Dr Daniel Griffin MD, PhD - gives an introduction to COVID-19. Dr Griffin is both a Specialist Physician in Infectious Disease and a Research Scientist. Since the very beginning of the pandemic he has been actively involved in the clinical care of COVID-19 patients at every stage - from the community outpatient clinic to the Intensive Care Unit.

Each stage and phase of the COVID-19 disease is explained using his research paper "The Importance of Understanding COVID-19 in Treatment & Trials" – published in Aids Reviews - as a reference, so you will have a good understanding of how the disease manifests itself in your body, how your immune system responds to a SARS-CoV-2 infection, and what treatments should be used at each stage of the disease. We touch briefly on the long term damage done to our bodies by COVID-19.

We also discuss Superspreaders and Superspreader events

https://europepmc.org/article/med/33556957

Kojala Medical presents COVID-19 The Answers. The show that delivers the scientific evidence based knowledge that can safely return us all to our pre-COVID lives. My name is Dr. Funmi Okunola, and I'll be hosting the show. Every week you can listen to me, interview a highly respected professional about the science that can reduce your risk of becoming infected with this coronavirus.

Hello and welcome to the second of three programs about SARS-CoV-2, COVID-19 and long COVID. You will learn about the seriousness of this coronavirus in the first three installments, which will lay the groundwork for the subsequent episodes of the series. Illustrating the technology that will be required to keep us safe from ever getting infected or reinfected with this virus, and therefore reducing our risk of developing COVID-19.

Hello, and welcome to episode two of COVID-19 The Answers, an introduction to COVID-19. I'd like to welcome back Dr. Daniel Griffin. Dr. Griffin is both a specialist physician in infectious disease and a research scientist. Since the very beginning of the pandemic he has been actively involved in the clinical care of COVID-19 patients at every stage, from community outpatient to ICU. So we are especially privileged to benefit from the experience of someone who can educate us on the latest available scientific evidence based knowledge and treatments for this disease. Welcome.

Oh, thank you. Thank you so much. I have to say, I really like the fact that you mentioned evidence based, because that's what I try to share. Not my personal opinion, but what is the science? What do we know when it comes to COVID-19?

So true. So Daniel, would you like to tell the audience what inspired you to become an infectious disease specialist and why you chose to pursue a PhD? This is a rare accomplishment for a practicing doctor.

It's a tough question because I did not take a straight path. I blame my mom, actually.

Great mom.

People may not know this, but as a teenager, I lived in Greenwich Village during, well say the early days of the HIV/AIDS pandemic. My mother though, no medical background, she was actually a community leader that worked with ACT UP, the activist. She worked with a young Anthony Fauci at that point, got very involved. Then over time, I really just viewed that as my community that had gone through that. As years went by when I finally ended up through my medical training, I always had a focus on taking care of the people that are often neglected. And in many ways that's the people that end up with infectious disease.

So sort of a long path, but as I was in practice, I got involved a little bit with research and then I realized that I wanted more training, went and got a PhD. So got an MD first, was in practice for about a decade, then went back, got my PhD and then have continued to where I am today. I mean, who would've thought, how useful having a PhD in immunology would be as a practicing infectious disease physician, but it's turned out to be quite valuable.

Indeed, and we're all very glad you got it. I always say that great men have very inspiring mothers. So I'm going to throw a curve ball here because before we launch into COVID-19, I'd like to cover a topic that I missed out last week, super spreaders. My understanding is 10 to 20% of people infected with SARS-CoV-2 are responsible for 80% of the infections that we all get. Is that accurate? What are your thoughts in general about super spreaders?

Yeah. So in general, I think that is accurate and it's a Pareto principle that we talk about with a lot of things and it applies to many things, not even just infectious disease. But what we've realized with the spread of COVID-19 is that most people actually never end up spreading it to someone else. It's probably only about one in five. So there's 20% of people that are responsible for 80% of this spread. So sort of an interesting issue. So it's really challenged our concept of, what is a super spreader? When we say on average, one person spreads it to three other people. What it really is, is one person out of five is spreading it to 15 other people, right? So, that's an interesting dynamic. How does this happen? Well, sometimes it could be a situation where you've got a group of 15 family members around a holiday meal table and it's, I like to always blame the uncle, right?

It's always that uncle that we don't like, and that uncle is very chatty and he's involved in all the conversation. He doesn't really respect that personal space, and the timing is during that acute infectious period. So, the acute infectious period for a person who has COVID-19 is maybe a day or two before symptom onset, maybe five days afterwards. This is the people with symptoms. So it's that narrow window, what you got to do is then for the virus be in a situation where a lot of people might be exposed, particularly as described that indoor setting, particularly in a home. Or maybe it's an office and you have a meeting, a bunch of teachers maybe get together in a small room, the masks come off and then one person is infected. That opportunity presents itself.

There's some interesting work. Actually, college in Boulder, Colorado, and they did an interesting study where they were doing RNA study. So it's RNA copy number, which has some relationship with viral load and seeing really about 10% of people had 90% of all the RNA of the virus. So really science supporting this, case controls supporting this. But this is really the challenge, now in homes what we often see, let's say mom, or the daughter or someone, and then you're in a suburban home. Those are going to be spreading issues as well. But no, in a lot of situations we've seen this Pareto principle played out where, it's one in five, so 20% of people do an 80% of the spread.

But we don't know which 20% do we really, so we all have to keep safe?

Yeah, we don't know. I mean, I know ... My wife wanted to know. She was like, "Maybe there's a test and we can avoid those people." I understand that. I'm not sure. We don't know, is it that it's really just a particular individual and maybe as I described, they like to talk a lot? They're really getting all those particles out there for us. Is it just circumstances? Just only about 20% of us end up in that super spreading opportunity for the virus. We'll see going forward, but we haven't really identified that blood test, that characteristic for who is that superspreader that we need to avoid.

Moving on to the subject at hand, COVID-19. So I'd like to start with some statistics to really emphasize the seriousness of COVID-19. These figures correlate to the Omicron variant deemed by some, to be mild. Worldwide it took two years and two months to reach 300 million cases of COVID. With Omicron, we have seen a further 100 million cases of COVID-19 in one month, with a worldwide total now of over 400 million cases. Omicron has infected so many people in the US that the number of daily deaths at its peak was more than it was last spring when vaccinations were just becoming available. Nearly 900 children daily were hospitalized in the US at the end of January 2022 and two to three children in the US were dying per day from COVID during the Omicron wave. So Daniel has COVID fatigue dulled, our senses to the gravity of the situation and the devastation this virus is causing?

So it certainly has. It certainly has. And it's troubling. I think those numbers that you put out there should for people be sobering. Anyone who uses the word mild in relationship to any of the COVID variants, I think needs to really think what they're talking about. Because those are the real numbers. Right now during the Omicron wave and numbers are coming down, we are seeing over 2000 deaths per day here in the US. We're seeing over 10,000 deaths worldwide. Those numbers I think are really frightening for children. We're seeing for the last two weeks that we have data, we're seeing an average of three children dying per day. So we had 21 children die. Then the most recent week, 23 children died in a week. I'm not sure that mild should ever be put in front of something that can kill that many children.

We are only now just getting down to the daily deaths per day, where Delta peaked getting down to that. So this latest variant mild is not appropriate. Let's go through, death is just the tip of the iceberg. We're approaching a million confirmed COVID deaths here in the US at least 6 million worldwide, and that is probably a wild under count. So not just deaths, but hospitalizations. So many thousands of hospitalizations, the thousand children a day getting hospitalized with COVID-19. So we have hospitalizations, we have deaths. But then all the people that don't end up in the hospital, what we're seeing with long COVID, the classic long COVID where I have COVID and now I can't get back to work. Now my brain isn't working. Now, I'm exhausted. Now I have all these new problems.

What we're also seeing is a significant increase in the risk of health outcomes in the 90 and six, say 90 days, then six months afterwards. There's a recent study that I was going through where we're seeing your chance of diabetes is doubled. New diagnosis rate doubled in the six months afterwards. Your chance of having a heart attack is doubled in the 90 days afterwards. Your chance of so many of these negative outcomes is so significantly increased. So this whole idea that it's okay, that I'm going to survive this viral infection and then have a lower risk of a reinfection. This is not a great game plan. We're seeing deaths. We're seeing hospitalizations. We're seeing diabetes, strokes, heart attacks, cognitive dysfunction, mental illness. This is a virus that really wreaks havoc.

With the risk of heart attack and the increased risk of diabetes, is that with young fit and healthy people too, or is that with people that would be predisposed to those diseases anyway?

Yeah. So it's all across the board and it does affect what is your baseline risk, right? So when you say your risk is doubled, if it was small to begin with, so it's not going to get that big. As we get older, let's say you're above the age of 50. I hate to think that's older. Then that doubling risk actually becomes quite significant when we get even older ages. But unfortunately we're seeing this in children. I mean, there was a really disturbing study in children more than twice is likely to end up with a new diagnosis of diabetes in the six months after infection. So this whole concept that it's somehow benign and it's okay for a child to get infected. It's really not. The ideal approach is vaccination. That's the best way for your body to learn the best way to get immunity. Getting infected is really a dangerous approach.

Truly frightening, really. Last episode, you explained the difference between SARS-CoV-2 and COVID-19. Just to remind us, there appears to be a confusion between the virus and the disease with both being described as COVID or COVID-19. Can you please remind us and explain the distinction between the two?

Yeah. I think it's an important distinction, but it's okay to get it wrong too. So the virus is SARS-CoV-2, really and why two, because there was a SARS one and this is now SARS-CoV-2, as far as a virus. The disease, like the diagnosis that the doctor gives you is you have COVID-19. I have the sniffles. I have a headache. Now, maybe I'm in the hospital or in the ICU. That's COVID-19, the disease. A lot of people say, "Oh, the COVID-19 virus." Well, it's a living language. People are killing it before our eyes, but that's the distinction SARS-CoV-2. I think it's important to realize that because what about SARS-CoV-3, the next virus we're worried about. But the disease is COVID-19 different from the virus.

Thank you. COVID-19 seems to present with a myriad of different symptoms, affecting people of different age ranges, varying health levels and ethnicities in different ways. Some people never know they have it, some end up in ICU or dead. How can we make sense of this scenario?

Yeah. I think it's important to realize that SARS-CoV-2, it's a virus. When you get infected with a virus, you're going to develop a viral syndrome. We've all had different viral syndromes. We would love to be able to say, this is the telltale symptom. If you have that, we definitely know what you have. But as we've seen some people with a virus, they get GI symptoms, gastrointestinal, stomach doesn't feel right, a little bit of loose stools. They might have a headache. They might have a fever. They might have congestion. They might have loss of taste or smell. They might have a sore throat. They might have a cough. Viruses present with a myriad of viral symptoms. The only way to tell an infection with SARS-CoV-2, the only way to tell COVID-19 from another viral syndrome is with a test because it can present with all these different manifestations.

Most of the next series of questions posed in today's program are largely based around a paper that Dr. Griffin has written with medical colleagues called, the importance of understanding COVID-19 in treatments and trials. It's published in AIDS Reviews. A link will be provided in the show notes. We will also have a transcript of this episode available approximately one week after broadcast. So Daniel, to best understand this virus, yourself, and a group of clinicians have collaborated to define the different phases and stages of COVID-19. Can you please explain to the audience why this is of importance and how your approach to the diagnosis and of HIV/AIDS contributed to this?

Certainly. I'm very proud of this paper. I'm glad it's being featured and discussed. Early on in the pandemic, it was really about April or so that I started talking with a lot of my colleagues, and this paper is 30 plus authors from all the way around the globe. All the different continents are represented, really trying to get people together and saying, what are you seeing? What are the stages of this disease? The whole goal was to get a consensus of the stages of the pattern of manifestation. So we could understand the disease, but also, so we could start looking at the timing of therapeutics. That's something that we've really discovered is so critical over time. A little bit of a shift in some of the time intervals, but really this clear distinction. The initial phase, when someone initially starts having symptoms this one week of the viral symptom phase, when we're seeing a lot of viral replication. Our ideas early on is that's the best time to be using those antiviral agents. Getting into that second stage, or that really second week is when people start having trouble breathing.

Some people were calling this the pulmonary phase or the cytokine storm phase, or we settled on the early inflammatory phase. When really this is where we talk about steroids, immune modulation, setting things down. And then we get into a next stage where this is when people might start having those bacterial infections, really trying to make a distinction. Not that first week, that first week it's a virus. 90% of the time antibiotics are not going to be what you want to use. Over time, these stages have really panned out. This is consistently what we're seeing. We're seeing therapeutics used at the right time, make a difference therapeutics used at the wrong time, fail to make a difference. So this has really served as a great blueprint for investigating certain medications, using certain medications, anticipating the time course and the development of the disease in individuals.

Good. So, and from my understanding, you kind of worked all this out from your experience of working with people with HIV and AIDS. Can you at elucidate on that a bit? I think there's some similarities in your approach.

Yeah. That was actually, that's why we put this in, I guess a journal that I'm familiar with. Is really trying to understand how important timing is and understanding. We'll do that as a parallel with HIV. When someone gets acutely infected with HIV, that's the virus AIDS can be the disease eventually. There really are these massive amounts of virus, really so critical to start that antiviral therapy, but even when the virus gets brought down, there's so many other manifestations. So really important to understand the mechanism, understand the timing, think about what are you actually trying to do? What are you trying to target? Not just really connecting the dots, saying, HIV, you get this. COVID you get this. Really understanding the disease, what's going on? What's driving the symptoms, is critical? You may control the virus with HIV, but now if they've got a parasitic or a secondary fungal infection, you've got to be addressing that. You can't just keep thinking in this rigid box format.

Thank you. You've pipped the post a bit on my question, but I'm going to go through each stage of your paper in turn for the audience. So the next series of questions will help Daniel to explain the different phases and stages of COVID-19. I believe this is important for the audience, as Daniel has said to understand. As different treatments are initiated at different stages of the disease with a narrow window for them to work, as he's already highlighted. So please start with the PRE-EXPOSURE period. From my understanding, this is a stage before you are even infected. I fully recognize that infection prevention is a massive topic unto itself and will be covered under a number of episodes in this podcast series. But can you briefly touch on the key components for our audience?

Okay. I'm excited to go through the stages and I think this is great. Briefly, you'll have to make sure I reign it in because I could talk about these stages well for hours. But let's start about, this is actually in many ways, the most important period, the pre-exposure you haven't been exposed yet. What can you do now to keep yourself safe? There's always a lot of discussion about this. We'll talk first about ventilation, outdoors versus indoors. The way you get this virus is doing that thing that we all do many times a minute, we breathe. We inhale. We bring things into our nose, into our mouth, into our lungs. This is a respiratory transmitted pathogen. So being outdoors, improving ventilation, which we actually think are going to help with a lot of other respiratory viruses as well.

So that's key. Opening up those windows, avoiding those closed spaces. Distance, we've talked a bit about that. Distance is great in certain settings, but if you get in that small, poorly ventilated area, everything's going to build on the ventilation. Then even if you're far apart, you're still breathing in that same air. So we have learned that being three feet away is good. Being six feet away is probably a little bit better. So distance can help us. Ventilation can help us. What about masks? That's a hot topic and we've gone back and forth. People are very emotional about masks. First, everybody was very upset because they weren't being told to wear masks. Now everyone is very upset, that they're being told to wear masks. Early on, why are you waiting for the science? You should just do this.

Now, the science is here, why are we still doing it? So one of the things about masks and I like to draw the distinction. If you are in a whole group and everyone's wearing the masks, those surgical masks, those cloth masks, they're really good at protecting others, some protection for us as well. If you want to protect yourself, and as we're moving in a lot of areas where masks are being removed. For people to protect themselves, the type of masks that we talk about are also called respirators. So the N95, the KN95. This is really filtering out let's say 95% of what you're breathing in protecting you, where the other masks protect us somewhat. But it really is when you cough, you sneeze catching that, trying to protect others. So this is going to be a topic as those masks start going away in many areas, how does a higher risk person keep themselves safe?

They may want to upgrade to these different types of masks or respirators. Hand hygiene, this is not mainly spread through contact through surfaces. There's been a lot of, we call it hygiene theater, people leaving their groceries and mail in the garage for 72 hours, spraying them with bleach. Boy, I think more bleach has been used in recent times than ever. I worry about that. But I do want people to keep washing their hands, not so important for SARS-CoV-2, but just good overall. I don't want people to stop washing their hands when this ends.

The other, and this is really the biggest thing. What is the biggest thing that you can do in the pre-exposure period to keep yourself safe? Vaccination, that's huge. Not only does vaccination significantly reduce your risk of getting infected, think of this as sunscreen, but if you do get exposed, if you do get infected, we'll get to this. It's also going to reduce your chance of serious illness. What else? So we've got mask, we've got ventilation, we've got washing our hands. Testing right, in this period. We just had a big sporting event here in the US. A lot of people went to these big parties. Some of them weren't feeling great when they went to these big parties. Testing before you get together in these high risk settings is another way during the pre-exposure period to continue to not put yourself in a risky situation.

Thank you for such an excellent answer. Okay. So next is the INCUBATION PERIOD and the DETECTABLE VIRAL REPLICATION period. When an individual is successfully exposed to the virus and it multiplies inside them. Could you please explain this stage and then relate it in the context of getting a false negative test result for COVID?

Yeah. I think that this is really critical. There's really a lot to cover in this area. So, maybe someone showed up at that party. They weren't feeling well. They didn't test themselves. Maybe the ventilation wasn't as good. Maybe you spent a little too much time too close to that person. Now the virus has actually gotten into your mouth, into your nasal passageway. It's actually gotten into the cells and it's starting to replicate. It's going to take a period of time before there is enough viral material for you to test positive. I think that's key. A test does not predict the future. What we've seen, someone starts to feel not so great. I think we need to realize at an individual level, getting tested within the first few hours may actually miss it. This is a little bit of a change. Early on with the original ancestral variant people usually were testing positive a day or two before they even had symptoms.

Things have really shifted a little bit to the left. We're certainly seeing a lot of individuals who start to feel poorly and they don't get that positive test until the next day. So I think that's important to think about with the sensitivity of the test, but what's going on? So the virus is starting to replicate. It's making that genetic material, that RNA. It's making those proteins to form those viral particles. You can't test positive until there's enough of that RNA genetic material to test positive on a PCR, or we call it molecular tests. There's not enough of that protein to test positive until you've actually started to really churn out the virus, probably getting about a million of these variances per microliters. So really getting to a high level. What we are seeing, and I think this is important in the viral replication phase is right about when people start to become contagious.

There's a really good correlation with our rapid tests. But remember you come in, I've been feeling crummy for three or four days. My daughter woke up this morning with a bit of a scratchy throat. If you do that rapid test, even if you do that PCR, she's not going to find out for two days. If you send that child back to school, you're running the risk of spreading that to the next person. So really important in the testing and the early viral phase to be thinking about how our tests work. One test, think about repeating that second test. Even if your test is 90% sensitive, 95% sensitive, a test that next day is going to really catch ones that you might miss. Why do we care so much? Well, not only do we not want to spread it to others, not only do we want to know, why do I feel crummy?

But we now are having therapeutics during this time. So this time is now getting quite complicated. If a person tests positive, we can do things that are helpful during this first week. We can actually do things that are harmful. So I want to discuss what we should do and what we shouldn't do. So, number one, we actually now have effective oral antivirals for our highest risk people. Here in the US, there's a medicine nirmatrelvir, I'm just going to say Paxlovid, because no one's going to remember the other one. This is something that if we start within the first three to five days, we're having almost a 90% reduction in progression. We now have the peer review data out, the New England Journal of Medicine article, the people that were treated there were no deaths. All the deaths were in placebo. So really an impressive option, but again, timing matters.

You got to start this in the first three to five days. If you wait, you're going to lose your benefit. Here in the US, this is picking up a phone, knowing who to call. There are online locator sites, telling you who to call. You pick up the phone, you talk to that pharmacist. You tell them what makes your individual high risk. You need to know kidney function for dosing, and you need to know if there are any medicine interactions, because there are some medicine, potential interactions. Number two, this is with the monoclonals and we still have monoclonals that are effective. We have new ones that are coming down the pike. So we have another one that just got approved here in the US. So we've got paxlovid, we've got monoclonals. The latest is remdesivir, outpatient IV remdesivir. Based upon a New England Journal of Medicine article, looking at about an 87% reduction in progression if you give this within the first three to five days, timing so critical here.

If you wait, start giving this to a person when they're in the hospital, we're not sure, right? The WHO isn't even impressed that the data is really there to support its use. But those first three to five days treating the virus during the antiviral. Molnupiravir, Thor's hammer this is a drug maybe not as effective, maybe about a 30% reduction in progression, not preventing all the deaths, but no kidney function adjustment, no drug-drug interaction. So another potential lift. But what should we not do? We can harm people, right? We've gone ahead, we've vaccinated them. Their immune system is ready to go to fight off this virus. If you give them steroids during that first week, you increase their risk of progression about sixfold. You increase their risk of death.

Steroids during that first week. That is not helpful. That is harmful. What about antibiotics? We're trying to be helpful trying to give them something azithromycin, doxycycline. Just another really great meta-analysis looking at azithromycin not helpful. Doxycycline, not helpful, actually potentially harmful. There were more deaths in the treatment group than placebo. So we want to avoid those antibiotics. We want to avoid steroids. We want to avoid unproven therapies. There is still the opportunity for clinical trials if there's something you're excited about. But we have really effective therapies, 90% reduction in progression, 87, 85, really top notch medications that we can employ during that first week, but we can also do harm. So don't do that. Don't give aspirin, don't give anticoagulants, give things that work that are evidence based.

Thank you. That was excellent. It's quite interesting about remdesivir because I remember earlier on in the pandemic, it was used much later and there wasn't such a good outcome. So it's really interesting now that it's been put in its correct place to be effective.

I like that you say that. I still remember, and actually part of the impetus of getting together with all these experts and creating this paper was, we were seeing therapeutics that potentially could be helpful used during the wrong time and actually ending up being harmful. So timing really matters.

Fantastic. Thank you. Right. So could you please explain the VIRAL SYMPTOM PHASE in the context of how much virus you have in your body? Are you viral low, load and what type of symptoms, if any, you would exhibit?

Yeah, so I think it's really important to realize this is a viral syndrome. This can present in many different ways. You can have headache, you can have fever, you can have sore throat. I remember in the last couple months, people started to get excited saying, "Omicron, it's a little bit different. A lot of people have GI symptoms. A lot of people have back pain." I went back to some of my early descriptions in April, March of the pandemic, people had GI symptoms. People had back pain, but so many healthcare professionals were so frightened.

They didn't want to walk in the room. They didn't want to ask these questions. So you can get back pain. That shoulder that always bothers you every time you get a virus is bothering you again. You can get that stuffy nose, that sore throat, that headache, anything that you associate with a virus can present, if you get infected with SARS-CoV-2. One of the interesting differences we saw, and I think this is really important. Is a lot of individuals, even though they might have risk factors, if they were vaccinated, particularly boosted, they may end up with a milder or even an asymptomatic experience when they get infected. So there's really a spectrum. What makes Omicron, mild? Being vaccinated!

Fantastic. Also, is there any correlation with viral load in the severity of your symptoms?

We're not sure. There definitely is a timing to the viral load. We're not sure, if a more significant exposure results in worse disease. We do know that individuals that get sicker that end up in the ICU, they have a longer period of time that we're picking up those high RNA levels, but we don't have any really great correlation. There was a long COVID study where if there's so much virus that you're actually picking it up in the blood, so viremia, which is actually usually not the case. Those individuals are at higher risk of going on to get long COVID. So there probably is some answers there. We just don't have them all yet.

All right. To just clarify to the audience viral load is the amount of virus that is in your body [phenometics 00:33:24].

Yeah, no. So this is great, because I'm a stickler for details. When they do those PCRs and they say, you've got all this RNA, it's actually a little bit tough. Is that effective virus? Is that virus that can affect other people or is it just a bunch of genetic material? So what we've seen, for instance, in people who are vaccinated, they may have a lot of RNA, but the vaccination is interfering with the virus, making new viruses, making replication, competent contagious virus. So a lot of times that high RNA number doesn't necessarily correspond to infectious virus.

Thank you. Once again, I'm not sure if you mentioned, are there any treatments or significant investigations that can be initiated at the viral symptom phase? Anything different from what you've already mentioned?

No. I think the viral symptom phase, when you start having symptoms, when you get that positive test, that's the viral replication phase. That's when we're thinking of the antivirals, the paxlovid, the monoclonals, the IV remdesivir, the molnupiravir not messing, not messing with the immune system, letting it fight off the virus. Pretty soon, we're going to get it to the phase when the immune system needs to start settling down. When the virus is gone, the immune system doesn't seem to realize that.

Okay. The last four stages describe the severe and deadly clinical manifestations of COVID-19. I.e the people who end up in hospital or chronically sick, however, most individuals who develop COVID-19, do not progress to these stages. Can you explain why Daniel?

The why is tough. So we do know certain things that put an individual at risk. For a lot of people, I'm going to say for 80% of people across the board, maybe even a little bit more, they go through that viral symptom phase, or maybe they don't even have symptoms. They pass through that viral replication phase. Then they end up doing well. They end up staying home. But about 20% of people and that ends up being a lot of people, they will start to have trouble breathing. Maybe their oxygen level will start to drop during that second week, this early inflammatory phase. We think that this is driven in part by cytokines, by the significant amount of inflammation. What puts you at risk? So a number of things, age being over the age of 65 in particular, really starts to go up, being overweight.

That's actually a significant issue. Diabetes, kidney problems, having problems with your immune system so that during that first week, you couldn't fight off the virus. Now we're seeing the highest risk group is the unvaccinated. But during that second phase, you could actually start developing problems where you might require pulmonary support. So during that first week, in addition to all the therapeutics, this is also when we start talking about monitoring. Every home, every little community should have a pulse oximeter, a little device that you can put on your finger, check those levels. Make sure those levels stay in the nineties, but for some individuals, those levels are going to drop down into the eighties, maybe lower. These are individuals where we start jumping in with therapeutics that can have help modulate the immune response.

Right. Thank you. Excellent. Another excellent answer. Let's start with the EARLY INFLAMMATORY PHASE , the first of the four remaining phases. This occurs one to two weeks after an infected person develops symptoms. This is where we truly see how dangerous COVID-19 is. Can you please describe the damage to the body caused by the disease at this stage?

So the tough thing is that at this stage, usually the virus is on the way down and what we're seeing the damage is all being driven by the immune response. So this is when people start dropping those oxygen levels down into the eighties. This is when we start thinking it's appropriate to start steroids. The standard is this dexamethasone six milligrams a day. Sometimes we can start that dexamethasone, it's an oral medicine and keep these folks out of the hospital. Keep that oxygen level from dropping too far. Sometimes we even set them up with home oxygen. We even start talking to them about sleeping on their belly. Interesting enough, sleeping on your belly, proning has mortality benefits and can help slow the progression.

For those individuals that end up in the hospital, this is when we start looking at anticoagulation, because part of the syndrome, part of the pathology is clotting disorders, large clots, but also small clots. So we're seeing inflammation. We're seeing destruction of tissue by the immune system. We're seeing clotting issues. So we're talking about steroids, we're talking about putting people on blood thinners to protect them. Then we're watching because most people will not have an infection at this point. We're really focusing on modulating that immune system we are focusing on preventing those clotting complications.

So the clotting complications are things like a clot to the lung called a pulmonary embolism or stroke. Is that correct?

So those are the big ones. So probably the most common are the pulmonary embolism. So seeing either large or small clots ending up in the lungs. One of the most devastating would be the strokes, which we're seeing sometimes at this early stage, but maybe even a little bit later. We're also seeing limb ischemia, unfortunately. We're sometimes seeing people block off their arterial blood supply to a limb. So we saw unfortunately people losing hands, feet, legs.

Yeah. I think people don't realize just how deadly COVID-19 can be. Can we please compare the damage done to the body by COVID-19 or the body's immune response versus potential very rare side effects of vaccinations such as myocarditis?

Yeah. So myocarditis is a perfect example, and we'll start off with, if someone ends up getting infected, they end up getting COVID-19 and we'll even pick that high risk group that people worry about. So the males, sort of 16 to 25 in that range there. If a person gets vaccinated, then sort of a lot of press about a one in 5,000 risk of myocarditis. What is that? A little bit of inflammation of the heart, tends to resolve within about 24 hours. It's very rare that they go to medical attention. We've now followed this for quite a while. We're not seeing any long term issues. So these people, little bit of inflammation and they get better. But what about an individual who actually gets COVID-19? We've seen from some of our athlete studies that a large percent and large, maybe 20% of athletes continue to have ongoing inflammation of the heart for months after. One in five, not one in 5,000 for 24 hours.

This is one in five for months affecting performance. We've had a lot of, I think, famous athletes not be able to compete in their sport. We've had triathletes, having trouble getting up and downstairs. So, anytime you pick something that you associate with the vaccine, the severity and the risk associated with getting COVID 19 is so much higher. Now in so many parts of the world, the masks are coming off, we're seeing more and more spread of the virus. You are really making a decision. Do I want to get that vaccination, which has a low risk of a not very severe side effect versus getting COVID-19 with all these tremendous side effects, including pretty serious damage to the heart.

Thank you for illustrating that so well. The SECONDARY INFECTION PHASE is marked by other disease causing infections, such as bacterial infections, fungal infections. What is happening to the immune system triggered by COVID-19 at this stage?

Yeah. So this is actually an intrinsic problem with the immune system from COVID-19, not even necessarily our therapeutics. We saw this early on, and early on we weren't sure how to treat COVID-19. So people would have that early viral phase. They would then end up in the hospital for that early inflammatory phase. We didn't know what to do. Most of them weren't getting steroids or anything. We were just trying to support them. Then that third week they would start to have all these complications. They would start to have fevers again, their blood pressure would drop. They would have more trouble breathing. We started to realize that there was this immune dysfunction. These people would start having bacterial infections. They would start having fungal infections. Now that we're treating them with steroids, we're getting them through that early inflammatory phase. We continue to see this.

So it's that second week in the hospital. It's that third week of disease, things start going in the wrong direction. This is when we have to do this diagnosis based approach. We need to repeat that chest X-ray. We need to do a thorough exam. Have they developed pneumonia? Have they developed a fungal infection? Have they actually had that pulmonary embolism? Maybe this is when they have that clotting complication or a stroke. So this is that time when you start thinking about antibiotics, you start thinking about antifungals. You start thinking about what could be going on. There is also a bimodal inflammation where you have that early inflammatory phase. They start to get better. They might start to have a secondary inflammatory phase during this third week as well.

Wow! The third of the four severe phases is the MULTI-SYSTEM INFLAMMATORY PHASE . This could occur in adults and children, but is rare occurring in less than 0.01% Of children, and I suspect less than 1% of adults. You stated in your paper that it is an autoimmune process. What is an autoimmune process? What is COVID-19 doing to the body's immune system here?

This is a tough part of the disease. When we initially saw this, we started hearing reports from our pediatric emergency rooms. They were starting to see these children. They were coming in blood pressure was low. They had evidence of vasculitis, inflammation of their blood vessels. Somewhat similar to something we call Kawasaki's disease, which is just this inflammatory process affecting the blood vessels. But they started calling [Kawashockey's 00:43:55], because they would also have dropping blood pressures. And nice thing a lot of these pediatric ER colleagues were talking, we started to realize we were seeing a much higher incidence of this than we had seen. Reports started to come out of the UK and France, other parts of Europe. What we started realizing is these were children who had, had exposures. Had either had mild or no symptoms, but now had evidence that they had had a COVID well say a SARS-CoV-2 viral infection, three to four weeks earlier, and now they were developing these problems.

The treatment has really approached this as if this is an immune or antibody mediated autoimmune disease. So those antibodies, instead of attacking a virus, instead attacking something that's far may seem to be actually attacking the blood vessels, attacking the individual themselves an off target effect. So treating these individuals with steroids, intravenous immunoglobulins, to try to redirect and clear those antibodies out of there has really helped. One of the hallmarks of this is finding evidence or history supportive of recent SARS-CoV-2 infection and also cardiac dysfunction. It's pretty much universal that the heart is going to stop functioning well. We're going to see decreased ejection when that heart tries to squeeze. So this is a pretty profound and a large number of these children are actually going to end up in the intensive care unit.

Wow. From my understanding, adults can rarely also present with the same progression and symptoms in this disorder?

They can and it is rare compared to the numbers, but we are at this point, thousands of children, thousands of adults, here in New York hundreds. So I think this might often go unrecognized, but there are thousands of adults and children here in the US alone that have actually developed this syndrome.

The fourth and final severe phase is the TAIL PHASE. Also known as post acute sequelae of COVID or long COVID. This is a topic that I'm very concerned about going forward. Our medical systems are currently strained to an uncomfortable level. We have the baby boomer generation turning 80 years old in 2026. And the combination of medical care required with aging and adding on long COVID to an already strained medical system could pose significant problems in the very near future. We will be discussing long COVID in more detail next week. But Daniel, can you please share with our audience, your definition of the tail phase and correlate this, if possible, to your experience of caring for people in the New York community with this phase of the illness?

Sure. I share that I am really troubled and have been really troubled over the last two years, by the long COVID, by this tail phase. Early on, there was this naive idea that COVID was a two week illness, right? You would have your viral phase, your early inflammatory phase, and then you would get better and then you'd move forward. But we started to realize very soon that people that had been infected in March, still not doing well in April, still not doing well in May. Now unfortunately some of those people are still not doing well two years later. So what is post acute sequelae of COVID? It really is symptoms past four weeks. So you've gotten four weeks out. You've gotten 28 days out either you have persistence of symptoms or new onset of new symptoms. So it's a pretty large umbrella post acute sequelae of COVID. Under the PASC umbrella is also long COVID.

Long COVID, a lot of support groups have really brought this to attention. This has a lot of features that are similar to chronic fatigue. These are individuals who either new onset or continuing from the acute have incredibly low energy. The majority of them have something called post exertional malaise. So they do try to, they go out, they try to push themselves a little, and now the next day they're completely washed out. Two steps backwards. The early idea, we'll send these to rehabilitation specialists, they'll exercise them back up. They're just deconditioned, that actually can make these individuals worse. Not only is the fatigue really prominent, but a lot of these individuals, self report, brain fog, cognitive dysfunction. It isn't just a fog. It's actually, college professors unable to sign their name on a check. Nurses and other professionals unable to return to prior employment. People having difficulty with normal cognitive tasks.

There's a number of skin manifestations. There's balding. I have to say, this can be very traumatic about three to four months after acute COVID a lot of patients I've taken care of have just had their hair just falling out in clumps. Really a myriad of different issues. A lot of effects on the circulatory system. Tachycardia the heart racing really quickly. Issues keeping blood pressure up. One of the most heartbreaking cases, a 16 year old girl that I'm taking care of prior to COVID a dancer full of life and energy. She developed such severe destruction damage to autonomic nervous system that when I first met her, if she ever even tried to increase the back, just raise her head a little bit. She would start vomiting. We've now gotten to the point where she can actually sit upright for 45 minutes at a time then has to rest again, but just tragic the tail, the amount of issues that follow after that acute COVID.

Wow. Sobering. What treatments are administered to people who are suffering chronically with long COVID?

So it is tough. We do not have a lot of great options. Number one, and this is something we noticed early on, a number of people with long COVID see improvement with vaccination. So the story here was early on when we first got vaccinations, a lot of the people with long COVID were my colleagues, health professionals that I knew physicians, nurses. So there was a little bit of trepidation, if I get the vaccine, will it make things worse? So really made a point of close follow up during the vaccination series. We started seeing that after that second shot, about 50% of these individuals were actually noticing that they remarkably improved. This has now been studied and validated in a number of trials. There is actually a really nice UK rapid report that came out this week. A number of studies showing that one of the first things we should be trying in these individuals is vaccination.

It looks like the sooner the vaccination is after acute infection the more reduction we see in an individual's risk and severity of long COVID. So number one is vaccine. Number two though, is looking at the symptoms. What are we treating? A lot of individuals will develop new onset migraines. So we'll actually focus, we'll treat these very much the way we treat migraines. We might use the Imitrex. We might use the triptan therapy. We might use some of our cardiovascular medicines. What about insomnia? That's another huge one. Interesting enough we're seeing quite a bit of success with melatonin. Five milligrams is an average before people go to sleep, really focusing on what are the different things. A lot of people have cardiac manifestations. We're working with our cardiology colleagues. A lot of people have lung and pulmonary issues. That's quite common. We're working with the pulmonary colleagues. Neurology, really getting them involved quite a bit.

And there are a lot of mental health impacts to COVID and it's not all in your head. It's really important that we don't gaslight these people. One of the most important thing is that therapeutic relationship is listening to what people have to say, acknowledging really listening to the story and actually a bit of a dialup. Because we are seeing a lot of people with these same patterns and that can really be encouraging to these people to know that it's not just in their head. This is a real illness and time, time is in our favor. A lot of people are gradually getting better over time. Not all, we still unfortunately have a chunk of individuals who continue to suffer. There's encouraging news that we are going to have these trials, that we're going to come up with new therapeutics. We're still waiting for those. We're still waiting for those answers.

Thank you. So Daniel, I always like to end on a positive note. What have been your most uplifting experiences as a scientist and physician during this pandemic?

I think the most uplifting, the most exciting, the biggest surprise was how quickly we translated those decades of research in the mRNA vaccine arena into actually effective vaccines. Then to see the numbers. I mean, we were talking about a 50% reduction, but to see the numbers, it's been incredible. It's been impressive. So the vaccine's tremendous. The others, I have to say a lot of my colleagues that I've worked with really their true colors have come out and you've just seen what incredibly caring, passionate individuals. This is physicians, this is nurses. This is really everyone involved, going in there, working these long hours. Early on, we didn't know. We were taking risks. We had no idea if what we were doing was safe. We were seeing our colleagues die.

And these individuals just kept going, going often for months at a time without taking a day off, just to continue to care for these individuals. So just seeing just the tremendous human beings that I have the privilege of working with, the scientists, working so hard to bring us therapeutics. Not only do we have the vaccines, but now we're getting these impressive antiviral therapeutics. We're hoping that we have more and more supply. I have to say I'm actually starting to get optimistic. I think we really are having some really effective tools. The vaccines are great. The therapeutics are great. What we just need to do is we need to do a better job of sharing. I want everyone to remember kindergarten, those lessons we've learned, right? You don't bring in a treat just for yourself. We have these tremendous tools, these tremendous vaccines, but half the world is still waiting for us to do a better job of sharing and getting them out there.

Thank you so much for another very, very rich episode. We are so, as I say, lucky and privileged to have you contribute and to really help us to understand what COVID-19 is about. Please do join us next week when we have several guests who will talk about long COVID.

Thanks for listening to this week's episode of COVID-19 The Answers. If you enjoyed the episode, please subscribe, rate, and review and do visit our website, kojalamedical.com/covid19theanswers.