The Yale LISTEN Study Town Hall: July 2023

February 28, 2024

Information

Drs. Harlan Krumholz and Akiko Iwasaki discuss preliminary findings and answer questions from LISTEN participants.

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00:05There you go. OK,
00:09so for anyone who's watching
00:10this now is being recorded.
00:11We've we've we've just welcomed everyone
00:14and now we're just starting the recording.
00:16So for anyone who's just joining us by video,
00:19we welcome you too.
00:21But so let me just anyone else got
00:26any comments midsubernally if you
00:28could go anything else before we go.
00:31OK. So again the the I won't take too
00:35long on this piece but just to tell you
00:38so listen studies consists of of people
00:40who are living with long COVID people
00:44who are experiencing adverse effects
00:48after having had the vaccine and other
00:51people controls we call them controls.
00:53We really mean are people who aren't
00:55suffering from either of those two
00:56things because we really in some of
00:58the studies are going to need people
01:00who are in a similar situation to you
01:02with regard to their demographics
01:04but are different from you in the
01:07sense that they're not suffering
01:08from a chronic condition.
01:10And so we're also encouraging many people
01:13within listen to if they can identify
01:15others to join this who can serve as
01:18sort of that reference population.
01:20Someone said they're they're
01:22not hearing the audios,
01:24most people hearing the audio.
01:25I can see people so I can just
01:27tell me so sorry Jose,
01:28but we're it seems like it's going so the
01:34so right at this point Kindred by the
01:37way has over 4000 people who have
01:40joined Kindred and I hope that's been
01:42a source of support for many people
01:43is that information has been passing.
01:45Kudos to that team. And the LISTEN study,
01:48which you're part of and that's
01:50the what we're talking about today,
01:53has, believe it or not, 20 / 2100
01:56people have joined the listen study.
01:58And you know, this is pretty novel in the
02:01sense that we didn't go to doctors and said,
02:03can you identify people in your practice
02:05who might want to join a study.
02:07And you know that there can be implicit
02:09biases in that where you know,
02:11some people are offered the opportunity
02:12to join a study and other people
02:14don't necessarily get the opportunity
02:15to join a study.
02:16And and and people may not, you know,
02:19come in through that pathway very
02:21well or you're not at a center that's
02:23been asked to be part of the study.
02:24So you're really not possible for
02:25you to be part of that.
02:27But in this study,
02:27what we wanted to do was go straight
02:29to people and then let people let
02:32other people know and through various
02:34mechanisms sort of just grow organically.
02:37And again, you know,
02:37this study has to be worthy of your trust.
02:39So if people are having a bad experience,
02:41no one's going to join it.
02:42So people have to feel like this
02:44is something that's worthy of them
02:46being part of.
02:47Now everybody came into Kindred and
02:50filled out a basic questionnaire to
02:53a variable degree of completeness.
02:55So one of the things I want to take
02:57the opportunity to do is to say we
02:59are doing things with the surveys.
03:01And I want to encourage everyone
03:02to be sure that they have filled
03:04out all their surveys.
03:05Plus we're going to start getting
03:07to the point where we're going to
03:08send out more surveys specifically
03:10from the listen study.
03:11So that's going to be an important
03:13part of what we do also.
03:14And we're going to be looking to you
03:16all as we begin to think about like,
03:18what should we be asking,
03:19how do we make sure we capture it?
03:20How do we in way advocate for
03:23what your voice is in this,
03:25what your experience has been,
03:26in addition to trying to advance
03:28the science to figure out how we
03:30can relieve some of the suffering
03:31or at most of the suffering that's
03:33going on out there.
03:34So this is another important piece.
03:36The connectivity to the medical
03:38records is another part.
03:39We're just going to start working
03:41on that as well.
03:42So many of you have connected your records.
03:44You know that Hugo is configured so your
03:46data doesn't move without your permission.
03:48There's no secondary marketplace,
03:50the data doesn't get sold it it's
03:53this has been like the whole idea
03:55was to give people agency over their
03:57own data to be able to pull that
03:59data together whether by wearables or
04:01health systems or insurers and payers.
04:04And so you're essentially have you
04:06accumulate those data assets and be
04:09able to share them into the study.
04:11This is a very unusual and novel effort here.
04:14And if we can prove that this can be done,
04:16I think it will spread as a mechanism
04:18to try to accelerate the way in
04:21which data can be aggregated,
04:23organized and analyzed so that
04:25we can learn in almost real time
04:27what's going on with people.
04:29And because the data streams
04:32with your permission,
04:32we're able to use it within the state.
04:34And again, we,
04:35we did agree in the consent that
04:38at some point we might allow other
04:41investigators to use the data,
04:43but we would have to de identify the
04:44data but enable other investigators.
04:46But what won't ever happen is
04:48the data won't be sold.
04:49It won't be commercialized in that way.
04:52It'll be only used for science to
04:54try to advance knowledge to try to
04:56make a difference to to what you
04:59guys are facing or or what people
05:01that you care about are facing.
05:03And so that's the configuration of this.
05:05So we're urging people to make sure
05:07they fill out the whole questionnaire.
05:09We we for some of the people we're
05:11actually adding some additional
05:12questions that are being done.
05:14But but we will be increasing I think
05:17the cadence of some of the information
05:20collection and then the the medical
05:22records are another important part of that.
05:23And then there's another piece of this
05:25study which is that there's a smaller
05:27group that we are working on to get
05:31to gather blood and saliva so that
05:33it can be analyzed in a Kiko's lab
05:35where now he's heading this effort to
05:37to organize this and it's collecting
05:39it in people's homes for a smaller group.
05:41And we are going to use that to
05:44try to correlate how people are
05:46reporting their experiences with
05:48what we can do from thousands of
05:51measures of of the immune system and
05:54and how it's functioning to try to
05:57begin to make some progress towards
05:59understanding and so quickly.
06:01I just also want to say that we we're
06:04if I were in your position I might
06:06be a little impatient like OK so when
06:08stuff going to start moving out the
06:10the the vibrations preprint is an
06:12example trying to move things out.
06:13We've got several other pieces
06:15that we want to move into preprint
06:17so you can see them.
06:18These are going to be basic descriptive
06:21studies that just help you understand
06:23who's in listen and and so we're
06:25going to do that for long COVID,
06:27we're going to do that for vaccine injury.
06:29We're going to do that for the combination.
06:30We're going to look at that all
06:32together and apart and and then
06:33we're going to look also people who
06:35have like we've looked at vibration
06:37and not we'd like to do that.
06:39Similarly for people,
06:40there are a lot of people
06:41have tinnitus ringing in
06:42the ears and not there's a
06:44lot of people who have pots.
06:46So they have autonomic dysfunction
06:48and we want to like look at that
06:51group specifically and we also are
06:53interested potentially in talking
06:54about people have central nervous
06:56system issues especially cognitive
06:58dysfunction and how does that look.
07:00Now there'll be overlaps in all these,
07:01but we're we're trying to
07:03characterize the group.
07:04So to manage your expectations
07:06there's these aren't going to be
07:08Nobel Prize winning contributions.
07:10What we're trying to do first is
07:12explain who's in the study what,
07:14what are some of these patterns
07:16We're doing some what's called
07:17cluster analysis to see, you know,
07:19who are what.
07:21I'll say like a sort of the what's the map,
07:22how are people organized with
07:24regard to their symptoms?
07:26Where are the areas where there's
07:27lots of people who have this cluster
07:29of symptoms versus this cluster?
07:30Because we believe that this label
07:32of law of of whether it's long
07:34COVID vaccine injury is too broad.
07:36It's it's it.
07:38They're probably different mechanisms
07:39but awful different manifestations.
07:42Just because someone's called long COVID,
07:43you may be very unlike some other
07:46people who are also called long COVID.
07:48And the more specificity we get the
07:50more likely we're to make progress.
07:52We start to build a a taxonomy around
07:54this a way to talk about this it's
07:57more sophisticated more precise and
07:59and for each of you it helps people
08:01understand who what you're experiencing
08:03and not putting you under some big
08:05categorization that actually doesn't
08:07really capture capture who you are.
08:09So in some thank you can't
08:12we can't thank you enough.
08:14Two we're urging you to to as
08:17much as you can participate with
08:19regard to filling out the surveys
08:20to connecting your records and if
08:23we're if you're asked about those
08:25blood specimens to give it some real
08:29consideration that would be great.
08:31We're going to start pushing,
08:32pushing stuff out.
08:33Some of the stuff will be very
08:35basic in the beginning.
08:36And again this idea of pre printing.
08:38So it's an Open Access link,
08:40we'll send it out to people and
08:42so it's there's no firewall,
08:44there's no price to it.
08:45It's just posted and it'll look like a paper,
08:48but it's there for public comment.
08:49It hasn't gone through peer review yet.
08:51It's just out there for your comments.
08:53So we're going to urge you to make
08:55comments and participate that way as well.
08:57And if anyone in the group wants to
08:58be more involved in studies or more
09:00involved in the things that we do,
09:02we need help. We're interested.
09:03We know you guys,
09:04I've got a lot on your plate
09:06just to deal with your health.
09:08So we don't want to impose or burden you,
09:10but I want to really extend the
09:12invitation that that many people
09:14have different skills in this group
09:16that could actually help help us
09:18advance and make more progress.
09:20So if you think there is a way that you
09:22want to be involved,
09:23then reach out to us and let us know.
09:25We for sure would want to hear that.
09:26And meanwhile, by the way,
09:27you also know there is a clinical
09:29trial we're doing with Pax Lovid,
09:3115 days of Pax Lovid versus placebo.
09:33It has been limited to three states,
09:36but we're about to expand it out.
09:39Leslie sent out a note to
09:41Kindred members I think today to
09:44say we're we're extending it.
09:45I hope we're going to extend it to all.
09:47There are a lot of exclusion criteria.
09:49So it's like any clinical trial,
09:51it's like you know there's this
09:53is there's certain ways you've got
09:55to satisfy to get in but and it's
09:57only going to be 100 to start.
09:59But again,
10:00every one of these people is going
10:02to get deep immune phenotyping in
10:04the Kiko's lab both before in the
10:07middle and at the end of the some
10:09of the data collection to help us
10:11understand whether one there are
10:14people who have maybe viral persistence.
10:16Are there people that are really
10:18responders to an antiviral like Paxlovid?
10:21And what can we learn in general about
10:23long COVID through this clinical trial?
10:25And I know there are others who may
10:27feel like either they don't qualify or
10:29they're not in the long COVID group
10:30saying when are you going to study us?
10:32And we're eager to.
10:33We're just need to figure out,
10:35hey, brass tacks we got,
10:36we have to figure out funding,
10:37we have to figure out how to do it.
10:38There's lots of stuff to get together.
10:39But the more momentum we get,
10:41the more we can convince others that
10:43this is real. We need to invest in it.
10:45We need to get answers and we need
10:47to help address the suffering.
10:48So with that,
10:49let me hand it over to to Tiana,
10:51who will just talk a little bit
10:53about the preprint and then she'll
10:55hand it over to Akiko.
10:57I'm here to share a little
10:58bit about the preprint.
10:59I'll share my screen. So I want to
11:02make sure everyone can also see it.
11:04Can you see the PowerPoint? OK, good.
11:08So this is one of the efforts that
11:10is ongoing in the Listen study.
11:13Like Harlan mentioned,
11:14there's many other avenues of
11:16questions that we're exploring,
11:19but this is just one of them.
11:20And this is specifically about internal
11:22tremors and vibrations as a symptom
11:25among people with long COVID and Listen.
11:29So the preprint is posted on Medarchive.
11:32If you want to take a deeper dive,
11:34feel free to look it up with this
11:36title on Medarchive and send us your
11:40comments or additional questions.
11:42As a caveat,
11:43some of the other results that I'm
11:45presenting today are more updated
11:47compared to what's posted on here.
11:50So if you hear something interesting
11:52today but you don't see it
11:54on the Med Archive page,
11:55it's because we have some new
11:57analysis that we haven't posted yet.
12:00So the motivating question that we
12:03had was this question right here among
12:06listen participants with long COVID.
12:08How do those with versus without
12:11internal tremors and vibrations
12:13differ from each other?
12:15And what's been described about
12:18internal tremors and vibrations has
12:21been this emerging definition of
12:24movement or a sensation of movement
12:26at any location inside the body
12:29occurring with or without external
12:32visible movement or muscle spasms.
12:34And the scientific literature
12:36that I've been able to find,
12:38we're mostly focused around Parkinson's
12:41disease and essential tremor.
12:42But I also saw in the chat,
12:44I think Angie posted something
12:46interesting about this being a
12:48perimenopausal or menopausal symptom.
12:51So I would love to hear more
12:52about what are other situations
12:54where this has been described.
12:56All of this is contextualized
12:59with the caveat that clinicians,
13:02researchers,
13:02patients might have different definitions
13:05for what is a tremor and how to
13:09classify different types of tremor,
13:11and that's still being actively
13:13discussed in the scientific literature
13:15about the best ways to approach that.
13:17For our methods,
13:19we particularly focused on the
13:21survey data and for the results
13:23I'm about to describe we have not
13:26utilized any of the biospecimens
13:28data or the electronic health
13:30records data that you've shared.
13:32And the surveys,
13:33if you some of you recall
13:35asked about your demographics,
13:37socio economic characteristics,
13:39pre pandemic medical and psychiatric
13:41conditions as well as current conditions
13:44at the time of taking the survey.
13:47Current health status which was
13:49measured by a standardized quality of
13:52life question and current symptoms,
13:54choosing from a list and having the
13:58option to say other or none and long
14:01COVID was defined by self report.
14:04Do you think you have long COVID without
14:06imposing any additional criteria
14:08around when the long COVID symptoms
14:11started or how long those have lasted?
14:14The way that The Who criteria
14:18imposes And for internal tremors,
14:20The specific phrasing in the
14:23questionnaire was internal
14:24tremors or buzzing vibration,
14:26and if someone checked that
14:28box then they were defined
14:31as having that symptom.
14:32So our statistical analysis
14:35took a two pronged approach.
14:38We first just simply analyzed a bunch
14:41of variables between the two groups.
14:43So demographics, socio economics,
14:45all the conditions and everything
14:48else that I have just mentioned,
14:51comparing them between the groups,
14:53the two groups,
14:54those with and without internal tremors.
14:56And two things I want to highlight
14:59here are that we also use the symptom
15:03questionnaire to calculate an
15:05approximation of something that the
15:07Recovery Consortium proposed which some
15:09of you might have read about in the news.
15:11So this is an NIH funded research consortium
15:16that suggested a preliminary scoring
15:18system for how to define long COVID.
15:21And just out of curiosity,
15:24not because we explicitly endorse or have
15:26any sort of opinion about what they propose,
15:30we just wanted to check how their
15:33scoring criteria might or might not
15:36apply in the listen population.
15:38And we also define something
15:39called new onset conditions.
15:41So that was calculated based on
15:43conditions that people reported as
15:45having at the time of taking the surveys,
15:48but were not reported as something
15:50they were having before the pandemic.
15:53The second branch of our analysis
15:55was a machine learning model.
15:58It was a gradient boosted tree machine
16:00and the focus of this particular
16:03analysis was just to see what symptoms
16:06are important for differentiating
16:08people with internal tremors from
16:11those without internal tremors.
16:17Here are some of our results in the
16:19overall group of listen participants
16:21with long COVID median age was 46 years,
16:25a majority were female,
16:26a majority were white, and 37%.
16:29A substantial minority reported symptoms
16:32of internal tremors or buzzing vibration.
16:35As a long COVID symptom and
16:38comparing the two groups,
16:39people with internal tremors were
16:41significantly more likely to be female
16:44with no significant differences in age,
16:47race, marital status,
16:49pre pandemic employment,
16:52pre pandemic household income.
16:55Something really interesting that I want
16:57to highlight is that the two groups
17:00were not different in their rates of
17:02any of the pre pandemic conditions
17:04that they had across 30 some pre
17:06pandemic conditions that we asked about
17:09but for infection characteristics.
17:11People with internal tremors were
17:13more likely to report it an index
17:16infection during the pre delta wave
17:21for health status which was measured
17:24by the Euro QOL quality of life scale.
17:28We found that the overall score that
17:31people rated their health status on
17:34for the overall group the median was 49
17:37and this is on a scale of zero to 100.
17:39Zero means the worst and 100 means the best.
17:43And we found that people with internal
17:47tremors were statistically significant
17:49in rating their current health as
17:52being worse than the other group.
17:55And here's also the recover score
17:57that I mentioned before.
17:58So it's an approximation because
18:01our questionnaire does not match
18:04the recover studies questionnaire
18:06directly in terms of the symptoms.
18:08But to the best of our ability we
18:12approximated using their scoring criteria
18:14and we found that overall across everyone
18:17with long COVID in this and listen,
18:20we have a score of around 16,
18:23a median score of 16,
18:25inter quartile range of 12 to 23 and
18:28people with internal tremors reported
18:30a median score that was higher than
18:33those without internal tremors
18:37for a new onset conditions.
18:39Comparing all of these conditions,
18:41rates of mast cell disorders,
18:44neurologic conditions,
18:45anxiety disorders,
18:46and trauma and stressor related
18:49disorders were significantly higher
18:51among people with internal tremors
18:53versus people without internal tremors.
18:55And again, this is new onset
18:58conditions that are occurring at
19:00the time of taking the surveys
19:02as opposed to anything that was
19:05reported as a pre pandemic condition.
19:10For the machine learning
19:11model that was created,
19:13here is a list of the top symptoms
19:16that were really important for
19:17differentiating the two groups.
19:19And I want to just highlight
19:20the top five right here.
19:22So hair loss was the most important,
19:24followed by floaters or visual lights,
19:28neuropathy, tinnitus and sudden chest pain
19:30and the other ones so on and so forth.
19:34On this list here,
19:37some of the early conclusions that we can
19:40draw are that participants with internal
19:43tremors and vibrations compared to others
19:45in listen who also have long COVID.
19:48They had similar demographics,
19:50similar health before the pandemic.
19:52But something about them might have
19:55been correlated with having different
19:57new onset conditions at the time of
20:00taking the surveys and having worse
20:02self reported health status measured
20:04by this quality of life scale and
20:07the machine learning model helped us.
20:10Understand that it is possible to
20:13differentiate the two groups from
20:15each other on the basis of other long
20:17COVID symptoms that people reported.
20:20Like Harlan mentioned,
20:21there's a lot of other studies that
20:23are ongoing right now and I want
20:25to specifically thank all of you
20:27on this call who participate bar
20:29participating in listen and some
20:31specific people including Sean,
20:33Kelly and Teresa.
20:34I want to thank all of you.
20:37That's it.
20:37Feel free to write more questions in
20:39the chat and I'll try to get to them.
20:43That was amazing. And for all of you
20:46on Tiana's actually medical student.
20:49And so we how are so fortunate to have
20:51people at all sorts of different levels,
20:53but to get a medical student at this
20:57caliber to help us is remarkable.
20:59Akiko, do you want to take on next?
21:03Sure. So I know that some of
21:05you have asked questions about
21:07what is the updated view of what
21:10might be causing long COVID.
21:13And so I wanted to just share
21:15a couple of slides as to how we
21:18are thinking about it. Let's see.
21:24OK,
21:28can you see this? Yeah, OK, great.
21:32So yeah, you know as you have
21:35heard me speak about this before,
21:37we we had four hypothesis for
21:41the root causes of long COVID.
21:44The first one being the viral
21:47reservoir or viral pathogen associated
21:49molecular patterns which is the
21:51nucleic acids of the viral genome.
21:54And these things can cause persistent
21:58symptoms because the either the
22:01viral antigen that triggered T or
22:05B cells chronically or viral RNA
22:08that can trigger this innate immune
22:11system to secrete certain types of
22:14inflammatory cytokines can both lead
22:17to chronic conditions and symptoms
22:20That that was our first hypothesis
22:23and and this is really related to
22:26the source COVID 2 virus that causes
22:28COVID 2nd hypothesis was autoimmunity.
22:32This is basically T and or B cells
22:36that react against self antigens.
22:38And we have seen a pretty striking
22:41evidence of auto antibody in
22:44severe cases of acute COVID.
22:47These patients either had prior
22:50existing antibodies against the
22:52immune factors that render them
22:55more susceptible to severe COVID or
22:58they developed auto antibody during
23:00the course of infection that target
23:03very various different tissues and
23:06cell types throughout the body.
23:08And once these things are triggered,
23:11it's it's very difficult to reverse them.
23:13And this is the second possibility
23:16as to why some people are suffering
23:19from the chronic phase of COVID.
23:22And the third hypothesis is dysbiosis
23:26of microbiome mainly we were thinking
23:30about the gut microbiome and potentially
23:34causing some leakiness in the gut
23:38epithelium that leads to inflammatory
23:40conditions and that's certainly been
23:42seen in MECFS and other conditions.
23:45We we also thought of reactivation
23:48of latent viruses that all of us
23:51carry a variety of viruses inside
23:54of our body which are latent and
23:57don't cause any symptoms or disease.
24:00But when there is a the immune pressure
24:02that's controlling these viruses,
24:04when they're lifted or when
24:06they're dysfunctional,
24:07these latent virus can become reactivated.
24:11And the the 4th hypothesis is tissue damage.
24:15This is it doesn't have to even
24:17occur at the site of infection.
24:19We demonstrated using a mouse model
24:22of mild respiratory COVID that even
24:25a lung infection that's transient
24:27in a mice can lead to very long
24:31term changes in the central nervous
24:33system that is not reversed even
24:36after weeks of weeks post infection.
24:39And the I've sort of highlighted
24:42each of these boxes with different
24:45colors to indicate that throughout
24:47the research that we've been doing,
24:50we are seeing as well as many others
24:53that are in investigating the causes
24:56of long COVID Viral persistence is one
24:59of the key hypothesis that still is
25:05supported by over 100 different publications.
25:09We still don't know if the virus
25:11that's persistent in some people are
25:14causing the disease or it's just a
25:16sort of what happens with COVID and
25:19that it doesn't relate to the disease.
25:22And one of the best ways to
25:25to figure this out is,
25:26is through this back slovid trial
25:30that Harlan already mentioned.
25:32What this allows us to do
25:35is kind of interrogate the immune
25:37system in people who have long
25:40COVID prior to the treatment with
25:43Paxlovid and during the treatment
25:45and after the treatment to see how
25:48the immune factors change over time
25:51and how does that change correspond
25:54to benefit for the patients.
25:57Since we think that there are
25:59multiple root causes of long COVID,
26:01we're not expecting everyone to
26:04respond positively to Paxlovid.
26:06But we're hoping that a subset of
26:09people who respond to PAC Slovid
26:11will tell us a lot about what are
26:13the biomarkers for responsiveness?
26:16What are the features that are
26:17common in the people who respond
26:19positively to PAC Slovid?
26:21And in the future trials can we enrich
26:24for those people with the biomarkers
26:27to provide a sort of better chances
26:30of people recovering or feeling
26:32better from COVID with PAC Slovid.
26:35So, so this is sort of a an area
26:38that we're heavily investigating
26:39and are very excited to be able
26:42to do this with you all.
26:45Of course we're recruiting some
26:46some of you through the listen
26:49study and and hopefully we'll be
26:51able to tell you what's going on
26:53once the the study's completed.
26:54But that that's a huge,
26:56I think it will give us a gives us a
26:59huge clue as to what might be driving and
27:02whether the reservoir has any kind of
27:05real evidence for disease autoimmunity.
27:08I kind of graded out a little bit,
27:10but this I haven't really dismissed,
27:13we haven't dismissed this possibility.
27:15It's just that in our studies we haven't
27:17found any common auto antibodies that
27:20are found in people with long COVID.
27:23If you look at the number of
27:25auto antibodies per person,
27:26they're not elevated necessarily in the
27:29long COVID participants compared to controls.
27:32And this is the study that Doctor David
27:35Petrino and our group have done together.
27:38It's called the Mylan COVID study and that
27:41is has been on Medarchive for almost a year,
27:45but it's finally accepted for publication.
27:47So we should be able to share
27:49the the latest with you shortly
27:52in the published version.
27:54But in any case,
27:55we don't see a clear cut evidence
27:57for auto anybody against human
28:00proteins that are expressed on the
28:02surface or secreted from the cells.
28:05However,
28:05it doesn't mean that there isn't
28:07AT cell mediated autoimmunity and
28:10it also doesn't mean there isn't
28:12a antibody mediated immunity that
28:15targets intracellular antigens.
28:16So we're still very much open to
28:19this idea and investigating further
28:23the the dysbiosis.
28:24We haven't really been able to look
28:27into the microbiome yet but we are
28:30looking at latent virus reactivation
28:32and this is showing us that in
28:35people with long COVID there appears
28:37to be an elevated level of Epstein
28:40Barr virus reactivation.
28:41As well as potentially there's
28:44zoster virus which is the the virus
28:48that causes shingles that may be
28:51reactivating much more frequently
28:53than people without long COVID
28:55who recover from COVID.
28:57And this has been reported not
28:58just by us but
29:00at least two other groups and it it's
29:02you know again we don't know whether
29:05this EBB reactivation is causing
29:06the symptom or it's just a sign of
29:10a dysfunctional immune response.
29:11But it is telling us there's some
29:13really biological difference in in a
29:15subset of people with on COVID and
29:18tissue damage we're we're continuing
29:20to use this mouse model and developing
29:22other mouse models to be able to
29:25look at the you know causal role of
29:28these inflammation induced damage.
29:30How do we reverse this you know
29:32such as the the the CNS impact and
29:36memory issues and brain fog and
29:38and so on that's reported.
29:40So this is sort of like the updated
29:43version of what I told you before
29:45and then you know ideally right
29:47we we we should have clinical
29:50trial coupled with deep biological
29:52analysis for all of these going on
29:55and there are some efforts going on.
29:57But I just wanted to kind of highlight
30:00I'm sorry the dog what we're doing
30:03here and then just sort of taking these
30:07insights into sort of the downstream
30:12effects and pathology that people are seeing.
30:15So the viral reservoir, autoimmunity,
30:17latent virus reactivation, tissue damage,
30:19this may be kind of happening in in
30:22concert within a person or one may be
30:24driving the disease in a subset of people.
30:27We don't know what the actual sort of
30:30connection between these wheels are.
30:32But what we do know is that there is also
30:36evidence of downstream pathology such
30:39as vascular damage that's reported from
30:42respiratory and and others including micro
30:45clots as well as platelet activation.
30:48These are two events that we are
30:51investigating in Els and study
30:53from participants who provided us
30:55blood and saliva.
30:57We're also looking at hormonal imbalance
30:59because one of the key defining
31:02factor that we saw in our long COVID
31:05participants was at reduced levels of
31:08cortisol as well as potentially other
31:10hormones and and so we're really looking
31:13into the this hormonal imbalance as a
31:17possible downstream sort of mechanism
31:20and mitochondrial dysfunction.
31:22This is also been reported both
31:25for MECFS and long COVID.
31:27We're investigating what the causes
31:30of a mitochondrial dysfunction might
31:31be and it may be triggered by the
31:35upstream events such as vascular
31:37damage and microcloth formation,
31:39which would then impair the ability
31:42of cells to acquire oxygen and
31:45properly conduct the the mitochondrial
31:48function in tissues.
31:50So these are sort of the downstream
31:52things that we also are looking at
31:55through the ELSN study and of course
31:58ultimately we'd love to identify
32:00biomarkers for different subsets of
32:03diseases and of course therapy and
32:07cure ultimately depending on what
32:09the driver of these diseases are.
32:11And so we,
32:12we are very excited to be able to
32:15do this with all of you and you
32:17know we're working very hard,
32:18Born Alley is working very hard in,
32:20in coordinating collection of
32:23biospecimen from a subset of
32:26you that's listening in today.
32:28So I'm going to just stop sharing.
32:30I,
32:31I think I took more than my share of time,
32:33but I'd be happy to address any questions.
32:37Of course
32:39we, I think we, we always appreciate
32:41when you take more time, it's great.
32:45There are questions that are both in the Q&amp;A,
32:49but some of that were sent to us before.
32:59So this person, there are a couple
33:00questions we're going to ask for
33:01you and then Bernal can answer one.
33:02But because this person said I've been
33:05tested and treated for micro clots,
33:06is this something that's going to be more
33:08readily available in the United States?
33:09I've been paying out of pocket
33:11to see a doctor.
33:12What do you think about microclots?
33:15Yeah, so we are also, as I just mentioned,
33:19very interested in our investigating
33:22microclots and in people.
33:23And we are seeing definitely evidence of
33:27microclots and platelet activation in some
33:30people with long COVID as well as some
33:33convalescent people who have recovered
33:35from COVID but have had COVID before.
33:39And right now I I don't want to make
33:41any claims that microclots are causing
33:44the disease because we don't know.
33:47We see some increases and it's variable.
33:50It's not that everyone has microclots,
33:52there are it seems to be a more
33:56activation in long COVID and and and
33:58even in post vaccine adverse events.
34:02However, we need to be very careful.
34:04First of all we need to have enough
34:06control to be able to say statistically
34:09significantly is is there an elevation and
34:12in the people who have these micro clots,
34:15what are the the the common common
34:17symptoms and features as well
34:18as immune markers do we see.
34:20So we we are cautiously approaching
34:24this with proper controls and trying
34:27to understand what that means.
34:29We don't know what it means yet.
34:31There are places that are doing
34:34the micro clot analysis.
34:37You know,
34:37I don't know which labs are doing them,
34:40but I know that there are some labs doing it.
34:42Hopefully they're doing it in a
34:44in a standard way because there's
34:47also variation between each labs
34:49in the outcome of these assays.
34:52So, yeah,
34:53it's it's very early days and I don't
34:57know what to recommend whether you
34:59should get the microcloth assay and
35:01and then what would be the treatment,
35:04you know,
35:05and so we're still in the discovery phase.
35:08Yeah. And I just endorse that.
35:09Also somebody asked me about this
35:11today in an e-mail and I said,
35:15you know, I think it's promising.
35:16I know a lot of people believe in it.
35:17I'm not sure about both the validity,
35:20the reliability that is test to test place
35:23to place because this isn't standardized.
35:25Like if you go get a potassium measured
35:29at one place and at another place,
35:31there are national federal standards that
35:33make sure that it should be the same.
35:35But you know we don't have those,
35:37that oversight right now on the micro clots
35:39and then ultimately is it actionable?
35:42And you know, some people think it
35:43is and some people think it don't.
35:45I know how much everyone's suffering.
35:46So I don't want to say what people should do,
35:50'cause, you know, there's a bit,
35:52there's a bit of desperation in all of it.
35:53But but just to say,
35:54on the science side,
35:55it's not there that we could say
35:57that with with confidence.
35:59Yet
36:01a couple other people were
36:04asking Akiko whether the damage
36:05that they're experiencing now,
36:07do they do we think that it can be reversed?
36:10Is it permanent? And,
36:11you know, my view on is,
36:13is I think you and I both heard
36:15stories of people who have been
36:17suffering for a long time and then it
36:19does resolve and they've gotten better.
36:21We've heard other people who,
36:22you know, it persists in,
36:23but I don't think we can say yet
36:25for sure what would be considered
36:27permanent or what might be reversible.
36:30And I I want people to have hope
36:32still and there's definitely not
36:33evidence to suggest that what
36:35lots of people are suffering,
36:37you know, wouldn't go away.
36:39So I I always try to encourage
36:40people to have hope.
36:41But I don't know what do you think of Kiko?
36:44Yeah, I I think, I I really hope
36:47there is a way to reverse it.
36:49And and you know certain
36:51tissues that are damaged,
36:52of course it depends on which organ and
36:55how replaceable those cells are and so on.
36:58But I definitely,
36:58I mean that's why we're doing this research.
37:01We really want to find something that
37:04would be helpful And we are doing because
37:06we have these mouse models of tissue damage,
37:09we are able to try all kinds of different
37:12agents to be able to reverse the damage.
37:15And that's what what some members of my lab
37:18are doing right now and we'll let you know,
37:21you know, if we find something.
37:22But we're doing this in a sort of way,
37:25you know, in which science has
37:28approached similar kinds of inflammatory
37:31conditions before with the drugs that
37:34are able to kind of restore and and
37:37replenish the damaged cell types.
37:39So I'm hopeful,
37:40of course we're not going to
37:42promise anything because you know
37:43that that would be irresponsible.
37:45But yeah,
37:47I am really hope that we can find something.
37:50You know, we know that some days
37:51it may be hard to have hope when
37:53you're facing all these things.
37:54So we, we want to encourage people
37:56not to give up and to feel maybe
37:58we can together all find answers.
38:00Bernal, you know,
38:01you answered this on the chat.
38:03Some people put it in the Q and AI know,
38:05you know, maybe you could just say
38:07out loud people listen who have
38:10had the deep immuno phenotyping,
38:12maybe you can make a comment or two.
38:13I'll just say to fit folks that it's
38:16not usual for us to be allowed to return
38:20research level results to participants.
38:23We want to be able to do that.
38:24But the the the regulatory
38:27bodies are concerned about.
38:29By the way Micro Klots is an
38:31experimental test as well,
38:33but because clinicians are ordering it,
38:36they can give it back to you.
38:37But when we're doing experimental
38:39tests in the lab,
38:41that for research there's reluctance
38:44because of a fear that people act on
38:46them in ways that aren't yet proven out,
38:49that even the tests should be acted on.
38:51But we think we found a path
38:53to share something.
38:54So Bernal, do you want to talk about that?
38:57Sure.
38:57So
38:58we right now have approval from
39:00the IRB to share research only
39:03reports and we are in the process
39:06of getting the reports ready,
39:08finishing off all the assays first
39:10and then getting the reports ready.
39:12And once we have them ready,
39:13we will reach out to you because
39:15that's the protocol that the IRB
39:17has proposed for us.
39:18We'll send out a mass e-mail to
39:21anybody in the study who has
39:23contributed biospecimens to our
39:25study and once they acknowledge
39:27and request for the reports,
39:29we'll individually be sending
39:30out those reports.
39:31But those will be research
39:33only reports not actionable.
39:35Thank you. A
39:38couple people, Akiko were asking about
39:41Epstein Barr virus and the reactivation and
39:46and and then somebody asked whether
39:49or not long COVID they asked whether
39:52can reactivate other viruses as well.
39:55But I think we're thinking like maybe
39:57those are the actual cause of the symptoms.
39:59But do you want to just say a minute
40:00what are you thinking about Epstein
40:02Barr virus Now as I know you mentioned
40:04as a mechanism this reactivation of
40:06viruses but in in in your lab you are
40:09you're you're following the stream,
40:10right as a as a way to sort of
40:12figure this out.
40:14Yeah definitely. So we are.
40:17Testing experimentally whether source
40:20COVID 2 infection can reactivate
40:23EBV in latently infected B cells,
40:26for example in the tissue culture.
40:28So we can do this just in vitro
40:32experiment to see whether there's any,
40:34you know interaction between
40:36the viruses and that would be
40:39a direct path to reactivation.
40:42But a indirect path would be that
40:44the source COV two infection led to
40:47impairment in T cells or B cell immune
40:50control of these latent viruses and
40:53that would be sufficient to reactivate.
40:56So that that's sort of the,
40:57the cause for reactivation but also
41:00the consequence of reactivation whether
41:02EBV treatment of against EBV reacted
41:07EBB or monoclonal antibodies or
41:10there's some other form of treatment
41:13to deal with the reactivated virus.
41:16Would that be helpful to people?
41:18And these things would obviously
41:20require some you know,
41:21form of clinical trials to be able to
41:24to understand the benefit of these drugs.
41:27But yeah,
41:28so we are still investigating like you know,
41:31what causes it and what is
41:32the consequence of it.
41:35Somebody was asking how can
41:37you tell that it's reactivated?
41:41There are two separate evidence.
41:44So one is the Cell paper that was
41:46published by Jim Heath's group last year
41:49where he was able to detect viremia,
41:53which means the EBV viral DNA
41:55was found in the blood of people
41:57during the acute phase of COVID.
42:00And when they follow these people over time,
42:03the ones that who had viremic EBV were
42:07the ones that were more likely to develop
42:10long COVID versus those who didn't.
42:12So this was a longitudinal
42:14study that Jim Heath,
42:15this group has done and there are
42:18Mike Peluso as well as our lab.
42:21We found that elevated antibodies
42:23against lytic protein of EBV which
42:26is normally hidden in latent cells.
42:29They don't express these proteins
42:31during latency and the fact that you
42:34have elevated IgG against these things
42:36are are quite indicative of recent
42:39reactivation with with the virus.
42:42So we're not saying that people who have
42:45these antibodies have live infectious
42:47CBB floating around in their blood.
42:49We actually can't find, you know,
42:52viremia in these people.
42:54However,
42:55we do see evidence for recent reactivation.
42:58So this may have happened during
43:00the acute phase of COVID or it may
43:03have happened a few months ago.
43:04We don't know,
43:05we we we don't have the
43:07longitudinal samples to,
43:08to tell what happened in the
43:10intervening time period.
43:11But yeah, so that's the evidence we have.
43:15Well, that's great.
43:18Somebody's asking about auto antibody
43:20testing that doctors can do and it it
43:24may be just an opportunity to reflect
43:26on this paper that's going to come out
43:28in nature where there was a panel,
43:29what is it more than 2000 auto
43:31antibodies that were tested.
43:32And and I don't know if you want us
43:34to say something about that Akiko,
43:36I mean sort of that we weren't
43:38able to identify much there,
43:41right, exactly. So this is the REAP
43:44strategy that was developed by Professor
43:47Ringslab and what it contain actually
43:51over 6000 antigens from human. Yeah.
43:54And of course there are you know several
43:58auto antibodies that are found in people
44:01with long COVID and people without
44:03long COVID and the healthy control.
44:05So and in fact all of us carry some
44:09form of auto antibodies against
44:11you know several auto antigens but
44:14they're not pathologic antibodies.
44:16And so but even though we didn't find it
44:19in that panel like I said you know we,
44:21we we haven't excluded the possibility that
44:24auto antibody against internal antigens,
44:27intracellular antigens or some
44:29nucleic acids or something else
44:31may be causing the symptoms.
44:33So even though you know that REAP didn't
44:37find clear pattern of auto antibody,
44:40we we certainly haven't given
44:42up on that hypothesis
44:45and somebody was raising an
44:47issue to us asking about you know
44:50that study was about long COVID.
44:52We also are going to be doing the
44:54same kind of analysis for those who
44:56are experiencing vaccine injury.
44:58I will say one thing about this issue
45:01of vaccine injury because somebody,
45:03I think you know who had come into the
45:05study with long COVID was wondering why?
45:08Why are you studying people with
45:09vaccine injury and want to say that
45:11it's clear to us that there are lots
45:13of people who are suffering and and
45:15there were a lot was a lot of overlap
45:17in terms of a chronic condition that
45:18had really unraveled people's lives.
45:20And it.
45:20It's important to know that these people
45:22who are reporting this about the vaccine.
45:25You know that most of every one of them
45:28that I've talked to like doesn't want to
45:30get involved in the politics of this.
45:31They're not anti Vaxxers.
45:33They got vaccinated.
45:34They they,
45:35they are people who have found
45:37themselves in a position where
45:40it's it's inconvenient for anyone
45:41to even talk about them because
45:43of what the way the politics
45:47occurred. And a lot if people with
45:51long COVID have found themselves in
45:52positions where people don't believe them,
45:54I can take it's even more intense
45:56for these individuals who are
45:58reporting symptoms after vaccination.
45:59And so, you know, I think when Akiko and I,
46:02you know, became aware of this
46:03and started talking about this,
46:04we recognized that there was some
46:07risk because of the political
46:08maelstrom about this. But we're,
46:11we wanted to approach us scientifically and
46:13we wanted to approach us humanistically.
46:15I mean people are suffering and
46:17we've developed a platform,
46:18we've developed a way to work together with
46:21folks and we thought that we should be,
46:24you know, we should be willing
46:25and interested and we weren't.
46:26We are, you know,
46:28in trying to find answers there too.
46:30So what what really I think in the
46:33end was there will be different
46:35mechanisms no doubt when we're talking
46:37about viral persistence that's not
46:38going to be the thing that is we'll
46:41we'll find that occurs for people
46:42who had problems after vaccination.
46:44And I want to say I believe,
46:46I know Kiko believes you know
46:48vaccinations are modern medical miracle.
46:50Millions of lives were saved because of
46:52the speed with which vaccines burned out.
46:54But it can be true and true that
46:57there still were some people who were
46:58harmed by the vaccine. You could.
47:00Both of those things can be true.
47:02The net value of it was immeasurable.
47:05And yet and yet there's still
47:06some people harmed.
47:07If you look at vaccines over the history,
47:09it's almost always true that
47:11there's some things that happen
47:13when people are vaccinated,
47:14in this case rare relative to benefit,
47:17but important to anyone who's affected.
47:20And I think our job is to understand how
47:22can we prevent in the future what is this
47:24and how do we help alleviate suffering.
47:26And again we're trying to to to take
47:29this in in a in a broad based way.
47:32So you know long COVID an injury there
47:35they may unlock some of the mechanisms
47:38that by which the immune system is is
47:41ends up conspiring against the best
47:43interest of the host and of the person.
47:46And so you know we're hoping that this
47:49all helps unlock this interestingly
47:51when we measure the health status
47:53in in listen of people with who are
47:56reporting vaccine injury and if people
47:57are reporting along COVID and by the
47:59way even the long COVID group we're not
48:01requiring people have had a positive test.
48:02We know lots of people got this before
48:04tests were available we're we're
48:06we're accepting what people say.
48:08And when you look at their health both
48:11groups are suffering about equally that
48:13that score of zero to 100 is is shows
48:17severe disabilities severe illness
48:19in both both groups about equally.
48:22Maybe we can use them to help us
48:24understand each each other because
48:25they can almost serve as controls
48:27for each other because like I
48:28said there's some things that
48:30would not have happened otherwise.
48:32But anyway I just wanted to to mention
48:34so we're we're just about a time
48:37let me just thank everyone we'll
48:38look for we'll look through and see
48:41if there are other questions that
48:42we can answer that we we missed.
48:44I'm going to give Akiko the last word here,
48:46but. But I just want to say
48:47from the depth of my heart,
48:49I want to thank all of you
48:50for being part of the study,
48:51being part of the team,
48:53being willing to come along.
48:54We are always interested in your
48:56comments and not just positive comments.
48:59Tell us what we're doing wrong.
49:01Tell us what we can do better.
49:02Tell us how we can we, you know,
49:04somehow be more responsive to this,
49:06how we can accelerate this.
49:08And also great deep thanks to
49:10the Listen research team at Yale
49:12who spent countless hours trying
49:13to move this stuff forward.
49:15And Akiko,
49:16let me hand it back to you for last comments.
49:19Yeah. Thank you, Harland. Yeah.
49:20It's it's I'm I'm really grateful to
49:22be part of this large team including
49:25so many participants here today
49:28to be able to investigate this.
49:30I think it's going to this is already
49:33revolutionizing the way we do science
49:35and and and and much thanks to Harland
49:37and his vision in in allowing this to
49:40happen and we're very much committed
49:42to figuring out what's going on with
49:45people with long COVID and people
49:47with post vaccine adverse events.
49:50And we we have collected the first
49:53set of samples from people with
49:55vaccine injury and we are just
49:58waiting for the results to come back.
50:00And so hopefully next time we can
50:02share some of the the collected
50:05data from that study.
50:07But we're very,
50:08very much dedicated to doing this and and
50:11we apologize for the slowness of the studies,
50:14even though we're doing
50:16everything at lightning speed,
50:17things take a long time even even with
50:20just the regulatory paperwork alone.
50:22So it's really,
50:23it's not an immediate answer
50:25that we can give you,
50:26but just know that we are really
50:29working hard and we thank you all.
50:34Thank you.