TWiV 669 All the wrong COVID-19 moves

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 4 October 2020

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

VR: From MicrobeTV, this is TWiV, This Week in Virology, Episode 669, recorded on October 2nd, 2020. I’m Vincent Racaniello. You’re listening to the podcast all about viruses. Joining me today from New York State, Daniel Griffin.

Daniel Griffin: Hello, everyone.

VR: How’s it going, Daniel?

DG: It’s going well. I have it set up so I could see you, Vincent, and I can see my notes at the same time.

VR: You mean this is the first time you could see both [laughs]?

DG: Yes, I probably should have just thought of that before. Usually, I have it overlaid, so while I’m talking I can barely see you [crosstalk].

VR: That’s okay. You don’t need to see me.

DG: New levels of intellectual acumen that I’ve now organized this as such.

VR: Daniel, I just have a quick question, seems like the numbers in New York are going up. I understand if it reaches 3% we have a shutdown, is that correct?

DG: It’s a moving seven-day average, is what they talk about. We hit 3% the other day. Just a couple of weeks ago, our listeners may remember, we were at 0.7% and then we were above 1%, and then we were up at 3%, and now we’re above 1% again. It’s been bouncing around a little. Considering the amount of tests we do, when you’re doing 80,000, 90,000 tests a day and you end up with 3% positive, that’s a lot of people. What I found disturbing, and I guess I’ll share this, is that we had those issues in some of our communities in Brooklyn where there were large numbers of people.

Basically, they were warned and said, “You really got to start behaving differently because if numbers get above a certain level, then we’re going to shut down some of the activities in these areas.” I have to say what I found really troubling is some of the religious leaders told their congregants “Please don’t get tested because if you get tested, they might shut us down.” That’s not how you approach this. There’s a degree of irresponsibility there. We need to know. The reason we have these thresholds for reacting is that we’re trying to balance.

We’re trying to keep people from dying, keep people from getting sick, and we’re trying to have schools and businesses and religious places open. You got to play by the rules. You can’t just say, “Let’s lie and let’s cheat and let’s not get tested.”

VR: All right. Another quick question before you start. I heard this week that of all the vaccine companies, only Pfizer thinks they might be ready before Election Day. What are they thinking about?

DG: [laughs] I am going to continue to do my best to stay bipartisan here Vincent, despite you sliding that out there. I did watch the debates. As I think our listeners probably know, however you went into the debate, you came out with the same opinion. One of the things in the debate is that the President mentioned Pfizer by name and then afterwards, as afterthought, threw in Moderna and Johnson & Johnson.

As far as the race to get efficacy data, Pfizer and Moderna may right about the end of October, beginning of November, start to have some of the preliminary efficacy data. It’s not safety data. That’s not saying, “Let’s rush out and get vaccinated.” Then we think with the Johnson & Johnson, it’ll be late November that we start to get some of the early efficacy data. I think that’s what we’re –

VR: You said we need 200 infections to start making efficacy data, right?

DG: That’s the goal in these studies, is 200 infections, but early preliminary stuff you’re going to start seeing trickles early on with less than 200 infections. We talk and I’m going to make sure I hit this here, but yes, that’s what they’re talking about. They’re talking about less than 200 infections but starting to say, let’s say 20 in the vaccine arm and 40 in the non-vaccine arm, starting to get some preliminary signal.

VR: All right. It’s all yours, Daniel. [laughs]

DG: Okay, [chuckles] now that you made me step in that. We start with my quotation. “The woods are lovely, dark and deep, but I have promises to keep and miles to go before I sleep, and miles to go before I sleep.”

VR: America’s poet.

DG: Robert Frost, right?

Vincent: Yes.

DG: I actually went up and visited the home where he lived. I think here’s a reminder that we’re still in the middle of this. It still strikes me when people say, “Back during the pandemic,” and there’s this whole reopening going on. We’re still in the middle of things. We still have a lot ahead of us. I have to say a lot of us are getting tired of this. I am too. This is tough. My dad called me today and he wants to go back to the office. He’s trying to figure out how to do that safely because it’s been a long time. We’re all trying to find a balance here. We have a lot ahead of us.

VR: Daniel, when it’s over, we won’t be able to chat like this.

DG: [laughs] That’s true, Vincent. I will disown you.

VR: Well, maybe you could come on –

DG: We’ll keep in touch.

VR: Maybe you could come on to TWiV regularly to talk about other infectious diseases. How about that?

DG: That is the amazing thing. There are so many interesting viruses out there. I was listening to the discussion about the Hantavirus. Actually, that dates me I guess. I was in medical school when the Hantavirus outbreak happened. I got a chance to go to New Mexico and meet with the infectious disease doctors who took care of those first patients. Then as a resident, I was involved in some of the trials looking at treatments for Hantavirus.

There are a lot of fascinating viruses out there. Everyone who’s tuned in just for COVID, there’s a lot of other really fascinating viruses out there. Hopefully the lesson people are getting from this is we need to know about these viruses. We need to understand them at all the levels. At the basic science level, at the clinical level, at the pandemic response level, so stay tuned.

VR: We could use the condition on TWiV afterwards now and then to talk about other things. Let’s explore that.

DG: All right, look forward to it. Let’s do my update here for our busy clinicians. I have started doing this, where I give a little bit of an update and follow-up on patients. I think people enjoy that part of this. I’ll continue there. I discussed my colleague, and she went home, and I did visit with her on Tuesday. She’s at home. She’s on her four liters of oxygen, but there were some hiccups in this transition home. My colleague was discharged Friday evening. I did this telehealth visit with her on Tuesday. Physical therapy had still not been arranged. Her prescription plan did not cover her clot-preventing medication.

She was not taking any medication, she was not getting any physical therapy, still barely able to make it to the bathroom before her oxygen level would drop and then she’d have to stop. The husband was there on the call. This really reinforces how important it is to have good follow-up after discharge. Also, not particularly impressed with our health care “lack of a system.” That here’s a woman that for all intents and purposes is safe, spent over two months in the hospital. Now she’s at risk of getting a blood clot because her plan does not cover the medicine and wants alternative medicine to be selected. We did take care of that but boy, I’m really glad that I scheduled that quick post-hospital visit.

That’s a call to action of our physicians here, too. When patients leave the hospital, they’re not all done. They continue to be at high-risk of clots for at least another month, maybe longer. Oxygen, physical therapy, there’s a long road. My World War II vet. This guy’s a character, calls me his meek doctor [laughs]. He can get away with that. He’s actually headed home. By the time people listen to this, he’ll be home. He did well, so that was nice. There was a little subtlety here. We started him on steroids, but he very quickly responded. He only got maybe one or two days of steroids, and for him that was enough. Don’t feel like it’s etched in stone.

You don’t have to give those 10 days if this is a frail elderly individual who responds quickly. You’re still doctors, not algorithms and order sets to manage these patients. An update on a lady, I think I presented her and told people about this. Woman went down to visit her daughter in Virginia. Her daughter was ill, was in the hospital, there weren’t quite sure what it was. She saw her daughter and, actually, when she was back in New York, she got the call that “Oh, we have figured out why your daughter is sick. It’s COVID.” The mother then got admitted, steroids remdesivir, anticoagulation, requiring high-flow oxygen. Started to improve. Here this week, we entered the third week. Started to have a rise in our neutrophils, started to get sweats, started to become very confused, started to now have an increase in her oxygen requirement. No change in her low level of D-dimer. I want our listeners, particularly the clinicians, to think about the phases of the disease. We couldn’t do this before, but here we are in week three, and what do we worry about?

We worry about clotting, her D-dimer’s low, she’s on her anticoagulation. We worry about bacterial infections and on her exam, I listened to the left lower part of the lung, there was decreased breath sounds. We got a stat chest X-ray and she has a nice left lower lobe pneumonia. Started her immediately on antibiotics and she quickly improved. Today, we were chatting about – actually, she grew up in Elmhurst, which apparently is where I was my first nine months of my life, so nice to see her. She’s now down on nasal cannula. She’s doing well, so it’s nice.

Again, I’m going to say we’ve learned a lot. This isn’t something where there’s just a protocol. This is where our physician understands the phases and in this case, we anticipate what we’re worried about. In her case, she was quickly put on antibiotics and now I think we’re going to see a good outcome here. I think this is a positive thing. I’m going to say to our listeners, I was talking to some of my fellow clinicians the other day, and it has been now months since any patient of mine that I’ve taken care of, either in the hospital or outside of the hospital, has died of COVID-19. What a difference from six months ago.

VR: Great. Congratulations.

DG: Congratulations to my patients. [laughs]

VR: Yes, them too.

DG: As far as news, and now that there was another little bit of news about one of these antibody cocktails, this is the Regeneron. They always have catchy names REGN-COV2. We didn’t get a lot of information, but the press release said that there was reduction in viral levels, improvement in symptoms in the non-hospitalized COVID-19 patients. This is cool technology. They have these VelocImmune mice, which are these humanized mice. They use this platform to generate these antibodies and then they screen and find ones that they think are interesting.

There were some interesting, I think, points in the limited amount of data they gave us. People who were early on, who didn’t have antibodies, tended to be the ones that had the benefit. If it was later, and you already were producing antibodies, it wasn’t really going to make a difference, and I think that makes sense. We think about the phases and I think I mentioned Paul Marik being upset last time that we didn’t really think about the phases when we do our research. Yes, this was something that reinforced that when you use these antibody cocktails early enough during the viral phase before the person makes antibodies, that’s when we anticipate seeing the benefit.

VR: These were non-hospitalized patients who were treated intravenously, right?

DG: Yes. I mentioned that a couple of the therapies are intravenous, but there’s also the option to do this as a subcutaneous injection, which will be nice I think for rolling this out to better access. This is just a window of therapy in many ways. Once we have an effective vaccine, and I’m optimistic we’ll get that, then everyone’s going to have their own antibodies so they won’t need the antibodies from the humanized mouse.

Case numbers, testing schools. We passed a tragic milestone. We now passed over a million people have died globally from COVID-19, and that’s huge. We are getting better as far as understanding this window of transmission and for most people, it’s about five days. It’s a day or two before you get sick, a number of days afterwards, but the broad is two to three days before up to nine to 10 days afterwards.

Millions of rapid tests are being distributed, so that’s encouraging. I do get a lot of questions still about this issue, the difference between isolation and quarantine and timing, so I’m just going to tell everyone just listen to TWiV next time they ask me. This will allow me to annoy my partner Anuja Lee again, because she tells me, “You can’t do that. You must actually answer. You can’t just tell them, “Listen to TWiV.”” I’ll still do give them an answer, but I’ve got to run through this again.

What is isolation and what is quarantine? I was asked this four times today and by clinicians. This is not easy. I’ll do it one more time, and this won’t be the last. Isolation is if you are infected. Think about the ‘I’ for isolation and the ‘I’ for infected. If you’re infected, you isolate. If you are a normal healthy person who stays out of the hospital, infected, isolation, 10 days from the date of that test or the date of onset of symptoms.

At the end of 10 days, you need to be without a fever, you need to be recovering. Without a fever on your own, not because you’re taking handfuls of Tylenol. If you’re a sicker individual who’s infected, who’s in the hospital, you’re going to isolate for 20 days. Little secret option number three in New York is if you’ve been infected, isolation with regard to ever going to a facility, a nursing home, long-term care facility, a hospital, that requires two negative PCRs more than 24 hours apart.

Now, what about quarantining? Think about the ships. These are people who may have been exposed. This is you go and you’re within six feet, without a mask for 15 minutes or more, you’ve had what we consider a true exposure. As my wife says, this is excessive, but the incubation time is anywhere from two to 14 days, and the biology of the virus has not changed.

If you get a test the day after you’ve been exposed, if you get a test three days after you’ve been exposed and it’s negative, that doesn’t predict the future. Anytime from two to 14 days after exposure, you can end up infected. You can end up shedding the virus. I know a lot of people are moving to, “Oh, you had a negative test. Don’t you worry.” Negative tests don’t predict the future. I was doing a presentation today and I gave the example and you can edit this out or people can cover their ears, but I said, “My oldest daughter went to college and right before she went we got a pregnancy test, so I don’t have to worry for the next four years.” Everyone chuckled.

You can’t predict the future. I can’t tell what’s going to happen during her senior year, and the same thing is true about the testing. If you’ve been exposed any time from two to 14 days, you can turn positive, you can start shedding the virus and a test at day 2, 3, 4 does not tell you about the whole 14 days. Also, at the end of those 14 days, if you don’t have symptoms, we know a chunk of people could be infected, shedding virus without symptoms, so ideally you have to test at that end of 14 days to know that you’ve missed that bullet.

VR: Why do we call them two different words, isolation and quarantine? Just to distinguish that there are different situations?

DG: It’s actually interesting. It’s historical. People who are infected, we put in isolation. People who might be infected, and the quarantine goes to the 40 days. This is you Italians, right?

VR: That’s right. Quarantana, yes. [laughs]

DG: Just everyone, you’re frustrated about 14 days, just remember it’s not 40. If we let the Italians run things, they’d have you sit on your ship for 40 days. [laughs] All right. As promised, let’s talk about Vitamin D today. This is something that people seem pretty interested in, so what is Vitamin D? Vitamin D, it’s a fat-soluble vitamin as opposed to water-soluble, and that’s really important. Water-soluble vitamins, if you take too much, you pee them out. Fat-soluble vitamins, if you take too much, you can get sick. These are the fat-soluble vitamins, the vitamins that can make you sick. For a tagline.

Also, they can be the vitamins that can keep you maybe from getting sick, which we’ll talk about today. Vitamin D is mainly known for its role in calcium and bone metabolism, but it also has a number of other roles, which we’ll touch on today. What are the basics? Where do you get your Vitamin D? In general, most humans get their Vitamin D from the sun. There are certain other sources. Not a lot of foods have Vitamin D unless they’ve been fortified. The foods that have them would be fish and eggs, but particularly fish.

You can think about what do you do if you’re living in Arctic nomadic population, there isn’t sun for half of the year. You can actually get your Vitamin D from some of these oily fish, salmon and the like. For most individuals, they’re getting the majority of their Vitamin D as we talked about from the sun through the skin. We’ll talk about why things have changed here.

Normally you have – and I’m going to try to keep this – I’ll actually throw some chemistry at people, okay? You’re going to survive, don’t worry. You start off with something in the skin called 7-Dehydrocholesterol. Then you’re going to get exposed to sunlight, you’re going to get exposed to UVB. The UVB is going to convert this into our Previtamin D3, and then it takes heat to go from the Previtamin D3 to Vitamin D3, the liver. You have a conversion to Vitamin D3 25D and then the kidney is involved to get us finally to the active form, our 1,25 Vitamin D. See, that was not very painful.

It’s that 1,25-Dihydroxyvitamin D that is the physiological active form of Vitamin D. Vitamin D, as mentioned, we think it plays a role in calcium, we think it plays a role in bone metabolism, but it also may have some role in proper functioning of the innate immune system and the regulation and balance between the innate immune response and our adaptive immune response. Maybe our immune colleagues can weigh in on some of the other episodes, but there’s this idea in COVID-19 individuals that certain of them like the young for instance, have the ability to address the virus with the innate immune system and effectively via interferons and they avoid this excessive triggering of the adaptive response.

There’s been some nice articles about the innate immune system, about interferons. Actually, in Science, “Inborn errors of Type I interferon immunity in patients with life-threatening COVID-19.” Maybe at some point we can talk a little bit more about interferons and the preliminary stuff we’re seeing and what role this might have for us in the clinic. Let’s talk a little bit about what are the publications looking at Vitamin D and COVID-19 and what do we know at this point? I’d like to go through the history of this. When did we first start looking at this? Well, people probably remember we were talking about Vitamin D, everyone was talking about Vitamin D early on. It was one of the go-tos that people were saying, “Maybe this is something that will help us.”

Back in April 2020, it seems so long ago, but a group in Glasgow, sure I pronounced that wrong as my – I think the kids of my colleague there at University of Glasgow, they always say, “Why does he talk so funny?” I’m sorry I have mispronounced that Scottish town incorrectly, but they actually looked at over 400 patients with confirmed COVID-19 infection, and they looked at Vitamin D levels, and they did not find that Vitamin D was not associated with COVID-19 infection after they adjusted for all the confounders things like race and other things.

Early on, didn’t see something there. Time goes by, and then in August 2020, there actually was an effect of calcifediol treatment and best available therapy versus best available therapy on ICU admission and mortality among patients hospitalized for COVID-19. A pilot randomized clinical study. At the end of the day, they were only looking at 76 patients. There was a suggestion of a benefit here, but to be honest, this was a very small series. There are a lot of the issues with this article, so it didn’t really leave us with very much. It left us with an, I will say, an open question.

A lot of people, again, I’ll say this is like the debates. If you were excited about Vitamin D going into reading of this paper, you came out excited. If you were not excited, you came out unexcited and if you were hoping for some clarity, you were left without a lot of content here. September 17th, there was a paper, “SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels.” Again, this was a retrospective study and they looked at Vitamin D levels measured at any time during the proceeding 12 months. They looked at almost 200,000 medical records.

They found about, well, it was 9% positivity rate in this group, and they actually found a strong correlation between higher circulating Vitamin D levels and lower SARS positivity rates. SARS-CoV-2 positivity rate was 12.5% in the group with levels below 20 and it was about half that actually, 5.9% in people with levels above 25. Then they went ahead, and I think this was really important, they started looking at all the different issues.

Maybe this is just a marker for people who have darker skin and issue synthesizing Vitamin D. They actually went and they looked specifically in zip codes where there were large numbers of Black or Hispanic. Actually, when they looked in those populations, they found a more striking difference. This left us with some interesting tantalizing information about Vitamin D.

VR: When you say a more striking difference, you mean serious COVID and lower Vitamin D levels?

DG: Actually, it was people diagnosed with COVID. People who had a COVID positive test correlated to the Vitamin D. We saw across the board about a two-fold higher risk of being diagnosed SARS-CoV positive if you had a low Vitamin D. When they went into basically communities of color, it was even a larger difference. Again, retrospective, a lot of issues here.

Any time during the last 12 months this could be a marker even within those communities for, as we mentioned, these are people who may be getting their Vitamin D mostly from diet, so this may actually be telling us other things. This is interesting. There’s nothing definitive yet. The case is still open and so I want to actually say as excited as people might get about Vitamin D, you want to be cautious here where the jury is still out. Again, this is a fat-soluble vitamin, so you want to be careful here.

Generally, someone should not exceed 4,000 international units per day unless specifically recommended by a physician. That’s the little disclaimer they always have on those commercials because if you take too much, as I mentioned, you can get sick. You can get hypercalcemia, you can start peeing out a lot of calcium, you can actually start peeing out a lot, which then you end up needing to drink a lot. You can get confused, you can vomit, you can actually have bone demineralization. It’s not like more is better.

If you’re interested in getting your Vitamin D checked, we actually have a huge Vitamin D deficiency problem in the United States because like Vincent, if people are watching our thing, he is fully clothed despite the fact that this is a beautiful sunny day. [chuckles] He’s indoors, makes it worse. We’re not spending that time that we spent outdoors as humans evolved. We’re not getting our skin exposed to UVB, we’re not getting hot, we’re not making that amount of Vitamin D. When they do surveys in the United States, particularly as we go into the winter months, Vitamin D deficiency is a broad issue and if this is related to COVID-19, that’s not positive.

Again, it’s, COVID-19, it makes sense to exercise, makes sense to eat right, makes sense to have an ideal body weight and if your Vitamin D is deficient, I don’t think there’s a problem with getting it into normal range. We don’t know if that will help, but don’t get it above the normal range. For people under the age of one year, I don’t know how many listeners we have, but that’s about 400 IUs per day. Generally 1 to 70, it’s about 600 IUs per day and when you get above 70, we recommend about 800, but if you’re deficient, it may take a more significant amount to get you up into the normal range. For those of you that want more about Vitamin D, we need more research.

VR: There’s a good summary in The Lancet Diabetes & Endocrinology, and they point out it’s been thought for years that it might have a role in respiratory infections in general, and in only one randomized clinical trial that it’s shown effective. They basically said everything you have, and that there’s a lady at Trinity College who says, “The circumstantial evidence is strong, we don’t have a randomized controlled trial, but how long do you want to wait in the context of the crisis? We know Vitamin D can be good for you, so as long as you don’t overdose, why not take it?” It seems to be reasonable as to what you’re saying basically Daniel, right?

DG: Yes, and with that caution, I think don’t overdose, go see your doctor, get your physical, get your Vitamin D checked. If it’s low, get it into the normal range. If it’s high, rate it back.

VR: All right.

DG: All right. Vaccines. Hopefully, everyone enjoyed my basics of vaccines and feels comfortable as we get back on that topic. They can go back and listen to that particular TWiV. It’s a very basic primer, so the hardcore scientists were upset that it didn’t go into the weeds on different adjuvants and toll-like receptors. Maybe we’ll talk about that at some point, on how much my clinician audience will look forward to me talking about toll-like receptors and adjuvants, but we’ll see. [chuckles] I will say we have some more results out to talk about. The J&J results of their Phase I and II came out in pre-print formats. It just gives us some context of this relative to the others.

When I was talking to some clinicians today, as I think I’ve mentioned before, UnitedHealth Group had set up this whole readiness trial. As the senior ID fellow, I was thinking maybe I’d get access to this data a little bit early. I didn’t, and I’m okay with that because we have a lot of issues now with someone getting the information before everyone else, transparency.

I actually feel like J&J did the right thing. When the results were ready to be shared, the results were shared with everyone. They shared the results of this multicenter Phase I/II, randomized, double-blinded, placebo-controlled clinical study. We know about our Phase I and II, this looks at safety. A little bit about reactogenicity and immunogenicity of this nonreplicating adenovirus 26 based vector that expresses the stabilized pre-fusion spike as protein of SARS-CoV-2.

Now that’s a mouthful, but I bet our TWiV listeners got all that. This is basically, we’re taking an adenovirus, we’ve got the spike protein stuck in there, and basically you’re given a whole bunch of this so the immune system can see it and hopefully learn from it. Get some good B cell production of antibodies and some good T cell help, and a little bit of maybe T cell activity as well.

In this study, they had a low dose and a high dose. They gave it as a single dose or as two doses spaced out 56 days. 18 to 55-year-olds, they gave it to almost 400. It’s actually 394 folks over the age of 65, so you get both in here. Standard reactions; fever, pain at the injection site, nothing really that was disturbing or concerning. Again, this is Phase I/II, less than 1,000 people. We’re not expecting to see those vaccine issues. We’re expecting to see what we saw, fever, pain at the injection site, etc.

They looked at a couple of things. Neutralizing antibodies, I’m going to say the nice thing, this is the one shot and you’re done vaccine. After a single dose, the zero conversion rate in forms of the neutralizing antibodies at day 29 in the younger cohort reached 92%, didn’t matter whether it was higher or lower dose, they hit that with the low dose alone. In the older cohort, there was 100% zero conversion in the low dose. As you can imagine, they’re going to be moving ahead with the low dose.

As far as just measuring antibodies, just doing your ELISAs for spike, 99% positivity in the younger individuals at either dose. 100% for the older individuals at either dose, so that was pretty impressive. Again, single dose. Didn’t really need that booster. They looked at the Th1 cytokine producing s-specific CD4 positive T cells. These are those T cells that are going to help the B cells make a durable memory response, and they saw over 80% whether it was younger or older respectively.

Not a lot of that Th2 that we’re worried about. There’s a nice Th1 skewed phenotype in both of the cohorts. It was, I’ll say, positive. Really appropriate as the FDA did to move this to a Phase III. Basically, what did they conclude, the safety profile immunogenicity after only a single dose? Good stuff and you don’t have to use the large dose, you can just use the low dose.

VR: Wow, so they’re starting a Phase III of 60,000 people on three continents. Wow.

DG: Yes, the Phase III is up and running. I think I talked about this last time. I’m sure we had some of our listeners actually go to United in Research and sign up. Maybe we’ll get some emails from our TWiV listeners who have entered into that trial.

VR: Nice.

DG: There are a couple of last things I wanted to leave our listeners with this week. Fortunately, there’s a growing appreciation that COVID-19 is not just a one to two-week disease for tens of thousands of patients. Even individuals that never required hospital care, the tail of COVID-19 can last for months. A lingering symptom for many is the brain fog. I’m just going to mention a couple of personal stories.

One of my patients that I take care of is a professor. Maybe Vincent and some of our listeners, this hits home. She was describing how this last week, and it’s six months after her acute COVID-19 in March, she was trying to write a check and she was unable to sign her name and write the check, so her husband actually had to come and help her. This is a professor at the college level unable to sign her name six months after disease.

Another one of my patients is a nurse and she’s lovely because as a nurse, she always asks me before we start, she goes, “Before we start, Dr. Griffin, tell me how you are.” Very nice. Not a lot of people ask and here she is, six months out, and she’s still wondering if she’s ever going to have the cognitive function to return back to work. A lot of times as we’re talking, she just can’t even find simple words. She just has trouble with word finding.

Hopefully, there’s going to be a nice piece coming out in The Wall Street Journal by Sarah Toy, I don’t know if people follow her work, but she’s going to be talking a bit about this tail of COVID and also about how many of the health systems of hospitals are setting up to provide care for these growing numbers of individuals. I applaud that because I know a lot of the hospitals’ health systems are struggling financially with what’s happened in COVID-19.

It’s a hard time to go to your healthcare system and hospital and say, “Hey, let’s start up a new venture, which may or may not be profitable.” I appreciate the fact that people are making this happen because we’ve got a lot of people suffering and there’s stuff we can do, there’s care that we can give. Now, my really final positive comment, and this is something I think many people are noticing, but I want to point this out.

Through better understanding of the disease, some improvements in therapeutics, a shifting in demographics of who’s getting infected, I think are doing a better job of protecting the most vulnerable among us, such as seniors, those in long-term care facilities. We are effectively transforming COVID-19 from a predominantly ICU disease into an outpatient and general hospital ward patient disease.

Although most of us are still expecting this rise this winter as far as case counts, this trend is positive and I’m optimistic that even as we see a growing number of cases, the proportion, the case fatality rate I guess I’ll say, I expect it to go down. As I pointed out, it’s been months since I’ve lost one of my patients and I think that we’re moving in this direction. If you get sick with COVID-19 now, you’re less likely to die, but also those vulnerable patients are less likely to get COVID-19. We’re doing a better job of protecting them.

VR: All right, Daniel.

DG: Now is my last, I’m going to close here. This is my call to action and a commitment, and then hopefully we can hit a few emails. I know many people in the U.S. and many of our listeners, be they clinicians or not, are watching closely to see if vaccines or medications are being rushed through without the usual safety process. I don’t know if you’ve heard that Vincent, from our listeners.


DG: It’s clear to me that somehow COVID-19 has divided us rather than uniting us. I just wanna remind our listeners, the politicians are not developing these vaccines or therapeutics. It’s scientists, it’s physicians, they’re working together to develop these and run trials to find out what works. Our listeners, as I mentioned, volunteers are stepping up and going to sites like and becoming citizen scientists and joining the efforts as volunteers for these therapeutic trials, for the vaccine trials.

I’m going to make a commitment. I think this is a commitment that we all share at TWiV, is that we’re going to continue to offer that objective analysis of what we’re seeing in the literature, what I’m seeing firsthand at the bedside, and this is going to be a source of information. Reliable, objective information on vaccines, on therapeutics, on diagnostic options. No one muzzles us here at TWiV. We tell you what we think is true.

My call to action is to ask you to go to and click on that donate button because for the next two months, Parasites Without Borders is going to be doing a supporting drive for Microbe.TV. If you donate on that site, we will do a two-to-one match up to $40,000 to support all the great work that Vincent and the other people at MicrobeTV are doing, to get this objective source of information out to as many people as we can.

VR: Hey, that’s cool. I didn’t know that was coming. Thank you.


DG: Thought I’d surprise you.

VR: MicrobeTV will appreciate it. It’s Thank you, Daniel.

DG: Oh, certainly.

VR: All right, John is looking forward to your Vitamin D discussion and he writes about a RCT Phase III trial published by New England Journal last fall, which showed no statistical benefit for early high dose Vitamin D versus placebo with respect to 90-day mortality or other non-fatal outcomes among critically ill Vitamin D division patients. He writes “The practice of medicine would become a stilted narrow endeavor with little joy if we were guided by iron-clad evidence to guide every decision. Many clinical questions will never garner the interest or the funds for evidence-based trials.

At best, a wise clinician will be guided by the best science, tempered with judgment that is often seasoned with anecdotal input. The older we get, the more tempting that expanding body of anecdotal experience becomes. We are human. With that in mind, it’s a particular challenge to step into the murky waters of Vitamin D science. It’s a pond clouded with previous high hopes and disappointing reversals. I’ve got a bottle of Vitamin D sitting on the shelf outdated probably. I am tempted to reach for it but haven’t yet. I still might. Stay well, and thanks.”

DG: All right, well, thank you, John. Hopefully, I’ve gone through and talked about the murky waters of the Vitamin D science. It is interesting when I was talking – I was doing a presentation this week and I did mention that to be honest, the humility is 90% of what we do in medicine is not based on randomized control trials. Yet, somehow we still muddle through. I think with Vitamin D, if you’re Vitamin D deficient, I think the lesson is we have a lot of information that it makes a difference to get Vitamin D up out of that deficiency zone. I love this story I used to tell when I used to actually go about and lecture on Vitamin D. This is back in my Denosumab Prolia osteoporosis days.

I used to have an osteoporosis center at Colorado. There was a clinician in London and he was taking care of a group of Muslim women. They’re in London, it’s overcast, it’s gray, and they’re wearing the full burkas. They would end up with pretty significant Vitamin D deficiencies. Now he didn’t know that, but what he knew was they came to him because they were having issues with gait disturbances, issues with falling.

Then he actually discovered this link that Vitamin D wasn’t just affecting bone and everything else, but actually affected our balance. If you look at Olympic athletes, they actually monitor their Vitamin D levels and try to keep them up. Yes, Vitamin D, it’s good stuff to do. It’s good stuff to have at least in the right range. I don’t think more is better at some point, so I’m not sure I want to take critically ill patients and just give them these massive high doses of Vitamin D.

I look at a trial like this and if your Vitamin D is at the level where you need it to be for your innate immune system and your adaptive immune system to function well, to make a proper level of interferon and coordinate, no sense pouring more in there. I’m not discouraged by the Vitamin D study in the New England Journal. I am looking forward to more information because yes, as you point out, there’s a lot of excitement and a lot of disappointment in the whole realm of Vitamin D and a lot of different diseases.

VR: It doesn’t seem to me that it would be useful for a hospitalized patient because their problem is their immune system overreacting.


DG: We talked about that early on actually when Vitamin D first came up. I think my suggestion was timing. Timing is key. I was trying to time it so I could jump in and interrupt you and then apologize for bad timing, but no. [laughs] When we think Vitamin D helps, is this coordination with a proper innate immune system that helps us fight against the virus? That’s always been the idea. Once you’re already sick, once you’re already in the ICU, I’m not really sure what high dose Vitamin D is going to do. Actually, it might be bad. Maybe that’s the one takeaway, it wasn’t bad in this study.

VR: All right. Tracy writes “’Hello, everyone’ is one of my favorite Dr. Daniel Griffin quotes.”


VR: Tracy says, “Since February, my family and I are dedicated listeners. We have merchandise for the family; coffee cups, t-shirts. If you make an umbrella, I’ll buy it, or baseball caps, my sister-in-law will. Okay. Questions for Daniel Griffin. Would he do anything else in addition to that regarding at-home prevention if he had a family member at increased risk? For example, transplant recipient, autoimmune diseases, lupus, and MS in particular. Since March with more time passing, day-to-day people with autoimmune diseases have increased morbidity and mortality. If the answer is yes, how so, at what part of the progression, and are they at increased risk for a cytokine storm?

DG: Tracy, things have changed for the better. I was in the ICU today and looking at them putting up all these new glass doors to make all the rooms negative pressure if that’s what we need. Back during April and May, we had so many patients in the hospital. I think I mentioned we had over 150 patients with COVID-19 at one point at one of the hospitals where I was working, to the point where we just opened up those doors and the entire intensive care unit where I was working basically became this large negative pressure room where people were being suctioned, they were being intubated. There were all kinds of aerosol-producing procedures. Basically the entire room, the entire ward was a COVID-19 hot zone.

During that time, I think I’ve mentioned to our listeners that have followed us since then, I would put on my N95. I would put on all my gear basically as I was still in the car. Then we would not – those of us working there, most of us would not eat or drink for the entire shift and keep all this protective gear on. Then when I would leave, I basically had termed my car, “the plague car.” No one was allowed in my car.

I would come in through the back where I would completely strip. All of my clothes would end up in the washing machine. I would shower, and only then would I interact with the family. That’s very different to now. Now, we have lower numbers. Before I go in to see a patient, they’re in a negative pressure room. I could put on the full gown, all the protective gear.

We have enough that it’s single-use. I can then take all of that off. I think that the steps that we take are different. I used to leave my plague shoes in the car, and I had slippers that I would put on when I would walk from the car to the house. I took basically all the precautions as if a family member had an auto-immune disease. Because as I was discussing with some colleagues today, different people are at different risks, but as we saw that young, thin, athletic college student just died, nobody’s at zero risk. Nobody is completely immune to this. I treated my family as best I could to keep them from getting exposed.

VR: Finally, Russell is a GP in the Northern Territory of Australia. “We have no community spread. It’s likely we will have devastating outcomes if this virus makes its way into the Northern Territory, in particularly beyond the confines of the main population center of Darwin, as we have significant populations of indigenous peoples at great risk living in close proximity to each other with much movement within and between communities. All our testing is currently PCR with major logistical barriers related to capacity in the remote clinics and distances.

It would seem a perfect scenario for use of rapid cheap antigen testing on a frequent basis if this were demonstrated to be effective. How good is the evidence to support the assertion of an antigen test reliably becoming positive before someone is infectious, or in other words, the false-negative rate of an antigen test detecting someone who was infectious? I expect this is currently impossible to know, but I would be interested in your opinions. Is antigen testing ready for primetime? If so, which?”

DG: I’m just going to start off with a yes. We’ve been through this a few times, and I think that there’s a couple of different ways to approach this. One was just, it took us a while to understand at what level of RNA copy number is a person infectious, are we seeing spread? As time goes by, the data gets better and better. It really looks like it’s this window of time for most people from about a day before they become infectious, maybe a day-and-a-half, till about three, three-and-a-half days afterwards. It’s really for most people about a five-day window. That’s the point in time when the RNA copy number is up in the millions.

For some people, that window is a little bit wider, but with contact tracing, with viral culture techniques, I think we’re getting more and more evidence that someone is infectious when they have millions of amounts. On the website, there’s a really nice graphic where they basically show a rather rapid rate at which it comes up, the level of RNA, and then how it comes down the other side, like a slide at the playground. If you can pick up with an antigen test, most of the antigen tests have a sensitivity down to about 50,000 RNA copy numbers, which is well below that million, that infectious dose.

Then I guess the last thing in this whole argument is, “Have we been using antigen tests to protect populations?” I think I talked last time about how in one of the skilled nursing facilities in Chester County, there was biweekly testing, which was really effective in protecting the population. We did testing for the NHL. We did testing and we continue to do testing for a lot of businesses. A lot of that testing is still PCR. What we’re looking for, and I think it’s reasonable, is where we use antigen testing in that role. Everything we know supports antigen testing.

The model, I think that we’re hopefully going to get up soon. Hopefully, our paper’s going to be submitted to New England Journal within the next 24 hours. We’re going to have calculators where we actually show, based upon which test you want to use, really what we’ve learned over time. Frequency is more important than sensitivity. If you’re testing people frequently, if you can detect 50,000 or more copies, that’s tremendous. So much better than infrequent testing with testing and resulting delays.

VR: Russell, I would go to They have a lot of detail about this whole issue and what is available so far. I think you’ll find that quite rewarding. That is our weekly COVID-19 clinical update with Dr. Daniel Griffin. Thank you again, Daniel.

DG: Oh, thank you so much. Everyone, be safe.

[00:52:06] [END OF AUDIO]

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