TWiV 806 COVID-19 Clinical Update #80

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 18 September 2021

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 806 recorded on September 16, 2021. 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: This is clinical update number 80, and I have a question for you at the onset here, Daniel. This is an easy one. In the past week since we’ve spoken, what are the numbers looking like in the New York area?

DG: The case numbers, and I think you can say this across the country, if you look at numbers, we seem like we’ve crested a little bit of a hump as far as cases. When you look at that nationally, not great, but again, we talked about that lagging indicator. Here in the New York area, and I’ll kind of hit on this, we’ve been seeing only deaths about 40, 44 instead of right around 40, low 40s. If you just think of how different that was from deaths back, above 2,000 a day in the New York area. So, I will say a few COVID cases in the hospitals in a highly vaccinated population, particularly in Nassau County where I see a lot of folks. Vaccines have transformed COVID from an ICU, from a hospital disease, to a largely outpatient disease.

I had a call yesterday from a clinician colleague of mine and he was saying, “Damn, I just was not feeling so great. I think it’s just a cold. I called my doctor and he said, ‘Oh it just sounds like a common cold.’” I’m like, “Really, like maybe a common cold Coronavirus, like SARS-CoV-2 after two shots of an mRNA vaccine?” He’s like, “No, no I talked to the doctor and he said it doesn’t sound like COVID.” I said, “You know, according to my good friend, Lisa Santoriello, it’s a viral disease. You realize that it can present just like a viral disease? The only way to tell whether or not what you have his COVID or not is to go get a test.” Vincent, can you guess what that test showed?

VR: I think it showed he was positive for SARS-CoV-2.

DG: Yes, it was positive and then he went ahead and tested his wife, his family, and he’s not going to be coming and doing consults with me for a little while till he finishes his isolation for the infected period.

VR: That’s interesting. In immunized people, it can present like a common cold, which is what the common cold coronas do in a largely immune population, right?

DG: It’s really interesting. I know we’ve talked about this from the beginning. If you got exposed to SARS-CoV-2 when you are younger, with that, it’ll be different later in life. Sort of– is this what will happen? Let’s say parts of the world that have not been getting vaccines, and what do we do in the future? If in the future, a lot of young kids, let’s say, in the first few years of life get infected with SARS-CoV-2, what will the future be there versus what we see now? Because I think we talked about with the other, the non-SARS-CoV-2, the common coronaviruses, and I want people to quickly think when they name those.

By the time you’re six years old, the majority of us have been infected. It tends to be in that first, under five, so it’d be interesting to see over time. I always like to say to you, to put that in context, “Vaccines are like sunblock. You can’t get vaccinated and then lay there on the beach in the tropics naked all day.” They reduce our chances and my colleague is fortunate that, for him, it was a mild case. But unfortunately, when we hear the death numbers, a few of those deaths every day, a number of those deaths every day are in the vaccinated, who have other risk factors, who couldn’t mount that robust immune system.

All right, let’s start with my quotation and enough people know I am recording this on Yom Kippur. It will not be sundown until 7:01 here in New York. My son, Barnaby, has some friends– He calls it, “An intimate gathering, daddy. It’s just a few of us, it’s not a superspreader event.” We were basically figuring out that they were not allowed to eat until 7:01 and my wife was like, “But they’re boys.” I’m like “They can wait, they can wait.” For those of you who I guess listen to this on Saturday, I hope that your fast was a good and gentle one.

Our quotation from Elie Wiesel. “The opposite of love is not hate, it’s indifference. The opposite of art is not ugliness, it’s indifference. The opposite of faith is not heresy, it’s indifference. And the opposite of life is not death, it’s indifference.” When I graduated medical school, Elie Wiesel was still alive and actually spoke at Carnegie Hall at our medical school graduation from NYU. Maybe, as we get a little further, I might throw in a little bit of the wisdom that he shared. At the time, it ruffled my feathers so to speak, in my young, arrogant, finishing medical school– but really a wise man and a loss that he’s no longer with us.

All right, I gave a little bit of an update right there, but I’m actually going to go ahead and introduce a preprint right here in my update because I think it introduces a really important concept when we’re trying to understand what is going on around us. This was the preprint, “The COVID-19 Hospitalization Metric in the Pre- and Post-vaccination Eras as a Measure of Pandemic Severity: A Retrospective, Nationwide Cohort Study.”Now, there was actually, I think it was an Atlantic article that discussed this, and I spoke to the author before he published his piece. Here in this preprint, the author suggests that there may be limitations at just looking at hospital numbers if one does not ask for a little more detail, or dare I say nuance.

This was, I think, a really smart, really clever the way these researchers went about trying to look at this data. The investigators used the electronic records from the health care system of the U.S. Department of Veteran Affairs and looked for March 1, 2020, through June 30, 2021. They included 47,742 admissions, they then identified 38,508 unique patients with laboratory confirmed SARS-CoV-2. Then a subset of this, they identified 28,731 that met the criteria for moderate to severe COVID-19.

What does that mean? They, I’m going to say, properly defined moderate to severe COVID-19 disease as a person who has a documented oxygen saturation of less than 94%. They were looking at these inpatient hospitalizations, they have a little look through and see if they could find that that occurred during the admission. Then they really looked at what percentage of these COVID-19 folks that were hospitalized actually had this criteria.

We’ve talked about this before, you have to be careful with geography, we talked about ICU. Putting someone in the ICU, there’s a different threshold. I’ll say here in the New York Tri-State Area than there was, for instance, at my first job when I was working at the VA in Helena, Montana. It was just me, I was the only guy there the entire weekend, a 100-bed hospital. People ended up in the ICU for closer observation with a lower threshold. You didn’t want to know. Are they in the ICU or not? You want to know why are they in the ICU? Are they in the ICU because it’s Dan all by himself? Or are they in the ICU because they really require that higher level of care?

What they report here is that prior to January 2021, so prior to when vaccines became available, 64% of folks admitted to the VA had that moderate to severe, had a documented saturation less than 94 versus 52%. It fell about 12% in this later period. Most strikingly, if you look at the vaccinated patients, only 42.6%, so the minority of the vaccinated admissions had an oxygen saturation less than 94%. Only 15.8% of those admitted vaccinated patients were sick enough that their physicians felt it was warranted to administer dexamethasone.

This has been taken both ways on social media apparently. Some people say you’re minimizing COVID, but what I think this actually is is a reinforcement of the efficacy of vaccines like we talked about with my colleague. Not all COVID-19 hospitalizations are the same. If an individual gets vaccinated, they end up in the hospital, “Oh my gosh, they must be so sick.” Well, if their oxygen saturation is above 94%, they’re there just for a 48-hour quick stay, not much more than observation. That is so much different than somebody ending up on high-flow oxygen, ending up in the ICU. Again, nuance when we look at those hospitalization rates. We want to really be asking, what are we seeing here, why are people being hospitalized and getting that nuance there?

I will say death is death. Despite all the nuance here, if you go ahead and you look at the at the Worldometer dashboard, how are we doing there? I actually looked a week ago when we recorded TWiV clinical update 79. That day, over 2,000, so 2,107 people had died that day. If you go back to September 9th, if you go back about a year ago, that number was 1,072, so that’s twice that number. Then if you look a little bit again, a little granular, if you look at places with high vaccination rates like here in New York, as Vince and I were discussing, we’re seeing about 40 deaths a day. If you go to Texas, you can imagine that count is much higher.

I just checked right before we recorded this. Yesterday, September 15th, 2,284 deaths for just one day. This is the issue. If you remove the mask, remove all the non-pharmaceutical interventions, and you still have a large, and we still have a chunk of our population that is unvaccinated.

Children, COVID, and mental health. Children are at risk for COVID. Wearing a mask is less traumatic for a child than being hospitalized. I went ahead and I looked at, and as I’ve mentioned the CDC has tracking, the American Academy of Pediatrics has tracking. We’re still seeing just an unacceptable number of children being infected here in the U.S. per week. We’re still in that quarter million a week level.

I should say, I’m part of this COVID Kids Consortium that was organized by Kirsty Short, she’s a virologist down in Australia. I don’t know, Vincent, you may know her. This was an interesting international group that Dr. Short put together. Our goal here is to provide meaningful data on COVID in children and adolescents and really to look at not only high, but middle, low-income countries with all the different quality, data challenges in different settings.

After this last meeting, I was forwarded a preprint, which I shared with Vince and I shared with Amy. I asked a couple other folks to look at this. The preprint was “Virological features of SARS‐CoV‐2 infection in children.” This preprint certainly will benefit from the peer-review process. There’s a couple painful things. They equate viral RNA copy number with viral load. I think we’ve been trying to point out that those are not equivalent, but they do viral culture, they do assessments of cytopathic effects, they report semi-quantitative viral titers. I thought it was worth a review and I look forward to it improving.

Some of the interesting things in here, the youngest kids do not have lower RNA copy numbers as assessed by RT-PCR. Lower age kids were not less likely to have culturable virus. It was really mostly in those first five days after symptom onset that virus could be cultured. The anterior nares samples looked like that was fine. We’ve talked about that before. In a lot of ways, just confirming a lot of things that we’ve been saying.

Just really dispelling a lot of these early myths, but then maybe a few takeaways. You can, in these children, particularly if you’re going to be doing serial sampling, you can do the anterior nares. You do not need to do that beautiful, potentially painful, and traumatizing deep blind middle turbinate brain biopsy swab, but again, this supports that we really need to understand what’s going on in children. They’re not some special class that when exposed, does not get the virus. Children can get infected, children can have replication-competent virus at high levels.

This is update 80. Hopefully something a little special here. The pre-exposure period is when we’re all worried about transmission, exposure, what can we do. I always say never miss an opportunity to test. Again, masks are cool, hopefully people remember that because the CDC updated their mask guidance with some really nice graphics. I have to say, it’s still shocking to me that this far into the pandemic, people are still wearing masks incorrectly. I find when I walk around, I need to ask people, “Do we need to get you a lighter mask? It seems to be falling down. We need the kind with the helium to keep it above your nostrils.”

Just a little refresher here, and actually, when we get to the end here, I’m going to bring out some samples. Maybe this will be the time people want to tune into YouTube to see some of the masks. We talk about masks, but really, what we’re talking about, and what the CDC highlights on their updated guidance, go to cdc.gov, types of masks is the end of the URL. They talk about masks. These are designed to contain your respiratory droplets and particles. They’re really source control, they provide only some protection for you, really mainly they’re protecting others. I’ve used the surgeon analogy, he’s got that so he doesn’t cough spit or infect the wound, he’s not so much protecting himself from the patient.

The other side, respirators. We throw them in with masks, but these are really designed to protect the wearer from particles and this is going to be something I will go through. They repeatedly, in their guidance here, reference nose wires. You want this mask to fit you properly. Maybe this is an opportunity, I would say, this is mainly started off as physicians listening, but every time you see a patient, here’s your opportunity to teach them how to properly adjust that nose wire, so that it fits properly. When I show the little props later, you can actually add a nose wire to a lot of masks, you can order these iron on, but you really want to make sure this fits properly.

They also comment a little bit about facial hair. We almost need Dickson here to show the issue with excessive facial hair, not just with masks, but also a scratchy microphone issue. I’m also going to do a little bit of a shout-out for an organization. They were talking about masks before anyone else was, perhaps. This is an organization called the American Conference of Governmental Industrial Hygienists, the ACGIH. This organization is a 501(c)(3). They’ve been around for over 80 years focusing on the advancement of occupational environmental health.

They actually have a really, I thought, a nice graphic where you get to add what if people around me are wearing masks? What if I’m wearing a mask? What about the different masks? Where does that put me from a safe point of view? With that said, I’m going to reach behind me and grab my props, Vincent. I have several masks behind me.

VR: I’m looking at this CDC site and they have a page of all the different kinds of facial hair you could have. I didn’t know.

DG: Isn’t that great? You didn’t realize all your options. I don’t know if people are going to come away with a better understanding of the impact on masks, or new ideas for personal appearance. Let me start off with the bottom of the heap, my so-called, this is my cloth mask without a nose wire. You can see, I put that on. Maybe there’s a little bit of decrease, but there’s a lot of air coming up around the nose. We have our cloth mask. Now, our cloth masks are probably our, we’ll say, least effective source control, least effective protection. That’s our cloth mask.

The cloth mask can actually be improved by adding a nose wire and making sure that the mask is fitted better to your face. This is our famous, “Masks are cool.” You can see here, if you’re watching on YouTube, that there is this nose wire. You may want to go over to the mirror, you want to make sure that nose wire is bent, so it goes in and then flares out so you get a nice seal at the top. This is one of those examples. You can put on your reading glasses, for instance, and you shouldn’t see much of a fog. As we go later, we’ll try that again with some other masks.

Now we move up. Those are truly masks. What is our last mask in the heap? This is our surgical mask. These are actually a material that actually has improved ability to create local source control. Again, it has the nose wire. Bring this up, and this is what you’ll notice that physicians, that surgeons, that healthcare workers, nurses, nurse’s aides, really a lot of folks in the hospital are wearing these almost at all times. A lot of hospitals, you have to wear them, I say almost at all times because people love to pull them off to speak and generate droplets, which I walk away quickly.

Then we move from masks to respirators. The first is the KN95. I know I’ve talked about this quite a bit. You can see here, this is a KN95. It also has the built-in metal. Again, you need to shape this. You can’t just pop it on your face. This actually creates a fairly reasonable seal, but again, this is a KN95, this does not necessarily meet U.S. NIOSH standards, the National Institute for Occupational Safety and Health. When we’ve studied these, which are actually approved, so the KN95 are approved by well, not kind of, they are approved by the Chinese. They are not quite as effective as the N95s.

The N95s, let’s hit that. I have a couple here before we move on. This first one here. Healthcare workers that are using N95s, these are actually fitted, we actually get tested. Since I work at several hospitals, I get tested everywhere. You could see there, the strap actually broke as I put this on. They’re not necessarily designed for multi-use, these fit really close. You’ll actually notice if I put my glasses on not much fogging. These are actually often designed, I’ll pull this off to vent the air away so it doesn’t– We have several options, here’s another one, sort of a flat duckbill, the 3M, this is my favorite.

The N95s, these are actually made up to a highest– Now I have to say, to be honest, we have these made in the U.S., supplies are better. Maybe I should say N95s they’re not just for healthcare workers anymore echoing the serial commercials, but those are our choices. I think this far into the pandemic, it’s pretty obvious not only that masks work, but I think it’s really critical that we understand masks, respirators, how to use them. If you see a friend, or an enemy, or someone in between, not properly wearing that mask, feel free to help them. It’s like someone with a crooked bow tie, I am sure they want you to help them out.

Again, in the string of points, making a line, we had another MMWR looking at the effectiveness of masks. This was the MMWR report “SARS-CoV-2 Transmission to Masked and Unmasked Close Contacts of University Students With COVID-19: St. Louis, Missouri, January through May 2021.” Just briefly in this MMWR they compared only mask exposures with close contact with unmasked exposures. You’re exposed to someone who has SARS-CoV-2, what happens if you get exposed to someone who has a mask or is unmasked? This is source control. Every one of those unmasked exposures, they found a higher adjusted odds of a positive test. Each additional exposure was associated with a 40% increase in odds of a positive test. Just people keep asking like, “Oh, where’s the data on masks?” Lots of data, there are lots of points here in the line.

Moving away from masks, back to testing. Perhaps one of my favorite topics. “Daily testing for contacts of individuals with SARS-CoV-2 infection and attendance and SARS-CoV-2 transmission in English secondary schools and colleges,” an open-label, cluster-randomized trial. I think we may have to discuss this in preprint form, but here it is peer-reviewed. This is a paper looking at test-to-stay versus the quarantine approach. You have an individual who’s had an exposure, you say, “Oh, you got to stay home for 10 or 14 days,” or you say, “You know what? You can keep coming to school, we’re just going to test you every day.” How well does the test to stay work in this study?

This involved 201 schools in England. They randomly assigned 201 schools, and there were 99 in the control group, there were 102 in the intervention group. This was a 10-week study from April 19th to May 10th of 2021. Then it continued into a pre-pointed stop date, June 27th, 2021. Get your 10 weeks. At the end of the day, not everyone participated, but 76 control schools at 86 intervention group schools actively participated. There were 59.1 per 100,000 symptomatic PCR confirmed cases in control. 61.8 per 100,000 per week in the intervention group. Not a significant difference.

Again, demonstrating the ability of these rapid lateral flow tests to actually perform very well in a test-to-stay school program. Because I think this is going to be a big issue in the future. Everyone is worried, “Oh, if we do all these tests, we’re going to have all these kids missing school when they don’t need to.” This is a way to say we can test and then we can actually continue to test and we can get people staying in school, continuing to have those educational opportunities in a safe environment.

All right. Active vaccination. We’re still in that pre-exposure period, never miss an opportunity to vaccinate. Vaccination is how this pandemic ends. I added a new one. This is sort of, I feel like I’m channeling you Vincent, vaccines, the jabs that keep you from getting sick.

VR: Very good.

[laughter]

DG: I wanted to talk a little bit about vaccine conversations, so back to Elie Wiesel. One of the things that he told me when I was there in Carnegie Hall, all full of myself because I had just gotten my MD degree. He said, “You know what? I know you guys, you think you know it all, but the first thing I want to impress upon you, listen to your patients.” I think that’s the big thing. When we have someone who comes in and sees us and they haven’t been vaccinated, that’s not the time to scold, that’s not the time to tell them how smart you are and how much you know. That’s the time to listen.

I think this is going to be more important because as we look in the coming weeks, vaccines potentially moving into younger ages, the anti-vaxxers are going to be on their home turf here. They’ve got all their arguments ready to go and they just need to pop something new in. Listen, find out what the concerns are. Let’s really focus on people who have questions. There’s a certain crowd, and I think going back to Elie Wiesel’s, which maybe we just don’t need to engage. We need to spend our time and resources on those people that are interested, that have questions, that are not really there just to– anyway.

Now a little bit about hybrid immunity. I like this preprint, so this is a preprint, “High genetic barrier to escape from human polyclonal SARS-CoV-2 neutralizing antibodies.” This is posted as a preprint, and here the researchers used an HIV-1 pseudotyped virion system with a synthetic polymutant spike that they generated by aggregating variant of concern associated and plasma selected spike mutations into a single polymutant spike protein. Quite a mouthful. Actually, I have to say, this was similar to the work that I was doing, actually just not too far from Vincent’s office, before the pandemic started.

Using this system, they were able to show that 20 naturally-occurring mutations in SARS-CoV-2 spike were sufficient to confer near complete resistance to the polyclonal neutralizing antibodies generated by convalescence and mRNA vaccine recipients. You put these 20 mutations in the spike and if you had an infection in the past, or you had a couple of doses of the mRNA vaccine, your plasma actually was not able to neutralize this. However, and in this discovery, plasma from individuals who’d been infected and then got the mRNA vaccine, they were able to neutralize not only SARS-CoV-2 but also diverse other viruses in the same coronavirus family.

Let’s just translate this a little, because I think this could be quite something. First of all, it’s about neutralizing antibodies and changes in the spike protein. It’s not the whole complete picture looking at T cells, which we think are less sensitive to changes in spike. The researchers went ahead and they did find these 20 changes in the spike protein ending up in this near-complete resistance to these neutralizing antibodies. Either people who had COVID infection or people that got the Pfizer or the Moderna vaccines, the Comirnaty or the spikevax.

They say mutations, but we’re really dealing with amino acid changes. The mutations in the genetic code that led to amino acids, which changed the spike protein. Now, they did show this, I think, rather interesting COVID first then two doses of mRNA vaccines. There were really, I thought, I’m going to say four interesting questions and I’m hoping the reviewers asked them to address these prior to full publication. What about people who were vaccinated and then got an infection? Like I described my colleague. What does the antibodies from that individual look like?

The next, and I think this is time-sensitive, what about an individual that gets that booster? We’re talking about boosters and certain individuals getting those. What about someone who got a booster and then got infected? I think that’s an interesting– is that we’re weighing now if we give boosters versus exposure. Are we risking trouble with boosters’ original antigenic sin or the butterfly effect? I’m going to leave that for a deeper dive with maybe our immune colleagues.

Then, of course, what about those folks that got the J&J vaccine, the redheaded stepchildren, they feel left out. What about people that got the J&J, how are they doing? Of course, boosters. We can’t not mention boosters, but that’s all I’m going to do here is just mention boosters. There was a very well-written and referenced viewpoint piece in The Lancet, “Considerations in boosting COVID-19 vaccine immune responses.” What I’m going to do here is I’m going to suggest that people not only take the time to read this brief three-page piece, but also go ahead and listen to TWiV 805.

Vincent, you guys did a great job of walking through the questions, the issues there. The FDA will have actually met prior to this dropping on Saturday, but really I thought this piece outlined a lot of the questions. The FDA wants their decisions, their recommendations, to be driven by the science and I think a lot of those questions about boosters. One is, is there really waning immunity that we’re concerned about? Two, if you give people a booster, is there a benefit? What is the safety profile? Who has the best risk-benefit? Should boosters be given out there? We’re redoing it now to individuals who have immune suppression. Organ transplant recipients, people with that level of immune suppression. We know the antibodies go up. We need to know, is it more than that? Is this really effective? And we can talk about that.

Passive vaccination, just to close out our pre-exposure period of time. Remember monoclonals after high-risk exposures in high-risk people. Now we move to the period of viral replication. It’s gotten through and now the individual is actually infected, and during the viral symptom phase, I say, the time for monitoring and monoclonals, not the time for antibiotics, and not the time for steroids.

I’m going to hit a little bit on steroids after I just bring to people up-to-date on what’s going on with monoclonals. People have finally fully-embraced monoclonals and now for the first time, there’s concerns about shortages. We’re shipping out 150,000 doses a week. I think U.S. Government’s paying about $1,000 a dose. I think we’re spending about $150 million a week on monoclonals. That’s a lot of money.

We got an announcement from the U.S. Department of Health and Human Services. Let me read this and put it in context. “The recent increase in the prevalence of the Delta variant of COVID-19 has caused a substantial surge in the utilization of monoclonal antibody drugs. It remains the goal of the federal government to ensure continued new developability of these drugs for current and future patients. As such, HHS is immediately implementing the following changes to help promote optimal and equitable use of the available supply of monoclonal antibodies while we continue efforts to procure additional product. Limiting immediate orders and shipments only to administration sites with HHS Protect accounts, and current utilization reporting and reviewing all orders for alignment with utilization.”

What is this? Basically, the federal government is jumping in saying, “We need to make sure that these products are used appropriately. We’re going to be sending them to sites that are giving us the data, so that we know what’s going on.” What is the HHS Protect? This is really an ecosystem. This is a secure platform for authentication, amalgamation, and sharing of healthcare information.

Really, looking for the ability to keep an eye and make sure that these drugs, which are now becoming in limited supply, as opposed to sitting on shelves, are really going to the people that need them. This is prompt that I think fear, fear about shortages that I hope are exaggerated. There was this idea for a while that, yes, you don’t need to get vaccinated because you can always get your monoclonals and now people are a little worried. Maybe I should get my vaccine because maybe I can’t just get that monoclonal.

The current U.S. administration reported that they will buy more than 1.7 million more doses of the monoclonal antibodies. They’re going to get the bulk 1.4 million from Regeneron, another 388,000 are coming from Eli Lilly, and perhaps we’ll hear about even more being purchased from GSK. There’s even a couple other companies out there trying to move for EUA for their products as well. Just to keep this on people’s radar, I’ve been bringing this up for a while, I’m waiting for the data to share, but we are expecting October, November, December applications for EUA of effective oral antivirals. We’ve got multiple companies working on several products, so some optimism there that we’re going to have another option.

I want to go back to steroids. This is the individual who shows up at a primary care office. Maybe they show up at an urgent care, they’re in that first week, and they’re in that viral symptom phase. We know some folks maybe they’re not listening to TWiV, they’re trying to do the right thing. They throw some steroids, some vitamins, some antibiotics at the patient. Is that harmless? Is that okay? This was a really nice, meta-analysis, a systemic review, “Steroids use in non-oxygen requiring COVID-19 patients: A systematic review and meta-analysis.”

They initially identified 6,411 studies, they then screened 2,990 after an initial exclusion, and then they finally narrowed it down to seven studies, which fit the criteria. We’re ultimately looking at 2,214 non-oxygen requiring COVID-19 patients. I think this is really critical. Overall, odds of progression to severe disease among the non-oxygen requiring COVID-19 patients receiving steroids was 5.97. Basically, by trying to be helpful by giving steroids in that first week, you were increasing a patient’s odds of progressing to severe disease almost six-fold, and you increase their odds of death 1.35. A 35% increase in their chance of death as compared to patients not receiving steroids.

You also increase the mean duration of fever. You increase the mean duration till viral clearance. If they did end up in the hospital, you increased their length of hospital stay with a median of 20.8 days. I’ve got to say this is just reinforcing. During that first week, we don’t have a lot, we can offer the monoclonals to a certain subset, but we certainly can harm these individuals. They have a really nice Figure Four in this paper where you can actually compare folks that did or didn’t get steroids and you can see the harm that could be done here.

Again, for the first week, this is the time for monitor and monoclonals. It is not the time for antibiotics. It is not the time for steroids. We can do harm. With steroids, we can significantly increase a person’s chance of ending up in the hospital. We also know, as we talked about with azithromycin, with doxycycline, other antibiotics these are not helpful and potentially harmful. I think we talked about the one doxycycline study where there was a five-fold increase in death, just giving them those antibiotics. Remember, we can harm people during this first week.

Then once they progress to that second week, this is when people often get hospitalized. We have really good evidence for benefit of steroids if they have an oxygen saturation less than 94%. That matters and timing really matters with COVID. We also had a nice review of steroids in the hospital setting. This was, “Review in Adults With Severe Critical COVID-19 Corticosteroids Reduce Mortality Versus Standard Care: An Analysis With or Without the Recovery Trial.” So this is seven randomized control trials, one cohort study, published in International Immunopharmacology.

I really like this, because I think we’ve talked a little bit about meta-analysis, but you have to be careful that your meta-analysis is not being swayed too heavily by just one study. Otherwise, it’s really not a meta-analysis– is that one study pushing things. The recovery trial done by the folks in the UK was a large trial. You want to pull that out and say without that, how do we do? A total of 6,771 patients from these eight prospective studies, seven randomized control, one prospective cohort, were included in this meta-analysis. The results showed that corticosteroid therapy at the right time in the right patients was associated with lower mortality in severe COVID-19, so an odds ratio of 0.70, so 30% reduction in mortality.

Since the proportion of recovery trial was so large, they removed that. When you remove that the odds ratio is 0.65, so a 35% reduction in mortality. Even without that study, we’re still seeing this 30, 35%. We’re seeing a clear mortality benefit. Remember this is when we’re using steroids, it’s when we’re using remdesivir, pulmonary support, anticoagulation and then only in select patients further immune modulation, such as tocilizumab or baricitinib.

The tail phase, long COVID. An exciting announcement, I will say, this last week. As we’ve been saying, COVID is not just a two-week viral illness for many people. On Wednesday, September 15th, the NIH announced, NIH builds large nationwide study population of tens of thousands to support research on long-term effects of COVID-19. The NIH awarded nearly $470 million to New York University, NYU Langone Health, New York City, which will make multiple sub-awards to more than 100 researchers at more than 30 institutions and will serve as the recovery clinical science core.

This combined population of research participants from new and existing cohorts called– the meta-cohort will comprise this recovery cohort. This funding is being supported by the American Rescue Plan. This is really an attempt– We’ve seen over the last 18, 20 months, a little longer now– A lot of money was spent. A lot of trials were set up. We don’t have the data we would like. This is really an attempt to say long COVID, it’s important post-acute sequelae of COVID. This is important. We need to do this right. We need to establish a cohort. We need to make sure this is studied properly. We need to be organized when we do this. It’s taken a little longer than a lot of us would hope to get this set up, but I really am optimistic that we are now going to do this correctly. I will mention NYU. That’s my medical school alma mater, so I’m sure they will do a great job.

All right. What about the rest of the world? No one is safe until everyone is safe. Is there really a false dichotomy regarding vaccinating the world? Perhaps the most selfish thing we can do is not vaccinate the world. TWiV is going to be looking at analysis, what is the best way to use our vaccines. One of the concerns that has been coming up is, “Are we allowing these variants to evolve, to develop in these areas?” There was a research article, “A year of genomic surveillance reveals how the SARS‐CoV‐2 pandemic unfolds in Africa,” it was published in Science.

In this article, the authors describe the genomic epidemiology of SARS‐CoV‐2 using a dataset of 8,746 genomes from 33 African countries and two overseas territories. Really interesting and, I think, what I’m going to do is I’m going to tell people keep listening to TWiV upcoming episodes where we get a deeper dive into the variants, and what’s going on, and what is the calculus with vaccines.

Coming up, we have the UN. I guess they’re meeting on Tuesday and there’s going to be a whole discussion about how we successfully vaccinate the world. Hopefully, a lot of creative ideas about how we get this done. On that note, I’m going to say, throughout the months of August, September, and October, go to parasiteswithoutborders.com, donate. Donations made to Parasites Without Borders will be doubled up to $40,000 in total in support for our Floating Doctors. Help them continue to do the great work they’re doing down there in Panama.

VR: Time for some email questions for Daniel. You can send yours to [email protected]. Allison is very concerned about children. She’s been thinking for a few weeks that the next 12 weeks are going to be full of thousands of children dying under 12 years of age. She wants to know, are any of the monoclonal treatments approved or in trials for people that young?

DG: That is a challenge. The same population under 12 that is not eligible for vaccination is not eligible for the monoclonals as well. I think if we look at the numbers, we’re not talking about thousands of children dying. A couple of things I’m going to say here, I’ve always talked about we need to care about children. When we talk about a pandemic of the unvaccinated, we are talking more and more about children when we say that.

Schools are opening and people are worried, but I think I’ve tried to point out several times and share some of the science on this, is that we can safely have children in these environments. It involves several layers of protection and, actually, can sometimes even be safer than keeping them out of the schools. It involves masking, testing, vaccinating all the people around them that can be vaccinated, testing. There’s a lot of ways to do this. We certainly can do it poorly, but no, I think we can do this safely.

I think we’re waking up. We’re being reminded, “Oh, my gosh. We are still in the middle of a pandemic.” I think we’re starting to see the numbers go down. I am optimistic here going forward. I think I’ve been suggesting that maybe by Halloween, there’ll be vaccines for the younger kids, but then again the FDA is getting a lot of pressure and what we really want is an FDA we can trust, an FDA that follows the science. When we do move to less than 12, we want to know what’s the safe dose. What are the things that we should be watching out for? How do we make this as safe and effective as possible? It is really hard, I know, during a pandemic to wait.

VR: Jeff is at Køge University and asks about what to do with students who test positive. They have a 96% vaccination rate, but when students test positive, they have to be quarantined. He writes, “Given the data that shows a rapid decrease in viral RNA as well as in the ability to detect infectious virus in vaccinated individuals following infection, it would seem reasonable to decrease the length of isolation time for vaccinated individuals because they would unlikely be able to transmit virus past say six days post-positive instead of 10 days. Of course, we’re going to continue to follow the New York State guidelines, but wonder if it would be reasonable to lobby these agencies for a reduced isolation time for vaccinated individuals. We’d love to hear your thoughts on this issue.”

DG: Actually, I’m going to say you bring up an interesting concept, the idea of lobbying organizations. I always think what my natural response is, is we need the science. The organizations can respond when we have the science. What we really need is not lobbying, but funding so that these investigations can be done because we have a growing body of evidence that there’s a certain window of time when a person is infectious– that two days before, that three to five days afterwards.

With an individual who’s vaccinated, do they really need isolation of the infected for 10 days? Maybe not. I think what we need is we need the science, and then you bring the science, and then the science helps us move forward. The other, I hope, is the concept of the test-to-stay. When an individual tests, positive maybe that isolation is shorter, but maybe the exposures don’t need to necessarily stay home quarantining. Maybe they can test-to-stay and that’s something where we’re seeing a growing body of evidence to suggest that could be safely implemented.

VR: Ingrid wants to know, “Should individuals who are vaccinated and test positive for COVID take monoclonal antibodies?”

DG: We say we don’t look at vaccination status when we’re making decisions about monoclonals. To be honest, did we study the monoclonals specifically in people who are vaccinated? We use the same criteria. If you are considered at a high risk of progressing, whether or not you are vaccinated, if you are symptomatic, then we’d recommend monoclonals. If you are completely asymptomatic and that’s a point here, completely asymptomatic individuals, vaccinated, unvaccinated, you need to at least have some symptomatology, and then one high risk or other feature for going ahead with monoclonals, but vaccination is in no way an exclusion.

VR: Finally, Dan is a pediatric pulmonologist who retired in 2016 after 36 years in pediatric medicine. “I’ve been an advocate of asthma education in the school and at home since. I’ve been following your updates on TWiV for several months. Appreciate your review of the literature. Since the pandemic began, I’ve been following local data in San Antonio. As a private citizen, I have been confused and do not understand why pediatric data are not reported similar to adult data?” Dan goes on to write about his experience with pediatric critical care early in his career, and how having such data would be important. He writes, “The low numbers do not reflect the tragedy at the local level as an asthma or flu. I question any death in a child as preventable, I’ve only filed intermittently. If you’ve discussed this issue before, let me know, but I’d like to know your thoughts on this.”

DG: No, I think this is great. I think I’ve always tried, for a while, to start off the updates with children and COVID and try to steer people towards where those resources are. The American Academy of Pediatrics, the CDC has a special site looking at this. It is interesting. You can’t just toggle and get this information more readily like the Hopkins or the Worldometer dashboard. “Just click if you want to specifically look at the age group that I’m focused on here.” I agree, and I think that, as I mentioned from the beginning, it’s been this odd touchy subject.

There’s also been a lot of, I think, false ideas where people say, “You know what, let me look at the date a year ago when the kids were locked in basements and they were not getting exposed to COVID, and boy there were no hospitalizations. I think we can safely just open the schools without masks and let them all get infected, they’ll be fine.” Now that they’re opening the schools and getting infected, we’re seeing that kids are not all right. We’re seeing thousands of hospitalizations per week. We’re seeing a couple of deaths every day on average. That is in no way okay. I share that we need to have this data front and center. Right now, the conversation is all about boosters. That’s fine and all. Let’s talk about the people that haven’t even had a first shot and who are at risk of getting infected.

VR: In the interest of time, I’ve been abbreviating some of these letters, but I encourage listeners to go to microbe.tv/twiv. You can find all the text of all of them online there. They’re very useful to read. That’s COVID-19 clinical update number 80 with Dr. Daniel Griffin. Thank you, Daniel.

DG: Oh, thank you, Vincent. You and everyone else be safe.

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