If you can, I'd like you to think back to the start of the COVID 19 pandemic. It was early 2020, and it was a scary time for everyone. In part, there was just so much we didn't know. It was an uncertain time for me as well. I was trying to cover the pandemic day in and day out on television and also on this podcast, which back then was called Coronavirus Fact versus Fiction. I have to tell you, I've been a doctor for 30 years now, and up until that point outside of HIV AIDS, I had not really seen a brand new disease class emerge so quickly, so transmissible, so dangerous, so deadly. There was a lot to learn and we all had to do it quickly. So now flash forward to 2023 more than three years later. And the truth is, we are all still learning. Perhaps no aspect of this pandemic has raised more questions than this mysterious phenomenon now known as long COVID.

I've been treated as COVID for 97 days. I'm pretty much in the throes of it.

They are known as long haulers diagnosed with COVID 19, but months later are still experiencing symptoms.

Everything from blood clots, seizures. Arm tremors.

My stomach is not what it used to be.

'A 2022 survey from the National Center for Health Statistics now estimates almost 7% of adults and more than 1% of children have struggled with long COVID at some point. That equates to millions and millions of people. So as we continue this journey through the brain on the podcast, I wanted to know how does Long-covid impact the brain? Does the term brain fog even come close to accurately describing what many people are experiencing? And perhaps most importantly, what can we do about it? Today, we're going to do a deep dive into what we know about the long COVID brain. And we're going to talk to someone who's been on the frontlines of this fight against long COVID.

My goal is always to have one more thing that someone can try that they haven't tried before.

I'm Dr. Sanjay Gupta, CNN's chief medical correspondent. And this is Chasing Life.

Okay, before we go any further, I thought it was important for you to hear directly from someone who has been dealing with long COVID. Because what I've heard is that unless you've had it, you probably can't truly understand what it feels like.

Can you just tell me a little bit. About your life before this? Like, what were you doing? What was your life like before all this happened?

I was an extremely busy person. Mom, wife. Dog Mom.

'This is Barbara VanMeter-Nivens. Barbara first got COVID in the fall of 2020, and it was an extremely bad case. She had to go to the hospital. She ended up in the ICU. She spent nearly a month in the hospital before being released. But here's the thing. Even though she got to go home, she was far from cured.

I went home on oxygen for 500 days.

Her symptoms were just not going away. And about four weeks later, she saw a primary care doctor hoping for some answers.

And I couldn't understand why I still felt so bad. Why? Everything hurt. I was on a walker. I was crying. And she padded my hand and she said, Barbara, you have long COVID.

Long COVID completely upended Barbara's life. When I first met her in mid 2022, she told me she hadn't worked in over a year. She missed her stepson's wedding, her niece's graduation, even her mom's funeral. And what's more is that she often had to deal with people who didn't actually believe she had long COVID. They were downplaying her symptoms. What I was really struck by was how she described the way long COVID actually feels inside her head.

I feel like there's a virus in my brain. And it's changing. It's changing things in my brain because I can't think. I can't remember. I you know, I just can't pull those things out. Like I did before.

It was that phrase changing things in my brain that really stood out to me. People often use the term brain fog. But to people like Barbara, the term brain fog undersells it. And it was people like Barbara that led my next guest to go on a mission to uncover the mysteries of the long COVID brain.

We were running out of beds. I still distinctly remember in my lab we had a we had a whiteboard and we had the number of free beds, free ICU beds just written on the whiteboard, and it was just going down every day.

This is David Putrino. He's a neuroscientist. He's also director of Rehabilitation Innovation at the Mount Sinai Health System in New York City. Before the pandemic, his lab was primarily focused on helping people recover from traumatic brain injuries. They had just launched an app for stroke survivors, a place for them to input their vitals and their symptoms so doctors could then track the recovery. But when ICU beds began filling up across the city, he wanted to make sure that the patients not sick enough to be admitted, didn't also get worse at home. So what he did was he adjusted the app to focus on respiratory failure and he started sending patients home with the pulse oximeter and instructions to log their vitals on the app.

'I still remember as March 15th, we had our first patient join and stop being monitored. And by April, we had about 8000 people on the app. Wow. And then the thing that happened was around. Mid-April, we we started having people who had been on the app for a while. Usually the trajectory was they get sent home from the hospital or they get on the app. They they monitor their symptoms at about two or three weeks later, they say, Well, thanks for everything. I feel good, you know, I'll see you later. By mid-April, there was like 20% of the people that joined onto the app just weren't getting better. And they were reporting new symptoms.

And he says those symptoms were different than what his team had been expecting.

Organically, people were coming up with extreme fatigue, cognitive difficulties, memory loss. You know, they were telling us that these were their problems. Breathlessness, They didn't say post exertional malaise. No one knew what post exertional malaise was, but they would say things like, you know, I went to get my groceries and then I crashed. So Crash was a big a big word that was being used. You know, I went downstairs, my groceries were delivered, carrying them up the stairs back to my apartment, caused me to crash. And I couldn't you know, I couldn't get out of bed for two days. And I still remember we huddled as a group and and we said, what are we going to do? You know, we we don't want to tell them to leave the app, but also the app isn't helping them that, you know, this is something else.

'Let me ask you a fundamental question. So you got these patients who you're following on this app and they're starting to describe other symptoms. How do you separate them out from people who may not have had COVID but are just dealing with a very significant amount of tumult and anxiety in society at that point? I mean, how do you how do you say for sure this is due to COVID, that this is even long-covid? I'm not I'm not suggesting it isn't, but I'm just saying as a control group, what was your control group here?

'Well, you know, control group is a term that we would use in research, Right. The the wonderful thing is we were running a clinical program which which gives us perfect license to say the one thing that all long COVID patients want to hear, which is, I believe you. In the early days when we had thousands of people on the app and several hundred were saying all of these symptoms, we didn't really need to say, Oh, that's that's long-covid and this is PTSD or, you know, or some sort of anxiety or depression due to, you know, very rightly sort of the world burning down around us or in the moment, we just had to say, okay, well, let's bring you in for an evaluation and let's let's talk through your symptoms and let's get a sense of what's going on. And what that got us very good at was learning to characterize all the different symptoms that we were seeing because we were very exacting about it. Okay, you have fatigue. Let's measure your fatigue with a fatigue severity scale, because I want to know how much fatigue. You know, it's not good enough for a clinician to say, oh, you're fatigued, and then write down patient complains of fatigue. But meanwhile, you're not really asking how how fatigued they are. What is the nature of the fatigue? Same with cognitive impairment. It's not good enough to write down brain fog in your notes, you know. Okay. Is it executive function? Is it short term memory? Is it long term memory? What what is the nature of the cognitive impairment that this person's reporting and let's measure it.

What about the brain itself? I mean, what can we say at this point happens to the brain after COVID, at least in some patients?

Yeah, You know, we're starting to learn a lot more about what is happening in the brain during an acute COVID infection. There was a truly alarming paper that was published in Nature about two years ago now where a bunch of scientists in the UK actually looked at brain imaging in not just people with long COVID, but everybody who had had COVID. And they showed alarming changes in brain size as well as changes in cognitive function after a COVID infection. Even if the person that they were studying didn't necessarily consider themselves to have long COVID. Their brains had been changed. And that was followed up with a study about myself, Akiko Iwasaki We were both really fortunate to team up with Michelle Mungai from Stanford University, and we published a paper in showing that when you infect rodents with a mild form of COVID that only affects their lungs. We were still seeing chemical changes in the brain because of the proliferation of these these chemicals called chemokines that then went into the brain and caused damage to the microglia, the cells that hold together our brain cells. And that was extremely alarming because when we published that work and we saw this one chemokine, that seemed to be the culprit, causing a lot of the Microglial activation. It was called HCL 11. When we tested our long COVID patients for CCL 11, we saw that it was overexpressed primarily in the folks who had cognitive impairment, meaning that there is some direct brain activity going on in even. If the virus doesn't make it into your brain. So we understand that even the systemic changes that can occur in long COVID can cause direct damage to the brain.

Basically, what Putrino is saying is that the virus can cause direct impact on the brain, even if it doesn't directly attack the brain itself. That's because chemokines, which are small signaling proteins, unleash a chemical reaction that can reach the brain and damage the very scaffolding for the brain cells themselves. And then there are the dangers to our circulatory system, our blood vessel system.

We're also, of course, seeing a lot of research around inflammation of the blood vessels that causes these small circulating entities called micro clots, which are, you know, very, very small clots. They're not they're not large enough to block a large blood vessel, but they are large enough to block small vessels. And we've not only have we've been able to show correlations between cognitive dysfunction and specific amounts of micro clots circulating in the blood of people with long COVID, we think that that could be the story for persistent virus and persistent COVID infection.

You know, I have three teenage daughters. And one of the things I've noticed just because they have a lot of friends who are around the same age that there have been a lot of teens and I would say specifically teen girls, although that may be my experience because I have all girls, but a lot of teen girls who've developed something known as Potts, which is postural orthostatic tachycardia syndrome, basically means a heart rate shoot up when they go from lying to sitting or sitting to standing. And even a little bit of activity will make their heart rate really shoot up and they may feel lightheaded. And, you know, these are girls who who before the pandemic were involved in sometimes two or three sports, you know, throughout the school year. And now one is is kind of maybe even overdoing it for them. What is the relationship between COVID and Potts, as far as you can tell?

'Yeah, we we published work in 2021 talking about how roughly 70% of long COVID patients who are coming to our clinic met American autonomic society criteria for parts. And certainly we've seen a lot of individuals with long COVID experience parts. We we believe that the most likely scenario of why Potts has co-occurring with long COVID is that the vagus nerve, which is this long nerve that runs through almost every organ system in your body and does a lot of a lot of what we call autonomous functioning for our body. You've heard of autonomously driven cars. We've got this system that just autonomously runs our blood pressure, our heart rate, our breathing rate, all of the things that our body doesn't want us to think about but needs to regulate so that we can walk and talk and do all the things that we need to do. The vagus nerve can get knocked out of balance by COVID in two different ways. There's evidence to suggest that it can be directly infected during the acute period, which causes inflammation and therefore dysregulation of the vagus nerve. But also just the general systemic inflammation. During the early days of COVID, we heard a lot about this, this concept of cytokine storm, which is our body producing all sorts of inflammatory molecules, while many of the inflammatory molecules that are specifically produced during acute COVID are irritants to the vagus nerve and they cause vagus nerve inflammation. So seeing disordered omega and pots associated with long COVID is very common for us.

So with all that in mind, how do you correctly identify if someone definitely has long COVID? Well, Petrino has also been working for years now to figure that out. In fact, his group at Mount Sinai recently teamed up again with Yale immuno biologist Dr. Akiko Iwasaki on a study to see if they could identify biomarkers for long COVID. And the results were recently published in the journal Nature. What they did was they compared the blood samples from nearly 300 people, some who met the diagnosis criteria for long COVID second, those who had COVID but who had fully recovered. And third, people with no evidence of infection. What they found is that the groups differed in one notable way the amount of the hormone cortisol, the long COVID patients had lower levels of cortisol in the morning compared to the people who didn't have long COVID. Now, normally cortisol levels are highest in the morning to help wake the body up and they are lowest at night. So the question was, is cortisol the key to knowing if you have long COVID? Is it the. Biomarker. I'll tell you that Petrino, who coauthored the study, doesn't actually think that's the case, but he does say it's a good start.

'You know, Akiko and I are still analyzing that data set, and we have a lot more papers coming with a lot more interesting findings around things that are different in the long covered population versus the healthy control population. So we need more of this work to be done. But the second thing is, you know, I think that there is an interesting utility for diagnostic tools like machine learning to identify cases of complex chronic illness. So there are lots of conditions out there. You know, hypertension is pretty black and white. You take your blood pressure. If it's over a certain level, you get diagnosed with the hypertension, you know, hyperlipidemia. Same thing. We look at your cholesterol levels and we make a decision over whether or not you you make criteria for hyperlipidemia for long COVID. Long COVID is an infection associated complex, chronic illness. That means that depending on your genetic history, depending on your infection history, depending on your past medical history, you will present completely different from the last person with long-covid. And some things will be elevated, some things will be diminished. And there's never going to be this one unifying. You definitely have long COVID biomarker. And so I think it's never as simple as just the one thing and the press, you know, read through the article and they said low cortisol, That's it. That's the biomarker. I'm like, please don't say that. That's that's true. You know, like that is not the biomarker. And there are going to be tons of people with Long-covid who do not have low morning cortisol and we don't want to have them get edged out of a diagnosis of long-covid, which is why we need, you know, to keep doing the research that we're doing and keep pushing forward.

Yet another study published just last month found that long COVID was actually associated with low levels of the neurotransmitter serotonin. That was yet another lead for researchers to try and chase down. But as Dr. Petrino and others continue their research, I guess the question is this How do you move forward when the world seems to have moved on from some of these COVID concerns?

Frankly, it hasn't been worked into the risk equation for most people. Most people are thinking how to avoid to keep COVID. And if you get acute COVID. You know, it's very binary. Did I die? No. Okay. Well, then I got through COVID unscathed.

We'll be right back.

'And now back to Chasing Life and my conversation with neuroscientist and long-covid researcher David Putrino.

'Does it surprise you that people are not more concerned about Long-covid?

'You know, I think it doesn't surprise me because the messaging around long COVID has been not very unified. You know, it's kind of presented as there is this group of people who aren't really recovering from COVID, but it probably won't be. And so I think, you know, one of the things that we always try to message on is, is the idea that we have no idea who is going to go on and get long-covid. And and now in 2023, our long COVID clinic is getting swamped with people on their third or fourth infection, and they got through their first few infections just fine. No worries. And this is the one that that got them and they can't seem to recover. So we advise caution. We advise infection prevention using all the tools in the tool belt. And I think that's the best advice we can give.

You know, part of the reason I really wanted to do this podcast was exactly what you said, the unified message. And I you know, a lot of times for me, I sort of liken it to I'm at a neighborhood barbecue, call it, and, you know, I'm talking to my neighbors and my friends and, you know, and they may be asking sort of sort of what is what is your level of concern, for example, regarding COVID and specifically long COVID? If you got asked that question, you wanted to give a unified message. And again, these are your friends and your neighbors. This isn't necessarily a your scientific audience or whoever. What would you say?

'You know, I tell people that I wish that Long-covid was being worked into the risk equation that people were were making because it frankly, it hasn't been worked into the risk equation for most people. Most people are thinking how to avoid to keep COVID. And if you get acute COVID. You know, it's very binary. Did I die? No. Okay. Well, then I got through COVID unscathed. So, you know, I understand that lots of people have really complicated situations. Kids are going to school, kids want to socialize. Then you need to socialize with the parents of the kids who want to socialize. And all of us are social creatures and we want we want to socialize as well. So typically, my my answer really lands on I will feel as though we're safe when we've made meaningful progress on treating long COVID. And if we all got together and focused on that the same way we focused on rolling out vaccines as quickly as humanly possible, we could really make some progress in the next few years. There are there are tons of drugs that we could be trialing that we're not trialing due to lack of funds and lack of interest. So, you know, my my message is always factor a long COVID in into your risk profile. And if you can do something outdoors, do it outdoors. If you can do something and wear a mask, it's not that disruptive to wear a mask for most people. And also just remembering that there are folks with disabilities, there are folks who are already vulnerable, who don't have that luxury of, well, if I get COVID, it's not such a big deal. So we need to protect those folks while we're still foundering on not having actionable treatments.

To be clear, treatments for COVID in general have come a long way since the earliest days of the pandemic. There's a lot we can do to make sure people don't necessarily have bad outcomes. It's especially true when it comes to things like vaccines. Just recently, the CDC and the FDA cleared the way for updated vaccines that are designed to combat variants that are currently circulating. Now, you might commonly hear them referred to as boosters, but you can also think of these more like the annual flu shot. There's likely going to be a new recipe, so to speak, every year. And the data is pretty clear. The vaccines go a long way in reducing the risk of severe disease. But what about long COVID? Petrino says for long COVID patients, the calculus around getting the updated vaccines that's a little bit more complicated.

'We still recommend people get vaccinated because it still demonstrably decreases. Your risk of getting infected. And getting infected is much more dangerous and much more of a risk factor for long COVID. But we are starting to become cautious around folks with long COVID taking RNA vaccines because many folks with long COVID show very clear signs of viral persistence, meaning that their body is unable to clear the SARS-CoV-2 virus after an infection. So the idea of further injecting your body with m RNA spike proteins we. You need to have a rational conversation around the fact that. This may not be good for people who already have circulating spike proteins causing damage. That doesn't mean that we're anti-vaccine. We're very pro-vaccine. We acknowledge vaccines are incredible tools for infection prevention. But we also have to acknowledge that there is a whole body of science emerging surrounding these folks who have not been able to clear the SARS-CoV-2 virus and who very observable get worse when they try and take a booster. And so, absolutely, we should be understanding the effect that many vaccines can have and trying to mitigate some of that harm.

I think that's really important message. I mean, I think what people hear from the CDC and I guess this goes to your unified message point, is that people should still get the boosters because it could decrease the the persistence of their long COVID symptoms. That that was one of their advisories, I guess, several months ago. You know, I think for a lot of people listening who say, look, I may have mild not dramatic, but mild long COVID symptoms. Boosters coming up now because it's the fall, should I get the booster or not? And if you're at that barbecue, you know, talking to Dr. Petrino, what does Dr. Petrino say?

You're asking this is a fraught barbecue, asking me all sorts of questions.

Well, do you get you get you get I don't know if you get these questions all the time.

I do get these questions all the time. And, you know, and it's a fair question. And my position on this tends to look to history. So at this point, lots of people with long COVID have had many boosters, you know, and they know what their symptoms do when they have a booster or not. And so the first question I usually ask folks with long COVID when they're asking, should I get a booster, is have you had a booster before? And did it make your long COVID symptoms worse? And I usually get a very definite yes or no to, you know, answer to that question. And if they say yes, my my recommendation is, look. Take appropriate precautions, you know, avoid area, you know, avoid situations where you're you're at risk of infection. And I would say don't set yourself back with with a booster right now. But if they say no, then I say, well. You know, a booster might flare your symptoms, but getting COVID definitely will for your symptoms. So from my perspective, I think it's just important not to speak in absolutes because these are complex problems. They're not simple settled science. We we're learning as we go. And you can't boil down a complicated message into 10 seconds.

We're also learning about who is most at risk for long COVID. For example, studies have shown that women have a higher risk of developing long COVID than men, which Petrino says is probably due to hormonal cycling that women experience. He also says there is a big concern when it comes to children.

We have never really seen that kids are immune from long COVID ever. You know, we were always noting in the epidemiological studies that kids were seemingly less likely to go on to develop long COVID. But one of the things that I'd say, you know, having run the clinic for so long now is that I would even question that because many of the symptoms of long COVID are just hard to verbalize or vocalize for a child. So what's interesting is across the board, the the most common symptom that parents come to our clinic with when when suspecting long COVID in their kids is a tummy ache, persistent tummy ache. That seems to be, you know, because we see a lot of GI issues and long COVID. And that seems to be the thing that, you know, parents notice that. You know, and then when you start asking the parent, well, have you noticed changes in energy? Do they seem to be sleeping more? Are they a bit more fatigued or are they a bit more emotionally labeled because they you know, because they're so tired all the time? Do they sort of run around and then crash? You know, then you start going down the list and the parents like, yep, yep, yep, that that's all happening. And so I definitely think we it's been a minimized area because we've wanted, you know, everyone needs to go back to school, go back to life. Don't worry, kids don't get affected. I don't think that that's accurate.

What do you tell people who are listening to this and say, look, I, I think that maybe I have long COVID. I, I have not been the same since my infection. I'm, you know, have some of the symptoms that Dr. Putrino's describing. What should they do?

'The ideal thing to be able to do and I'm going to start with the ideal and then we'll move down. But you know, the ideal thing is to try to get yourself to a long COVID center with clinicians that have experience treating long COVID. Unfortunately, some of them are shutting down, but there are still quite a few long-covid centers that are open. If that is not a possibility, then you know, the next thing that I recommend is to reach out to a physician and show up with some sort of written documentation of this is what Long-covid is. And so therefore, these are the things that I want tested, you know, and I would say I want a full immune panel. I want a full hormone panel. I want to be tested for evidence of co-infection, you know, reactivation of Epstein-Barr virus, herpes virus, etc.. I want to be tested for parts and disorder number because then at least providing these cues to to a physician that may not have experience with long COVID, so long as they're a trusted physician who in good faith will run all the testing, Then as the abnormalities start to emerge, we can treat those one at a time. So, you know, at this stage, my best advice is don't ignore it. I would also say reach out to communities. You know, the patient led research collaborative is is phenomenal in pulling together lots of patient voices. We've recently been working with a wonderful app called Visible Health. They have thousands of people with long COVID myalgic encephalomyelitis in their community doing daily monitoring of symptoms and providing insights on, Hey, when my heart rate variability drops, my fatigue is worse. Or, you know, when this happens, I'm going to have abdominal pain. And, you know, this is really truly a, you know, a community of folks with complex chronic illness. So to the extent that you can't gather expertise from from clinical care in your area, the next best thing or maybe even a better thing is to reach out to the community and groups like Visible that that can provide you with community derived wisdom.

We're always trying to balance hope and and honesty. Honesty should lead the way. But it doesn't mean that there there can't be hope. And hope, I think in and of itself has intrinsic value. What would you tell somebody? I mean, should they be optimistic? You know, that they're not going to deal with this their entire lives. Well, what would you tell somebody?

What I tell my long COVID patients is, is the same as I tell my folks with spinal cord injury and stroke, which is we're with you. We're going to keep searching for four new interventions. And in the meantime, I promise you that some of the interventions that we already have to offer will at least make you feel a little better. So we're going to start there, small progress and we're going to shoot for big progress. And I'm not going to give up. My team's not going to give up. You know, my goal is always to have one more thing that someone can try that they haven't tried before. Through that process, we haven't run out of ideas yet. We've got more ideas than we've got time or bandwidth to trial. And so I think that the future is hopeful.

Next time on Chasing Life.

I actually think depression evolved as a way of helping us cope with adversity, even though it's very painful. I don't endorse depression as a good thing, but I actually think that it is part of our deepest human inheritance is this capacity to get depressed.

That's next time. Thanks for listening. Chasing Life is a production of CNN Audio. Our podcast is produced by Eryn Mathewson, Madeleine Thompson, David Rind and Grace Walker. Our senior producer and showrunner is Felicia Patinkin. Andrea Kane is our medical writer and Tommy Bazarian is our engineer. Dan Dzula is our technical director and the executive producer of CNN Audio is Steve Lickteig. Special thanks to Ben Tinker, Amanda Sealy and Nadia Kounang of CNN Health.