New Research on Long COVID

Brian Lehrer: It's The Brian Lehrer Show on WNYC. Good morning again, everyone. Some new research sheds light on distinct biological changes in the bodies of people with Long COVID and maybe offer some hope for folks who suffered with debilitating cognitive symptoms weeks, months, even years after coming down with COVID.

In a study published in the journal, Cell, a team of researchers at the University of Pennsylvania proposed a link between diminished levels of serotonin in the body and some cognitive and neurological Long COVID symptoms. Even after acute COVID symptoms peter out, these researchers say, remnants of the virus linger in the gut and trigger a reduction in serotonin. We'll spend a few minutes now delving into the research and discussing how it could help clinicians diagnose patients and develop effective treatments for Long COVID.

Joining me now, Dr. Daniel Griffin, MD, Ph.D. infectious disease physician with a Ph.D. also in molecular medicine, researcher at Columbia, chief of the division of Infectious Disease at Optum, president of the group Parasites Without Borders, and co-host of the podcast This Week in Virology. Dr. Griffin, always good of you to give us your time and expertise. Welcome back to WNYC.

Dr. Daniel Griffin: Oh, thank you, Brian. Always nice to be back.

Brian Lehrer: By way of background to start, what role does serotonin play in the body, and how might depleted serotonin contribute to Long COVID symptoms as outlined in this new study?

Dr. Daniel Griffin: Serotonin, it's involved in a lot of things, but I would say our listeners are probably most familiar with serotonin's role in mental health in, really, the revolution that the serotonin-targeting SSRI medicines, really brought us with regard treatment of depression. Serotonin's involved in the brain. it's involved in mood. It's also involved in digestion. It really has a lot of roles.

Brian Lehrer: What are some of the specific neurological and cognitive symptoms of Long COVID that depleted serotonin could explain?

Dr. Daniel Griffin: I have to say, this is great that we're talking about this and this article has gotten a lot of people excited because we had that recent article where there was a potentially connection with cortisol being low and the low energy. Serotonin really makes sense when you start talking about the neurological manifestations of Long COVID.

Not only is there what people refer to as brain fog, which is that cognitive debility that comes with Long COVID. There's a whole mood aspect to Long COVID that we've been trying to sort out. Are people feeling so incredibly devastated because they're aware of what they're going through and how much they've lost? Or is there an actual part of Long COVID of the mechanism of Long COVID, maybe here with low serotonin levels that's actually making them feel so despondent?

Brian Lehrer: The authors of the study say this research could connect a number of different hypotheses about the causes of Long COVID. What are some of those theories about how and why Long COVID symptoms develop in the first place, and how does this new study try to tie them together?

Dr. Daniel Griffin: I think it's great to always ask what is going on with Long COVID because we're always trying to sort this out. One of the clear things with Long COVID is there is ongoing activation of the immune system. The big question has been why. Is there some remnant of the virus that is provoking this ongoing inflammation? Is it viral replication, active virus still replicating, or is it just bits of the virus, RNA protein that is triggering this?

Their investigation tries to pull this all together with the ideas there may be remnant viral RNA and that remnant viral RNA-- We don't know whether or not the virus is replicating, but still some of that SARS-CoV-2 RNA in the gut, which as we like to point out in [unintelligible 00:04:19], SARS-CoV-2 is a GI, it's a diarrheal illness. The idea that this viral RNA is in the gut, it's turning on our interferon, our antiviral system, which is then leading to a drop in platelets, hypercoagulability, and a reduction in serotonin.

Brian Lehrer: Explain the gut connection here. The researchers do propose, you were just referring to this, that remnants of the virus in the gut in particular trigger the reduction of serotonin levels in the body. How do they think that happens?

Dr. Daniel Griffin: I'd say, they have a great graphical abstract. It's really nice to walk people through. You can look at this, it's open access, at least the graphical abstract is. What they really have is this connection where you have the activated cells that are recognizing the viral RNA. The interferon is actually directly interacting with enterocytes. Those are really just cells in the gut, as well as these Enterochromaffin cells. Don't worry, you don't have to worry about those.

Really, this connection where we're making serotonin from tryptophan and the interferon is interrupting that. The serotonin levels are dropping. The serotonin is not helping with that nice vagal calming tone, leading to these neurocognitive effects leading to that rapid heart rate, that feeling of anxiousness and unease. Then also directly, the serotonin probably interacting with how we feel, the mood, and just the view, the outlook, the ability to be motivated.

Brian Lehrer: Now listeners, we can take some phone calls on the links between serotonin and some Long COVID symptoms as outlined in this new study by researchers from the University of Pennsylvania that our guest, Dr. Daniel Griffin, is discussing. Long COVID sufferers, you get first priority on the phones for the next few minutes.

212-433-WNYC, 212-433-9692 with your stories and questions. 212-433-WNYC. Call, or text, or tweet @BrianLehrer for Dr. Griffin.

Here's a text that's already come in. A listener asks, "Please, ask about the use of serotonin-stimulating supplements like 5-HTP as a possible treatment."

Dr. Daniel Griffin: That's great. I think that that is the hope with this publication is that it's going to actually provide some ideas for things to try. One of the first things people would say is, "Oh my gosh, we should be putting people on things that are going to raise that serotonin level." I think it's important to put this in context. In this cohort, this group of folks, they found that low serotonin. They also found it in a group in Cork, Ireland.

Another group, they didn't find it. It makes sense to start thinking about identifying individuals that may have this as part of what's driving it, and looking at ways of targeting the serotonin and seeing if we can't make a difference. Maybe this isn't the right treatment for everybody, but for certain people targeting serotonin may be the right thing to be trying.

Brian Lehrer: Another listener texts, "What might be the correlation between gut health and Long COVID's unremitting brutal and constant headaches, not brain fog?"

Dr. Daniel Griffin: I think that this is great because we always think of our systems separate, but we really should. It was a study a few months back that really caught my eye where some gastrointestinal researchers were looking at trying different probiotics, really targeting people with this just ongoing gut issues with Long COVID.

The interesting thing when they did these Bifidobacterium probiotics is they had a really significant impact on cognitive function. Something like 30% of the individuals were actually reporting what benefit were they getting. They were getting benefit in being able to think more clearly. There seems to be a growing amount of evidence that there's really a connection with gut health and our cognitive functioning.

Brian Lehrer: A couple of listeners now are texting if SSRIs, those antidepressants that are used to help people with serotonin issues that cause depression, if SSRIs can be used for this.

Dr. Daniel Griffin: They do help some people. They haven't been the game changer. They haven't been the fix-all for everybody. A lot of medications that target the SSRIs can be helpful in certain subsets. Some individuals will actually use the more stimulating, so things like Wellbutrin and Cymbalta. Definitely targeting this system, looking at interactions with serotonin, norepinephrine, dopamine, definitely in the list of things that we're trying, and with some success in some patients.

Brian Lehrer: Here is Sue in Long Beach calling on behalf of a family member who she thinks might have a Long COVID side effect. Sue, you're on WNYC with Dr. Griffin. Hello?

Sue: Thank you, Dr. Griffin, and thank you, Brian. I read the article in The New York Times, and this is so fascinating. Wanting to know if you think there's any correlation also with a COVID-onset dementia and dementia-type symptoms. Someone, it doesn't run in the family, ran every test, doesn't technically have dementia, but now has memory loss issues right after having COVID and since. Want to know what you think?

Dr. Daniel Griffin: I actually think that you're right on target with this. Unfortunately, we have seen a lot of individuals there. There's an acute delirium with COVID. We do know that there's acute changes in the gut microbiome when you get COVID. We're trying to piece all this together. We certainly see confusion that develops after acute COVID, confusion that continues and it is challenging because they don't necessarily fit into one of our classic boxes. The onset is, as I think you're describing here, as we see quite often, quite dramatic, quite acute. It's not that subtle, Dad is starting to forget a few things here and there, starting to get confused. It often is a rather dramatic change over a matter of days, weeks.

Brian Lehrer: I hope that's a helpful answer, Sue. On the possible use of antidepressants as a treatment for Long COVID, if it really is from a connection from the gut depressing serotonin levels, I understand there's a clinical trial for Prozac as a Long COVID therapy that's underway, and maybe Tryptophan 2. If people want to sign up for those, is that ongoing in our area or do you want to say anything about those particular studies and the questions that they're asking?

Dr. Daniel Griffin: Sure, sure. The first, I guess I'll try to put this in context, this is more evidence. We're learning more about Long COVID. It is great in certain individuals that we actually have something objective that we can measure, and there are ongoing trials. The huge initiative, the RECOVER cohorts. It's being run and financed out of the NIH. A lot of the management and coordination is occurring here locally through NYU but you can actually go to the RECOVER website. You can sign up, you can find out about these trials. That's how we learn a lot.

The scientists have their names up there at the front of the study, but all the individuals, the 58 Long COVID patients, the 60 individuals with acute COVID, the 30 individuals who were symptom-free when they got better, these are all the individuals that are actually heroes as well. They're stepping up. They're participating in this trial. That's how we're moving forward.

Brian Lehrer: Mark in Jersey City has some anecdotal evidence. Mark, you're on WNYC. Hello.

Mark: Hi. Yes, I had COVID back, I had the original gangster version of it in March of '20 and pretty stout case of Long COVID. One of the main things that I noticed, that popped up for me in the article in the Times, was the effect of COVID on the gut. Anecdotally, I have celiac, so I know what having a gut disruption is like.

Through that whole course of Long COVID, I felt like I was back on a wheat diet, like there was something wrong with my gut for months. It wasn't until that actually cleared up that I actually started to really recover. I had brain fog. I couldn't read a paragraph of anything. I couldn't pay attention to anything. Once my gut cleared up, all of a sudden, I started getting better.

Brian Lehrer: What does that story tell you, Dr. Griffin?

Dr. Daniel Griffin: Mark, thanks. I think it's great that we shine a light on this because there's been such a focus on COVID as being a lung disease, COVID pneumonia. A lot of people, the illness acutely and the illness long-term is actually gut-focused, and not just gut-focused. All these different studies talk about subtypes of Long COVID, but it's always subtypes that are gut predominant, neurocognitive predominant. A lot of times, we see this. We see people with ongoing gut disturbances. As those get better, we see neurocognitive, we see other things getting better. Yes, there definitely is plural of anecdote is not data, but you get enough anecdotes and okay, you start moving towards data.

Brian Lehrer: Thank you for your call, Mark. We've been talking so far about the study indicating a possible connection between Long COVID and the gut and serotonin levels. Another recent study, this one from researchers at Yale and Mount Sinai here in New York, found that people who have experienced symptoms for months or longer show different immune and hormonal responses to the virus than people not diagnosed with Long COVID. This study, as I'm looking at a description of it, partially zooms into the hormone, cortisol. You're familiar with this, right?

Dr. Daniel Griffin: Yes. This was a study that a friend of mine, Akiko, up at Yale, and actually David Petrino at Mount Sinai published. Well, they were the last authors or lots of authors, a tremendous study actually worth reading as well. What got Akiko the most excited about this was that they found the strongest predictor for defining folks with Long COVID were these low cortisol levels. Now, that's not going to necessarily be for every group, every cohort. People are worried that, oh, if they measure my cortisol and it's not low, well, I'd be told I don't have Long COVID.

These are really the patients that have the worst cases of Long COVID. These are patients who are sick for over a year. To just connections or does this validate what we're seeing in this study, they were seeing ongoing immune dysfunction. They're seeing exhausted T-cells, changes in the B-cells, the non-classical monocytes.

Yes, I think that the great thing we're starting to see here is we're learning more. Even in this study out of Yale and Mount Sinai, were the fact that it looks like some of those dormant viruses that EBV and CMV may actually be reactivating, and that reactivation may also be involved in this ongoing immune dysfunction that these people are suffering from.

Brian Lehrer: Another listener writes a text message question about if we're talking about a gut relationship to Long COVID. Listener asks, are there diet recommendations to address the gut biome problem? Probiotics, probiotic-rich foods?" they ask, Anything else?

Dr. Daniel Griffin: Yes, there are, actually. I think maybe that's good for us to point out, is having Long COVID-- if your doctor throws up their hands and says, "We don't know what to do," that's not actually true. We are starting to learn. We're starting to have therapies that patients are benefiting from. I mentioned that if you are looking at probiotics, there is that evidence that maybe a bifido bacterium probiotic is appropriate.

A lot of patients with Long COVID find that the processed food, the simple sugars, really are making things worse. The dietary changes can make a big difference. Yes, we are starting to learn from these studies. We're starting to come up with things that are helping our patients.

Brian Lehrer: Sandra in Atlanta, you're on WNYC with Dr. Daniel Griffin, as we talk about studies, trying to find the causes of Long COVID and therefore treatments. Hi, Sandra.

Sandra: Hi, Brian. Big fan for many decades, and Dr. Griffin, every time you speak, it's very interesting information. I'm very grateful for you taking my call. I'm calling because my son, a 33-year-old healthy young man, after taking a flight from Paris to New York, ended up in emergency with blood clots in his stomach, in his abdomen. As I understand, this is very, very rare. I wanted to know, since you're speaking about the gut and microbiome, if there's any relation or any studies that have connected this to COVID.

Dr. Daniel Griffin: Yes, thank you for calling in. That was one of the early observations. We had young individuals having clotting problems. We actually had individuals in their 30s and 40s coming into ERs in New York City with strokes. In this study, they're actually suggesting a connection here that interferon triggering this activation, this hypercoagulation, this platelet depletion. There clearly is established during acute COVID, particularly in our hospitalized patients, increased risk of clotting. There actually is a continued increased risk of clotting-related problems after COVID. Yes, so, not sure. I don't know if I got enough on this particular situation, whether it was triggered by COVID. We're certainly seeing things that we did not see before because of this hypercoagulable state induced by COVID.

Brian Lehrer: Can the insights from this study help to uncover additional targets for treatments for the different symptoms experienced by patients with Long COVID? We've been talking about the depletion of serotonin that this study is focusing on, but there are all these symptoms that don't necessarily express in the same way.

Dr. Daniel Griffin: Yes, I think that's, for me, the most exciting about this study [unintelligible 00:19:59] Patients are very excited that we now have different objective tests we can do to be able to say, "Hey, what you're saying is consistent." Now we have a profile on blood testing that's consistent. When you start looking into some of the issues here, a lot of patients have PoTS, the Postural or Static tachycardia syndrome, which we think has to do with vagus nerve, maybe some other neurological damage. We have individuals with ongoing neurocognitive deficits. If we try different interventions, and then we can show a change in serotonin correlates with benefit, we're going to finally have a biomarker to track our interventions.

In addition to what can be tough with long COVID is that there's days when you're better, days when you feel worse. It sometimes can be hard to keep track of are you making progress or not? I really am optimistic that we're moving to a time when we're going to be able to have some evidence-based, growing number of evidence-based therapies to offer.

Brian Lehrer: More anecdotal evidence. Listener writes, "I had COVID in December, and after that, my digestive system was unbalanced and it was hard to eat. I took probiotics and digestive enzymes, which helped a lot. I'm still taking them. When I stop, I don't feel well." That, again, like the caller who referenced her son's blood clot in the gut or in the abdomen after having COVID, here's a specific gut-related symptom, which was not even the point of the study, right? It was saying that effects on the gut could depress the serotonin levels, which give you various long COVID symptoms. Now we see some people are checking in with stories of gut-specific symptoms.

Dr. Daniel Griffin: Yes. I could take this beyond a collection of anecdotes that in the study from Mount Sinai and Yale, in the more recent study with serotonin, when they define these subgroups, these different types of long COVID, there is always a group that is reporting gastrointestinal issues as a main concern, as a main debilitating aspect of their long COVID. If you've had COVID and you have ongoing gut issues, these may be a form of long COVID.

Brian Lehrer: The listener asks in a text, "What are Dr. Griffin's thoughts on COVID's potential impact on other microbiomes? Vaginal, for example."

Dr. Daniel Griffin: Yes. Here, we have more information, and we're talking about the effect on the gut microbiome. Every part of our body has its own microbiome. I think it's just a matter of time before we learn more about the impacts on all these other areas. Excellent question.

Brian Lehrer: Finally, a listener asks for your comment, I'm paraphrasing here, your comment on testing positive for a long time. They don't say how long, but can you give us your best take these days on how long you have to test positive before we call it long COVID, or if a positive test after five days, or 10 days, or whatever the current guidelines are, aren't really indicative of being currently infected or currently contagious?

Dr. Daniel Griffin: Yes, so there's several things there I'll jump in on them. Just let me know if I'm running out of time, because there's a lot to unpackage there. One is that we have noted, and there are studies supporting, say the person who clears quickly and ends up with a negative test is less likely to end up with long COVID than the person who has that prolonged PCR positivity on those nasal swabs. The big question that they're looking at here is, is there some remnant of RNA or something in the gut that is driving this ongoing inflammation.

We still don't know if that's active replicating virus. There are several studies looking at prolonged courses of the antiviral, Paxlovid, to see if that has any impact, an empiric, let's treat and see if there is replicating virus and we're going to make a difference. We're not sure.

I was at a conference in Boston last week where we looked at patients that were transplanted from organs from folks that did not survive their acute COVID infection, 11,000 infections, 11,000 organs transplanted into patients that were immunosuppressed, and no replication of the virus in those recipients of the transplants, other than two folks that got lungs that were early on, actually had virus still in the lung.

We do not know if the virus is replicating, but we are seeing evidence here that there may be residual fragments of the virus that are still triggering ongoing immune dysfunction.

Brian Lehrer: I'll throw in one more here. It's really two, but I'll combine them. One text, hearing what you were just saying a minute ago asks, "Is he saying the mRNA vaccine might have contributed to what's being seen with some long COVID cases?" Then another one, and this always comes up, "Is there any indication that long COVID will be reduced with greater immunity?" Which I assume means getting your latest vaccine?

Dr. Daniel Griffin: Actually, this study and the mechanism they're putting forth would actually suggest that the mRNA vaccines do not drive this pathogenesis. That was actually the Nobel Prize for Kataleen and Drew down at UPenn, is they modified the mRNA that was used in the COVID vaccine, so it wouldn't stimulate this toll-like receptor, this interferon response. That, and I think also growing evidence that getting vaccinated before or after reduces your risk of long COVID.

It actually looks like vaccines have figured this out. They're actually protective. If anything, this would be more evidence that they don't drive where, unfortunately, an infection with SARS-CoV-2 getting that, "natural COVID-19" can give you this risk of long COVID.

Brian Lehrer: Dr. Daniel Griffin, infectious disease physician with a PhD in molecular medicine, researcher at Columbia, Chief of the Division of Infectious Disease at Optum, President of Parasites Without Borders, and co-host of the podcast This Week in Virology. Thank you so much for the long COVID information.

Dr. Daniel Griffin: No, thank you. Everyone, be safe.

 

Copyright © 2023 New York Public Radio. All rights reserved. Visit our website terms of use at www.wnyc.org for further information.

New York Public Radio transcripts are created on a rush deadline, often by contractors. This text may not be in its final form and may be updated or revised in the future. Accuracy and availability may vary. The authoritative record of New York Public Radio’s programming is the audio record.