Long COVID: 2023’s Enduring Medical Mystery

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Mark Masselli ( 00:04 ):
Many times this year, we focused our program on discussing long COVID. Who is affected, what it is,
where research studies are underway, to sort out the mystery and how to treat it. Our guest brought
great insight to our conversations about the lingering effect of COVID that continue for months and
years after the acute phase.

Margaret Flinter ( 00:26 ):
As we look back on 2023, we bring you highlights from these interviews. It's a fascinating recap of a
complex and evolving medical story. This is Conversations on Healthcare.

Mark Masselli ( 00:47 ):
Welcome to Conversations on Healthcare. There are three key reasons why this programming devoted
so much time to long COVID in 2023. First, it really fits our mission that's focused on healthcare
innovation and policymaker. Figuring out long COVID is indeed taxing to researchers and it's requiring
policymakers to respond in kind with financial resources. Second, there did not seem to be a lot of
consistent coverage of long COVID in other media outlets. And third of all, the interest from all of you,
our audience, was very strong.

Margaret Flinter ( 01:24 ):
And we know there are people out there really suffering from long COVID and we want to pay attention.
There were new developments in the long COVID story throughout the year. We'll get to a big one in a
bit, but we start with a review of the answers that we heard when we asked guests to define long
COVID. We start with Yale University researcher, Akiko Iwasaki.

Akiko Iwasaki ( 01:45 ):
Long COVID is definitely a condition that is heterogeneous and variable and it's difficult to pinpoint
because we don't have a biomarker, but it's essentially a disease that happens after the acute phase of
COVID that lingers over four weeks from the starting of the acute phase. And in some people it's lasting
for over two years now, and it contains multiple different symptoms. Over 200 different symptoms have
been reported involving pretty much every organ system, and as I said, it's a heterogeneous disease that
requires more investigation.

Mark Masselli ( 02:24 ):
Margaret, we had Dr. Leora Horowitz, one of the leaders of the National Institute of Health study of
Long COVID, and Dr. Horowitz is also the director for the Center for Healthcare Innovation and Delivery
Science at NYU Langone Health. An important part of her work has been getting to working definition of
long, so we're all on the same song sheet. In fact, she's been instrumental in creating the 12 symptom
scoring system.

Leora Horowitz ( 02:53 ):
We have over 14,000 patients in this study right now. And so what we have been doing is asking them
questions every three months about tons of different symptoms. Asking, "Do you have this? Do you
have that? Do you have this other thing?" In fact, we asked about 37 different symptoms that people
might experience. And what we did in this first look at the first 10,000 of these patients, these
participants, is we looked to see which of those symptoms are more commonly present long - term in

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people who did have COVID versus people who didn't have COVID. Because remember, lots of people
have symptoms of all types and that's not necessarily related to COVID. So what we were looking for are
symptoms that were more prevalent in people with COVID than in people without. And it turns out just
about every symptom is more common in people who had COVID than people who didn't.
[NEW_PARAGRAPH]And people have all these different kinds of symptoms, and it's not so surprising
because we took this list of 37 symptoms from patients themselves. So we started with a list that we
knew that people were experiencing. So that's kind of cumbersome to manage and to deal with because
that's a lot of things to try to keep track of. So what we did is we did a lot of math to try to figure out
which of those symptoms were most helpful, most different between people with COVID and with that,
and that got us down to 12. But I want to be clear that the people who had those symptoms, they also
had all the other ones too. So it's not that those are the only symptoms that people get. They're not
even the most common necessarily, but they're the ones that help us most distinguish between people
who had COVID and who didn't.
( 04:32 ):
And then we looked to see which of those were especially different, which of those were a little bit less
different, and we gave points to them depending on how different they were. So for example, loss of
smell and taste was very uncommon in people who didn't have COVID and really quite common in those
who did. So that gets a lot of points. Something like fatigue is also very common in people who had
COVID, but also kind of common in people who didn't. Many people are fatigued, so that gets you only
one point. So we gave points to each of these symptoms and it so happens that the number 12 comes
up again. What we found was that a total number of points of 12 points or more made it very likely that
that was a person who had COVID in the past, probably as a person who had long COVID, whereas very
few people who didn't have COVID had 12 points or more of symptoms.
( 05:29 ):
That doesn't mean they had all 12 symptoms. It just means they had 12 points worth of symptoms. And
so we used that as a cutoff to say, above here is very probable that this is a person with long COVID.
Again, it doesn't mean that someone who has fewer points doesn't have long COVID. Certainly there are
people who have long - term symptoms from COVID that don't quite have 12 points. But above that, we
feel pretty confident that that's somebody with it. And that means we can do science on those people.
We can study those folk and try to understand what's going on in the body, what is happening over
time. Are they getting better?

Margaret Flinter ( 06:07 ):
We also asked Dr. Lisa Sanders to explain the scope of the problem. She's the director of the Yale New
Haven Long COVID Multidisciplinary Care Center. She also writes the diagnosis column for the New York
Times.

Lisa Sanders ( 06:21 ):
We don't see patients until three months after their infection because we know that symptoms that
occur within that period often are gone by three months, and that seems reasonable. But even for
people who have symptoms that last longer than three months, the people that I see, there are some
studies that show that the vast majority of these people feel better. I don't say well, but feel better
within a year. So I think that the prognosis for this is pretty good. On the other hand, a year is a really
long time to suffer and there are lots of patients that I see who have been suffering for much longer

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than that. Most people get better within a year. Most, not all. I would say that fatigue is hugely
common, hugely. I mean, almost no one comes to us who doesn't complain of fatigue.
( 07:15 ):
And it can be really a debilitating fatigue. It's hard to get out of the house, that kind of fatigue.
Sometimes it's hard to get out of bed, that kind of fatigue. So fatigue is a common problem. Brain fog or
some sort of cognitive change that people notice is also a very common symptom. Most patients who
come with cognitive changes talk about word finding difficulty and also problems with attention or
concentration. It's hard for them to attend the way they used to. In fact, that probably has a lot to do
with the other most common complaint, which is short - term memory problems. If you're not attending
to the situation, it's very hard to remember. There might also be another component of the memory
loss or the memory difficulties, but I think that the attention plays an important role.
( 08:16 ):
So fatigue, brain fog, those are probably the two most common problems I see. But then there are a
whole bunch of other problems. People feel short of breath. People have chest pain, people get dizzy
when they stand up. People talk about tachycardia. So we try to figure out what to do with each of these
problems, try to face them as they are. Because at this point there is no treatment for long COVID.
Based on the definition, the definition of long COVID is you had COVID and then you felt bad. That's a
pretty broad definition, and when you see patients with long COVID, they have different manifestations.
Like some people are suffering from something that COVID did to them at the time that they had it.
People with shortness of breath often have some problems, some problems caused by COVID to their
lungs.
( 09:17 ):
Other people have disorders that are a little bit less easily attributed to instant damage from the COVID
itself. Maybe it's their immune system is different or maybe it's an autoimmune disease or maybe it's
just some other kind of problem. So people say that there are six different kinds of long COVID, and
when you have something like that, there's not going to be, I don't think, a single cure.

Mark Masselli ( 09:48 ):
We really enjoy our reading her columns, Margaret. In our interviews, we consistently asked one
question; how do you address skeptics who think people saying they have long COVID are making it up
in some form or fashion. At Aspen Ideas Health in June, we spoke with Dr. Anthony Fauci, the former
Chief Medical Advisor to President Biden, who explained we still do not understand the pathogenesis of
long COVID.

Anthony Fauci ( 10:17 ):
It's a real phenomenon. It varies in its severity, from fatigue based on exercise to incapacity to be able to
do something and a variety of other signs and symptoms, autonomic nervous system symptoms,
unexplained tachycardia, temperature dysregulation, sleep disturbances, brain fog or inability to
concentrate. It varies. I mean, for some people who have all of that and are really, really, their lives have
been really negatively impacted, to those who get a degree of fatigue that lasts for four or five, six
months and then gets better. So it's a wide spectrum. The problem is we don't know what the
underlying pathogenesis is. Is that a triggering of an aberrant immune response that you can't turn off?
Is it residual viral particles that are not replication competent but are still there? We don't know what
the answer to that is.

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Margaret Flinter ( 11:15 ):
Dr. Sanders at Yale New Haven explained how she deals with those who think long COVID is in people's
heads, that it's somehow made up.

Lisa Sanders ( 11:25 ):
Educate people. I don't know about educating people. I educate the patients who come in and their
family members, and when I speak in public about long COVID, I certainly try to persuade people that it's
real, but not having a blood test or some sort of biomarker doesn't mean the disease doesn't exist.
There are lots of diseases that we diagnose based on clinical symptoms, so that's kind of a bogus claim,
and you have to understand that tests are questions. And if you've ever played 20 questions, it's
possible that the answer to your first 20 questions will be no. And that's where we are with long COVID.
The first 20 questions we ask for many people, the answer is, "No, it's not that." But tests, there's no
test that says, "Wow, are you okay?" Tests don't work like that. So it has to be a very specific question
and we don't even know what the question is for many of these symptoms.

Mark Masselli ( 12:36 ):
Well, we know from so many of our patients, it's certainly not made up. Margaret. We also heard from
Yale's Akiko Iwasaki on this issue.

Akiko Iwasaki ( 12:45 ):
I'm just surprised to see that there are some skeptics that are still doubting the validity of this disease.
So we've done a lot of immune profiling in people with COVID, long COVID versus those who recovered
and we're seeing distinct features of immune responses that are not found in the control groups, and so
just by immunological features alone, we can distinguish people with long COVID and it's very difficult to
just imagine that.

Margaret Flinter ( 13:15 ):
Patient advocate, Fiona Lowenstein, editor of the Long COVID Survival Guide, explained why she thought
there were so many hurdles for getting clinicians to believe their patients.

Fiona Lowenstein ( 13:27 ):
None of these issues are new. Inequal access to healthcare has been an issue certainly in our society and
in our country for a long time. And so I think it's important to understand that these structural barriers
were very much here before the pandemic, but were of course exacerbated by the healthcare
overwhelm that occurred and continues to occur on a seasonal basis when we have these huge surges,
case surges for now not just COVID, but of course we're seeing for flu and RSV as well. And so the stories
in our books, we have stories from patients who came from communities that were disproportionately
impacted by those high caseloads of acute COVID, right? We have a patient in our book who writes
about getting sick in the first wave in an urban Black community in Baltimore and what it was like to try
and fight for care continually.
( 14:18 ):
We have a story from a Latina woman in Los Angeles, the same thing, trying to get doctors to take her
seriously. And so I think for medical providers and for those treating long COVID, it's important to
understand that some of those patients who don't have that initial COVID - 19 diagnostic test or may not
have that record of being treated for post COVID symptoms early on in their illness experience may have

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been facing some of those structural barriers, medical racism, medical sexism. These are very real
barriers that existed prior to the COVID - 19 pandemic, but have definitely been exacerbated by just the
level of healthcare need that is going on right now.

Mark Masselli ( 15:00 ):
However, a short time later there was a breakthrough. In September, scientists reported they had found
distinct differences in the blood of people with long COVID. This is seen as the first key step in the
development of a test to diagnose the illness. That was such great news for the estimated 65 million or
more people around the world that still are coping with long COVID. What does the treatment look like
for them? Well, Dr. Greg Vanichkachorn leads Mayo Clinic's COVID Activity Rehabilitation Program, and
he explained how it works.

Greg Vanichkachorn ( 15:39 ):
So the loss of taste and smell, that's something that we have all heard about during the acute infection,
but for some folks it does last for quite a bit of time, several months, and that can be quite a miserable
few months, if you imagine. You can't taste or smell anything or sometimes things that normally taste
and smell good, taste bad. The nerves that are involved in taste and smell, they have this ability to
regrow. It's called neuroplasticity, but essentially they can be regrown. And by using odors to stimulate
the nerves that are involved in smell, we believe that we can help them regrow properly and form the
proper connections that bring back normal taste and smell.
( 16:20 ):
There's also some additional research that using things like olfactory retraining can help rewire some of
the deeper parts of the brain to actually help improve cognition. The process is pretty straightforward.
We have individuals smell four different odors twice a day for 30 seconds at a time, and we had them do
that quite frequently for, sorry, quite a prolonged period of time, about three months, and patients will
notice an effect. It's subtle, but a subtle effect of getting better faster versus later.

Mark Masselli ( 16:50 ):
Are you planning to publish on this or have you published on this?

Greg Vanichkachorn ( 16:53 ):
People are ahead of us on that. One thing I will say is that we try to stick to only the research driven
interactions or interventions here at Mayo, so that comes from after seeing some similar results in the
research.

Margaret Flinter ( 17:06 ):
Very important to get out into the primary care field where people may not be as familiar with the
literature. So thank you so much for sharing that. That's certainly a low risk intervention for people.

Greg Vanichkachorn ( 17:17 ):
Absolutely. A very easy risk.

Margaret Flinter ( 17:19 ):

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I noticed another piece of advice that's been attributed to you is that long COVID patients should focus
on resistance activity instead of things like walking and cycling. Counterintuitive, somewhat. My answer
to almost everything is take a brisk walk, you'll probably feel better, but in this case, you're saying they
shouldn't do activities that elevate the heart rate. Why is that?

Greg Vanichkachorn ( 17:43 ):
Absolutely. So first of all, I'm a big proponent of exercise in healthcare, and so I'm never going to say the
exercise is a bad thing, but because of what we see in long COVID, we think that pushing the body too
hard, and the too hard part is the key here, can actually make things worse. Because of long COVID and
its inflammatory changes that we think underlie it, individuals with this condition, they don't have the
normal physical responses to activity and exercise. So for example, most of us, when we start to go for a
brisk walk or do some more vigorous exercise, there's that warmup period where our body adapts and it
goes from being a horrible experience to being something enjoyable. That change doesn't seem to
happen well in individuals with long COVID, and it's kind of similar to some of the problems that we see
with things like postural tachycardia syndrome, or POTS.
( 18:37 ):
So the body's just not adapting to that. So in individuals with long COVID, if they try to push themselves
too hard and just grit their teeth and exercise their way fully back to recovery in a sort of no pain, no
gain attitude, their bodies just crash and they experience increased inflammation and then their
symptoms get worse for hours or days. That leads them to arrest, and these are further deconditioning
and then they get stuck into this vicious cycle. So it's not so much about not doing activity or exercising,
it's just about a slower pace to that activity. Interestingly, in those folks who have conditions like
postural tachycardia syndrome or things like chronic fatigue and fibromyalgia, they're able to tolerate
more recumbent resistance exercises before they can get to tolerating things like cardiovascular
exercise. That's why we have people start with things like the recumbent cycling or rowing. Once the
musculature regains its strength some in tone, we think the body is better able to push around blood
flow during activity, and then they're able to transition to the cardiovascular exercise.

Mark Masselli ( 19:47 ):
He also gave us an overview of research that's occurring.

Greg Vanichkachorn ( 19:51 ):
I think there's two phases of research that's going on right now that are both important. One is, what's
really underlying the condition of long COVID? On a chemical level, what is the process that's going on?
We still don't understand that. Or the process that's going on for potentially similar or the same
conditions like chronic fatigue and fibromyalgia, so I'm always on the lookout for anything that could
indicate, okay, there is a new inflammatory marker that may underline some of these changes. There
has been some good research, such as the genetic research that came out recently involving the FOXP4,
I believe it was, gene, and how that may be more present and somehow related to long COVID.
( 20:28 ):
I think if we can get the answers to what's going on on an underlying level, that will open up a whole
new doorway of therapeutics that we could use and be able to focus where our treatments are. The
other thing that I'm looking out for is exactly that randomized clinical trials, well - designed, about
treatments. And right now there's hardly anything out there in that level. There are some anecdotal

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pieces as well as some smaller observational studies that have given us some hints on things that we can
use, but we're still quite lacking in this area.

Mark Masselli ( 21:02 ):
Yeah, I think she has 15,000 people in her study, which is probably closer to the size that we'd like to
see.

Greg Vanichkachorn ( 21:11 ):
Yes, exactly. Exactly. For example, we have a lot of people who are wanting to use Paxlovid for the
treatment of long COVID, and I've had plenty of patients with long COVID who took Paxlovid during the
acute infection or even afterwards, but I'm not ready to say that Paxlovid doesn't work. What we need
are the large numbers, like the studies that are being done by the NIH, including here at Mayo. We're
partnering with them on that. That's the kind of information we need before we can say yay or nay.

Mark Masselli ( 21:37 ):
We had Dr. Ashish Jha in the show yesterday and former Biden COVID czar there, if you will, and now
back at Browne as the dean who I think Margaret was really pushing Paxlovid as sort of a treatment for
those over 50, but as you say, there's probably more data out there.

Margaret Flinter ( 22:02 ):
As a preventive, not for long COVID.

Mark Masselli ( 22:02 ):
Right, no, as a preventive for sure. I was just wondering about the level of financial support that you
think that's out there. I'm wondering if too much of this, it's now in the rearview mirror, is influencing
the financial support that's really needed to do these very detailed clinical trials. What are you feeling or
seeing out there?

Greg Vanichkachorn ( 22:27 ):
Yeah, this is probably my greatest fear when it comes to long COVID. We've had postviral conditions for
the longest time, since all the way back to the Spanish flu, even influenza, Lyme disease, but there hasn't
been a lot of emphasis on this because it just hasn't been raised to a good level of awareness. When the
pandemic came, that all changed and now everyone was focused on long COVID and there was lots of
support for research and such, but these things take time. The pandemic's behind us, we're seeing less
numbers of long COVID, but it's not going away, so I am worried that the financial support is going to run
out behind trying to figure out these really serious conditions that are affecting millions of people out
there. But fortunately, by having discussions like we are right now, we can keep this on the forefront
and keep the science moving forward.

Mark Masselli ( 23:16 ):
Are you seeing anything maybe internationally? We've been keeping an eye on the UK and other places,
anywhere that you and your team are looking at for if it's not happening in the States, where other
people are taking a leadership role here?

Greg Vanichkachorn ( 23:34 ):

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I would say the UK has been really paramount in a lot of the early research, and we do have some
connections there as well through Mayo Clinic, and so if we were to branch out across the world in
which we hope to do, that would be my number one choice. We've also had some good success working
with our folks down in Australia.

Mark Masselli ( 23:51 ):
Yeah, that's right.

Margaret Flinter ( 23:53 ):
Dr. Van, the concern among so many others is around health disparities also with long COVID, and
maybe you could comment on this as a starting point of health inequity and health disparities,
inflammatory diseases, chronic illnesses, disparities in access to healthcare. Based on what you are
seeing, do people present differently based on factors like race and ethnicity as well as age? We're
hearing young women may be more likely effected, which is not as apparent to some. Tell us about that
and how do we address that? Part of it is the research and making sure those studies are large,
obviously like the All Of Us Project nationally, but could you comment on that a bit?

Greg Vanichkachorn ( 24:43 ):
Yeah, thank you so much for asking about that. I think that's something that's really quite overlooked.
This disparity part about long COVID is something I'm really passionate about. Long COVID affects
everybody across the population, right? That's got to be the case. Here at Mayo Clinic, what we have
noticed is that certain individuals are able to access care for long COVID, and that's the same across
other institutions. A person that typically can go to a specialty clinic for long COVID, they've got support
for things like financial support, paid time off, long - term disability through an employer, all those kinds
of means for travel and such. That's not something that's available across the board to all individuals.
For example, we have not seen in the research or in our clinical practice, individuals who work more on
the forefront of our industries, let's say farmers or agricultural workers or line workers from automated
factory.
( 25:37 ):
We know those individuals must be out there and suffering symptoms, but we're not seeing them get
care. And health disparities, of course, they existed long before COVID came around, but if anything, the
pandemic and the long COVID phenomenon has exacerbated that disparity. So we are actively working
with some of our local groups, community engagement boards and so forth to see if we can improve
that, reach out and improve that disparity. One area that we are particularly worried about are
individuals who are already living with disabilities. It's very difficult for them to get care already. How are
they doing now if they have long COVID?

Margaret Flinter ( 26:18 ):
Patient advocate, Fiona Lowenstein, shared great advice for anyone who's still dealing with long COVID.

Fiona Lowenstein ( 26:23 ):
Well, the first thing I would say is if you are experiencing or think you are experiencing long COVID
symptoms, track your symptoms and also track your daily activities. I think in the support groups, we
found it really helpful to look at not only when you're experiencing symptoms, but what might have
predated that symptom because a hallmark symptom of long COVID tends to be something we call post

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exertional symptom exacerbation, the worsening of symptoms following a period of physical, mental, or
emotional exertion, so that can be quite helpful as a starting point. There's a lot of great advice in this
guide. I would say it's a good place to start. Dr. Iwasaki wrote a beautiful afterword as well, kind of
sharing with the reader what the future of research for this disease might look like, but there's also a
piece of advice that stands out to me right now from Dr. Donna Kim Murphy, who is herself both a
provider and a long COVID patient.
( 27:16 ):
She writes that your provider should be your partner in your long COVID journey, and that if you are not
finding that kind of intellectual curiosity and partnership in your provider, you deserve to find that and
you should pursue that by whatever means necessary. Obviously, everyone, we all have limitations in
terms of time and money and access, but I think it's important for patients to feel empowered and know
that that is what they deserve, and that there are providers out there like Dr. David Putrino and others
who are part of this book who are really committed to forging that relationship with patients. There is
not a patient doctor divide on this issue. A lot of us are really working together, researchers, providers,
patients, to solve this collectively, and so we're very grateful to folks like Dr. Iwasaki and Dr. David
Putrino and others who are working with us to do just that.

Mark Masselli ( 28:05 ):
Early in 2024 will mark the fourth anniversary of the first COVID case in the United States. As the
American Medical Association points out, long COVID is still an enigma. AMA writes, "The mystery of
Long COVID reminds us of the virus's capacity to leave a lasting imprint, prompting the paradigm shift in
how we perceive and manage the aftermath of COVID - 19."

Margaret Flinter ( 28:33 ):
As we get ready to start a new year, we pledge to you to stay on top of long COVID developments and
invite the leading clinicians and researchers to join us. Be sure to go online to CHCradio.com, sign up for
email updates. You can also share your thoughts and comments about the program. Happy Holidays and
Happy New Year. This copyrighted program is produced by Conversations on Healthcare and cannot be
reproduced or retransmitted in whole or in part without the express written consent from Community
Health Center, Inc. The views expressed by guests are their own, and they do not necessarily reflect the
opinion of conversations on healthcare or its affiliated entities.

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