TWiV 856 COVID-19 Clinical Update #98

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 22 January 2022

pdf of this transcript available (link)

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

From MicrobeTV, this is TWiV, This Week in Virology, Episode 856, recorded on January 20th, 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: Too bad you’re not here, Daniel.

DG: I was going to come in, Vincent, but then you said you weren’t going to be there.

VR: Well, I’ve been here all day, no problem, but now you’re going to Africa for a couple of weeks.

DG: Yes, I will not be in the next two weeks. Hopefully, if technology works in our favor, I will be recording remotely from Ghana.

VR: All right, we’ll see how that works.

DG: All right. Well, let’s get right into it. I’m going to start with my quotation. I actually have a lot to cover, it’s amazing. Earlier today I was going through proofing some of the transcripts from March of 2020, if you can imagine. Boy, really bad sound quality when I was sitting in my car in the parking lot.

VR: Yes, the car was– but that’s what we could do, right?

DG: Yes, I still remember going out to the car, recording in the stairwell trying to stuff under the door, because I didn’t know how safe it was, but all right, here we are in January of 2022, just about two years later. I’ve got two quotations. First one is by William Osler, “One of the first duties of the physician is to educate the masses not to take medicine.” The second is from Voltaire, “The art of medicine consists in amusing the patient while nature cures the disease.”

I had a call today, and we’re going to get into this in a few different places. At the end of the call, hearing all the details, my bit of advice was, do no harm, stand back. I expect things to go well, don’t do anything that will change that outcome, but we’re now starting to get to the point where we actually I think have some solid therapy, so we’ll be talking about situations where we actually can offer something helpful.

Let’s get into my update. I did my update yesterday for our tri-state urgent care physicians and really focused a lot on what we’re seeing here in New York, what we’re seeing in the tri-state area, what we’re seeing nationally. I can be positive, we seem to have reached a peak here in the northeast, in the New York tri-state area, in Boston. We are actually seeing the number of patients in hospital has really plateaued, maybe we’re starting to come down the other side.

I did comment that just Tuesday, January 18, this is my bit of not sunshine, we had reported over 400 deaths just here in New York that day. We haven’t had a day with over 400 deaths since May 2020 and the seven-day moving average for deaths is still climbing. We’ve certainly reached a plateau, I think, in terms of cases and hospitalizations but it takes time to die and, unfortunately, we’re continuing to see deaths. I had another one of my patients die today. Just a word of caution and we’re going to get into this about everyone who talks about, “oh, it’s the army cold, Omicron is just mild.” That may be true if you have a normal immune system and you get vaccinated, but it’s quite a bit different. The gentleman that died today had made the decision not to get vaccinated and now he’s no longer with us.

All right. Children, COVID, and mental health, and this is going to hit right on this issue. Children are at risk from COVID. We continue to have record numbers of children in the hospital and we’re not doing a great job of vaccinations in our youngest. Let’s talk a little bit about some data that just came out of South Africa today as we’re recording, and this is a rather concerning report from the Government Employees Medical Scheme, GEMS. This is the largest medical scheme in South Africa and the title of what came out today was, Trends in SARS-CoV-2 cases and admission trends in the Omicron-dominated fourth wave from the Government Employees Medical Scheme, GEMS. We’ve had this discussion about whether or not we are seeing overall lower admission rates and deaths relative to case numbers as far what might be causing that.

Now a common and concerning narrative that is actually widespread on social media and in the mainstream press is that the Omicron variant of the virus, the virus itself has become intrinsically less virulent and this has unfortunately prompted people to intentionally get infected and in some cases, those intentional infections have led to deaths. Well, what about children?

We’re actually seeing more children being hospitalized during the Omicron wave and what did we hear from GEMS as far as that issue? What happened during the South African Omicron wave? What we got was that they saw higher case admission rates amongst persons under the age of 18. For persons between the ages of zero to four, the risk-adjusted increase in the case admission rate was almost 50%, and in the five to 17, it was increased by 25%.

I just want to repeat that. In South Africa, this “mild variant” resulted in an increased case admission in the youngest, zero to four of almost 50% and in the five to 17, of 25%. I’m going to go ahead and actually just read a comment they made. “This may be a manifestation of the fact that Omicron has coincided with increasingly high vaccination rates and possible immunity from previous infections in terms of what they saw in adults but children are being severely impacted.” Any thoughts on that, Vincent?

VR: I think it just goes to show that you need to be very careful in first analysis of disease and really take your time, and in particular, look in multiple locations before you make a conclusion.

DG: Yes. It’s really tough and we’ll get to some data about reinfection and all the rest but unfortunately, I am hearing even among physicians, this sort of throwing up one’s hands, everyone’s going to be getting Omicron before you know it. But just to point out, if you are unvaccinated, we do not have compelling data that intentionally getting Omicron is a good strategy. All right.

The CDC is now officially recommending high-quality masks. We mused a little bit about that, they were thinking about that, they’re now doing it, no more recommending low-quality masks, now the high-quality mask. There are a couple of bullet points in this update from the CDC. They clarified that people can choose what we call respirators, these are the N95, the KN95 masks, and they actually pointed out that there do not currently seem to be supply shortages. A lot of people are worried, “Oh my gosh, you can’t recommend this, we’re going to run out.” We look to be in good shape as far as supplies. They also clarified that the N95, the KN95, these are really the way to provide the best protection to the wearer of the mask.

VR: Daniel, are there good data for this decision?

DG: It’s a good point, Vincent. I would love right here if I had– and here’s the paper that they base this on. I think this is an accumulation of evidence over time. Yes, there is– I would like, CDC, if you’re listening, I love when stuff comes out like this if there can be a really nice paper referenced behind it.

VR: I did look on the CDC website this morning, and they still say a double-layered cloth mask is effective and, Daniel, I think that compared to other masks are all going to stop droplets, the real key is the fit of the mask, whether there are gaps or not. I don’t think the material makes all that much difference, but that’s just my opinion. What do I know?

DG: I should ask because I could see your edges in The Brian Lehrer Show when we were talking about facial hair and the potential– you feel like your close-cropped facial hairstyle is allowing you to get that good tight, close-fitting?

VR: Yes, I make sure it’s tight all around the edges. I have the kind where you can tighten the two ear parts and there are no gaps and I have the metal wire over the wire. So I– wear. Unfortunately, Columbia now will not let me on campus with a cloth mask, I have to have a surgical mask or some other KN95 or something. I think it’s not a really great decision, frankly, at this point, Daniel.

DG: All right. The other, and I thought this was interesting, and I really enjoyed the deep dive and I recommend everyone listen to TWiV 854. Even if you were on that episode, go ahead. If you were one of the co-hosts, listen again. I think that that was a really great deep dive into a lot of factors that go into the calculus of, I’m going to call this, correlates of infectiousness. How do we figure out if someone who’s been infected is actually infectious? It was a great discussion about time from onset of symptoms or time from first positive test, viral RNA copy number, which is not viral load, but that being just part of the metric, vaccination status being in there, maybe even the variant of SARS-CoV-2.

One, unfortunately, I’m seeing a lot of this, I’ll say misinterpretation of the CDC guidance about ending isolation after day five. I just want to clarify that per the CDC, people with COVID-19 should isolate for five days and if they’re asymptomatic or their symptoms are resolved without fever for 24 hours, follow that by five days of wearing a mask running around others to minimize the risk of infecting people they encounter.

I want to point this out. This was a pragmatic recommendation. Nobody is saying that at day five you are no longer infectious and can go have some big indoor party in your suburban home. I guess you can, but if you invite me I’m not coming. Just that clarification. This was the CDC anticipating major staffing shortages and trying to come up with a pragmatic solution. Nobody is saying with any certainty that day six you are no longer infectious. I’m seeing people being really loosey-goosey and using that updated guidance as justification. All right.

We’re going to talk a bunch about T cells today, Vincent. The reassuring paper, Ancestral SARS-CoV-2-specific T cells cross-recognize Omicron was published in Nature Communications and I say reassuring because this really confirms a basic immunology principle in terms of SARS-CoV-2 and how T cell immunity works. Many, many are worried about the so-called race between the variants and the vaccines. I understand how this can be driven by a narrow focus on B cell responses, neutralizing antibodies, vaccine efficacy narrowly focused against infection, but what are we seeing in terms of T cells vaccine efficacy against disease? Let go into what the authors show us here.

Here, the authors looked at SARS-CoV-2 spike specific CD4(+) and CD8(+) T cells induced by prior infection and by mRNA vaccination. I’m going to hit both of these today. We’re going to be talking a bit more about prior infection, what happens to the immune system and vaccination and they found that for mRNA vaccination, there was comprehensive heterologous immune reactivity against the Omicron variant. Pairwise comparisons across groups further revealed that SARS-CoV-2 spike reactive CD4(+) and CD8(+) T cells exhibited similar functional attributes, memory distributions and phenotypical traits in response to the ancestral strain or Omicron.

They found that established SARS-CoV-2 spike specific CD4(+) and CD8(+) T cells, especially after mRNA vaccination, remained largely intact against B.1.1.529, the Omicron variant. This is not behind a paywall, so people can look at these beautiful figures. They conclude with an important comment and this I’m going to just quote, “We found that SARS-CoV-2 spike specific CD4(+) and CD8(+) T cells cross recognized,” Omicron, that’s my addition, “less comprehensive in convalescent versus BNT162b2,” so Pfizer-BioNTech vaccinated individuals suggesting that booster immunization may provide benefits that extend beyond the induction of broadly neutralizing antibodies to enhance natural protection against recurrent episodes of COVID-19.

All right. Along the same line we’ve talked a bit about the concept of boosting to perhaps temporarily augment vaccine efficacy against infection, but what about this idea John Mascola put forth? What we’re really trying to do is finish off a three-shot series, timing that third shot at the right time because we’re really still focused, we still care not only about infection, but we care about severe disease, hospitalization, or death. John’s going to be on, right, coming up, Vincent?

VR: Yes, next week.

DG: All right. If he listens to this, he can tell me if I’m misquoting him so John, I will definitely listen to your episode. The article, Effectiveness of BNT162b2 COVID19 booster vaccine against COVID19 related symptoms and hospitalization in England was published in Nature Medicine. I’ve gotten in the habit of picking my favorite article each month. This is my favorite this month.

In individuals aged 50 years and over, the vaccine effectiveness against hospitalization 14 to 34 days after a BNT162b2, so a Pfizer-BioNTech booster dose, relative to unvaccinated individuals was around 99%. A similar high protection was seen in the younger age group with vaccine efficacy around 98%. There was little evidence of any waning in vaccine efficacy against hospitalization up to 69 days after the booster.

I think it’s a very exciting report here that vaccine efficacy against hospitalization or death with a primary series followed by a Pfizer-BioNTech booster ranged from around 97% to 99% in all age groups irrespective of the primary course with no evidence of any waning for up to 10 weeks. There were a couple little things as far as the timing of that booster. Basically, if it was a shorter interval between dose two and the booster, 25 to 29 weeks, not quite as good really sort of arguing that there was a sweet spot for extending that third shot.

VR: What variant here, Daniel, was prevailing?

DG: This is tough and I love that you asked that because that’s going to change as we go forward. I think that’s really critical and frustrating. As you do these studies it comes down to what variant is circulating. We’re going to get into a next study where we see that actually it depends what you’re talking about as far as efficacy. Are you talking about Delta? Are you talking about Omicron? I don’t know if you got a chance to see this article before.

VR: I did. I looked the at it last night. The key is, what was it with two doses? It was about 90-something percent already.

DG: You’re already doing really pretty darn well.

VR: Better than most other vaccines. Right?

DG: Yes. This was predominantly Delta so we’re talking here about Delta. This was done when Delta was circulating. This is going to be a great question, so we’re going to get into what the deal is when Omicron is circulating. Because we’re going to talk a little bit in this next article about a comparison between viral infection induced survivor immunity during Delta, pre-Delta, and then we’re going to muse a little bit about post-Delta compared to vaccination. Here was an MMWR early release, COVID-19 cases and hospitalizations by COVID-19 vaccination status and previous COVID-19 diagnosis, California and New York, May through November 2021.

Now I’m going to start by saying this. This was not an easy paper to get through, Vincent. I went through a couple things. I made my own charts and kept going back to try to– I know it’s already out there, but I would’ve liked this to be a little bit easier to access the data. But what did they find? The authors broke down people into four groups or cohorts. Group number one, we had vaccinated people who had never been infected before, we had vaccinated with prior infection, we had unvaccinated without prior infection, never seen anything, and unvaccinated with prior infection. Yes, I’m going to correct that. I missed that. We have vaccinated with and without infection, unvaccinated with and without. We’re going to focus on a couple because there’s really a lot of data here.

Let’s focus first what we saw as far as hospitalizations in California in the pre-Delta period, June 13 to June 26, for example. We’re first going to talk about, among vaccinated persons without a previous COVID-19 diagnosis, 27.7-fold lower hospitalization rates. Pretty impressive. What about among vaccinated persons with a previous COVID diagnosis? 7.1-fold lower. I was a little surprised by that. I would’ve thought that that was– we talk about heterologous boosting, that should be even better. A little surprised it wasn’t quite as good.

Among unvaccinated persons with a previous COVID diagnosis. This is how much is that vaccine, that virus-induced immunity, survivor immunity can give you? Six-fold lower. If it was a horse race, the vaccinated people with no infection, they did the best, vaccinated people with prior COVID, not quite as well. Just eking out a win among the people that were relying on prior infection.

Now this is where it gets interesting and this is where we get into the mass media headlines. When the Delta variant became dominant, here we’re going to look at October 3 through 16, among vaccinated people without a previous COVID-19 diagnosis, 19.8-fold lower. That’s pretty good. What about unvaccinated people with a previous COVID-19 diagnosis? 55-fold lower, and among vaccinated people with a previous COVID-19, 57.5-fold lower.

We’re going to get into that a little. Pretty wide confidence intervals. We’re like 27 to 83, 29 to 86. Pretty wide there on that. They have a really nice figure. What you can really see from this figure, and sometimes I feel like we’re fighting the wrong fight, is it is the unvaccinated with no previous COVID-19 diagnosis that are filling up the hospitals. That’s where it goes way up, comes a little down, starts to go back up again. If you look at people that are vaccinated, you look at the previously infected, those are really pretty low as far as the hazard rate.

There’s a couple of things because I know a lot of people saw this and they’re back to where we started, it’s true, I should go out. I should get Omicron, then I don’t have to get that nasty vaccine. What about boosting? Oh, then it’s not fair because now you’re giving a third shot. Maybe now you are going to win, but that’s not fair. You keep giving all these shots. What about Omicron? This is Delta data. What’s going to happen if you get infected with Omicron? Vincent, this is getting a lot of attention. Any thoughts?

VR: Why is it getting attention? What’s the reason?

DG: There are, interesting enough, a lot of people who are, dare I say anti-vaccination, that would like to have data supporting how wonderful it is to get infected instead of getting vaccinated.

VR: I think these data don’t jive with some previous data we’ve seen that say, if you were infected and recovered and get one dose of vaccine, you have great immunity. We’ve seen a number of studies that say that, correct?

DG: That is correct. That is correct.

VR: These numbers, where if you compare unvaccinated with previous COVID in both groups, pre-Delta and Delta, the numbers are the same and I don’t get that. That doesn’t make sense to me.

DG: There were a few things. One, I was really surprised and maybe that’s why I found this paper difficult. I want to say impenetrable, but difficult to penetrate is– how was this that vaccinated people without COVID-19 were better than vaccinated people with a previous diagnosis? Then just these tremendous differences between pre-Delta, during Delta. Not really consistent with what we’re seeing.

I have several patients who I treated early on, on oxygen in hospital, who decided not to get vaccinated because they thought, one and done, and certain people out there claiming you can never get COVID twice. Well, we’re seeing them and they’re sick and they’ve got lots of SARS-CoV-2. It’s a reinfection. This just doesn’t really fit with a lot of different things. Don’t go out, don’t go get yourself a dose of Omicron and try to have one of these parties. Let’s get a little more data because this is a little bit of an outlier.

VR: As you just said, there is a downside to getting infected. You could die.

DG: Well, you could die. You could end up in hospital, you could end up with Long COVID, yet it is not innocuous. We talked about in all the millions, hundreds of millions of people that were vaccinated here in the U.S. with J&J, there were eight connected deaths. Eight deaths compared to hundreds of millions of doses of vaccines. The vaccination route to immunity is incredibly safe. Getting one shot, two shots, three shots, this is all good stuff. There’s no exhaustion to the immune system. We’re not hiding dead people anywhere, by the way. Vaccination is really a much safer way to protect yourself. All right.

Now along those lines, and I know this is an area where we are not doing a great job here in the U.S. Pregnant women. This is the paper, SARS-CoV-2 infection and COVID-19 vaccination rates in pregnant women in Scotland. This was published in Nature Medicine. This is a pretty robust study. The authors used whole population data from a national prospective cohort in Scotland.

They reported that 25,917 COVID-19 vaccinations were given to 18,457 pregnant women. You could see a lot of one dose, not a lot of double dose here. Vaccine coverage was substantially lower in pregnant women than in the general female population. Only about 32% had gotten two doses compared to over 77% in all women. We knew from a number of studies prior to this, that compared to non-pregnant women of reproductive age, pregnant women with SARS-CoV-2 infection are more likely to be admitted to critical care, more likely to end up on a ventilator, more likely to die. We knew that COVID-19 in pregnancy was associated with increased risk of pregnancy-specific complications such as preeclampsia, preterm birth, stillbirth.

Now here they’re saying, well, what about the babies? When the babies are born, if somehow they get through this gauntlet, they were looking at the perinatal mortality in the 28 days. They were seeing a fourfold increased risk of the babies dying if a mother was not vaccinated. You just want to get vaccinated, get vaccinated before you’re pregnant, get vaccinated if you’re pregnant. This is going to protect the mother, it’s going to protect the unborn child. It’s also going to continue to provide a better likelihood of a good outcome once that baby’s even born.

All right. Passive vaccination. EVUSHELD, the U.S. government announced that it is now going to buy half a million doses, 500,000 doses of the tixagevimab and cilgavimab EVUSHELD used to treat COVID-19. This is the AstraZeneca long-acting antibody cocktail. We’ve actually been starting to give this to our highest risk people. This is still in limited supply, but we’re are starting with the highest risk people. We’ll be moving forward.

We’re expecting delivery of these hundreds of thousands of doses. They say the first quarter, so that’s right here. That’s February, March. Really encouraging because one of the things as people want to get back to normal, we have a lot of people who would like to have that immune protection, who for some reason have the inability to produce these protective antibodies. Here is a therapeutic that we can now offer.

Now, this is the meat of today. This is that period of detectable viral replication. Now it’s time to get those hands out of your pockets because we have some options that have some really good evidence behind them. On January 14, the NIH updated its guidelines. Their therapeutic management of non-hospitalized adults with COVID-19, they have a really nice graphical recommendation. One of the big things that is unique here is there’s actually an order of preference. They’re giving us a flow sheet. I’m going to go through this flow sheet with our listeners.

The first thing you and the clinician want to decide is, is this an individual who is at high risk of progressing to severe COVID-19? If the person’s low risk, that’s as we talked about, keep your hands in your pockets. Things are probably going to go well, do not mess it up. Don’t give them steroids and mess with their immune system. Don’t start giving them unnecessary antibiotics. Step back, let things go well.

In those high risk people, this is that first early week, that viral replication phase. This is for individuals who are not yet hospitalized, hopefully won’t be. Not on supplemental oxygen. Number one recommendation if available is PAXLOVID. You’re going to pick up the phone. You’re going to call that pharmacy in your area where you know that they have this. Maybe it’s the hospital pharmacy if you’re up in Connecticut or somewhere else. You’re going to run through with the pharmacist. Do you have the drug and is this patient appropriate in terms of their kidney function and other medicines that they were on?

If the answer is no, this second consideration. So we’re going from an 89% and 88% reduction in progression to hospitalization during the first three and five days with PAXLOVID to sotrovimab. This is, I’m going to say, about an 87% reduction in progression. They go in, this is an intravenous infusion at this point, limited supply. Some places here in New York, Vince, and we’re actually doing this in the home in certain circumstances, we pick up your phone, back to the days where we got the FDA to expand this. We’re doing this in the home, we’re doing it at some of the hospitals.

Next, if you can’t get sotrovimab, this is a new one, outpatient IV remdesivir three-day treatment. We’re going to talk a little bit about where did that come from? This is recommended as your third option. I was just talking again with the head of our urgent cares here in New York. We’re setting this up, it’s logistically a little challenging, but the individual is diagnosed, you make a determination they’re high risk, you have dropped down to option number three, you give that first 200 milligrams right away, they come back the next day for 100 milligrams, they come back the next day for that last dose. It’s a three-day, they’re there for about an hour each. We’ll go into details.

If you can’t do one of these, your option of last resort, molnupiravir. This is no issues with kidney function. No issues with drug interactions. You do not want to give this to women of childbearing age if they are pregnant or going to get pregnant. You want to have that pregnancy test, you want to be a little careful there. Otherwise, these are our options. Let’s talk a little bit about remdesivir.

A little twist here. This is a three-day early treatment with remdesivir. This is for within seven days of symptom onset, you have to be 12 or older, you have to weigh 40 kilograms or more. The NIH does comment that since this is an IV infusion for three consecutive days, there may be some logistical constraints in many settings. This is interesting. Remdesivir is currently approved by the FDA for use in hospitalized individuals, and outpatient treatment would be an off-label indication recommended by the NIH. That’s interesting there. They do make a couple comments about how patients should be monitored during the infusion and then observed for an hour afterwards. You’re tying up a room for a little bit of time, remember, and this is a person who is highly infectious.

Why are they recommending this? They do reference, and I love this, they reference the PINETREE study, which I’m going to talk about here. I don’t know if we actually spent much time on the PINETREE study, but this was the article, Early Remdesivir to Prevent Progression to Severe COVID-19 in Outpatients, published in The New England Journal of Medicine. This was the result of a randomized, double-blind placebo-controlled trial involving non-hospitalized patients with COVID-19 who had symptom onset within the previous seven days, and who had at least one risk factor for disease progression.

Either 60 years or older, obesity, certain coexisting medical conditions, and the patients were randomly assigned to either receive this three-day intravenous remdesivir or placebo. The primary efficacy endpoint was a composite of COVID-19-related hospitalization, or death from any cause by day 28. Five hundred sixty-two patients were randomized, 279 remdesivir, 283 in the placebo group.

What did they find? I am going to say just right up front, no one died. This is all about progression to hospitalization. COVID-19-related progression to hospitalization or death from any cause occurred in two patients, so 0.7% in the remdesivir group, and in 15, so 5.3% in the placebo group, so hazard ratio, 0.13. That’s an 87% reduction in progression. As mentioned, no patients died, no difference as far as adverse events.

Early inflammatory phase. Now we’ve failed to keep people out of the hospital, they’ve broken through our initial therapeutics. Early inflammatory phase, this is when they’re in the hospital, the virus is usually on the way down. Another immune modulator we’ll talk a little bit about today, baricitinib. So what is baricitinib? Just to give a little bit background before we go into the article, baricitinib is a small molecule, janus kinase inhibitor. This is going to inhibit a number of those cytokines, so IL-2, IL-4, IL-6, some of the interferon, some of the growth factors. This has been in the guidelines and is now in the WHO guidelines as well. If for some reason you cannot give tocilizumab, so the steroid tocilizumab protocol, if instead you can’t give steroids, this is another immune modulation option.

The article, Real-Life Effectiveness and Safety of Baricitinib as Adjunctive to Standard-of-Care Treatment in Hospitalized Patients With Severe Coronavirus Disease 2019 was published in Open Forum Infectious Disease. Here the authors reported on two center observational retrospective cohort study of 369 patients, and they’re looking at standard of care versus baricitinib. What did they find? They actually found in real life settings, the addition of baricitinib to standard of care was associated with a decreased mortality, no concerning safety signals.

While I’m here, let’s just– a little reminder on timing matters when you’re messing with immune modulation. The hope is that with proper stewardship we’re giving drugs at the right time. I’m talking a little bit about the timing of tocilizumab. This is a study we did talk about before. A patient ends up in the hospital, they’re on nasal cannula. You can remember this from the movies with those little prongs up the nose, they’re maybe getting two to four liters per minute of oxygen. This starts to escalate.

Well, we had this study, Impact of timing of Tocilizumab use in hospitalized patients with SARS-CoV-2 infection. This is now, we discussed it early on but it’s now peer reviewed and published in the journalRespiratory Care. Here the authors reported on a retrospective chart review of 11,512 patients infected with SARS-CoV-2 who were admitted to a New York health system from March to May of 2020. These are actually my friends at Lenox Hill, by the way.

In this very large cohort study, they reported that hospital mortality was significantly reduced in the tocilizumab group when tocilizumab was administered at the nasal cannula level, so 10.4% versus 22%. In patients who receive tocilizumab at the nasal cannula level, the progression of mechanical ventilation was reduced versus subjects who are initially on higher levels of oxygen support. Really critical here is that in this study, there was no improvement in mortality when tocilizumab was given at the time of requiring non-rebreather, high flow nasal cannula, non-invasive ventilator or invasive ventilator.

The reason I bring this up is in the stewardship programs at some hospitals, some hospitals say you cannot give tocilizumab until the patient’s escalated to non-rebreather, or high flow nasal cannula. Ultimately, if that’s your protocol, you’re basically recommending giving it after the therapeutic window. Make sure we get the timing correct on these stewardship recommendations.

Now, yes, my second favorite is this one, the preprint, Association between vaccination status and reported incidents of post-acute COVID-19 symptoms in Israel, a cross sectional study of patients tested between March 2020 and November 2021. Now, I think as we’ve talked a lot of times, we care about mortality. We care about hospitalization. I care a lot about Long COVID. I care about infections too.

Here is really looking at this question: what is the impact of vaccination on a person’s risk of getting Long COVID? Still, I continue to take care of individuals who are just– their life has been taken away, is ruined by Long COVID. I actually took care of a girl, I’ve been taking care of her for a while, in her early 20s. She had to drop out of university. Had just been doing great, but following COVID had developed intractable migraines to the point where she couldn’t continue in school.

This is a little bit of a rosy story, because when I saw her on Tuesday I said, “You are doing great.” She’s going to be starting back at university. I said, “You only kind of need to see me as needed because you are doing so well.” Really positive there. I have to say, for a lot of individuals, they’re not so afraid of death and hospitalization. They’re really terrified that they might end up with Long COVID. So, what’s the data here as far as vaccination and Long COVID?

Here in this study they included 951 infected, 2,437 uninfected individuals as a reference control. Of the infected, 637, so 67%, were vaccinated. They found that those who received two doses of vaccine were less likely than unvaccinated individuals to report any of the symptoms. They went through a number of these different symptoms: fatigue, headache, weakness, persistent muscle pains.

Basically, the conclusion, the wrap up here, when they looked at the vaccinated people who had been infected and compared them to people who had not been infected, they were not seeing evidence of Long COVID in people that got COVID post vaccination. Now, I don’t think that the authors overreach and I think that’s really nice. The authors say, rather than suggest that vaccination completely eliminates the chance of getting PASC or Long COVID, they conclude vaccination with at least two doses of COVID-19 vaccine was associated with a substantial decrease in reporting the most common post-acute COVID-19 symptoms. Our results suggest that in addition to reducing the risk of severe acute illness, COVID-19 vaccination may have a protective effect against Long COVID. Really, really encouraging data on a lot of individuals that are worried about Long COVID.

All right. Add, reaching out and thinking about the rest of the world. No one is safe until everyone is safe. I alluded to this early on, when I record next week I will be in west Africa. I’ll be I think in the capital city Accra of Ghana. I’m looking forward to talking to some of my colleagues. I’m going to go by and visit Dr. Margaret Lartey, the Dean of the University of Ghana Medical School in Accra. Oumou Maiga up in Kumasi at the Kumasi Center for Collaborative Research in Tropical Medicine. Looking forward to being able to share firsthand what things are like on the ground in Ghana.

I did want to highlight a news feature that was recently in Nature, The pandemic’s true death toll: millions more than official counts. In this piece, the authors discuss the number of confirmed COVID-19 deaths, and they look at modeling, how many actual excess deaths do we think have occurred due to COVID-19? As people can imagine, the estimates are much higher than the number of actual confirmed cases.

On that note, I will remind everyone the clock is ticking. For the rest of January, we will continue to raise money to support MicrobeTV. I think we’re going to be able to be quite a bit more generous than we had initially thought, so it’s good for– well, thank you everyone. Thank you everyone who sends us letters, who sends us financial support. We can’t do this without you, but drop whatever you’re doing. Go to, click on that donate button and be part of the solution because we are going to get out the other side of this.

Our internship opportunity, Vincent. We’ve been getting a bunch of applicants, a bunch of CVs and cover letters. If you are interested in our internship, our educational internship, global health coordinator internship where you can work with Parasites Without Borders, learn a lot about our mission, help us support what we do, please send a cover letter and a CV to

VR: The description of the position will be at and also on the show notes for this episode of TWiV. It’s time for your questions for Daniel, you can send them to Gladys has a question. “For my daughter who is seven weeks pregnant, due for a booster and just caught COVID last week and was quite sick. My question is, should she still get the booster in the second trimester having had COVID while pregnant at seven weeks?”

DG: Yes. This is a question that comes up all the time. Someone gets COVID, do you consider that a dose of vaccination? Do you consider that a true boost? We don’t know, and this is one of those things. I try to use analogies. If you said, “Hey, I’m going to go ahead. I’m going to give you your booster. I’m not sure how much. I might just give you a little, I might give you a whole bunch.” You’re like, well, why don’t you give me like the standard dose? That’s the challenge.

We don’t know when someone gets infected what dose they get, how much of a boost they get. We still make the across the board recommendation. We’ve certainly seen a lot of reinfections and so go ahead. When you’re no longer isolating because you’re infectious, when you feel better, go ahead and get that boost. I wouldn’t let that infection change your timing.

VR: Scott sends us a link to include in your show notes, to request four free at-home rapid antigen SARS-CoV-2 tests from the U.S. government, it takes about 30 seconds to fill in your information and submit. We’ll put that in the show notes. Thank you, Scott for that.

Imad writes, “I listen to Daniel Griffin’s weekly updates. I’m very excited to hear his report regarding risk factors for severe COVID in vaccinated, paper in MMWR. He reported, when 0.015% of vaccinated individuals developed severe COVID outcomes, 0.0033% of vaccinated individuals died. This sounds amazing. Daniel compared this to a pre-vaccine risks of 10% to 20% of individuals getting infected ending up in hospital, 2% case fatality rate. My concern is he’s not using the same denominator, namely the number of individuals who got COVID. The paper states, among 1.2 million persons who completed primary vaccination during December, October, a total of 2,200, 18 per 10,000 developed COVID and 189, 1.5 per 10,000 had a severe outcome, including 36 who died.

This seems to translate to 8.4% risk of developing severe outcomes and 1.6% case fatality rate. This is perhaps slightly better than the pre-vaccine numbers. Obviously being vaccinated reduces your risk of developing COVID in the first place, but that benefit seems to have decreased significantly with Omicron. Is Daniel painting much too rosy a picture here or am I misinterpreting the data?”

DG: I think this is reasonable. Don’t worry, Imad. You lost everyone when you started doing math in your email, but that’s okay. This is a tough thing. Now, one of the things that I will say is not in the calculus here is the reduction in your risk of even being infected to begin with, which is actually one of the things that vaccines give us. Then, if you’re going to go down this road with math, you’ve got to realize we’re talking about a veteran study here, right? These are individuals– I was probably rosy when I said only 10% to 20% of elderly veterans end up hospitalized, only 2% case fatality rate. Yes, this is challenging to take this data and then really translate and compare. This is, I think, like the hamster data comparing historical numbers. You need your unvaccinated placebo control group to really do the true calculation. No, it’s a point well taken.

VR: John writes, “I have a question about episode 850. Your and the the team’s focus on severe outcomes in death when talking about vaccination, you highlighted very high rates of cognitive impairment and fatigue in the meta-analysis about Long COVID in this episode. Looking at the paper, it seems that objective measures of cognitive impairment found an even higher rate than asking people subjectively 36%.

It also seems that hospitalization and overall acute disease severity is not a good predictor of Long COVID severity. From what studies I’ve seen so far, vaccines are probably about 50% protective against Long COVID and people who do get infected. Please let me know if this is inaccurate. Many studies also seem to show that symptoms continue to persist at the end of whatever the study period is. We don’t know whether they will ever resolve at this point. In light of all this, doesn’t it make sense as a public health goal to consider vaccine efficacy against infection and try to prevent all infections, not just keep people out of hospital? This seems particularly relevant for younger, previously healthy people and children.”

DG: Let’s hit that first because he’s got a little more here. I think we, well, I know I have and I can speak for everyone else. I’ve always tried to focus with the vaccines, really just with COVID-19 in general, on deaths, hospitalizations, Long COVID saying it’s not just about death and hospitalization. What do we know so far about vaccinations and Long COVID? You start off here with what we first started to see, people who had gotten COVID, who had Long COVID.

We started observing about a 50% reduction in people continuing to have symptoms of Long COVID. About half of the people that got vaccinated were reporting significant improvements. That was good. What we talked about today was the study looking, and we’ve talked about this before, vaccination and then infection and showing that that’s really the best way for vaccinations to prevent Long COVID.

We talked about another paper where we looked at timing of vaccination after COVID. A patient comes in the hospital, they’re unvaccinated. Do you have a conversation about vaccination? I usually don’t on the first day. A person comes in first day. They’re not feeling well. They mention they’re not vaccinated. I say, “Okay, we can work with that.” Now we develop a relationship. Usually this is when I have that second discussion about vaccines. I say, “Okay, let’s talk about vaccines.”

We talked about this study on a prior TWiV, getting a vaccine within the first 30 days after infection, really significant reduction in going on to develop Long COVID. Remember, people can feel better and then 30 days later they start having those symptoms. If you wait 30 to 60 days, you still get a benefit. If you wait past 90 days, that’s when you’re only seeing about that 50% reduction. You can connect with these people.

I see stuff in the media and I find it upsetting, “Oh, health care workers are exhausted, they’re at wits end dealing with unvaccinated people.” I don’t think that’s true. We take care of people who are sick, that’s why we chose to do this and if someone decides not to get vaccinated, they made that decision. These are good people, these are good people who made what I would think is not the best decision.

I was taking care of a gentleman last week in his late 50s, decided not to get vaccinated. We started talking about Carrie Grant movies, he loves dogs. This is a nice man and at the end of his stay in the hospital I say, “Hey, we’re going to set up home option, we’re going to send you home. We’re going to set up a time for you and me to talk but I’m going to encourage you to get vaccinated. It’s going to reduce your chance of a reinfection, good data on that. It’s also going to reduce your chance that a month, two, three from now, you’re still seeing me because you’ve got cognitive impairment and Long COVID.”

VR: His idea of preventing infection, well, that’s going to be hard if we don’t boost every six to eight months, which I don’t think is a good approach.

DG: I don’t think as a public health approach it’s tenable to be vaccinating people every, well, four to five months, it’s just-

VR: I agree. His second part is actually the point made by the previous email about the pre- and post-vaccine numbers, exact same point.

That is COVID-19 clinical update number 98 with Dr. Daniel Griffin. Thank you, Daniel.

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

[00:52:12] [END OF AUDIO]

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