Latest on Long COVID: NIH Study Leader Leora Horwitz, MD

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Mark Masselli ( 00:05 ):
An estimated 65 million or more people around the world are still coping with long COVID. Scientists are
racing to understand why some people develop long - term symptoms after an infection, as well as how
to detect, treat, and prevent it.
Leora Horwitz ( 00:19 ):
There is an association with the severity of underlying disease. So the number of comorbidities that
people have is does seem to be associated with how likely they are to go on to develop long COVID.
Margaret Flinter ( 00:32 ):
Dr. Leora Horwitz is one of the leaders of the National Institute of Health Study of long COVID, the
director of the Center for Healthcare Innovation and Delivery Science at NYU Langone Health, where
they're integrating the research activities of almost 200 clinical sites.
Leora Horwitz ( 00:48 ):
Vaccination does reduce the risk of long COVID. And this goes just along with that general understanding
that we have, that the sicker you are initially, the more likely you are to have long COVID. And one thing
that vaccination does very well is it prevents people from getting very sick.
Margaret Flinter ( 01:02 ):
And this is Conversations on Health Care.
Mark Masselli ( 01:13 ):
Well, Dr. Horwitz, welcome to Conversations on Health Care.
Leora Horwitz ( 01:17 ):
Thank you for having me.
Mark Masselli ( 01:18 ):
Yeah, there's so much we want to get to here, but let's start with what Dr. Fauci recently told us. He says
we still do not understand the pathogenesis of long COVID. However, we do know research has found
biological changes that may occur in association with symptoms following a person getting COVID. I'm
wondering if you could share with our listeners what more you could fill us in on this.
Leora Horwitz ( 01:43 ):
Yeah, that's definitely true. Both statements that we don't yet know much and that we're learning a lot.
We still don't perfectly understand what is causing people not to recover from their COVID infection and
have symptoms that last months, perhaps even years. But there are increasing numbers of studies
coming out to show all kinds of different derangements in the body. We have had some evidence of the
virus itself persisting. We have some evidence of inflammation or irritation of different parts of the
body. We have evidence of tiny little blood clots, and we have evidence of scar, all kinds of different
things that we're seeing in the body, some or all of which might be contributing to the symptoms.
Margaret Flinter ( 02:29 ):

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Well, a key part of your work, as I understand it, has been getting to a working definition of long COVID
that lets us all be on the same song sheet. Incredibly helpful. And I understand that you've been
instrumental in creating the 12 - symptom scoring system. I think our viewers and listeners would be
really interested in hearing about this. Tell us more about the 12 - symptom scoring system.

Leora Horwitz ( 02:52 ):
Sure. So the National Institutes of Health has funded this RECOVER program, researching COVID to
understand recovery. And among the studies in that umbrella, in that program is a large study of adults.
This study includes people who have had COVID and people who haven't had COVID, and includes
people who have long - term symptoms and don't have long - term symptoms. So we have a big variety of
people in the study. We have over 14,000 patients in the 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 people who did have COVID versus people who didn't have COVID.
( 03:59 ):
Because remember, lots of people have symptoms of all types, and it'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. 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. 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 without. And that
got us down to 12.
( 04:44 ):
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. 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.
( 05:33 ):
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. 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.
( 06:11 ):

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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? We can look for all the things that other people have reported in
studies and see is that true in this group that we feel pretty confident about.

Mark Masselli ( 06:45 ):
Well, there were certainly 12 reasons why there's no single test that can definitely diagnosed long
COVID, is a unique condition. But I'm wondering, what are the current diagnostic and treatment options
for people who believe they may have the condition?

Leora Horwitz ( 07:02 ):
Yeah. Well, there's two approaches to treatment for any disease. One is to treat the symptoms, and the
other is to treat the underlying cause. Right now, because we're just not sure what the underlying cause
is, most of the treatments for long COVID are more focused on the symptoms. So if you are a person
who's having trouble breathing, we focus on treatments that we know are good for people who have
trouble breathing. If you are a person who's having trouble thinking and concentrating, we apply
treatments that we know are good for people who have difficulty thinking and concentrating for
whatever reason, post - concussion or whatever. So the treatments right now are mostly symptom -
focused rather than underlying disease - focused. But there are a lot of clinical trials happening right now
that are trying to get more at that underlying cause to try to see if there's something we could do that
will actually fix the underlying.

Mark Masselli ( 07:57 ):
Is there any relationship to the variants that have come out? Are they impacting this assessment as well
as you walk through them? And you're probably trying to keep track of the more underlying indicators
of which one of the many variants, and Dr. Fauci walked through the whole numerology that is
associated with these variants.

Leora Horwitz ( 08:29 ):
There are definitely differences in the kind of illness that people are getting with the different variants.
We know that that first variant, that original variant, was very severe. People became very ill, and many
are having long - term symptoms just from that initial insult to the body. But in RECOVER, in our city, we
have people from all those different time periods. And even when we look at people who had the most
recent, the omicron variant, and who were vaccinated, we still are seeing a pretty substantive rate of
long - term symptoms. We found about 10% in this study of those folk who are omicron - infected and
vaccinated. So although it probably does matter what variant people have, we are seeing long COVID
even with the less severe variants.

Margaret Flinter ( 09:21 ):
Dr. Horwitz, besides which variant, what are we seeing as the risk factors for long COVID? I know one
thing we've certainly seen written about is, if you were sick enough to require hospitalization, that was a
risk factor, but what other risk factors in terms of people's health, history, age, gender, comorbidities,
anything else are you seeing now as defined risk factors for long COVID?

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Leora Horwitz ( 09:47 ):
We're actually just looking at that as we speak in our recovery data. So I look forward to being able to
tell you the results of that from RECOVER. But there are lots of other studies that have looked at that
too. And the findings so far are actually relatively similar to the sorts of things we see with other
postviral conditions. So it seems to be more prevalent in women than in men, even though men did get,
being male was a risk for being more severely ill, at least in the early strains. But here, we're seeing
more women than men. There is an association with the severity of underlying disease. So the number
of comorbidities that people have does seem to be associated with how likely they are to go on to
develop long COVID. And people have begun to look at other things like lab tests and medications, and
things like that, but nothing really definitive yet.

Mark Masselli ( 09:47 ):
We -

Leora Horwitz ( 10:41 ):
I just want to make -

Mark Masselli ( 10:41 ):
Okay.

Leora Horwitz ( 10:43 ):
I want to make one other comment, which is that although it's more common to have long COVID with
severe initial illness and more common to have long COVID if you are yourself ill at baseline, the sheer
numbers of the pandemic mean that there are probably more people who have mild disease and people
who have no comorbidities, who have long COVID than the reverse. So even though the risk is higher,
the sheer numbers are such that there are plenty of people who had mild COVID who are perfectly
healthy, who now have long COVID.

Mark Masselli ( 11:16 ):
I want to pull the thread on Margaret's question there. And we were involved with NIH All of Us
program since the IRB development, and one of the reasons that Dr. Collins put that initiative together
was really to make sure that any cohort represents all of us. So in addition to men, gender, and age, how
reflective is the group that you're looking at that would reflect all the diversity within our country?

Leora Horwitz ( 11:50 ):
Yeah, actually, that's something we work really hard and prioritize highly. So recover, the adult study is
located in 33 different states across the country, plus Washington, DC, plus Puerto Rico. We set as a
target at the beginning of the study that we should enroll certainly to look like the US population, but
ideally even overrepresent, underrepresented, or minority populations because they were at higher risk
for getting COVID in the first place. Our population now looks exactly like the US. We are about 16%
African American. National average is 14%, we're at 17% Hispanic, national average, I think, is 19 or
something like that. So we're very close. We are well overrepresented in Asian populations. We're at
about 7% versus national average of one or two.
( 12:46 ):

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So we really have worked very hard to make sure that our population in the study looks like America.
And that's partly why we took about, it's been about a year and a half to enroll our participants, who are
at about 95% done now, and we slow - walked that a little bit on purpose so that we could make sure we
were outreaching to communities that really don't often participate in research and need to be
represented.

Mark Masselli ( 13:15 ):
Well, I think that would be a great confidence to the American public, and NYU does such a great job in
terms of the diversity of people. There's been research reports indicating that long COVID leads to
worsening or underlying neurological conditions, including Alzheimer's and Parkinson's disease. What do
we definitively know now about those relationships?

Leora Horwitz ( 13:39 ):
That's a good question. We don't definitively know anything really about anything. Clearly, cognitive
symptoms, brain fog, confusion, trouble concentrating, trouble remembering things are a cardinal
symptom of long COVID. They are among the most common things reported independent of a formal
diagnosis of any kind of dementia. We know that the initial COVID infection often caused strokes or
ministrokes in people, and that could also be contributing to people's difficulty in concentrating. And
then, of course, we isolated all of our most vulnerable elders for good reason to keep them alive. But
that definitely worsened people's cognitive trajectory because they had fewer social interactions. And so
it could be that people who had Alzheimer's previously have worsening cognition, not so much because
of the COVID proper, but because of the change in their experience. So it's hard to disentangle all of
these things.

Margaret Flinter ( 14:45 ):
You have a very challenging body of work here with all of the complexity, but we'll add another one to it.
There's some preliminary research from the Harvard T.H. Chan School of Public Health that suggests that
people with high stress levels were more likely to develop long COVID after an acute infection. Love to
get your thoughts on that. And is there a behavioral health component to this, perhaps maybe more
than we first realized?

Leora Horwitz ( 15:11 ):
Well, this has always been a longstanding question with a lot of these postviral illnesses. You will notice
if you look at the list of the 12 symptoms that anxiety, depression, mood disorders are not in that list.
They didn't make it because they're not as distinctive. People who haven't had COVID have plenty of
anxiety and depression, and stress, and the pandemic world was stressful for everybody. So we don't
find that to be a cardinal manifestation, although we do see a high prevalence of anxiety and depression
and mood disorders, and so on in people. We are actually really explicit about that in RECOVER, we ask
not only questions about people's physical symptoms, we ask about their mental health, we ask about
their experience with loss and with grief because we know that's an issue in the pandemic time, we ask
about PTSD, we ask also about... we have a perceived stress score index that we measure, and we also
measure their community. We measure people's... their experiences of discrimination. We measure
their neighborhood cohesion and what their neighborhood is like.
( 16:21 ):

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So we really try to get a sense of the other factors, the non - biomedical factors, that influence people's
not only their symptoms but their ability to recover from illness, their ability to take off time if they need
it. All of these things that we know affect people's health. So we will be looking at that. But
fundamentally, I do just want to say that this is not primarily or exclusively a mental health disorder.

Mark Masselli ( 16:51 ):
I'm wondering how much time it's taking for patients with long COVID to get better. There are reports
they're getting better quicker than first fear. And I guess throw into the equation is Paxlovid, also sort of
being evaluated in terms of separating them out, those who either took Paxlovid or who didn't, into
your study.

Leora Horwitz ( 17:14 ):
We measure that in this observational cohort. And I should mention that RECOVER, the umbrella, has a
number of other studies. There is a study of children, there's a study of people who have died after
COVID, and there's an electronic health record study that has millions of electronic health records. And
that study is looked at the effective Paxlovid on longer - term COVID, and those results think are coming
out shortly.

Mark Masselli ( 17:39 ):
Anything that you've heard on that that you might want to share with us?

Leora Horwitz ( 17:42 ):
Actually, just -

Mark Masselli ( 17:43 ):
Even a glimmer?

Leora Horwitz ( 17:44 ):
... I don't know. I can't share those results, but I don't really really know them. But that is a core interest
of ours, for sure. So we will look at it in the future. We haven't looked at it yet. There are clinical trials
starting with Paxlovid, including in the NIH RECOVER program, because of this theory that... one of the
theories is that maybe there's viral persistence, so maybe even without having an active infection,
maybe Paxlovid will be helpful. Those clinical trials are ongoing.

Mark Masselli ( 18:13 ):
But are you seeing that people are recovering quicker, or what are you seeing right now?
Observationally.

Leora Horwitz ( 18:20 ):
We certainly see a path of improvement. People who have symptoms at three months, fewer of them
have symptoms at six months. Fewer of them have symptoms at nine months. Among the people who
have had symptoms for a year or more, there's less improvement. So people definitely get to a plateau.
In the study that we just published, that first look from RECOVER, we had a certain number of people
who were measured at six months and at nine months after their infection. And about a third of the

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people who met that 12 - point criteria at six months didn't need it anymore at nine months. So we
certainly were seeing improvement there, and I certainly hope that that continues as well.

Margaret Flinter ( 18:58 ):
Well, Dr. Horwitz, all of this really speaks to me to the need to get vaccinated for COVID. We're nearing
our annual flu vaccination season, and it's a good time to remind people about that and that getting the
COVID booster shot is a good idea, and that really does help people avoid getting long COVID, doesn't it?
Do you think we're emphasizing that message enough?

Leora Horwitz ( 19:21 ):
I hope so. I emphasize it every time I speak, so thank you for giving me the opportunity to do that again.
We have now ample evidence, including from the RECOVER EHR studies and this most recent study that
we did, that vaccination does reduce the risk of long COVID. And this goes just along with that general
understanding that we have that the sicker you are initially, the more likely you are to have long COVID.
And one thing that vaccination does very well is it prevents people from getting very sick. You might still
get COVID. I got COVID despite being vaccinated, but I was barely ill. And so we know that the
vaccination reduces the severity of acute illness, and there is now good evidence that it reduces the risk
of long COVID as well. I do think that hopefully we embed this into our annual flu cadence so that you
come to the fall, you get your flu and your COVID, and then we can try to... hopefully that becomes just
a standard for people usually.

Mark Masselli ( 20:20 ):
The website stat looked into long COVID and posted a headline that said that, "The NIH has poured a
billion into long COVID research with little to show for it." And that's a quote. It pointed out that there
were been delays and says a sense of urgency is missing. I'm wondering if you could give us your
perspective on the impact of the investment that's been made and how you all are leaning into this
research project.

Leora Horwitz ( 20:52 ):
Sure. Well, setting aside the fact that it's taking up 24/7 of my time and everyone else's time, we
certainly feel a sense of urgency. But let me comment on a couple things. So one is that Congress
allocated a billion dollars for the RECOVER program as a whole. That includes all of the RECOVER stuff,
the clinical trials that have yet to happen, the cohort follow - up that has yet to happen, all of the other
infrastructure. So we have actually spent only a small fraction of that billion dollars because it's intended
to last for many years so that we can do all the research we need to do. So I just want to first comment
on that. The second thing I want to say is that we have to always balance the need for rigorous and
reproducible science with the need for speed. And that's just a constant challenge.
( 21:45 ):
So, as we talked about earlier, we made a deliberate decision to make sure that our cohort looks like
America. We could probably have filled it really fast with a bunch of 40 - year - old white ladies like me,
who were very connected and very engaged and had great access to healthcare and were very computer
literate, and could get to our website and fill it out quickly. But we didn't want to do that. We wanted to
make sure that our study really looked like our country, and that takes more time. And the same is true
for the pediatric study. They took a little extra time to get going because it's really important to set up a

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study that is going to be safe for children that are participating. The third thing I want to say is the
amount of information and data, and stuff that we've collected already, I think is spectacularly fast.
( 22:36 ):
We, the NIH, awarded the sites and the coordinating our bodies in around May of 2021. We had a full
protocol for this outrageously complicated study developed within a month. We had contracts, an IRB
protocol, approvals, all of that stuff for 200 something sites around the country in place by September.
We enrolled our first participant into RECOVER - Adult in October. I cannot think of another study that
has happened that fast and with that speed. And we have enrolled well over 14,000 people since then,
just in the adult. And there's well over 9,000 in the pediatric study. And of course, many billions in the
electronic health record study. Electronic health record cohort has published already dozens of papers.
We have already our first results paper out, and I am anticipating now a tsunami of studies now that we
have 14,000 people who have filled out questions every three months, who have also provided
laboratory tests, who have provided blood tests for future testing, who have undergone x - rays, who
have undergone physical examinations and assessments.
( 23:53 ):
We have the largest set of rigorous data of anyone in the entire world in this study. And I think it is going
to just be a tremendous resource for many years to come, not only for long COVID but for the postviral
condition community in general. We have ignored myalgic encephalomyelitis/chronic fatigue syndrome
for many years, and many of the characteristics that people with long COVID have are also similar to
those that people with ME/CFS have. I think we will learn not only for our long COVID patients but for
this huge community of people who have been suffering for a long time from postviral conditions that
we now will have some better insight into.

Mark Masselli ( 24:36 ):
Well, thanks for level setting on that. That's very important, and it's really almost warp speed relative to
how long these things take, so that's impressive. Tell me, will the data be available to the scientific
community, and what's the timing on that so people can also build on your research?

Leora Horwitz ( 24:55 ):
Absolutely. All data that's sort of funded by the NIH will be publicly available, as is their standard. In
terms of the timing for that, we are working as quickly as we can to organize that. We are needing to
organize the data to clean it up, to connect it to the appropriate specimens, and so on. So I actually
don't know the timing for that, but it won't be very long. We're not going to wait 10 years to make this
available to the public. And in the interim, we're also still trying to make it available even within
RECOVER investigators, we have thousands of investigators within RECOVER that are interested in using
the data too.

Mark Masselli ( 25:36 ):
Wonderful.

Margaret Flinter ( 25:37 ):
Well, Dr. Horwitz, given all of this, it almost seems preposterous. I have to ask you the next question, but
you've spoken before about physicians who are doubtful about recognizing long COVID as legitimate. Is
that situation improving, or they're still skeptics that there is such a phenomena as long COVID in the
medical community?

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Leora Horwitz ( 25:58 ):
I think there are. I certainly think there are. We don't have good data about that nationally. I don't think
anyone has surveyed doctors to see what they think. So it's hard for me to put numbers on it, but I hear
all the time from our participants, I went to my doctor and they didn't believe me, or I went to my
doctor and they told me I was fine, or I went to my doctor and they told me I had these 10 other
diseases, or whatever. So I think that is still a problem. I also will point out that it's not just doctors, the
general community also is not yet fully aware, and one of the challenges we have in recruiting from rural
communities, from minority communities is that often they haven't heard about it either, or there's a
stigma associated with this idea that you might be weak and you just haven't recovered, and everyone
else around you has, and there's something wrong with you. So I think that's a challenge not only for
doctors but for the general public.

Mark Masselli ( 27:00 ):
Dr. Horwitz, I know the answer to this question, which is if people think they're suffering from long
COVID, what they should do is obviously go to their provider. But you've raised an interesting point,
when they're a provider who is dismissing that, should they look for a clinical trial to enroll in? Are there
support groups? What else can they do on this journey? Which can often be very difficult because of the
complexity of the impact that COVID had on people.

Leora Horwitz ( 27:31 ):
Yeah. One of the most amazing things I think about this pandemic is the degree to which patients
themselves have self - organized and have provided that kind of knowledge and support. That honestly
was really missing in the medical community, and much of what we knew early on and still to this day,
what we know comes from patient groups and patient advocacy organizations, and there are a number
of them that are very active on Facebook and Instagram, and elsewhere to support people and let them
share their symptoms and their challenges and their treatments, and so on. There also are long COVID
or post - COVID clinics in many cities, they are oversubscribed that way. Times are long, and that's a
challenge, but they do exist in many places, and there has been new interest in new federal funding
opportunities available for centers of excellence for treatment of long COVID that are in the process of
review right now. So hopefully there will be more of those as well at this time.

Mark Masselli ( 28:38 ):
What are you doing with your international colleagues on this issue? Because, obviously, COVID is a
global problem, the pandemic was global. Is there anybody you're looking at? I know England and a
couple of other people were probably a little more advanced in some of their data gathering, but who
are you keeping your eye on internationally?

Leora Horwitz ( 29:03 ):
Yeah, we've actually had a number of phone calls and attempts to coordinate our questionnaires and
things like that with groups overseas. We talked to the WHO regularly, people in England, there are
groups in most of Western Europe that are working on this. So we've really tried to make sure that the
sorts of things we're asking about are aligned and the questions that we're asking are similar.

Margaret Flinter ( 29:31 ):

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Great. Well, thank you, Dr. Horwitz, for joining us. I want you to know that our past shows on long
COVID are some of the most watched on YouTube, so we know this is a very important topic, and thanks
to our audience, there's more online about Conversations on Health Care, including a way to sign up for
email updates, and our address is chcradio.com. Dr. Horwitz, thank you. We will continue to look
forward to the results of your research.
Leora Horwitz ( 29:56 ):
It was a great pleasure, and thank you for having me.
Mark Masselli ( 29:59 ):
Yeah, absolutely. Continued success, and thanks for all the work that you're doing. Probably seven days
a week, 24 hours a day, but...
Leora Horwitz ( 30:07 ):
It feels that way.
Margaret Flinter ( 30:07 ):
It's very healthy.
Mark Masselli ( 30:08 ):
All right, take care now.
Leora Horwitz ( 30:10 ):
Thank you.
Margaret Flinter ( 30:15 ):
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