Public Health

The latest long COVID research on symptoms, testing and treatments with Akiko Iwasaki, PhD


AMA Update covers a range of health care topics affecting the lives of physicians, residents, medical students and patients. From private practice and health system leaders to scientists and public health officials, hear from the experts in medicine on COVID-19, medical education, advocacy issues, burnout, vaccines and more.

Leading long COVID researcher, Akiko Iwasaki, PhD, sterling professor of immunobiology at Yale University, joins to provide an update on the latest long COVID studies and clinical trials—and what their findings mean for physicians and patients. Dr. Iwasaki discusses what we know now about the causes of long COVID, the ongoing challenges with diagnosing it and the timeline for potential treatments. AMA Chief Experience Officer Todd Unger hosts.


  • Akiko Iwasaki, PhD, sterling professor of immunobiology, Yale University

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Unger: Hello and welcome to the AMA Update video and podcast. In this episode, we're talking about new long COVID research and how it can help with diagnosing and treating the condition. Here to discuss is Dr. Akiko Iwasaki, the sterling professor of immunobiology at Yale University. I'm Todd Unger, AMA's chief experience officer, in Chicago. Dr. Iwasaki, it's a pleasure to have you back.

Dr. Iwasaki: Thank you. It's great to be here.

Unger: Well, your video from earlier this year was one of our most popular and most watched videos, and so there's clearly a lot of interest in finding out more about long COVID. Since we talked the last time, there have been a number of studies that were published on the topic, including one by your team at Yale.

Dr. Iwasaki, before we dive into those findings specifically, where would you say we are in terms of our overall understanding of long COVID? Obviously, we know more than we did when it first emerged, but do we still have a long way to go in learning about the condition?

Dr. Iwasaki: We as a field have made a lot of progress, over the last three plus years, studying this disease, and even compared to when we spoke last time in May, there's been a lot of progress made in terms of characterizing the various biological differences seen in long COVID patients. There's a lot that we have learned, and the knowledge is converging to paint a more clear picture.

Since long COVID is not one disease, but is a collection of, likely, multiple endotypes of diseases, in terms of looking at specific biomarkers that can distinguish these endotypes, we're still not there yet. However, the drivers of illness themselves are becoming better identified and defined. This includes persistent virus infection, autoimmunity, latent herpes virus reactivation, and hypercoagulation and inflammation.

Unger: I'm curious how studying long COVID has been different or more challenging than studying other post-acute infection syndromes, and what do you find are barriers that still exist there?

Dr. Iwasaki: Yeah. So, I would say that we are in a better position to study long COVID than other post-acute infection syndromes, including MECFS. We know what triggers long COVID and when it was triggered, whereas other post-acute infection syndromes, sometimes, people don't know what triggered it. And so it's much easier to know the causative agent.

We also have millions of people who develop long COVID around the same time, which makes it more feasible to recruit participants and to be able to study the underlying disease mechanisms. However, studying long COVID is still challenging in many ways. For example, when people use different clinical definitions to define "long COVID," It is difficult to compare studies head to head.

Also, long COVID immune phenotypes shift over time, so we really need to be mindful of the time that elapsed between the infection, and the disease, and the analysis to be able to map out the disease time course better. And, finally, we do need more funding to be able to carry on our studies with long COVID research.

Unger: Now, in terms of your own research specifically, the last time, we talked about a study that your team was doing that looked at distinguishing features of long COVID that you had identified through immune profiling and that study has since been published. Can you remind us of the key findings in that study and if anything changed from the time that we talked about it in May until it was published in late September?

Dr. Iwasaki: Yes. The study we spoke about in May was recently published, I guess, September, and we have made a lot of refinements to the original findings that we posted on a preprint server, medRxiv. For example, we specifically matched the participants' age, sex, days from acute COVID symptom onset and vaccination status to be able to conduct a machine learning strategy to identify selective factors that distinguish people with long COVID. And so it was made stronger and better justified.

But the key finding still stands, which is that we found lower levels of cortisol, morning cortisol, in people with long COVID, compared to those who had recovered, or compared to those who had never had COVID. We also see, in a subset of patients, the reactivation of latent herpes viruses, including Epstein-Barr virus and varicella zoster virus. We also see increases in activation of B cells and T cells. Particularly, a subset of T cells that secrete certain types of cytokines are elevated in people with long COVID.

And then, finally, we see enhanced antibody responses to the spike protein in the people with long COVID, suggesting persistent viral antigen that's driving this elevated levels of antibodies.

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Unger: Now, less than a month after your study was published, The New York Times covered another significant study involving a connection between serotonin levels in people with long COVID. You were also quoted in that particular article. Can you tell us a little bit about what the study found, and how, when it is looked at in context with your own research, it contributes to our understanding of long COVID?

Dr. Iwasaki: Sure. So, this is a fascinating study from the lab of Doctors Maayan Levy and Christoph Thaiss at the University of Pennsylvania. Their team used both human data and animal models to study the mechanism and impact of reduced levels of circulating serotonin, which is a neurotransmitter that they found to be reduced in people with long COVID.

The researcher focused on a subset of people with long COVID that had elevated levels of viral RNA in their stools, suggesting that these people had persistent virus infection, and in the setting of this persistent virus replication, antiviral cytokines, such as the type I interferons, they seem to reduce the circulating levels of serotonin through diminished tryptophan uptake, so this is the precursor of serotonin, and also increasing in hypercoagulability by using their mouse models.

And then they also found that peripheral serotonin deficiency impairs cognitive function in the animals, due to reduced vagal signaling. So these findings suggest that restoring the levels of circulating serotonin, which is separate from serotonin levels found within the brain, this might improve long COVID symptoms.

Further, if persistent virus is really driving these reduced levels of serotonin, then getting at that root cause, by using agents like Paxlovid, or the antiviral agents, as well as monoclonal antibodies, to get rid of the root-cause persisting virus, that may also be helpful. And so it does converge, in terms of looking at persistent virus and how we might be able to target that, and there are clinical trials ongoing for both of these mechanisms, and we're involved in the Paxlovid trial ourselves.

Unger: Now, I know, Dr. Iwasaki, that the hope of your research is that we can make diagnosing easier, and obviously, point the way toward treatments. Let's talk just quickly about diagnosing, first. Given what we now know, are there certain tests or questions that primary care physicians should be asking to determine if someone's symptoms are possibly related to long COVID, and if so, what are the steps they should take to determine if they are?

Dr. Iwasaki: So, the ultimate goal is for us to develop laboratory tests that the doctors can order to determine whether someone has long COVID or not. But because of the complexity and the many drivers of disease, we haven't got there yet. However, there are fantastic physicians, like Dr. Lisa Saunders, at Yale, who is taking a lead in diagnosing patients with long COVID. She's taking a holistic approach, and is doing a deep dive into patients' medical history and physical examination to eliminate other possible causes of someone's symptoms and rule in long COVID as a diagnosis, after this very thorough interview and examination.

And once someone is diagnosed as having long COVID, there are many symptom management strategies that can be employed to minimize disease exacerbation, and suggest possible therapies to alleviate various symptoms. We need more of these sort of multi-specialty clinics dedicated to diagnosing and treating long COVID patients.

This allows physicians who are adept at diagnosing long COVID and referring patients to specialists in a streamlined manner, so that the burden is lifted from the patients to go around looking for the most appropriate care for their symptoms, but rather, having a centralized location where these patients can go to and get the right referrals.

Unger: You mentioned upfront, of course, that this is a collection of different things. You also mentioned using Paxlovid to address possibly the root cause of the problem. Do you see any new treatments, or improvements in existing ones, that can be used to treat long COVID?

Dr. Iwasaki: Yeah, so, the goal is for us as a community to translate the latest research findings into treatments. And that kind of process, unfortunately, it does take a long time. But, certainly, these kinds of efforts are underway. You know, for example, our Paxlovid trial, it's basically testing whether a 15-day course of Paxlovid can improve the patient's symptoms, but coupled with biological marker analysis.

So, even if, say, 10% of the patients, or 20% of the patients benefit from Paxlovid, we will be able to tell who will benefit from a particular treatment, because we're now measuring biomarkers before and after the treatment, and to be able to associate certain markers with improvement with certain medications. And similarly, this kind of marker can be applicable for monoclonal antibody therapy that is targeting the viral antigens and spike proteins.

The other types of insights that we gained through research is the reactivation of EBV, as I mentioned already. And there are clinical trials of antiviral strategy against EBV that are also being contemplated. And, finally, the inflammation that I mentioned, there are also some very potent immunomodulatory agents that are already FDA-approved for use against other types of inflammatory diseases that can be also tried in this way. So, we're all working hard to find signals that could help people with long COVID based on scientific insights.

Unger: Well, we now know that some people have been suffering from long COVID for months, maybe even years. If physicians and patients take away one thing from what we've learned so far, what would that be?

Dr. Iwasaki: That there is a clear biological basis for this syndrome, and that we're defining the root causes that drive these different endotypes of disease. And I'm personally very excited about and hopeful that science is moving forward at an extraordinary pace.

Understanding disease root causes and treatment takes many, many years. But I think there's a lot of talent and dedicated people with desire to find diagnostic tools and therapies that can really be used to improve the lives of people with long COVID, and this kind of research will also inform treatment strategies for other post-acute infection syndromes, including MECFS and chronic Lyme.

So, I think we need to ensure continuous funding in this field, so that we can grow the next generation of scientists to carry the torch. But I'm personally very excited about the future.

Unger: Dr. Iwasaki, thank you so much for being here and for all the critical work that you're doing to help us better understand this disease, and we'll look forward to hearing your progress as you make more. That's it for today's episode. We'll be back soon with another AMA Update. You can find all our videos and podcasts at Thanks for joining us today. Please take care.

Disclaimer: The viewpoints expressed in this video are those of the participants and/or do not necessarily reflect the views and policies of the AMA.

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