagnosed over 700.”

Well, I point out, “Well, yes. Monday we diagnosed over 600. Tuesday we diagnosed over 600.” This is not going in the right direction. Again, I guess this is my venting. You read the popular press, the trends going in. I’m not looking at this seeing a trend going in the right direction when we’re diagnosing over a thousand cases per week.

VR: I think you can’t say anything about trends because we’re not testing enough, right?

[chuckles]

DG: Well, I’ll bring that up actually because I think that’s really important. We just had the first reported death of someone here in the U.S. with monkeypox, that was in Texas. Now, this was an immuno-compromised individual. We’re not sure if they died with monkeypox, what was going on there. I really am a bit concerned because I keep seeing individuals who go weeks with what to me looks fairly compelling but yet they do not get diagnosed. I’ll share a couple of stories.

The first. I saw several patients this week with monkeypox. One was a teenager. This teenager, he’s a virgin. I think people still use that terminology. He has yet to have vaginal sex with his current girlfriend but they’re intimate in other ways. Last month he noticed several umbilicated papules down on his lower abdomen. These are little raised red areas but they sort of look like they have an indent in them. He was told, “That is not monkeypox, no. That is molluscum.”

We know what that is. They started treating them with cryo. They started freezing them. Well, these spread. He’s very scholarly. He has a PowerPoint presentation showing me of every stage of the different things. At this point, he has such a severe penile lesion that he’s going to require penile reconstruction. It’s been over a month since this process has started.

I just saw a young lady earlier today. I stayed a little late to see her. She noticed some little bumps. Wasn’t quite sure what they were. Came to realize that her boyfriend had cheated on her with a woman. These lesions were PCR positive for the monkeypox. Again, these are individuals who are not right in your face saying this is monkeypox. We’re seeing it in teenage heterosexual boys. I’m seeing it just in my small experience but we’re also as we’re saying. If we don’t test and a lot of people are not testing. You got to start testing. This is not an obvious thing. You should be doing a lot of false. You should be doing a lot of tests that come back negative to be testing enough here. We’re not doing enough testing.

VR: Daniel, if someone wants to, can they test someone who doesn’t have any lesions, or do you need a lesion to be tested?

DG: All right. That’s exactly the point, Vincent. You need something to swab. We don’t know. Could you just test people’s saliva? Could you just screen people? We’ve talked a little bit about that. At this point, most of our testing is doing the lesions and we talked about a study before that. That’s really sort of where the gold is. That’s where you have your highest sensitivity. Sometimes we are seeing positivity in saliva samples.

This case which is really interesting. This woman had lesions but she didn’t recall her boyfriend, cheating louse, having any lesions. She was not aware. Some of these rashes they really look like, they might come and say, “I’m getting adult onset acne.” It’s not always clear that you can just look at someone and know that you don’t have to worry. I particularly worry about school opening because a lot of teenage lads are going through that period of life and lasses who have actually acne so to make that distinction is going to be a challenge.

VR: I think it would be worth to do a study where you do mucosal swabs of random people, even anal mucosal swabs because some of those have turned up positive, and see in the general population how much virus do you pick up in the absence of lesions.

DG: I’m thinking with schools and things like the wrestling team, other sports where there’s a lot of physical contact, is there a way that – Well, one, we’ve got to do a better job making this diagnosis because it’s already outside of this target population that everyone talks about all the time. If we don’t do a better job and come up with better ways of picking this up, we’re just going to start seeing it spread in the schools and other populations.

I will say transmission, this is predominantly through contact. We say it usually requires significant contact, I think that’s true. No sex required. Testing, currently that’s where we are. We’re swabbing these rashes. We’re using non-cotton swabs, recommended that you send two of them off in the liquid median. You want to refrigerate or freeze that, some of the labs will toss them if they show up at room temperature.

I’m a little disturbed by why they would do that. His DNA got about 20,000 years to run the assay so I’m not sure what’s going on there, why they’re being tossed. Remember Occam was not a physician, Hickam was. A patient can have as many diagnoses as they darn well please so be thinking about other stuff. About a third of the time we’re seeing something else going on as well. Fortunately, these last two individuals that I discussed, they had no other infections detected, it was just the monkeypox. Vaccines, we’ve got them but still very limited access. Clinical course and treatment, we’re still doing the TPOXX and the Viroptic We’re still waiting for the data. The studies by the Brits and hopefully by us as well about the efficacy of this.

All right. Moving on to COVID. Yes, still here, going strong. Let me start right up front in the COVID section with the article, “Characteristics of Reported Deaths Among Fully Vaccinated Persons with Coronavirus Disease, 2019 United States January through April 2021.” Published in CID. This is a close look at who are those vaccinated people that died despite vaccination during this period of time. Those who died were older. Median age 82. More likely to reside in a long-term care facility.

Actually, the majority of the people that died during this period lived in a long-term care facility. That gives you some sense of the demographic. More likely to have greater than or equal to one underlying health condition associated with risk for severe disease, that was 64%. These are not young healthy people bouncing around. These are older individuals. These are folks in long-term care facilities. These are folks with multiple medical problems.

When you look at what puts you at risk for dying of COVID, being over the age of 85, being an older individual. It’s like a 300-fold increase in your risk of death. It makes me wonder when we talk about limiting Evusheld to just the quote-unquote immune compromised, there’s a certain age at which just you are immunosenescent immunocompromised. Something for us to be thinking about.

Now, with about 500 people still dying per day from COVID here in the U.S. and about 3,000 people per day worldwide, how is it that people are still suggesting Omicron is mild and nothing more than the common cold? I joke about these 500 mild deaths per day. How did this start echoing around? How did we get in this situation?

The article, “Spike Protein-Independent Attenuation of SARS-CoV-2 Omicron Variant in Laboratory Mice,” is now available as a pre-proof with upcoming publication in Cell Reports. As we go into this, remember the saying, mice lie, monkeys exaggerate and ferrets are not people, TWiV 55. Was it coined on TWiV 55 or has that been going around, Vincent?

VR: We had already said it beforehand. That’s not something that we made up. Although we may have modified it. I think we heard somebody saying it for a while so we just codified it in the title of that. I really have believed that ever since.

DG: OK. All right. Well, I will suggest that based on the report that Omicron variant only caused milder disease in laboratory animals, that were those Syrian hamsters and more upper respiratory. People really wanted this to be true. A lot of people just started suggesting, they didn’t wait to see what the data had to show, they didn’t wait to see how many people would die. They didn’t wait to see that, for instance, in the UK, more people died this summer than died last summer.

People started saying that Omicron was the vaccine the pharmaceutical companies fail to make, and we actually had a number of people actively go out and get themselves an Omicron infection. Well, this publication demonstrated that this lower viral load and milder disease in mice was due to a post-entry block in laboratory mice. Just a word of caution of jumping too quickly using the word mild, because people respond and when you did those interviews when all those people did those interviews out there and got excited about this, people ran out and they got infected and a lot of those folks are not still with us.

Children, COVID, and other vulnerable populations. An update here on, “Children are at risk from COVID.” I just want to point out that according to data from the CDC. Back in April, we had about 20 children a week hospitalized. That number was about 100 children hospitalized per week in July. A fivefold increase this summer with the mild Omicron that’s been circulating. Keep that in mind when we well, when we talk about vaccinations in children.

Preexposure transmission and testing the article “Concordance of SARS-CoV-2 Results in Self-Collected Nasal Swabs vs Swabs Collected by Health Care Workers in Children and Adolescents,” was published in JAMA. These are the results of a cross-sectional study of 197 symptomatic children and adolescents, self-collected swabs that were positive for SARS-CoV-2 agreed with results from healthcare workers collected swabs in 97.8% of participants while self-collected swabs that were negative agreed with healthcare worker collected swabs in 98.2% of participants.

Not bad, child labor here, right? The children are doing a great job, so those SARS-CoV-2 detections in nasal swabs that were self-collected by school-aged children and adolescents following simple instructions demonstrated a high agreement with the results following collection by those highly trained healthcare workers. Let me share a fun article. Now, recently, some family and friends with two children, two cats, and two dogs, all got COVID, they asked when I would be willing to stop over and enter their poorly ventilated suburban home.

They did not mention the poor ventilation but that is given despite what anyone says about their suburban home. Perhaps this next article explains why I suggested it would be a long time coming before I come over for a visit. “Probable Animal-to-Human Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Delta Variant AY.127 Causing a Pet Shop-Related Coronavirus Disease 2019 (COVID-19) Outbreak in Hong Kong,” published in CID. This study suggested probable hamster to human transmission of SARS-CoV-2.

Active vaccination. Remember never to miss an opportunity to vaccinate and vaccinated people still get infected. They are just less likely to die. Yes, Andy Slavitt, we have been saying that. August 1, the U.S. FDA amended the EUA of the Moderna COVID 19 vaccine and the Pfizer-BioNTech COVID 19 vaccine to authorize bivalent formulations of the vaccines for use as a single booster dose at least two months following primary or booster vaccination, just two months.

The bivalent vaccines, which we will also refer to as updated boosters, contain two mRNA components of the SARS-CoV-2 virus, one for the original and the other in common between BA.4 and BA.5 of the Omicron variant. To evaluate the effectiveness of a single booster of Moderna COVID 19 vaccine bivalent for individuals, 18 years of age and older, the FDA analyzed immune response data among approximately 600 individuals, 18 years of age and older who had previously received a two-dose primary series and one booster dose of monovalent Moderna COVID 19 vaccine.

Now I know in the popular press, there’s all these articles that these are being approved and they’ve never been given to human beings. These are human beings, so 600 human beings right here, and to evaluate the effectiveness of a single booster dose of Pfizer-BioNTech, COVID-19 vaccine bivalent for individuals, 12 years of age and older, the FDA analyzed immune response data among approximately 600 adults greater than 55 years of age, who had previously received a two-dose primary series and one booster dose with the monovalent Pfizer-BioNTech, COVID 19 vaccine. So, 600 more human beings, so over a thousand human beings have received these.

We have data, we have data on the responses, we’ve been following for safety issues. Now there’s going to be an ACIP meeting. It’s actually partly occurring the day we’re recording this and then Friday and I understand they will be discussing the updated boosters for the fall. Moderna and BioNTech have gotten their submissions to the FDA. We read the FDA response, so now we’re waiting for the ACIP, and then we will wait for Dr. Walensky. We’re actually anticipating booster approval, booster recommendations next week, right after Labor Day.

El MMWR, “Laboratory Confirmed COVID-19-Associated Hospitalizations Among Adults During SARS-CoV-2 Omicron BA.2 Variant Predominance. COVID-19-Associated Hospitalization Surveillance Network, 14 States, June 20, 2021 through May 31, 2022.” Here, we see that despite vaccines being available and free, the majority of hospitalized patients are still unvaccinated. This will eventually end for one of two reasons. One is that an estimated 100,000 to 200,000 projected COVID-related deaths per year, going forward is a bit of a war of attrition. These folks can’t just keep dying.

The other is that getting COVID and not dying should be giving some degree of protection against severe disease death and in this case hospitalization. People keep asking, are the percentage of people being hospitalized? Are they vaccinated? Are they unvaccinated? In many ways, I like to say, this is the wrong question, much like the movie iRobot. Per this publication as of July 6, 2022, 91.6% of adults aged greater than equal to 65 had received a primary series, 64.4% had received one booster or additional dose, 22.2% received a second booster or additional dose.

We are really hitting the highest risk population. It still amazes me that we still can keep filling the hospitals with mostly unvaccinated individuals.

The major article, “Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)-Specific T Cells and Antibodies in Coronavirus Disease 2019 (COVID-19) Protection, A Prospective Study.” Now, this is a little bit, I want to say interesting for discussion. This was published in CID and I hope this is the first in a line of articles that will better explore this topic but they looked at IgG titers, right? Those serology tests that everyone is getting. It looked at specific T-cells and a number of other parameters, and looked at whether there was a correlation between different parameters and infection rates. I was a bit disappointed at this point and not surprised that those with the lowest levels, with the most likely to get infected, those with the highest levels, the least likely, I was hoping in these 5,340 Moscow residents, we would get some information about disease severity, who was vaccinated? When was the vaccination? Who had prior infection et cetera? I look forward to more data.

VR: I guess they don’t listen to TWiV in Moscow.

DG: They probably don’t. I got to give Putin a call. I don’t think he listens either. Passive vaccination, Evusheld. We keep talking let’s not turn this into Evu-shelf. Currently, there is limited access only to the immunocompromised those who could not get or could not mount an adequate immune response to COVID-19 or who we don’t think would mount an adequate immune response. I did mention maybe immunosenescence, maybe being over a certain age should qualify as a certain degree of immune compromise. That’s really not in there. Just putting that out there.

Here we are the meat of it, early viral upper respiratory nonhypoxic phase. What I want to say right before I, this is when you get a positive test. As we talk about this, I’m recommending to all our listeners, to all the clinicians who are listeners and patients should have an action plan. They should know what to do. If you get a positive test, what do you do? Who do you call? Who’s going to give you the advice you need? Who’s going to get you access to the right treatments and what are those right treatments? Number one, Paxlovid, but what about folks that are vaccinated? What about folks that had a prior infection? Where’s the data on those folks.

Well, we talked a little bit last time and I promised this time I would discuss the article, “Nirmatrelvir Use and Severe COVID-19 Outcomes During the Omicron Surge,” published in El New England Journal of Medicine. This is data for all members of the Clalit Health Services, that’s in Israel. Here they say a total of 109,254 patients met eligibility criteria, of whom 3,902 received Paxlovid during the study period. Among patients, 65 years of age or older, the rate of hospitalization due to COVID-19 was 14.7 cases per 100,000 person-days among treated patients as compared with 58.9 cases per 100,000 person days among untreated. We’re looking here at an adjusted hazard ratio of 0.27. The adjusted hazard ratio for death was 0.21. Here, we’re looking at about a 73% reduction in progression to hospitalization and a 79% reduction in progression to death. I will add, if you look at table 1, 90% of the treated patients had previous immunity induced by vaccination, infection, or even both. This is really looking at previous infection, vaccinated, immunized individuals getting Paxlovid and with Omicron.

VR: Daniel, these are 65 and over, do we have any data on 65 and under?

DG: Yes. From the same data, and that’s of course what made the headline, if you treat a person who’s not going to end up in the hospital, they’re still not going to end up in the hospital.

[laughter]

DG: Surprise, surprise. We actually know this from Pfizer as well. This is a drug that keeps high-risk individuals from progressing, ending up in the hospital, ending up dying. There’s no point to give this to someone who’s not headed to the hospital, who’s not at risk of death.

VR: It’s just amazing to me how people interpret things, right?

DG: [laughs] Yes. “I’m 43. I hear Paxlovid will do nothing to help me.” I’m like, “Yes. Yes. It’s not for you.” Remdesivir, that’s option number two, poorly operationalized. Remember, we get a lot of folks but maybe this is to clinicians but also the patient, we get a lot of folks who end up in the hospital in that first week. They’re just so crummy, feeling poorly at home, can’t keep stuff down orally. They end up in the hospital during that first week. Remdesivir is a great option in that situation. Remember remdesivir as number two, suggesting about an 87% reduction in progression if given in that first week. Number three, monoclonal antibodies, it’s here with molnupiravir. As I mentioned, I want to keep this really straight, Bebtelovimab is now being purchased, not necessarily supplied, by the government.

A little email went out recently in our local area that patients are, please come in, get their monoclonals. Hopefully, their insurance will kick in, but the charge is $12,000 for this wonderful opportunity so sort of make some of these other less expensive options a little bit more exciting. We will talk about molnupiravir a little bit this time. “Real-World Effectiveness of Early Molnupiravir or Nirmatrelvir-Ritonavir (Paxlovid) in Hospitalized Patients with COVID-19 without Supplemental Oxygen Requirement on Admission During Hong Kong’s Omicron BA.2 Wave: A Retrospective Cohort Study,” published in El Lancet Infectious Diseases. Omicron, real-world effectiveness. Now, this data might seem familiar because I think we discussed this as a pre-print, but in this study, patients were eligible for inclusion if their admission date was within three days before or after confirmation of their COVID-19 diagnosis.

This is really interesting. We have these drugs for preventing hospitalization, for preventing deaths, but now we’re looking at individuals who end up hospitalized in that first week, this early viral replication, viral symptom phase, not that second week, not that hypoxic early inflammatory. Those who were admitted to hospital more than five days after symptom onset, were younger than 18 years, had a history of oral antiviral use before admission, required oxygen, had drug-related contraindications, severe renal, liver. They were excluded. We’re talking about those people in their first week. Patients who received the oral antivirals molnupiravir or nirmatrelvir-ritonavir were matched with controls using propensity score matching in a ratio of 1:1. The primary outcome was all-cause mortality and secondary outcomes, including a composite outcome of disease progression.

This is all-cause mortality ending up on a ventilator, ending up in the ICU, or need for oxygen therapy, and each of these individual disease progression outcomes had time to reach a low viral burden, so an RT-PCR cycle threshold of greater than or equal to 30. Low RNA copy number burden and I’ll translate there. They ultimately included 1,856 molnupiravir recipients and 1,856 controls, 890 got Paxlovid, 890 matched controls, a lower risk of all-cause mortality was observed in the molnupiravir recipients, so hazard ratio of 0.48. That was a 52% reduction in all-cause mortality. Paxlovid, hazard ratio of 0.34, so that’s a 66% reduction. Oral antiviral recipients also had lower risk of the composite disease progression outcome. Molnupiravir hazard ratio of 0.6, 40% reduction. Paxlovid 0.57 so about a 43% reduction. Need for oxygen therapy, molnupiravir 0.69, Paxlovid 0.73, compared with controls. Time to achieving a low viral burden was significantly shorter among oral antiviral recipients than matched controls and then we get some data on that. Fully vaccinated rates were only 6.2% and 10.5% for molnupiravir and Paxlovid. This is really a real-world study on unvaccinated individuals.

I like to say let’s avoid doing harmful things during that first week. No steroids. That’s actually going to increase your risk of progression. No unnecessary antibiotics and right there, I’m going to go to the IDSA has added a narrative section to their COVID treatment guidelines addressing the issue of antibiotic overuse. I quote, “Despite the majority of patients with COVID-19 being treated with antibiotics on admission early in the pandemic, existing studies have found bacterial co-infections to be uncommon.” They mentioned that in a meta-analysis of 24 studies, bacterial co-infection was only seen in about 3.5% of patients with COVID. Smaller studies have congruent reports ranging from 3.1% to 4%. Let me remind our listeners COVID can give you a sore throat, sinus pressure, a cough, can even give you pneumonia. Giving unnecessary antibiotics is not helpful and potentially harmful.

The early inflammatory lower respiratory hypoxic phase, often when folks end up in the hospital, this is when steroids at the right time in the right patient at the right dose, anticoagulation, pulmonary support, maybe remdesivir if early, perhaps immunomodulation. Remember, avoiding those unnecessary antibiotics. If you are giving them to the majority of your patients, you are giving them the majority of the time in a manner that is not helpful or beneficial. We will close out with the late phase. The article, “Distinguishing Features of Long COVID Identified Through Immune Profiling,” was posted as a pre-print yes, a pre-print. This is out of Akiko Iwasaki’s lab. In this investigation, 215 individuals were included in an exploratory cross-sectional study to perform multidimensional immune phenotyping in conjunction with machine learning methods to identify key immunological features distinguishing Long COVID.

A lot in here, but in summary, they found marked differences in specific circulating myeloid and lymphocyte populations relative to match control groups, elevated humoral responses directed against SARS-CoV-2 among participants with Long COVID and increases in antibody response directed against non-SARS COVID 2 viral pathogens, particularly Epstein-Barr virus. That keeps coming up. Also a number of circulating immune modulators and various hormones were different with levels of cortisol being uniformly lower among participants with Long COVID relative to matched controls.

I did want to make sure I put in a link to the review article, “Unexplained Post-Acute Infection Syndrome,” published in Nature Medicine. People keep asking, “Is this unique to COVID? Do we see long other infections?” There’s really a nice discussion and review of the many post-acute infection syndromes. Folks can take a look at all the different viral pathogens, Dengue, polio, SARS, Chikungunya, West Nile, Ross River, Coxsackie, flu et cetera. This is not new. I will close here with, no one is safe until everyone is safe. Remember the rest of the world is still out there. We’re moving forward, but a lot of folks are still unvaccinated, still do not have access to therapy. We’re still seeing 3,000 deaths a day.

I want everyone to pause the recording right here, go to parasiteswithoutborders.com, click on the “Donate” button, even a small amount helps us to continue our work, and right now we are in our Floating Doctors fundraiser. During the months of August, September, and October, donations to Parasites Without Borders will be matched and doubled by PWB up to a potential donation of $40,000 to help with our work, and also help with the work down there in Panama.

VR: It’s time for your questions for Daniel, you can send yours to [email protected]. Meghan writes, “I have some questions about full boosters. I talked to my doctor but I’m interested in your thoughts as well. I’m a 36-year-old, no major risk factors other than asthma. When I got the Pfizer booster after the primary series last fall, I got persistent tachycardia that my doctor feels was vaccine-related. It’s finally cleared up, but I’m honestly pretty wary of making it happen again, so I have kind of a two-part question. First of all, is a booster really necessary; and second, realizing this goes outside of science, my doctor and I discussed boosting with Novavax instead. Thoughts? If it’s relevant, I had COVID in July, tired for several weeks and cough but otherwise, OK, kind of like a mild flu.”

DG: Yes, part of we’re still learning but what do we know so far? Early on and we talked a bit about this before Omicron, the immune evasiveness that we’ve experienced, two shots were doing a really good job of keeping people out of the hospital, protecting people against severe disease, protecting people against death and as Paul Offit and I have discussed, once Omicron appeared, really that third shot made sense and part of it is that do you need that third shot? Or is it just, we gave the second shot too soon? Could you get one shot another six months and get what you got with that third shot? We’re still talking about third shots, giving us this protection but now you’re raising an interesting issue.

Next week, right after this drops, everyone, it’s going to be a large number of individuals recommended to go ahead getting boosting for the fall. Well, what are you trying to achieve? I think that’s the important question here. Will there be a temporary reduction in your risk of infection? Probably the superpower we talked about where for a period of time when you have those very high antibodies before they contract, there is some reduction in your risk of getting infection. How much of an increase are you going to have as far as your risk of progression to severe disease?

That’s where this and I think in your situation, becomes a discussion with your physician. It sounds like you had an issue potentially with that prior boost. Novavax is out there, but it’s not approved or licensed as a booster and under the EUA, that’s not really what we’re supposed to be doing. Scientifically, does it make sense? It makes sense but again, just discussing the regulatory environment. Not an easy, not a straightforward and hopefully we’re moving from just everyone go get it and if you don’t get it, you’re a bad person, to people might want to have that discussion as it sounds like you’re having with that physician, and really work through what’s the best decision for you.

VR: Alexander writes, “Am I correct that a less than 12-year-old undergoing treatment for cancer is at high risk if they get COVID? If so, given that Evusheld is only approved for over 12 years of age, what options exist to protect such a child from COVID when they’re in school?”

DG: Yes, this is a challenge actually, when you have a limitation like that, like so suddenly on that eve of your 12th birthday, you’ve become eligible for this protection, and when you’re younger than that it’s outside the EUA. That is a challenge because that would be what you would think of as a great way to protect an individual who’s immunocompromised. Currently, we have the vaccines, we have a series of vaccines, an immunocompromised individual like this, it’s actually four doses and there’s a schedule for that. If there is an access to Evusheld which I sort of described the regulatory issues, you really want to have an action plan because we can do a certain amount with vaccines, but we also can do another bit as we’ve demonstrated with quick rapid treatment or involvement of anti-viral, the vaccines and have a plan.

VR: Greg writes, “I had bovine aortic heart valve replacement on June 1 and was told by my physician that Paxlovid can’t be used in my case, is this correct?”

DG: Yes, it’s not.

[chuckles]

VR: OK, there you go.

DG: You can use Paxlovid, it’s fine.

VR: All right, Bria writes, “I’ve listened”– by the way, Daniel in California, would that be subject to censorship by this new panel?

DG: It’s interesting. I think that and I would talk to the doctor a little bit more, why do you say that? Is it that I’m on one of these direct oral anticoagulants? Is there a drug interaction? It’s not the heart valve, it has nothing to do with cows and it may be that there’s a communication issue there. He may be saying because of the drugs you’re on, there’s an unacceptable interaction here and instead, you’re going to be someone that should get remdesivir, maybe someone who should get the bebtelovimab, maybe you’re someone who get the molnupiravir but yes, the heart valve itself is not – it doesn’t sound like this physician is out there, misinforming, I think they’re just maybe – I’m hoping this is just a communication challenge.

VR: OK, good. Bria writes, “I’ve listened to your show from the days when you were in the stairwells at the hospital. I have a 50-something-year-old friend with rheumatoid arthritis taking methotrexate. Her family was testing positive one by one with COVID this week and when she finally tested positive late Friday night, her doctor referred her to a web form at the local big-name university to determine treatment. When the university medical center called her back, they told her they no longer recommend Paxlovid for the immunocompromised because of the risk of rebound. Because of this, they were recommending she do monoclonals, they told her to feel better and they would prioritize all the monoclonal referrals over the weekend and the scheduler would call her on Monday, they told her monoclonals are the safest option for immunocompromised. I found this very contrary to your recommendations.

Assuming she has no contraindications, she has recent labs and none of her meds interact, I’d expect that they will want to start Paxlovid as soon as possible, she’d have her first dose by Saturday. Instead, they told her to feel better and call on Monday. She’s convinced this is because she had only mild symptoms at the time, but I understood you’re not supposed to wait until you feel bad to treat. Have you seen any data to support the risk of rebound outweighs the benefits of Paxlovid in the immunocompromised? Are monoclonals really the safest option?”

DG: Yes, this is a painful letter and let’s go through the detail. What is this Paxlovid rebound that everyone’s talking about? I’m not sure exactly I understand what it is because it’s a moving target. Is it that people have a viral phase and then during the second week, they get a cytokine storm and they get hypoxic? Well, that is actually the disease itself and if you look at the studies, you really can’t tell the people that get Paxlovid from the people that didn’t get Paxlovid as far as this “rebound” but what you can tell apart is a 90% reduction in the people that end up requiring hospitalization and almost 90% reduction in people that end up dying.

So, no, this is not a great situation to wait and see, this is a high-risk person and once they die and I think we outlined who dies. The immunocompromised, the elderly, the people with multiple medical problems. Five-hundred people are dying a day, every physician who got up there and got on CNN or whatever they got on to talk about their experience of Paxlovid rebound, you did a disservice. There’s a lot of folks out there who are hesitant to take what is really an effective and frontline and an easy lift, you can go out and get that the same day you’re diagnosed.

Now, I did mention with the monoclonals, nowadays this is now big bucks, $12,000 for everyone who comes in and get their monoclonal, and I’m sure they’re not paying $12,000 to get the monoclonal, they’re paying about one. There’s a big financial incentive to medical centers getting people in for those monoclonals. And a big issue with the monoclonals, they’re not bad. We have absolutely no efficacy data on bebtelovimab at this point, we’re crossing our fingers and hoping it works. But there’s this delay, and we do know that as you delay, limited benefit. When you’re getting that monoclonal on day seven or day eight, I don’t know how much it’s doing, you’re better off getting molnupiravir on day one. And Paxlovid rebound, is it symptom rebound, is it test positivity rebound, but it’s not a rebound that ends you up in the hospital, it’s not a rebound that ends up with you dead. We really need to stop worrying about this Paxlovid rebound, really put it into context.

VR: I don’t understand why more physicians don’t listen to you, Daniel, and all they have to do is listen to this relatively brief update every week, right?

DG: My colleagues here at Optima tri-state, they listen.

VR: Well, that’s good. Good for them. All right, last one is from Arthur. “My son had a case of shingles at age 38, recovered with minimal scarring, no residual pain, should he get Shingrix? Can he even get it since he’s not yet 50?”

DG: Yes, it’s a licensed vaccine so his physician can certainly go ahead and get him set up with that. It’s a routine across the board starting at 50, but if you have shingles you’re at risk of having it again so it would make sense to go ahead and get those two shots.

VR: Daniel in the first year of TWiV, I got shingles.

DG: Was it that stressful that first year of TWiV?

VR: No, it wasn’t bad at all.

[laughter]

This week I got my first dose of Shingrix, actually last Friday, and really minimal side effects, just a sore arm. Any of you who are scared of it, just do it. It’s not that bad. That’s TWiV Weekly Clinical Update with Dr. Daniel Griffin, Thank you, Daniel.

DG: Thank you so much and, everyone, be safe.

[music]

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