This article is part of our February 2024 special issue. Download the full issue here.
Post-acute sequelae of Covid-19 (PASC), also called long-Covid, has been the subject of increasing research. PASC describes the ongoing, relapsing, or new symptoms or conditions present 30 or more days after infection, and it has become a major clinical and public health concern. This roundtable discussion focuses on cognitive, cardiovascular, and autoimmune effects of long-Covid. Roundtable experts include naturopathic oncologist and Editor-in-Chief of the Natural Medicine Journal, Tina Kaczor, ND, FABNO; cardiovascular expert and clinician, Daniel Chong, ND; and immunologist and professor Heather Zwickey, PhD.
Karolyn A. Gazella: Nearly 18 million people have or have had long-Covid since the pandemic began, with more than 26% of those individuals reporting a significant negative impact on quality of life. Long-Covid symptoms can last for months or even years following the infection. Dr. Kaczor, I'd like to start with you regarding brain function. What new information exists about the connection between long-Covid and brain function?
Tina Kaczor, ND, FABNO: I think the most intriguing new finding is from a paper that was published in the journal Cell in October of 2023. In this paper, the authors propose that there may be a unifying theory in at least a subset of people who present with long-Covid. The heart of this unifying theory is a low amount of circulating serotonin. This is from Penn Medicine, which is at the University of Pennsylvania. They recruited 58 patients who came to their medical center with the complaint of long-Covid and broke them out into 8 different types of long-Covid according to their records of 1,500 plus people. They recruited 58 of those 1500 original as representative of different ways of presenting with long-Covid. The second group was 30 people who had just had Covid acutely and recovered completely. A third group was 60 people with acute Covid.
The researchers looked at the blood samples of all 3 of these groups. Using metabolomics and specifically looking at amino acids between these 3 groups, they found the level of circulating serotonin dips during acute viral infection, which is normal—it happens with viral infections in general. But what was intriguing is that those with long-Covid had low circular serotonin, while those who fully recovered had serotonin levels that recovered completely.
The researchers postulate that serotonin never fully recovers in those with long-Covid. They also looked at the stool samples of their long-Covid patients and found viral particles in the stool—specifically RNA remnants of the virus that persisted long after the acute infection was over. The theory is that those viral remnants that persist in the gut long after the acute infection is over induce type I interferons, an inflammatory reaction to be produced. Type I interferons are made in the small intestinal cells. Those interferons set up something akin to a slow simmer of inflammation in the background.
Ultimately what the researchers proved is there’s a block in this pathway that stops the absorption of tryptophan in the intestines. Tryptophan is the substrate for serotonin production. So, it blocks the absorption of tryptophan from the gut into the bloodstream, reducing the storage of serotonin in the platelets and enhancing the action of enzymes that metabolize serotonin.
Those interferons basically lead to the lower serotonin and circulation by blocking absorption, lowering storage, and enhancing its breakdown. There is no lowering of serotonin within the brain; this is not a direct relation. What the study found, and this is the part I found the most intriguing, was it involves the gut-brain axis. They found that the low circulating serotonin leads to a reduced activity of the vagus nerve. The vagus nerve innervates the gut directly and goes straight to the brain. It's associated with hippocampal dysfunction, memory loss. Basically, the brain is tricked into responding as if there's an active viral infection. Ultimately, it’s due to the RNA remnants that are informing the vagus nerve and leading to less vagus nerve signaling in the brain.
That gut-brain axis is really at the heart of all of the low serotonin. This is a mind-blowing new theory to me. We all knew parts and pieces of this, but they put it all together into one singular theory. This is just one of many, and it’s not unique to post-Covid. This is postviral — any symptoms that mimic long haul Covid or long-Covid that are post viral.
Gazella: How can we use this new information to help inform treatment decisions for long-Covid patients?
Kaczor: I think we use it as one of the many theories that we have. It melds very well with some of the theories we have for chronic fatigue syndrome. Will serotonin reuptake inhibitors help? Maybe. I don't know. It doesn't seem like the serotonin is really the issue; it's the gut. So, this is good old naturopathic medicine—heal the gut. These are RNA remnants; they're not active virus. I would imagine anything we can do to heal the duodenum, in particular, would be helpful.
Heather Zwickey, PhD: I'm so excited you brought up that paper because there was a study that came out of Germany in 2022 that showed the kynurenine pathway, which is essentially what you just described, was heavily involved in post-Covid syndrome. When you don't shuttle tryptophan into the production of serotonin, instead you shuttle it into the production of kynurenine and the quinolones. What they showed was that people with long-Covid had higher levels of kynurenine and weren't making serotonin, they were making kynurenine. The researchers thought that that could be a useful marker. As of right now, the diagnosis is just symptom-based. There isn't a lab test that we can do that says this person has post-Covid syndrome. In Germany, they're planning to try kynurenine measurement to look at whether or not people are suffering from post-Covid.
That fits with exactly what you said, Dr Kaczor. I think that's super exciting. I was at Mayo this fall and talking to some of the doctors there. They have a study that shows that 80% of people who are experiencing post-Covid may not have GI symptoms but still have dysbiosis. We like to say dysbiosis is happening when people are experiencing diarrhea, constipation, gut pain, but 80% of these folks are experiencing dysbiosis in their gut with no symptoms.
There have also been 2 studies by the same group looking at luteolin, which is a component of olive oil. The suggestion is that liposomal luteolin works for brain fog associated with chemo brain, and it may work for brain fog associated with post-Covid, although it has not been tested in people with post-Covid. It makes me curious as to the mechanism: If it's reducing inflammation, is it reducing those type I interferon?
Daniel Chong, ND: I’m seeing a lot of postural orthostatic tachycardia syndrome (POTS), various arrhythmias, and different things that that you might categorize at least partially in the cardiovascular realm. I saw another study related to that, which ties into what Dr. Kaczor was saying. It looked at the vagus nerve again, but in this case, they did postmortem analysis and found SARS-CoV-2 RNA together with inflammatory cell infiltrates literally in the vagus nerves of patients who had suffered POTS-like syndrome. The essential conclusion was that SARS‑CoV‑2 virus directly induces vagus nerve inflammation. That leads to autonomic dysfunction, which could contribute to the level of critical disease status these people had, but also to the dysautonomia that's related to long-Covid.
A second study just came out in July using transcutaneous auricular vagus nerve stimulation (tVNS) for the treatment of long-Covid. It was a pilot study, with 20 patients who are all suffering from long-Covid and exhibiting dysautonomia-type symptoms, as well as many other symptoms, with fatigue being the most common one. These people did 10 daily 30-minute sessions with this little auricular or ear nerve stimulation treatment using a Parasym device. Every patient at least had some significant improvement in just 10 days. Just stimulating the vagus nerve by itself helped relieve a laundry list of long-Covid symptoms.
Gazella: While we’re in the cardiovascular realm, what do we know about long-Covid and heart disease?
Chong: Covid, whether it's acute or post-acute Covid, is not very nice to the cardiovascular system. In the acute phase, there's a wide variety of very common things that can happen. Even with mild or asymptomatic cases, there's still the potential for direct injury to the heart, cardiovascular system, the endothelium, et cetera. We're seeing a number of different related long-term issues, especially myocarditis, potentially clotting, potentially increased risk for both the genesis of plaque in the vascular system and also the instability of plaque that's already there, leading to increased risk for a heart attack or stroke. Anybody seeing long-Covid patients should be doing very thorough cardiovascular workups because the cardiovascular system doesn't always give you direct symptoms that there's a problem going on.
Another very important point to mention is exercise. Even patients with asymptomatic or very mild illness should not exercise for 10 days after the symptom onset or a positive test. People with moderate disease should not exercise for 10 days after the resolution of symptoms. And then people with anything more severe should be really sort of thoroughly evaluated before they get back to exercise. So that's an important thing to mention. I hear a lot of people say, "Oh, I felt fine, so I was still able to exercise," and that makes me a little bit nervous given the potential for serious cardiovascular issues.
Kaczor: I think it’s important to emphasize Dr. Chong’s point about taking the time to do nothing when you have Covid, and not to resume regular activity, especially if that activity is strenuous. Don't resume regular activity until your body is 110% recovered. Don't push yourself. Rest now so you don’t end up with long-Covid.
Gazella: How much do we know about what may be causing the connection between Covid and cardiovascular concerns?
Chong: You can categorize it into direct or indirect injury. During the acute phase, the virus can cause direct damage to the heart cells and endothelial cells. That can result in a wide variety of acute circumstances—arrhythmias, myocarditis, inflammation of the endothelium. There’s also indirect injury, which would be from the massive levels of inflammation created in response to the virus. That’s harmful to the vascular system because of the chemical nature of the inflammatory response.
Furthermore, the hypercoagulability or increased clotting that can happen in response to Covid is can have direct effects on the vascular system as well. And hypoxia occurs during acute Covid, that also will lead to injury in the vascular system. There are so many different angles of harm, which is why so many people exhibit cardiovascular symptoms.
Zwickey: I just add one additional mechanism by which Covid can impact the cardiovascular system, and that’s related to the gut microbiome. Metabolites like trimethylamine N-oxide (TMAO) can be detrimental to the cardiovascular system as well. So if people are experiencing gut dysbiosis, we're also adding that onto the damage when the virus binds to the angiotensin-converting enzyme (ACE) receptor on the heart muscle. Downregulation of ACE2 has all these other effects that Dr Chong so eloquently described.
Gazella: What is the research telling us about the connection between Covid and the development of autoimmune conditions?
Zwickey: There is an obvious increase in the development of autoimmunity with Covid. We've known that for all sorts of viral and bacterial infections that they do stimulate autoimmunity both through molecular mimicry and through bystander effect, which is this idea that we have higher levels of inflammation, so we can activate an immune response in a tissue that is peripheral to what we're trying to attack. If we're trying to attack the virus, but the virus is in the pancreas, we're going to develop diabetes. So that's been well known, this idea of bystander effect and molecular mimicry. What we are seeing right now with post-Covid is as much as a 42% higher likelihood of acquiring an autoimmune condition within 3 to 15 months after infection. That’s really significant because usually, we say 3 to 18 years to develop an autoimmune disease post-infection, and Covid has seemed to shorten that window.
Gazella: Are specific types of autoimmune conditions associated with long-Covid? Is it dermatologic mostly, is it joint, is it GI, or is it all of the above?
Zwickey: It's all of the above. One of the things that's starting to be sorted through is whether different variants of Covid are triggering different types of autoimmunity, but as of right now, we're seeing a threefold increase in rheumatoid arthritis and lupus. We're seeing a twofold increase in inflammatory bowel disease and type 1 diabetes. Psoriasis has increased. In Korea where they've done a large study, they saw a lot more dermatological conditions, so a lot of alopecia as well. In general, it's consistent across all age groups, and this is different as well. Usually we see more autoimmunity as people age, but with Covid, we're seeing it in teenagers and in children.
Gazella: A stressful event is often a trigger for the development of an autoimmune condition. Is it too simplistic to say, Covid is stressful; you had an underlying predisposition to autoimmune conditions and now you have one?
Kaczor: For any complicated and chronic condition, it's going to be multifactorial. I do a lot of cancer care. In that case too, sometimes people have a ton of stress and it does affect the immune system. Is that what caused someone's cancer? Maybe it contributed, but we don't know. So I would say that's an oversimplification, but stress does have clear ramifications on immune function. And the hypothalamic-pituitary-adrenal (HPA) axis, is very much involved in autoimmune disease and in controlling the disease. When I'm seeing someone with an autoimmune condition, I concentrate on 2 systems: the HPA axis and the gut.
There are very old books from the ‘50s and ‘60s where they used antibiotics for rheumatoid arthritis, and that seemed to help. What that shows is an underlying change of the microbiota in the gut can change symptomology. I go back to good old naturopathic medicine over and over. You can't go wrong with creating a healthy upper intestine and gut in general. And that's true for the brain health as well. I mean, I don't care if it's Covid or Parkinson's or Alzheimer's. We now know that changes in the microbiota, and dysbiosis in general, can precede these dementias and they are closely related. Back to your question on stress, I think it changes the way we digest food and it changes the way our HPA acts, so yeah, I think it can be a contributor.
Zwickey: I completely agree. Immunologically, the cytokine TGF-beta can control autoimmunity and TGF-beta production is in the gut, and it is related to the production of short-chain fatty acids. We think about food that leads to us making short-chain fatty acids, which then leads to the production of TGF-beta, which then shuts down an autoimmune response. What we're eating absolutely is going to impact whether or not we go on to develop an autoimmune reaction. Unfortunately, the standard American diet is not a good producer of TGF-beta. Interestingly, as Dr Kaczor mentioned earlier, fasting increases the taxa that produce short-chain fatty acids. So all of a sudden those microbes in your gut, instead of making toxic metabolites like TMAO that might contribute to cardiovascular risk, start producing short-chain fatty acids that reduce risk of inflammation.
Chong: Autoimmune responses may also contribute to cardiac issues because of their effects on the various tissues in the heart. This autoimmune theory helps explain some of these long-lasting, clearly cardiac-related issues that are happening in people with long-Covid, long past the persistence of the acute activity of the virus.
Gazella: I’d like to hear from each of you: What's your clinical bottom line when it comes to this topic?
Kaczor: We have to recognize that we no longer treat sickness and convalesce as we should. We need to slow things down and ignore our cultural bias for the go, go, go. Anytime you’re sick, convalesce, take some time off, eat well. I think that fasting and eating lightly may be part of the way to get through this successfully. And again, taking the time to convalesce, proper hydration, and sleep, and taking it easy is something that we don't do so well anymore.
Chong: I have a mantra that I repeat over and over again: Test, don't guess. When we're talking about cardiovascular health and preventing the variety of things that are happening to people out there, don't just assume things are fine. I'm a big proponent of thorough, proactive assessment, not the classic waiting till you have chest pain and then checking it out. That needs to be emphasized now more than ever in light of Covid.
Zwickey: I think we need to be looking at things with compassion because so many people are experiencing so much pain. Being able to look beyond what we're experiencing to see the pain of others and to treat them with love and compassion because we don't understand what they're going through. We know that this is presenting differently in every single person, likely due to the fact that we all have different genetics and we have different microbiota and different epigenetics, and so we're going to have to be creative, and we're going to have to think outside the box. But mostly, we're going to have to treat people with compassion.
This is an edited and condensed version of our interview. Listen to the full interview here.
About the Experts
Tina Kaczor, ND, FABNO, is editor in-chief of Natural Medicine Journal and the creator of Round Table Cancer Care. Kaczor is a naturopathic physician board certified in naturopathic oncology. She received her naturopathic doctorate from the National University of Natural Medicine and completed her residency at Cancer Treatment Centers of America. She is also the editor of the Textbook of Naturopathic Oncology and cofounder of The Cancer Pod, a podcast for cancer patients, survivors, caregivers, and everyone in between.
Daniel Chong, ND, is a licensed naturopathic physician who has been practicing in Portland, OR, since 2000. He earned his naturopathic doctorate from National University of Natural Medicine. Chong’s focus is on risk assessment, prevention, and drug-free treatment strategies for cardiovascular disease and diabetes. In addition to his degree in naturopathic medicine, Chong has completed certificate training in cardiometabolic medicine at The Academy of Anti-Aging Medicine, a BaleDoneen Method Preceptorship, and served for 4 years as a clinical consultant for Boston Heart Diagnostics. He currently maintains a telehealth-based practice. You can learn more about him at cardiowellnessconsults.com.
Heather Zwickey, PhD, is a professor of immunology and chair of the Department of Health Sciences at the National University of Natural Medicine in Portland, Oregon. She launched the Helfgott Research Institute, which advances the science of natural medicine. Zwickey founded the school of graduate studies and developed masters programs in research, nutrition, and global health. Zwickey has received the Champion of Naturopathic Medicine Award from the American Association of Naturopathic Physicians. She currently leads a National Institutes of Health–funded clinical research training program focused on integrative medicine research and studies the gut-brain axis in neuroinflammation.