TWiV 698 COVID-19 Clinical Update #42

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 26 December 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 698, recorded on December 24, 2020. 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: I should say the vaccinated Daniel Griffin, right?

DG: Yes, yes. I feel very excited and privileged for two reasons. One is to get the vaccine, but also the fact that I have had zero side effects. I want to take that with a bit of humility, because, as we know, some people have had fevers, headaches, soreness, the reactogenicity we talked about. I count myself lucky on multiple fronts.

VR: When did you get it, yesterday?

DG: Yesterday morning, 09:15.

VR: No soreness, no malaise, no fatigue, no pain at the injection site, none of that stuff.

DG: You know, Vincent, I went to the pharmacist who gave it to me and I asked him, “Was I in the placebo arm? What happened? How come I don’t feel anything?” No, just a joke.

VR: Well, you sent me a video, and if you don’t mind, we’ll insert it in right now so people can see it. Does that work for you?

DG: Okay. That’s great. People can watch.

VR: You’re wearing your COVID socks.

DG: Yes, I got the COVID socks.

[laughter]

DG: These are my COVID socks with COVID toes. I didn’t even feel a thing.

VR: Oh. That’s good. Okay. We’re going to have you monitored for about 15 minutes. I’m going to write the time down. They’re going to monitor you on the other side.

VR: Daniel, you have to go back in two weeks for a booster, right?

DG: Actually, I did the Moderna shot, so it will be four weeks before I return.

VR: Excellent. Congratulations. Well deserved.

DG: People asked what’s going on here, “Biden and Pence got Pfizer, you and Fauci got Moderna.” It was what they offered me.

[crosstalk]

DG: Yes, it’s whatever you could get.

VR: Someone said last night, “The way I look at it, whatever beer is put in front of me, I drink that one.”

[laughter]

DG: That was one of your Irish friends, I take it.

VR: Probably. Yes.

DG: All right. Well, we have a lot to go through today, and I know around the holidays people are going to be busy, so I don’t want to take too much time, so let’s go right for it.

All right.

DG: I’ll start with my quotation. “If you judge people, you have no time to love them.” That’s a Mother Teresa quote, which I think is, hopefully, appropriate for this time of year. Now, over the last year, I’ve quoted Winston Churchill many times and I’ll do that again. I’ve also quoted Ursula Kayla Gwen, Taylor Swift, Ruth Bader Ginsburg, and now this is actually the second time for Mother Teresa. I was trying to pick a quotation that sets the tone for what I’m going to be speaking about.

Actually, many years ago, and it is many, when I was working in Kathmandu, Nepal, I was actually invited to work with Mother Teresa. In my usual, I was much too busy doing other things and missed that opportunity. She’s a complicated woman, like many of us, so I just thought that that was an appropriate quote for this time of year. Let’s go through, and also for what I’m about to say as far as patient updates. I think people are probably aware that things are not going well in the United States right now. We’ve had many days now with over 3,000 deaths per day.

Some of our hospitals have gotten so busy that you’ve probably heard word that there’s actually triage of medical care where there’s concerns with not enough hospital beds, not enough ICUs. Patients in the hospital are being triaged If they don’t look like they have a good chance to be put under hospice care, put on morphine drips, comfort care. This is not good. This is not what we want to see around the holiday, so it is heartbreaking.

There’s lots of travel going on right now in the U.S. and lots of people are actually getting together for the holidays. What I like to like to point out is that shaming does not actually help. Shaming actually increases bad behavior. People have made plans, people can get together, so I think our role as physicians is to be helpful. What can we do to help people? One of the things that I keep reinforcing is frequent testing. If someone gets tested, that’s not a free pass, but if that test is positive, that person is hopefully not going to go to the Christmas dinner or the New Year’s party. Some people go to that New Year’s party anyway. That’s something to keep in mind.

If people do get sick, we’re going to talk about some of these therapies as we go forward, but this is a time to have conversations. Talk about what you’ve learned. If people have had vaccines, a great time to share your experiences over the holidays. If you’re going to be communicating or seeing in person the ones you love. Talk about monoclonal antibodies, other things. I think it’s important to have dialogues. We’ve got to stop breaking up into camps.

Schools, not much here. We’re actually on a Christmas break here in the U.S. If we can only speed things up, we can get those teachers vaccinated very soon. We’ll talk a little bit about the change in the hierarchy, the phases. Everyone is now in phase one, A, B, or C. We’ll talk about that. The U.K. variant. Just in time for the holidays. This has been covered quite well. I thought a Christmas story would be appropriate. A holiday story. When I was on a FaceTime call with I’m going to say a friend of mine.

It’s actually the parents of one of my friends. I think that I’ve become friendly with the parents. We actually have had a connection through the pandemic because it was actually in January when it was my friend’s, Gareth’s father, actually asked, “What does Dan think about this whole virus thing?” We looked back at the text at the time and it was, “Yes, I think this guy actually may be falling.” I think this is going to be a significant issue.

I was talking to him a little bit about what’s going on in there in the U.K. I see these numbers rising. He’s like, “I don’t understand it. We’re being so careful. When I go to the pubs every night, all the windows are open. When I’m riding on the bus, all the windows are open. When I’m on the train, everyone wears a mask except when they’re eating or drinking. I always try to have something to eat or drink because I don’t like wearing the mask. The wife and I, we were planning on going out to a Christmas Eve dinner together, but the tables in the crowded restaurant, they were all going to be spaced apart and the windows were going to be open, we’re going to wear our jackets. We were going to be very safe.”

I said, “Well, what did you do today?”

“Well, apparently Boris has decided to shut down the country again tonight at midnight, so we all ran out to the supermarkets to get all our shopping done, and it was so nice. We got to see everyone. Everyone was out shopping.” I don’t think you need a U.K. variant to explain what’s going on as far as spread in the U.K. at the moment.

VR: Thank you, Daniel, because I have to say first, we had the D614G variant, more transmissible. Now we have the U.K. variant, supposedly more transmissible, and another U.K. variant, supposedly more transmissible. This ain’t the way viruses work. Something’s amiss, and I hope they sort it out.

DG: Vincent, as you heard, they’re being so careful, when they crowded in the pubs for their beers the windows are open. How could the virus spread in such a setting?

VR: There you go. Thank you, Daniel.

DG: Now, last time I promised I would touch on vitamin D and ivermectin. I think it’s important that I comment on this because I don’t want to leave a vacuum. “Why isn’t Dr. Griffin talking about these two things?” Vitamin D is going to be very straightforward. The last time I spoke about this was October 4th, and we had reached a million deaths in the world from COVID at that point. I think I’m echoing what Anthony Fauci said. Very simply, there’s no good reason to be vitamin D deficient. We know that, particularly in Northern climates, in the winter, the incidence of vitamin D deficiency goes up.

There does appear to be a consistent correlation between people who are low in vitamin D and getting infected. There also seems to be now several studies suggesting that people with low vitamin D have worse outcomes. We haven’t shown benefit of giving vitamin D once you’ve ended up in the hospital. This looks like something you want to be doing ahead of time if it’s going to be a benefit. Since this is going to drop after Christmas, there’s a rumor that Santa Claus is putting vitamin D in my children’s stockings. Take your vitamin D. There’s no reason to be deficient in vitamin D. There’s no evidence of harm. Maybe there’s a benefit here. We’re seeing a number of studies.

Now, what about ivermectin? I’m going to say, this is a little bit more complicated. I get this question quite often because as people who listen to This Week in Parasitism are aware, that I’m a parasitologist, and prior to the pandemic, I was probably one of the few physicians in the U.S. that was using ivermectin on a regular basis, so extensive experience with this medicine prior to COVID-19.

What is ivermectin? This is, I got to say, a fun story. In the late 1960s, there was a Japanese microbiologist gathering soil samples, growing things up, testing them for any active compounds being produced. Near a golf course in southwest Tokyo, he collected some dirt and was able to grow a bacterial species, Streptomyces avermictilis. This bacterial species produced an active component, avermectin. This was chemically modified to ivermectin, and there was a collaboration here between Satoshi Ōmura, in Japan, and William Campbell who actually has been on TWiV or TWiP. He’s been on TWiP. He actually received the Nobel Prize for ivermectin.

What is ivermectin? It’s a compound that binds to the glutamate-gated chloride ion channels which are found in invertebrate nerve and muscle cells. This leads to increased permeability in the membranes, hyperpolarization, and eventually, death of the parasites that we classically use this in. What’s going on with an antiparasitic agent and COVID-19? December 8th, Pierre Kory, he’s a pulmonologist, critical care specialist, testified before Congress about ivermectin. He went through a lot of studies that have been done to date. He’s actually part of an organization, the Front Line COVID-19 Critical Care Alliance, which was started by Paul Marik, another critical care specialist.

I have to say, I know these physicians, actually. I’ve emailed, I’ve co-authored a couple of papers with them. They’re bright academic clinicians who care passionately about their patients. They’re not quacks. They’re not lunatic fringe. These are people who are in the trenches, seeing people die in front of them, and desperate for a solution. How did ivermectin and COVID get started? It goes back to a paper we discussed on TWiV early on, in April.

The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. I’ll be honest, I felt like that was a dishonest title. It is FDA approved but not for COVID-19, not for inhibiting replications of SARS-CoV-2. Immediately, I was flooded with, “Wow, there’s an FDA-approved drug for SARS-CoV-2.” I said, “Well, yes, not really.” There were also some concerns about concentrations being used, could this be actually realized in a human host, something about 10,000 times the amount of what we normally would do?

I did not like this article. Actually, I felt it was misleading in the title. It did start to raise a bunch of questions. It got people interested in ivermectin, and it raised issues, “What do we think ivermectin is going to do if they’re going to be using it?” I always say, you can’t eat the entire cake and still have it. Is the thought that ivermectin is an antiviral? Is it anti-inflammatory? Is it boosting the immune system because one or the other, timing would matter? Does it do something entirely different? Are we using this in, I’ll say, areas of the world with heavy parasite burden, and we’re actually treating parasites and maybe that might be born out?

Back in July, some of my other friends, and these I’ll say even closer friends, I hang out with these folks, published a paper, COVID-19 and Dexamethasone: A Potential Strategy to Avoid Steroid-Related Strongyloides Hyperinfection. This was published in JAMA. The first author was William Stauffer. I met him in Thailand up near the Burmese border. I was staying at the Queens Malaria Station. He and I hang out there for a few days and swam in the river there. You had to go make sure you knew where the king cobra was before you went in.

Also, Pat Walker was there. She was the prior president of the American Society of Tropical Medicine and Hygiene (ASTMH). We spent about three weeks together. This is back in the summer of 2016 in Thailand, in Cambodia, went to Angkor Wat, I think she was there when I ran the marathon with the princess. What they actually were raising this concern, and I think our TWiP listeners will think about this and it will ring some bells, what if this dexamethasone, what if the steroids that are now being encouraged to be used in COVID-19, are being used widely throughout areas in the world that have parasitic issues, particularly strongyloides?

Our TWiV listeners, what are strongyloides? You have to listen to TWiP now. Many parts of the world, we say 10% to 40% of populations can actually have a chronic infection with this parasite. Some areas of the world, I’m going to say, Egypt, Bangladesh, parts of Peru, particularly parts of Peru with HTLV-1, a viral co-infection, they can have rates as high as 70%. When you start giving these people a 10 or a 15, because I’ve seen longer courses of steroids, you actually will be presented with some cases you are a risk of triggering a stronger release of hyper-infection. These parasites can actually come through the bowel wall. They can lead to a gram-negative sepsis and death in many standpoints.

They actually, at that point, were raising the issue not thinking of an antiviral effect but thinking about a lot of parts of the world you may have a mortality issue from this and the use of steroids that supersedes any benefit you think you’re going to get from steroids. When I started hearing and seeing all these ivermectin publications, it started making me look into this issue. Where are these studies? Peru, Egypt, Bangladesh, India.

As some of our listeners may know, particularly with a colleague of mine, Dr. Kurapati, we’ve been managing and trying to help assist management of patients remotely in parts of the world like this, in India particularly. It is amazing what goes on. Once they heard about steroids, a patient will get 10 days of steroids, will get ivermectin at one hospital, they won’t be doing well, they’ll transfer into another hospital, they’ll get another 10 days of steroids. They’ll get another five days of remdesivir.

It’s an interesting, complicated issue, and I know these clinicians are seeing these studies come out of parts of the world, and they’re seeing and actually, there are some small randomized control trials, and they’re a little difficult to sort out. There’s doxycycline still in there, there’s azithromycin, hydroxychloroquine is still being used in these areas. I think there’s potentially an interesting story here. My understanding is there’s a few studies that will be coming out in January. I look forward to getting more information.

I don’t quite understand what’s going on here right now, to be completely honest, which is tough because having said that, I mentioned in the U.S., 3,000 people are dying a day. If I had an individual from an area in the world where there was a high incidence of strongyloides and I was starting steroids, I probably would want to check a strongyloides serology. I probably would want to check the stool for larvae.

I think it’s worth trying to understand what’s going on here. Don’t run out and grab your veterinary ivermectin. Don’t start taking the medicine that your dog or your cat is supposed to be taking. I think there’s a backroom here right now. There are clinicians at the bedside, they have patients dying in front of them. They’re trying to figure out what to do. I think it’s important that I at least raise this, and as we get more information, I’ll return to it.

Just to say, ivermectin is a very broad spectrum antiparasitic. We use it for onchocerciasis. People may know about the river blindness mass drug campaign. We use it for strongyloides, ascariasis, we use it for gnathostomiasis, hookworm, lice, mansonella, scabies, that’s off-label by the way, wuchereria bancrofti. There are actually some studies showing it can have an effect on malaria. There’s a lot going on here and I’ll be very curious to see what pans out. Just to say, these are not fringe physicians. These are passionate, bright people trying to figure out how to save lives, and I think we need to work together and figure out what to do.

VR: Can I ask you, just quickly?

DG: Yes. Go ahead.

VR: Is it likely that we’re going to have a double-blind, randomly controlled trial for ivermectin and COVID-19, or is it going to be just compassionate use right off the bat?

DG: It is FDA approved, which means that if you make a judgment call and want to give this to a patient in the context, you can. There are randomized control trials that are going on right now. Actually, there’s several of them that are going on here in the U.S. We will have data. I know that sometimes, and we’ve gone through the different approaches to medicine. I’m really swayed by a well-done randomized, controlled, blinded study. I don’t think you can just know what works. I think you actually have to do the science.

We’re going to be vaccines, active vaccines. I saw a very curious– I think it was an anti-vax post. I’m not sure, actually, and it was where a person was saying, “You people with your vaccines, instead of a vaccine, couldn’t we just expose people to a weakened version of a virus and then let them develop an immune response to it?” I was thinking medicine, I’m like, “Don’t we call that an attenuated vaccine? Maybe we’re just mixing words here.”

VR: We do.

[laughter]

DG: I thought it was interesting. Big news since we last talked, I think everyone is aware, EUA for Moderna. I actually got my Moderna here, but what about prioritization? This keeps changing. Who gets the vaccine when? The first thing that’s been in the newspapers, and I think this is upsetting to all of us, is how slow the rollout is going. Ten million doses of vaccines have been distributed, only a million have ended up in arms.

That’s going to take us, at this rate, like 6.6 million years. No, 6.6 years to vaccinate the entire U.S. population. The U.K., they’re doing about 140,000 a week. They’re basically going to finish vaccinating their country a little bit after the time that they have to start again, so we really got to pick up the pace. One of the challenges is, right now, we’re in phase 1A where we’re trying to do healthcare personnel.

A lot of the healthcare personnel that have started with are what are considered higher priority, so ICU, ER, and they’re working in busy hospitals. The vaccines have been sent to those busy hospitals. It’s really a challenge for these facilities to try to vaccinate all their workers, and at the same time, take care of more COVID patients than they’ve ever had before, triaging staff, and personnel, and resources.

I’m hoping we learned from this. Don’t just keep throwing stuff on the top of the hospitals during a pandemic. Let’s see if there’s other organizations that can jump in and help, but the prioritization changed as of December 20th, so let’s get everyone up to speed. Phase 1A we’re familiar with. That’s long-term care facility residents and staff that fired up this week, and that looks to be going well. A captive audience, right?

That is going to be, I think for us in the acute care settings, a gamechanger. That was what flooded us in the first wave in New York back in April. Half of the deaths were in individuals in the long-term care facility. If these individuals could be protected, and the people that take care of them protected, that’s huge. The healthcare personnel, I think that’s really important from a morale standpoint.

I think a lot of us have learned how to take care of ourselves. In the U.K., they’re not doing it the same way. In the U.K., they’re focused on the older individuals, but we’ve got the older individuals here in the U.S. right behind us, phase 1B, which is now individuals who are 75 and older, as well as frontline essential workers. I’m going to go through what is a frontline essential worker.

Then we have phase 1C, and that’s everyone aged 65 to 74, or anyone under 65 but with a high risk of medical problem, and all the other essential workers. What are frontline essential workers? I’m hoping as I go through this list, people are going to say, “I want to sign up and be one of those for–” Well, because now they realize that this is a frontline essential worker, or two, they think, “If I’m doing this job, I get vaccinated early.”

Either way, first responders, those are the firefighters, the police. What about the EMTs? The EMTs are actually supposed to be in 1A, so they should be being done sooner. Education, these are the teachers, the support staff for our schools, the daycare people. That’s right at the top of our frontline essential workers. We also move into people working in food and agriculture. You got to eat.

You move into manufacturing, people who work in corrections, the postal service, people who are transit workers, public transport workers, grocery store workers. That’s about 30 million people in the considered frontline essential workers, and then in 1C, you move into the other essential workers as well as those slightly younger, 65 to 74. That’s going to be more transportation and logistics, more food service, construction, finance, IT, and communication.

Actually, we talked about that. Think about our medical practices if the IT goes down, that’s a problem. People working in energy, legal, public safety, wastewater.

Then what are those high-risk medical conditions? It’s cancer, kidney disease, chronic obstructive pulmonary disease, heart conditions, immunocompromised, obesity above a certain level. Pregnancy, interesting, is a prioritization in 1C, sickle cell disease, diabetes.

A couple of challenges that we have in front of us. We’re not meeting the first challenge of getting the first shot in, but these are two-dose vaccines that we have in front of us. The literature that we have from other vaccines is the majority of people don’t get that second dose. This is critical, and we’ll keep reinforcing this. If you only get one dose, you may only have about 50% protection.

We also don’t know how long it lasts, and we’re probably never going to do great studies on that, so really commit, get that first shot, get that second shot.

Getting lots of vaccine questions. Just to go through a few of them, still the questions about fertility. Going forward, we’re going to actually be hopefully just posting, because the questions continue to flow on what are the different issues.

I’m going to jump right from active to passive vaccination, which really sort of falls into the second stage. Back to monoclonal therapy, and here, again, it’s a difficult issue. It’s out there, I said with the active vaccines, of the ones that are out there, only 10% have actually ended up in people’s arms. With the monoclonals, only about 20% have ended up in people, of the ones that are sent out, and it’s a couple of issues.

One is an access problem with physicians, not the patients. You call your physician, “I’m not doing well.” You’ve gotten a test; a physician’s been involved or a healthcare provider’s been involved. Physicians are either not able to understand how to access this and the access is very easy, I want to say. I’m actually going to give you some numbers here. If you’re driving, you could pause, you could rewind.

Don’t crash or try to write this down while you’re while you’re driving, even if you have a Tesla that is supposed to drive for you. Since a lot of this is our weekly information session for ProHEALTH and RiverSide, Optum Tri-State. New York, we have a Long Island Bamlanivimab Hotline, where people just dial 516-918-6089. Physician calls, gives the history, and often, they can get access to the medication the same day.

Tents are being set up outside of ERs, other settings. Nationally, to find out about the access in your area, it’s 1-855-545-5921. This is just for Eli Lilly, but Regeneron is right on the heels there, so I’ll have to get access to those numbers once those roll out in our area as well. What’s going on here? A lot of doctors, actually, and this sort of goes back, they’re not impressed with the data. This is an EUA based upon limited data. We just did phase I and II, we thought it was really impressive.

It rolled right into EUA, and a lot of physicians have said, “This is not an FDA-approved drug. You’ve looked at it in a few hundred people.” As impressive as it might be with the Eli Lilly with about a 70% to 75% reduction in progression to requiring medical care, in the Regeneron, being maybe about a 50% with that cocktail, there really is still that question of, does this stuff really work? There are plans for a large EUA trial, which I will definitely share more about as soon as we get the green light from the FDA.

Early inflammatory phase. A reminder, I want to say that steroids are non-indicated in the first week, they’re not for everyone. Second week, people with hypoxemia. If we have listeners in parts of the world where there are co-infections, strongyloides, malaria, ascaris, other things going on, keep that in mind.

I think as my colleagues published back in July, if you’re going to be using high-dose steroids for any period of time, you’ve got to be thinking about what else might be going on there. This was a big change, right? Well, not that, but what I’m about to say is a big change. We’re now reinforced in our recommendation of prophylactic dosing of anticoagulations.

I think I mentioned before that I’m the infectious disease physician who was put up to be on the American Society Hematology (ASH) panel to work on the guidelines for how to use anticoagulation in COVID-19.

After much back and forth and going through 100, 200 papers, the ASH guideline panel suggested using prophylactic intensity over intermediate or therapeutic intensity anticoagulation in patients with COVID-19. That’s for both critical and floor patients. Then they did say, that’s your baseline. If you’re going to have an order set, you’re going to start people on let’s say it’s Lovenox, that would be your 40 milligram subcutaneous, once a day, would be your prophylactic intensity.

You might adjust that based on weight, if there’s extremes variation there. Then saying, on a case-by-case basis, the panel acknowledges that higher intensity anticoagulation may be preferred in certain patients judged to be at a high thrombotic risk and a lower acceptable bleeding risk. A couple of trials, active. There are actually three trials where they were looking at prophylactic, intermediate, and therapeutic intensity anticoagulation. In the patients that were in the intensive care unit, these are the ones that we think are at the highest risk of clotting. They actually stopped the routine full dose arms because they were actually seeing mortality impact.

Basically, stepping back to, I’ll say, the guidelines that we’ve recommended here. I think this is a reminder because the COVID wars, so to speak, that were described in The New York Times, there were physicians who are passionate that if you were not putting patients on full-dose anticoagulation, you were killing them, you were letting them die for science so that you could just get your answers.

Here we’re finally seeing some data, and I feel like this is solid data. This helps us. I think we’re moving forward.

Secondary infection phase. We’ve talked about this before, this is week three, things start to go in the wrong direction. You want to start looking for, is there a bacterial infection? Are we having progression of the inflammatory process or are we starting to have a thromboembolic or thrombotic complication?

Don’t just think about bacteria, but also think about fungal issues. We see these, or we saw these, more when people using anakinra here in the States, there certainly are a lot of these in a lot of other parts of the world, like what I described in India. In India, we’re actually seeing a lot of not just Candida, but actually seeing Mucor because people are just getting so many courses of antibiotics and high dose steroids that this is setting them up for severe fungal infections.

Look at the context here. Be careful with the antibiotics. Don’t just keep overdoing it, we’re going to lose all our antibiotics. The steroids, you’ve got to weigh the harms. If you have a 70-pound frail woman, maybe you don’t even have to use the full six milligrams, you might drop down to four. I had a woman today that I put on steroids, but at four milligrams, that may not even go for the full 10 days. There is some customization here, the trial six milligrams times 10 days, that isn’t necessarily a one-size-fits-all.

That was just a study, trying to get an answer to a specific question. Moving into the end of this segment, I’ll say that also the tail phase and D.C. planning. I just want everyone to keep in mind that when these folks are clapped out the door, for a lot of these individuals, that isn’t the end of COVID. There was a little bit of attention recently to the fact that if you look at the all-cause mortality, individuals discharged with COVID are about six times as likely to not be alive at two months post-discharge compared to other conditions.

About 10% of them will actually get out of the hospital, but then die in the next two months. About 15% will bounce right back to the hospital. It’s important, don’t just clap these people out and forget about them. They need ongoing care, they need monitoring, they need support. Let’s finish off here. I’m going to spend a moment here. Our fundraiser, we’re now helping to raise money for the Peace Corps HIV and AIDS programs.

We’re all one year older and what have we done? While we’ve been focusing on COVID, HIV, malaria, parasitic diseases, all these neglected diseases are really gaining ground. We worry and the estimates are that we may have lost about 10 years. This is devastating. Here, the end of the year as we’re all thinking about all these other things, help us continue to do our work because when we come out of the other side of this, there’s really going to be a lot of work for us to do.

VR: Right. Thank you, Daniel. I have a couple of emails for you. First one is from Bart who is confused about PCR testing. He writes, “I’m reading various articles suggesting that even four to five days after infection, note not symptom onset, but infection, PCR tests still have notoriously poor sensitivity. Sixty-seven percent false-negative four days after infection in one study. I’m confused. I understood that the onset of symptoms, on average, occurred for the bulk of patients around that time and that the viral load was at its peak just before and after an infection symptom onset, I think.

PCR is incredibly sensitive if virus is present so four or five days after infections, most patients should have enough detectable virus in the body. I thought a PCR test should be able to pick this up and result in a positive test. Why are PCR tests reported to have such high false-negative rates, and more importantly, if you’re not exhibiting symptoms, when is the best time to get tested to increase the chance that the test will be correctly positive if you actually have been infected? Please help.”

DG: Okay. This is well put out; this is not simple. I’m going to go through, there’s a little bit of terminology here to hit on, but also people are going to have to have a graphic visual in their head. What are the different terms here? There’s a point at which a person is exposed, this is the time of exposure. If you’ve been exposed and successfully infected, there is an incubation period. That incubation period can be from two to 14 days. You are infected, there is a virus that is replicating. At any time between two to 14 days, you may or may not get sick.

Fifty percent of people never show symptoms but let’s use this symptomatic person as an example. Let’s say you’re going to be one of those people who takes the full 14 days before you get sick. You’re going to get sick at day 14, that’s about 2% or 3% of individuals will get sick in the last couple of days of that window. The PCR will stay negative on you all the way out to about 2.4 days before symptom onset. There’s a little bit of a confusion here.

What is infection, and what is symptom onset? The infection is the time that the virus actually gets into your cells and starts to replicate. It will stay below the level of detection for, often, many, many days between, I’m going to say here, one to about 12 days. Because say you get sick on day 14, you’re probably starting to get detectable virus by 14. If you get symptoms, right at the time that you get symptoms is typically when a person has the highest amount of RNA.

That’s the point when a person has the highest likelihood of being picked up by one of our testing modalities. Once you get out to about five days post symptom onset, the virus has really come down. On the way up, it’s about 2.4. On the way down, we think it comes down at about five, but then some people will be positive out to nine, a lot of people will start to turn PCR negative by day 10. There’s a couple of things going on here. When we talk about infection, and this feeds into a test does not predict the future.

You can be infected. You could be in the incubation period for out to 14 days. At any point in time, a test will not predict what’s going to happen the next day. In most cases, the virus comes up rather quickly within hours to a day, but now we’ve seen more kinetic studies where some people gradually come up over two days. The other is there may actually be an intermittent positivity, where someone’s positive, negative, positive. We’re usually not seeing that till we get down to the lower limit of detection. People that have been sick for five-plus days, and then we’ll often see that. Usually, if you can get the CT values, the quantitative, instead of the qualitative testing, they’re going to be in the high 30s at that point.

VR: Next one is from Carolyn, who writes, “It would be great if you could comment on very promising results with the SSRI fluvoxamine. It seems to act through the sigma-1 receptor in the ER unrelated to serotonin reuptake inhibition. It may impact cytokine secretion and/or impact virus replication directly. A small outpatient placebo-controlled clinical trial was published in JAMA, there are more data accumulating,” and she gives some links. “Steve Kirsch who started the COVID Early Treatment Fund has funded some of the work. Thank you.”

DG: Yes, thanks for bringing that up. I think this is a challenge. I was worried that I’m leaving things out. I certainly am. There’s a list of therapies that are being tried in COVID. I don’t know if I’m at a point where I feel like I have anything compelling that I can share other than what you did in your email, but we’ll be keeping track of this, and when something that I think is ready for primetime and something is moving into practice or when I’m working with physicians that are using these things, and I can relay some firsthand experience, I will do that as well.

VR: All right, our last one is from Char who writes, “Dr. Griffin, if you keep missing your vitamin D doses, it’s okay to take it weekly. If you choose to use 4,000 per day you could take 28,000 units on Sunday because it’s an oil-soluble vitamin. If you take it with food that contains some oil or fat it should all get absorbed. Yes, an RCT of vitamin D and COVID would be great, but the paper you shared is compelling and Dr. Seheult shared a reference list on MedCram on December 10th. Also, vitamin D itself is very inexpensive, so the high cost you’re talking about must be the tests, and the prescription vitamin D.

I’m always looking forward to your weekly updates so I can share the information. I want you to stay healthy and continue full steam ahead.” Char is an MD internist, mostly retired but still helping where he can in Portland. Daniel, he gives a number of other paragraphs which I will not read, but you might be of interest, experience from his primary care practice with vitamin D.

DG: I appreciate it. I think I may have mentioned before, I’ve actually been interested in vitamin D for a while. I love the story of the– I think I’ve related this before, of the physician in London who was taking care of the Muslim women wearing burkas, they came in with gait disturbances, he tied this to vitamin D. I have gotten better. My vitamin D, I sit it out right next to the toothbrush. I’m trying to do a better job. I’m a pasty guy who spends way too much time indoors, so trying to get my vitamin D. My son, Barnaby, he drinks like, I don’t know, probably a gallon of vitamin D fortified milk a day. He’s going to be okay, but, hey, there still may be some vitamin D in the stockings.

VR: All right. That’s COVID-19 clinical update number 42 with Dr. Daniel Griffin. Thanks again, Daniel.

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

[00:41:38] [END OF AUDIO]