Podcast: Brain-related issues can linger after patients recover from COVID-19

Jim Dryden (host): Hello, and welcome to “Show Me the Science,” conversations about science and health with the people of Washington University School of Medicine in St. Louis, Missouri … the Show-Me state. During the first two years that we produced this podcast, we focused entirely on how School of Medicine doctors, researchers and trainees responded to the COVID-19 pandemic. But more recently, we’ve also started reporting on some of the other research, lifesaving, and just plain cool work being done at the School of Medicine. But even as we hope to put COVID in the rearview mirror, thousands of people who were infected previously are continuing to suffer from problems related to long COVID. A common issue for those patients involves neurological symptoms, particularly brain fog, which is both common and troubling. Think about those days at work when you forgot where in the garage you parked your car. Now, think about living every day like that. Washington University infectious diseases doctor Robyn Klein directs Washington University’s Center for Neuroimmunology and Neuro-Infectious Diseases, and she’s been studying how this respiratory virus is having such a big impact on people’s brains.

Robyn Klein, MD, PhD: We did not find any evidence that this virus enters and replicates within neural tissue in the central nervous system. The other things we found were there were specific and brain-specific areas where there was disruption in something called the blood-brain barrier.

Dryden: So, although the virus doesn’t seem to affect neurons, it may affect the brain by disrupting the blood-brain barrier and allowing immune cells and other molecules in, and when that happens, it can cause debilitating problems. Dr. Ziyad Al-Aly, a clinical epidemiologist at Washington University School of Medicine in St. Louis and the Veterans Affairs St. Louis Health Care system, found that in the first year after an infection, patients are at increased risk for strokes, memory problems, depression, anxiety, migraine headaches and other neurological issues. So, he says, when someone shows up at the clinic reporting problems weeks or months after an infection, it’s important that health professionals listen.

Ziyad Al-Aly, MD: The first thing is really acknowledging it. And I think this is really very, very, very, very important because a lot of people, a lot of patients, are going around and seeing a lot of doctors, and they’re not really getting their doctors to really recognize it. The first thing is really to acknowledge, look them in the eye and really acknowledge like, “I hear you, I understand you. You are not alone. This is a real thing. You’re feeling it. You’re feeling this fatigue. You’re feeling this brain fog. It’s real.”

Dryden: Al-Aly analyzed the risk of 44 different brain disorders in more than 14 million de-identified medical records from a database maintained by the U.S. Department of Veterans Affairs. Patients in the database included all ages, races and sexes. Al-Aly’s team found that the virus isn’t always as benign as some people may think. And he says risks get even higher in those people who’ve had COVID-19 more than once.

Al-Aly: We’ve actually also done research on this, and it’s very, very clear that the people who do get multiple infections, more than one infection, are at an increased risk of developing problems, both in the acute phase, in the first 30 days of having the infection, meaning that cough and fever and all of that, that they’re certainly at risk of these manifestations in the acute phase, but also in the long-term phase. Now, we know for certain that reinfection is happening, and it’s happening at scale. This is not a rare event. If you had asked me about reinfection a year or a year and a half ago, I would have told you like, “Yeah. It exists, but it’s quite rare,” a year and a half ago or a year ago. But it’s no longer the case. The reinfection is happening, and it’s happening at scale in the U.S., in Europe, and Australia and elsewhere. And we now know also that reinfection is not benign. It’s absolutely not benign, in the sense that getting reinfected again puts you again at risk of problems in both the acute phase, the first 30 days, and also in the post-acute phase and the long-term phase.

Dryden: And one of the things about these most recent findings was that although there was some protection from vaccination, it was not like if you’re vaccinated, you won’t have these problems.

Al-Aly: Vaccines do a very, very, very good job reducing the risk of hospitalization and death in the acute phase, and they were designed for that. They were designed to really run this 100 yards, and they do a very, very, very good job at it. What the vaccines are not very good at is really reducing the risk of long-term sequelae very well. They do reduce, they do work somewhat, but minimally reduce and do not fully abrogate or do not fully eliminate the risk of long-term problems. What I tell people, “You have to think about it almost as an athlete who trained all his or her life to really run 100 yards. They probably can do very well there and maybe win a gold medal at the Olympics. But that same athlete is not necessarily going to be able to win also a marathon, right, because it’s a different game altogether.” So we’ve designed the vaccine in an era that preceded our, even, realization that long COVID existed. When we designed the vaccine more than 2½ years ago, we did not even know long COVID existed. So, now that we know that this virus produces long-term manifestations, I think we have to up our vaccine game and design vaccines that reduce both the risk of acute disease and also mitigate or reduce the risk of long-term disease.

Dryden: Now, in addition to doing these very large studies of many, many, many people, you also see patients in the clinic. And if you see a patient in the clinic who’s having some of these manifestations of long COVID, what can you tell them?

Al-Aly: The first thing is really acknowledging it. And I think this is really very, very, very, very important because a lot of people, a lot of patients, are going around and seeing a lot of doctors, and they’re not really getting their doctors to really recognize it. The first thing is really to acknowledge, look them in the eye and really acknowledge like, “I hear you, I understand you. You are not alone. This is a real thing. You’re feeling it. You’re feeling this fatigue. You’re feeling this brain fog. It’s real. It’s not imagined.” Because unfortunately, by some physicians — not here in our system but in other systems — they’re being told, “It’s all in your head, and it’s not real.” So the first thing is really acknowledging it is real and also assuring them that this is happening and happening at scale, “You’re not alone,” and then subsequently figuring out exactly what the problem they’re presenting with and how can we best address it clinically to help them sort of regain as much function as possible and get better?

Dryden: Late last summer, Robyn Klein published a paper in the journal Brain investigating the causes of brain problems after COVID-19 infection. Her team studied the brains of hamsters and of people who died from COVID-19.

Klein: The most important thing I think we determined, which has also been found by others, is that we did not find any evidence that this virus enters and replicates within neural tissue in the central nervous system. The other things we found were there were specific and brain-specific areas where there was disruption in something called the blood-brain barrier. So the blood-brain barrier occurs at the level of the capillaries, and it’s really a series of specializations of the cells that really limit entry of cells and molecules into the brain, and it’s a protective mechanism. And in certain brain areas that are associated with memory, such as the hippocampus, and areas associated with movements, such as areas within the brain stem, there was blood-brain barrier disruption. Most importantly, what we found, which had not been found before, was that — it has been known, and it’s somewhat controversial, but I think people are now accepting — that new neurons are generated throughout life. And in the hippocampus of hamsters that had been infected with SARS-CoV-2 and in patients that succumbed to the virus, there were no new neurons being made.

Dryden: And the lack of those new neurons would do what?

Klein: So neurogenesis has been linked, especially, to different types of learning and memory, and it’s long been shown that the generation of new neurons is very important for learning and memory. And so, if you’re no longer generating new neurons, although it’s unclear exactly how that contributes to the laying down of memories, it’s known that it’s important, and that in animals that have been engineered so they don’t generate new neurons, they have very difficult issues on memory tasks. They can’t perform them well.

Dryden: So the virus isn’t getting into the brain itself, but there is some evidence that it’s causing some damage. But then what’s happening in the brain after that?

Klein: So one of the other things that I didn’t mention was that we saw — in these brain regions — we saw activation of brain immune cells called microglia. There was evidence that there was not only activation of the microglia but expression of cytokines that are not normally expressed in the brain. And also, we found that neurons in the hippocampus were expressing cytokines as well. And the two different cytokines that we detected are both cytokines that are known to limit neurogenesis.

Dryden: And when you say cytokine, you mean a molecule that immune cells use to kill things.

Klein: Can be. And in fact, most cytokines have been discovered in peripheral immune cells. But as it turns out, cytokines are really important in the brain. And in fact, many cytokines maintain brain function in homeostasis. So they’re not only for the immune cells; they’re also for the brain. But the levels of cytokines that we saw were pathologic. So these were higher levels that you don’t normally see in the brain and are associated with changes in brain function.

Dryden: Way back in March and April of 2020, when people were showing up in emergency rooms and going on ventilators and getting very, very sick from this virus, we heard about cytokine storms, that what was happening to many of these folks was that they were being infected with the virus, their immune system was becoming activated, and it was killing them, essentially. Is what you’re saying that something similar is going on in the brains of people and hamsters with COVID-19?

Klein: That could be very well true. And in fact, we called them microglia because of the way they looked, but it’s also possible that there are cells that are coming from the periphery into the brain, and that these cytokine storms that you’re speaking of have to do with an overexuberant immune response. So we’re working on that now and looking at whether or not it’s possible that there’s peripheral immune cells coming into the brain as well as activation of resident immune cells in the brain.

Dryden: Now, I guess there might be some good news associated with this finding in that there are agents that can prevent some of this cytokine business.

Klein: Yeah. In fact, one of the cytokines that we detected in microglia is a cytokine called interleukin 1 beta. And we had previously shown that in a model of post-West Nile virus infection where animals also developed learning defects, we could treat the animals with an FDA-approved drug, an antagonist of the IL-1 receptor. So it’s very possible that anti-cytokine medications could be very helpful.

Dryden: Because this is a long-term effect. I mean, a fairly large percentage of people develop brain fog during the acute phase of this illness, but then a number continue for weeks and months afterwards.

Klein: Yes. And in fact, there’s been some studies published recently that have looked out 18 months after infection and have observed that people are still having memory impairments and difficulty with memory tests on examination. So this is a big problem. And even though it’s possible that there are many viruses that may contribute to this kind of brain fog, memory disturbance, whatever you want to call it, the sheer numbers of people that are infected and continue to be infected with this virus, I think really makes this a public health emergency in the sense of, ‘What’s going to happen to folks who don’t regain their memory function or actually continue to worsen?’ And there’s a question of whether or not viruses can be a contributor to dementing illnesses and diseases of pathologic forgetting.

Dryden: Those include diseases such as Alzheimer’s disease. And interestingly, Al-Aly’s work showed that compared to people who didn’t get COVID-19, about two more people per 1,000 who did become infected with the virus went on to develop Alzheimer’s disease. He says it’s unlikely the virus caused Alzheimer’s because Alzheimer’s is a disease that normally develops over the course of decades, but he suspects that perhaps in some people who were at very high risk, the virus may have pushed them over the edge. In general, he says, long-term neurological issues remain a major risk of COVID-19 infection.

Al-Aly: And what we’ve seen is that people with COVID-19 go on to develop a variety of neurologic disorders, not only brain fog. So we came into this thinking that we’re going to find brain fog, and we, of course, did find brain fog, but it was really much, much more than that. People were having strokes. People were having seizure disorders, headache and a variety of other neurologic disorders.

Dryden: You mentioned brain fog. We often hear about that as being a symptom of COVID-19. But as you said, there were a lot of problems that people developed that were far more extreme than that. Are you certain that they were linked to COVID?

Al-Aly: We think our experiments are very detailed and rigorous and do establish that, indeed, COVID-19 is a risk factor for developing these neurologic disorders. And it really spans the gamut, again, not only brain fog or cognitive changes or cognitive impairment, but also inflammation of the brain, strokes, headaches, seizures and multiple other disorders, including also peripheral nervous system disorders. So we definitely think that COVID-19, in a way, is sort of affecting the nervous system in people in the post-acute phase.

Dryden: The number that sort of blew my mind was the idea that the virus may have contributed to about 40 million new cases of neurologic disorders around the world. Now, do you expect some of those problems to go away? Could they resolve? I mean, there are people who’ve had other long COVID symptoms who eventually get better. What about these neurologic symptoms?

Al-Aly: That’s really the ray of hope here, that some of the manifestations that we’ve seen, for example, headaches or maybe brain fog, actually, some of this may actually improve with time. Those are potentially reversible conditions. But at the same time, we’ve seen conditions like strokes and other disorders that could — in some people, not everyone, but in some people — leave them with permanent damage. Those are lifelong consequences. So it’s really a big basket of things. Some conditions could potentially improve with time, and that’s really where we sort of say, there is a ray of hope here, that not all these conditions are going to be permanent lifelong conditions. But also, we have to pepper that with the reality that it is very, very clear that some of these conditions will leave some people with lifelong disease and disability.

Dryden: Is the hypothesis that the virus is somehow affecting nerve cells or that it’s the immune system’s reaction, or have you gotten into that sort of look as to why?

Al-Aly: This is a very, very important question. So a lot of intense research now is being done to try to understand why some people — that’s not everybody, but some people — sort of end up having these long-term consequences. And there are several hypotheses. One of them is really the idea that in some people, they don’t fully clear the virus. And some of the virus or even fragments of it may remain or persist in some people for a length of time, provoking inflammation and subsequent disease. The other idea is that the intensity of the immune response reaction during the acute phase might also provoke what we call autoimmunity, meaning that the body starts attacking itself. And that could explain some of the manifestations. It does not explain everything. It does not explain sort of the full range of long COVID or the full range of the neurologic manifestations that we described, but it’s certainly a viable hypothesis for a small percentage of people. And a third hypothesis also sort of suggests the idea of a microbiome dysbiosis, meaning that within us, there are actually more bacteria than human cells. Believe it. We call ourselves humans, and we walk around as humans, but within us, there are actually more bacteria than our human cells. And that microbiome in some people get substantially dysregulated or substantially changed after a SARS-CoV-2 infection, leading potentially to disruption of health and inducing a disease state. So there’s a lot of hypotheses that are being worked on to try to help us understand why this virus now, SARS-CoV-2, infected at scale, literally, a lot of people in the U.S. and around the world, is leading in some cases to long-term manifestations that we now collectively call long COVID.

Dryden: Al-Aly found that in that first year after an infection, people do have a risk for brain problems. And that’s not even to mention the non-neurologic issues associated with long COVID. But the good news may be that perhaps one of those FDA-approved agents studied in Dr. Robyn Klein’s laboratory that helped reverse cognitive problems in animals infected with West Nile virus, one day soon may be shown to help people who have similar problems caused by the SARS-CoV-2 virus.

“Show Me the Science” is a production of WashU Medicine Marketing and Communications. The goal of this project is to introduce you to the groundbreaking research, lifesaving, and just plain cool work being done by faculty, staff, and students at the School of Medicine. If you’ve enjoyed what you’ve heard, please remember to subscribe and tell your friends. Thanks for tuning in. I’m Jim Dryden. Stay safe.