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What is long COVID? What are the signs of long COVID? Does getting COVID multiple times increase long COVID risk? What long COVID treatments are available?
Akiko Iwasaki, PhD, Sterling Professor of Immunobiology at Yale University, discusses new long COVID research, emerging treatments for long haul COVID, and the latest from the Yale Long COVID clinic.AMA Chief Experience Officer Todd Unger hosts.
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Speaker
- Akiko Iwasaki, PhD, Sterling Professor of Immunobiology, Yale University
Transcript
Iwasaki: It's possible that some people might not even realize they have long COVID. There are several reasons for this. First, the wide range of symptoms makes it difficult to pinpoint the cause to long COVID.
Unger: Hello and welcome to the AMA Update video and podcast. Today, we're talking about the latest on long COVID with Dr. Akiko Iwasaki, the Sterling Professor of Immunobiology at Yale University in New Haven, Connecticut. Dr. Iwasaki has a PhD in immunology. I'm Todd Unger, AMA's chief experience officer in Chicago.
Dr. Iwasaki, your segments are always so popular. There's so many people looking for information on long COVID. We're so glad you're here to join us today.
Iwasaki: Thank you. It's great to be back with you, Todd.
Unger: It's actually been a while since we checked in with you. And in that time, our understanding of long COVID has changed a lot. We're starting to see that it goes far beyond symptoms like chronic fatigue, brain fog, things like that. It can impact many areas of the body. What does that mean for how we think about and define long COVID today?
Iwasaki: We now understand that long COVID is likely not a single disease, but rather an umbrella term that encompasses multiple distinct endotypes that's triggered by acute SARS-CoV-2 infection. So studies have identified at least four potential root causes—persistent viral reservoir in different organs, autoimmune reactions triggered by the infection, tissue damage and dysfunction, and reactivation of latent herpes viruses, like Epstein-Barr virus.
So these diverse mechanisms help explain the heterogeneity we see in long COVID presentations. Some patients may primarily have a neurocognitive issue, while others might experience cardiovascular or gastrointestinal issues.
Additionally, we found evidence for hormonal changes, such as lower levels of cortisol and also sex hormone differences, such as lower levels of testosterone in females. So the complexity poses challenge for diagnosis and treatment, and we're working to develop better biomarkers that can classify patients into different endotypes so that we can diagnose and treat patients better.
Unger: Wow, with so many different kind of pathways that you talked about right there and symptoms, it's really complicated for someone to get help and get treated for long COVID. Is that right?
Iwasaki: That is correct. And it's possible that some people might not even realize they have long COVID. There are several reasons for this. First, the wide range of symptoms makes it difficult to pinpoint the cause to long COVID. Second, the symptoms may be associated or assigned to other conditions, such as normal course of aging or attributed to pre-existing health conditions.
There's also the lack of awareness about long COVID. Over a third of Americans have not heard of long COVID. And finally, the fluctuating symptoms, because the symptoms come and go in varying in intensity over time, making it difficult for individuals to realize that this is related to long COVID.
Unger: On a prior AMA Update with Andrea Garcia in our health and science unit here at the AMA, I believe she said that up to 8% of people had experienced long COVID at some point. That's almost 1 in 10. That's a lot of people, isn't it?
Iwasaki: This is a lot of people. And those are the ones that recognize the disease as being long COVID, but there may be others, like I mentioned.
Unger: So given what you really just talked about, let's talk about the average physician out there who's seeing someone come in with this kind of variety of potential symptoms about long COVID. How should they approach that assessment? And are there any signs or lesser-known symptoms that they should be on the lookout for?
Iwasaki: Yeah, that's a really good question. Due to the lack of diagnostic tools, physicians really have to conduct comprehensive evaluations and also consider potential other drivers of disease. But some of the less discussed but fairly common symptoms of long COVID include things like internal tremor. We studied this. Over one third of long COVID patients report experiencing internal vibration or tremor sensations that are without visible external signs.
Second, there's this Postural Orthostatic Tachycardia Syndrome, or POTS, that many patients have where physicians may not necessarily associate with long COVID. There's post-exertional malaise and hormonal dysregulation and sleep disturbance. These are all common manifestations of long COVID that are not very well discussed, and many physicians may not be aware of this.
Unger: Do people, then, generally get treated for those particular symptoms at this point?
Iwasaki: Yes, if the doctors can recognize these symptoms, and if there are any sort of treatments available, they are treated for the different symptoms. But they may not be linking it necessarily to long COVID.
Unger: When we last talked last year, we discussed that studies have shown that vaccination can reduce the risk of long COVID. Is that still the case, particularly for those who haven't gotten, say, the most up-to-date vaccine and might be catching COVID for a second or even third time?
Iwasaki: That seems to be correct, that the risk of long COVID appears to increase cumulatively with each infection. Since vaccination has been shown to reduce the risk of developing long COVID to some extent, it is important that people get vaccinated to boost their immune response against the virus.
In terms of people who already have long COVID, we did a small study, a longitudinal study, involving 16 people with long COVID, who showed that vaccination improved health status in 10 of these individuals, while three had no changes and three others had worse outcomes. So what we need to have is a bigger study to see whether we can predict the health outcomes of vaccination to improve their symptoms and prevent reinfections.
Unger: So basically, besides getting vaccinated, which hopefully would prevent getting COVID in the first place, and as you point out, the cumulative impact of multiple infections, is there anything else that people can do to reduce the risk of developing long COVID?
Iwasaki: Yeah, well, the best way to avoid getting long COVID is to avoid infection. So wearing masks indoors and increasing the ventilation in crowded spaces is still very important. However, it is not possible to completely avoid getting infected even if we are careful.
So when you get infected, reducing the replication of the virus by taking antivirals like Paxlovid might help mitigate long COVID. For the immunocompromised people, pre-exposure prophylaxis with Pemgarda can help reduce the acute, severe symptomatic infections. This may also prevent long COVID, but this has not been tested yet.
Unger: All right. Well, thank you. Back in August, you published an article in Nature that touched on many of these topics. And in it, you also outlined some existing drugs that could potentially be repurposed to treat long COVID. Tell us more about that.
Iwasaki: Yes, so depending on the root causes of long COVID, we could be and we should be doing randomized clinical trials to existing drugs to see if that helps. For example, if the cause is persistent virus replication, antivirals and neutralizing monoclonal antibodies against SARS-CoV-2 should be tried because it should help.
If it is the latent herpes virus reactivation, we should be trialing antivirals like valacyclovir. With Dr. David Putrino, we are—we have an ongoing RCT to trial antivirals like Truvada and Maraviroc for long COVID. And to target the chronic inflammation, we should be testing things like immunomodulators, JAK inhibitors and checkpoint inhibitors. And to target the autoimmunity, we should be targeting things like FCRN inhibitors to reduce circulating antibodies, or B cell depletion therapies.
But as you can see, these interventions must be targeted to the particular root cause of disease. Otherwise, it will not be effective.
Unger: All right. And in that same article, you also mentioned that some ways we need to rethink how we're approaching clinical trials for long COVID giving what you've talked about, which is this multifaceted, complex condition that we're looking at. What kind of changes do you think we need to make?
Iwasaki: Yeah, there are a few things that we can be thinking about for better success of clinical trials for long COVID. So the first thing is the heterogeneity of disease and having a validated biomarker going in to subclass the endotypes that I talked about would greatly simplify the drug development and make it attractive to the biotech and pharmaceutical industry to collaborate and do a larger study.
Another thing we need to work on is how best to define the inclusion criteria for any given medication. And accurate and standardized clinical endpoints for long COVID is also important. Improve patient-reported outcomes specific to long COVID that takes into account the cyclical nature many of the disease manifestations are also needed to assess the true success of therapeutics.
Unger: Dr. Iwasaki, this research that you're doing is so vital, and thank you for everything you're doing to help us better understand long COVID. We appreciate you joining us today.
If you found this discussion valuable, you can support more programming like it by becoming an AMA member at ama-assn.org/join. That wraps up today's episode. We'll be back with another AMA Update. Be sure to subscribe for new episodes and find all our videos and podcasts at ama-assn.org/podcasts. Thanks for joining us today. Please take care.
Disclaimer: The viewpoints expressed in this podcast are those of the participants and/or do not necessarily reflect the views and policies of the AMA.
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