What do we know about long Covid?

June 28, 2021

Information

Akiko Iwasaki, Ph.D. shares what her team has done to understand the long COVID disease, its relation to inflammation and the impact of vaccinations.

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00:03Hello and welcome to the what do
00:05we know about Long Cove and how
00:07might a vaccine help webinar?
00:09Please put any questions for
00:10the speaker in the Q&A panel,
00:12and Please note that this session
00:14is being recorded. Thank you.
00:21Good morning everyone and
00:22thank you for joining us.
00:24For Akiko of Esaki's presentation
00:25on long COVID and how a vaccine
00:27may help as the director of Alumni
00:29Affairs at Yale School of Medicine,
00:31it gives me great pleasure to welcome
00:33you to our first and hopefully last.
00:36Virtual reunion weekend.
00:37For those who have not had the
00:40chance to meet or hear Akiko present
00:42before allow me a brief introduction,
00:44she joined Yale as a faculty member
00:47in 2000 and is currently the wall
00:49to more of an xet fits professor
00:51of Immunobiology and Molecular,
00:53cellular and developmental biology.
00:56The genealogy and my microbial
00:59diseases professor of molecular,
01:01cellular and developmental biology.
01:04The Howard Hughes Medical Institute.
01:06Her research is focused on
01:08understanding how viruses are
01:09recognized in eight community and
01:11how that information is used to
01:13generate protective adaptive immunity.
01:15She has received numerous honors
01:17during her career and most notably has
01:20been newly elected to the American
01:23Academy of Arts and Sciences.
01:25If you enjoyed her presentation
01:26and I have no doubt you will,
01:28please seek out more of her
01:30work and insights.
01:31She is very active on social media and
01:33gained a following on Twitter for her
01:35public health advice about COVID-19.
01:37Advocating for social distancing
01:38early in the pandemic.
01:39I will moderate our Q&A in the end,
01:42so please submit any questions you
01:43have in the chat feature and we will
01:46address as many as we have time for.
01:48I will now turn it over to Akiko.
01:52Thank you Aaron for the
01:54very kind introduction.
01:55I'm happy to be here today to give
01:58you a update and what we are doing
02:01to help people with long COVID.
02:04So I'm going to share my screen.
02:11OK, so today I want to tell you about
02:16long COVID an how might a vaccine help?
02:20And this is really an ongoing work
02:22that involves a large number of
02:25people here at Yale and elsewhere.
02:30So my laboratory has been collaborating
02:33with a large group at Yale to try to
02:37understand the outcome of COVID-19 disease,
02:40particularly from the standpoint
02:42of the immune response.
02:44We know that COVID-19 can
02:48cause asymptomatic infection.
02:51And all the way to fatal infection,
02:54and this really did depends on the host
02:58immune status as well as age and sex.
03:01So we know that the outcome of Cobett
03:0419 disease really differ between the
03:07different age group as well as sex as
03:10well as core mobility and pregnancy
03:13status and many other things that
03:15could affect the host immune response.
03:18And so, for instance,
03:20we've been looking at.
03:22Hospitalised patients immune response to
03:25COVID-19 from moderate to fatal disease
03:28and discovered so many different insights.
03:31For example,
03:32the severe COVID is really a company
03:35by a misfiring of the immune response,
03:39meaning that different parts of
03:42the immune system are engaged,
03:44normally reserved for fighting
03:46fungal or parasite infection are all
03:50being engaged in the severe COVID.
03:53And this becomes a maladapted immune
03:56response to fighting a viral infection.
04:00We also know that in fatal COVID cases.
04:04Things that should have happened earlier
04:07during immune response didn't happen,
04:09and that really results in uncontrolled viral
04:13replication and severe to lethal disease,
04:15and that is really seen for both the
04:19innate immune response which should
04:21happen within hours to days of primary
04:24infection to neutralizing antibodies.
04:27We found that people who don't develop
04:32neutralizing antibodies within
04:34the 1st 14 days of symptom onset.
04:36Are enriched in the lethal COVID group,
04:39so this kind of delay in the onset
04:43of appropriate immune response is
04:45really at the basis of our failure to
04:49cope with this virus and therefore
04:52succumb to infection.
04:53We've also done a lot of work on comparing
04:57sex differences in immune response,
05:00and this was really initiated by the
05:03support of Women's Health research
05:05at Yale here and has really taken
05:09off since then.
05:10Now there are numerous reports showing
05:14differences in male and female immune
05:17response to COVID and how that might explain.
05:21The risk factor for males being having
05:25a higher risk factor for lethal and
05:29severe COVID compared to female patients.
05:32And we've also been looking at the
05:36impact of COVID-19 in pregnancy,
05:39and have seen both subtle to severe
05:42consequences of kovit infection in
05:45pregnant women as well as impact on the
05:48placenta from a respiratory infection.
05:52Really highlighting that this
05:54particular virus,
05:55even though it's just a respiratory virus,
05:58has a huge impact throughout
06:01the body without.
06:03Infecting the Oregon it can have
06:05affect remote effect because of the
06:07information that's happening in the lung.
06:12There are others that Yale who are really
06:15investigating what happens in children.
06:18Doctor Kevin Harreld's group, for example,
06:21reported that there is a robust
06:24immune response that can control the
06:26virus in children and therefore most
06:30children recover with mild infection,
06:32whereas there are a handful of children
06:35who have multi organ involvement.
06:38Inflammatory diseases,
06:39which also is a mystery right now.
06:43Why do these handful of children
06:45become so severely ill from COVID?
06:47And that's a work of a doctor?
06:50Carrie Lucas in the same
06:52department looking at these issues,
06:54but today I really want to
06:56focus on long haul or disease.
06:59First of all,
07:00what is long COVID and what
07:02are the symptoms associated?
07:04How long do they last?
07:06What are the people affected?
07:08And finally,
07:09I want to start talking about
07:11potential therapy for lung COVID
07:16so long COVID was already detected
07:19last summer as people were experiencing
07:22very extended symptoms from COVID.
07:26And you know, some people even had very
07:29mild to asymptomatic infection but are
07:32beginning to develop very long term
07:36symptoms afterwards and so long COVID
07:39patients experience a large number
07:42of symptoms which I will go into.
07:47Weeks or months after infection
07:49for extended time period.
07:51So most common symptom is fatigue and
07:55this isn't just a little bit of fatigue,
07:59it's a severe fatigue that people
08:02become debilitated from this this
08:05disease and post exertional malaise is
08:08a second top symptom that long COVID
08:11patients experienced and cognitive
08:14dysfunction is also a large symptom.
08:18That longer population experience and.
08:22Majority have evidence of multiple
08:24organ disease, which I will get into.
08:27The long COVID,
08:29unlike the severe COVID that we
08:31study in the hospital,
08:33the long COVID patients are more
08:36dominated by younger female,
08:38so the Middle Age Group 30 to 50
08:41year old and that is really the
08:44most affected from long COVID and
08:48that also happens to coincide with
08:51the demographic most affected
08:53by autoimmune diseases.
08:54So the estimates of how many people develop.
08:59COVID vary between different studies,
09:01some of them say 5%.
09:03Some of them say 70%,
09:05but roughly about 10 to 20% of the
09:09COVID survivors develop Long Cove in,
09:11and this you know estimates about
09:145,000,000 cases of expected long
09:16COVID in the United States alone,
09:19which is a huge problem because
09:21these people are no longer able to
09:24function as they did before and would
09:27have a significant consequence,
09:29both economical.
09:30As well as health care costs
09:33associated with one COVID.
09:34And another study showed that the loan
09:37COVID percentages decline overtime,
09:39so it's not that everyone who has
09:42long COVID is going to suffer forever.
09:46The numbers and percentage decline overtime.
09:48So for example,
09:5013% of the participants had
09:52symptoms lasting over 28 days,
09:54but then that percentage drop after weeks.
09:58So after 12 weeks the percentage
10:00dropped about 2%.
10:02But there are people who are suffering.
10:05Suffering for more than
10:07a year with long COVID.
10:09And as I mentioned,
10:10it's a really debilitating disease.
10:1240% of cases require reduction in workload
10:15and 22% are unable to return to work,
10:19so this is a major crisis going forward
10:22even after we contain COVID with a vaccine,
10:25there will be millions of people
10:28suffering from long term consequences.
10:32And as I mentioned, long COVID is
10:35not just one organ, one symptom.
10:38It really has over 120 different symptoms
10:41that have been reported and that appear
10:44to involve so many organ systems.
10:47Systemic effects such as fever,
10:49fatigue, and post exertional malaise.
10:53Other symptoms that appear
10:55to just kind of be systemic,
10:58whereas there are distinct neuro
11:00psychiatric impact memory deficit,
11:02loss of ability to concentrate,
11:05and mood disorders.
11:06This is really, really severe in
11:09some people and there is dizziness,
11:12headache, blurry vision.
11:14Many different endocrine cardiovascular,
11:17pulmonary, musculoskeletal,
11:18and GI tract symptoms have been reported.
11:24And just to kind of reiterate,
11:27the demographic data being quite
11:29different from severe COVID.
11:31This is a study from a Mount Sinai
11:34group of Precision Recovery program
11:36that they have in in this group.
11:39Again, women are dominant at
11:4169% of the their patients are
11:44women and mean age is only 44,
11:47so 12 to 81. It varies,
11:50but mean is really is around 30 to 50.
11:54No, that range group.
11:56And the BMI it again.
11:58The BMI high BMI is a risk factor for
12:02severe COVID and for Long Cove it,
12:05it appears that the mean BMI is normal and
12:08then there are other sort of comorbidities
12:12that are associated with long COVID,
12:15but there's not a unifying.
12:18A picture of what people had
12:21before they developed long COVID.
12:25And if you look at the symptoms,
12:28severity and the number of symptoms overtime,
12:31what you see is something like this
12:34where vast majority of this severity
12:37score that goes extends to seven
12:40months are the moderate group,
12:42whereas a severe and very severe.
12:45They tend to decline over time,
12:47which is great.
12:49People are kind of converting to
12:52from CV or two a moderate to mild.
12:55Disease overtime.
12:56And then very mild goes up
12:59and then no symptoms.
13:01These are the people who stayed low.
13:04And if you look at the average
13:07number of symptom as I mentioned,
13:09everyone has a variety of symptoms,
13:12but the ones that don't
13:14recover for up to 90 days,
13:16they really do have numerous
13:18symptoms ranging in the teens.
13:20So meaning that they have numerous
13:23different organ involvement and symptoms
13:25that last for extended time period,
13:27whereas those that recovered with an
13:30acute or recovered within 90 days.
13:32They are symptom number declines.
13:35Quite rapidly and within three
13:37months they are devoid of symptoms,
13:39so really we're interested in this kind
13:42of people who are unable to recover
13:45over 90 days with numerous symptoms.
13:50So what is long COVID?
13:52What is how is it cost?
13:54We have a couple of hypothesis.
13:57One is that there is a viral reservoir
13:59that is remaining in these people even
14:02though they cannot detect any PCR
14:05positive virus from their nasopharynx.
14:07There may be virus in different tissues
14:10that cannot be accessed by such a
14:14nasal swab and that may be causing
14:16a chronic in long term symptoms.
14:20And the other possibility hypothesis
14:22is that there is autoreactive immune
14:25responses that are occurring,
14:27so these are the T&B cells of the
14:30immune system that are now attacking
14:32the various different cells or
14:35factors within different organs,
14:38and that might be leading to the
14:41multi organ symptoms that I explained
14:44to you before,
14:45and so both of these possibilities
14:48are still remaining valid.
14:50And there is ample evidence for
14:53both of these types of disease
14:57to be happening with COVID.
14:59And so just share with you a couple of these.
15:03This is a study that biopsied
15:05intestine of patients with COVID.
15:08This is a 92 days from the symptom onset,
15:12so months after they have had started
15:15the symptom and looking at what this is
15:18looking at is really source code V2,
15:21which is the virus that causes
15:24COVID new nucleocapsid protein,
15:26which is indicated in green here and
15:28you can see that these intestinal
15:31sections contain cells with.
15:34Very distinct patterns of the nuclear
15:36protein that you can see within the
15:39cytosol of these cells and this is
15:42from the terminal ileum and this
15:45is from the duodenum.
15:46You can see that there are these
15:49nucleocapsid positive cells that
15:51are mostly epithelial cells that
15:53are in the intestine,
15:55and they found five out of 14
15:57people who had positive staining.
16:00For SARS Co V2 antigen.
16:02After an extended time period.
16:04Indicating that the viral reservoir could
16:07be happening in the long COVID patients.
16:13Another possibility is the autoimmunity
16:15and this is a work that we published
16:19very recently where in collaboration
16:21with Doctor Aaron Rings Laboratory,
16:24we dissected the existence of auto antibodies
16:28and COVID-19 and I want to take you through
16:32some of the key data from this study.
16:36So doctor ranks laboratory developed a new
16:39tool called rapid extracellular antigen.
16:42Profiling rape this is a powerful new
16:46technology in which you can assess the
16:50ability of a patients antibody to bind
16:53to variety of self antigens that are
16:57about 3000 different human EXO proteome,
17:00which means that proteins that are either
17:03extracellular or secreted are included
17:06in the in this East library and each
17:10cell expresses different type of human.
17:13Conditions and when you bind your antibody
17:17to these cells and you can pull down the
17:21cells that are bound by the antibody,
17:24and then you can figure out what
17:27kind of antigen was expressed by
17:30such east by doing deep sequencing.
17:33And this enables doctoring to determine a
17:36wide variety of autoantibodies from a patient
17:39in a very high throughput and comprehensive,
17:43unbiased manner.
17:44So with this his group and we
17:47collaborated to look at auto
17:50antibodies and COVID-19 patients.
17:52These are hospitalized patients
17:54who had severe disease.
17:56Here moderate disease,
17:57mild to asymptomatic who are not
18:00hospitalized in negative controls.
18:02And the brighter the yellow,
18:04the more autoantibody there is in a
18:08patient and each patient is a column here.
18:12And what we found was quite striking
18:15that there are auto antibodies against
18:17so many different host proteins over
18:20120 different host proteins are bound
18:23by COVID-19 patients antibodies,
18:25and here particularly prominent are
18:28the antibodies against interference,
18:30which are the very factors that
18:32the host immune responses used to
18:35fight a viral infection.
18:37So obviously if you have auto
18:40antibodies against your own weapon.
18:42Then you cannot deploy those weapons
18:44well to fight a viral infection,
18:47and that's really what's happening in
18:49the severe cobett COVID patients that
18:52these patients are unable to fight
18:54the viral infection because of their
18:57autoantibody against the very protein
18:59that's needed to combat viral infections.
19:01But in addition to these,
19:03there are so many other yellow
19:06boxes you see here,
19:08which are autoantibody against variety
19:10of different immune cells themselves.
19:12Which is kind of scary,
19:14which means that these autoantibodies
19:16are actually dampening our own
19:19ability to fight a viral infection.
19:21Just to give you a couple of examples,
19:24this is looking at cumulative autoantibodies
19:27that exist in COVID-19 patients and a
19:30severe moderate patients who are in the
19:32hospital developed a large number of
19:35auto antibodies against all of these
19:38different immune factors and cell types.
19:41And when you look at the functional
19:44consequences of these autoantibodies,
19:46it is quite striking that,
19:48as I mentioned,
19:49the top left box corner that had these
19:53interferon specific autoantibodies.
19:55If you look at those patients ability
19:58to control the viral load over time,
20:02inbred the patients with these
20:04interferon specific autoantibodies
20:06were unable to clear the virus,
20:08whereas those patients without work.
20:11Able to decline in viral load and
20:14ultimately control the virus infection.
20:17Indicating that these
20:18autoantibodies are not only there,
20:20but it's functionally impairing our
20:23ability to fight a viral infection.
20:27And one more example of autoantibody
20:30against different immune cell types.
20:32So you've probably heard
20:34a lot about antibodies.
20:35Antibodies are really important
20:37to fight a viral infection,
20:39and the cell types that produce these
20:42antibodies are known as B cells and
20:45B cells themselves are absolutely
20:47critical for making the antibody.
20:49And yet in some people we found that
20:52COVID patients developed an antibody
20:54against the B cells themselves.
20:57So it's like a real like a suicidal
21:00antibody that you know bind to the
21:02B cells and then then kill them.
21:05And these antibodies interesting Lee.
21:07Those people who had these peaceful
21:09specific anybody have very low B cells
21:12as well as inability to mount and a
21:14antibody response against the virus.
21:17So really,
21:18indicating that these autoantibodies
21:20have a impairment induced impairment
21:22in the immune system so that people can
21:25no longer fight the viral infection.
21:28And in addition to these immune
21:31factors and cell types,
21:33we found auto antibodies to a wide
21:35range of tissue associated antigens
21:38that are in the brain vasculature,
21:41connective tissues, cardiac tissues,
21:43hepatic tissues, saliva skin,
21:45GI tract, and many others.
21:48So this really paints a picture of a
21:52diverse autoantibody causing all kinds of,
21:55you know,
21:55immune mediated damage across
21:57variety of different organs.
21:59And that was my second hypothesis of
22:02how along COVID might develop now.
22:05These are really patients who had like
22:08severe disease enough to be hospitalised,
22:11so it's not really the typical
22:13loan COVID patients were right now
22:16looking at long COVID patients SERA.
22:19To see if we see a similar kinds
22:22of autoantibodies an if So what the
22:24nature of these autoantibodies are,
22:26you know what kinds of tissue
22:28or antigens are they binding?
22:32So it seems that there is very little that we
22:36can do right now to help long COVID patients.
22:40We don't have a therapy, we don't even
22:43have a great diagnosis for the long COVID.
22:47Finally, the CDC has a guideline for
22:49COVID diagnosis for the long COVID,
22:52but there is one kind of ray of hope here
22:56because I've been looking and hearing
22:59from people on Twitter that patient.
23:02Patient based group reporting.
23:04About 40% of the long haulers.
23:07Feeling better after vaccination.
23:09And so, as I mentioned,
23:12long COVID may be caused by
23:14persistent viral reservoir or and or
23:17autoantibody or autoimmune response.
23:19And so we think that the vaccine may
23:22improve long covered symptom by inducing
23:25robust antibodies and T cells against
23:28the virus to clear the reservoir.
23:31Or it may temporarily sort of suppress
23:35the autoreactive cells ability to cause
23:38toxic immunopathology in the patients,
23:41and So what this means is that,
23:45for instance, the M RNA vaccines.
23:50Induce both innate and adaptive immune
23:52responses and the innate immune
23:55response cytokines combined two and
23:57suppress the autoreactive cells and
24:00therefore improve the symptoms or the
24:03adaptive immune responses that are
24:05engaged by the vaccine with antibodies
24:08and T cells that are attacking the
24:12virus of our and controlling the
24:15persistent virus in these patients,
24:17and maybe both of these things are happening.
24:22Depending on what the patients
24:24have with respect to long covin.
24:27And so we thought that this would be a
24:31great place to look into the underlying
24:36mechanism along COVID as well as
24:39potentially defined therapy against it so.
24:43We formed a Yale COVID recovery study
24:46and when I say we it's really a superb
24:51leadership of Harlan Krumholz and his
24:54post grad associate Daisy Massey,
24:56who really put this forward.
24:59And now we have a study up and
25:02running where we are recruiting among
25:05COVID patients with who have not
25:08gotten the vaccine yet,
25:10and then we're following
25:12their immune response overtime
25:14after they become vaccinated.
25:16To see what kind of changes occur in the
25:20immune response in the long haulers and
25:23what those changes mean with respect
25:26to their recovery from the symptoms.
25:29And this is again of a large
25:33collaboration between Charles de la Cruz,
25:35Natalie Lambert Arm Ring,
25:37who I already mentioned is the
25:40creator of the Reed technology.
25:42Erica spots as well as these other
25:45younger investigators who are really.
25:48Recruiting and consenting
25:49and studying the patients.
25:51And so I'm very fortunate to be involved
25:55in this large group who are really
25:58looking at the impact of vaccine on
26:01long hauler with respect to every
26:04immune parameter that you can imagine,
26:07we're throwing everything at this disease.
26:10Whatever the cutting edge technology
26:13we have on hand.
26:16So the mission is really to understand
26:19the immunological determinant of
26:20disease pathogenesis of long COVID.
26:22In order to inform rational therapy.
26:25And we're very excited to to
26:28carry on with this effort.
26:31So I want to acknowledge
26:33the number of people here.
26:35First of all, I was able to only
26:37discuss a little bit of our research
26:40today that has to do with the diverse
26:43autoantibodies in patients with COVID-19.
26:45But I also mentioned some of the misfiring
26:48of the immunological responses that
26:50happen in severe COVID with fatal COVID.
26:53I also mentioned there's a delay in
26:55the neutralizing antibody titer and
26:57then sex differences in immunity
26:59that I mentioned earlier.
27:01And these are the are the real heroes.
27:04They're the ones that really
27:06carried out the study.
27:08The names are listed here and my
27:10lab members who have been absolutely
27:12amazing over the entire pandemic period,
27:15not only looking at the immune responses,
27:18but also creating an animal model
27:20to study COVID as well as really
27:23getting involved in the surveillance.
27:25The PCR testing for the health
27:28care workers which were able to
27:30pick up some early exposure cases.
27:32Back in the spring of last year,
27:35when testing was quite limited
27:37and this entire set of work that
27:40are listed here is enabled by the
27:42impact deal BIOREPOSITORY,
27:44which is run by Doctor Albert Co at
27:47the school public health as well
27:50as all the others listed here.
27:52And I want to thank the funders for
27:55allowing us to carry on this research,
27:58so I'm going to stop sharing here
28:01and take any questions.
28:15Still no.
28:21OK, can you hear me now?
28:23Yes yes wonderful ekigho sorry everybody.
28:25We're having some technical difficulties
28:27on my end so thank you for your patience.
28:30Wonderful presentation.
28:30Thank you very very much.
28:32This is just extraordinary work and I
28:34appreciate you giving kudos to the team.
28:37'cause as everyone knows,
28:38this is a true team partnership and we're
28:41so excited that you're leading the way.
28:43I am actually shocked to see that we
28:45don't have any questions in the chat.
28:48So please, I know this group.
28:50This is not a shy group of alumni.
28:52Submit your questions and luckily
28:54we did have a couple people submit
28:56to me just a few days prior because
28:58they were so excited they couldn't.
29:00They couldn't wait to ask you, Akiko.
29:01So let me let me jump right in with
29:04some of our pre submitted questions.
29:06The first is why do you think women
29:08are more at risk of getting lung COVID?
29:11Yeah, so that's a very interesting question
29:14because as I mentioned in the seminar there,
29:18the demographic for the long COVID
29:20is quite distinct from what we see
29:24with the hospitalized patients who
29:26are much older and males are more at
29:29risk for severe disease with COVID,
29:32whereas the long Cove it is really
29:35dominated by younger women 30 to 50 year
29:39old there dominated in that group so.
29:42There are a couple of reasons
29:44why this might be.
29:46One is what I alluded to,
29:48which is this group of women are
29:50also a high risk for developing
29:53autoimmune disease such as lupus,
29:55arthritis and many others,
29:57and so if that's the group that's
30:00sort of developing a long COVID,
30:02it's potentially possible that
30:04the autoimmune disease is the 2nd
30:07hypothesis that I have about long COVID
30:09may be happening in those patients.
30:12In that you know they they were sort
30:14of prone to developing autoimmunity.
30:17But this virus kind of tipped
30:19the balance forward to developing
30:21a severe autoimmune disease,
30:23in which in which case you know they
30:26developped these autoantibody to variety
30:28of cell types in you know that may
30:31be causing these multiple symptoms.
30:34So that's one hypothesis.
30:36There may also be some you know factors
30:39that are related to sex hormones or.
30:43Other issues that we haven't
30:45been able to tackle yet,
30:47which may be also happening in this group.
30:51OK, great, thank you and the second
30:53question is do people who are severely
30:55ill from COVID also get lung COVID?
30:59Yeah, that's a really good question.
31:01In fact, as I mentioned that the percentage
31:04of long haul or disease really differ
31:07between different studies and one of
31:09the key differences in these studies
31:11is that when you follow patients who
31:14were sick enough to be hospitalized,
31:16and some of them got, you know,
31:19mechanical ventilation and so on.
31:20These sort of the patients who sustained
31:23lung damage in other organ damage,
31:25which tend to be very long
31:28lasting because it's.
31:29Really hard to repair these tissues,
31:31especially because these people are
31:33also in the older age group whose repair
31:36functions have declined over time.
31:38So you know if you ask these people,
31:41do you still have lingering symptoms?
31:43The answer is vast.
31:45Majority is yes, so about 70 percent.
31:4875% of people who've had sort of
31:50severe enough COVID to be hospitalized.
31:53They still have lingering symptoms.
31:54That's different from what we're calling
31:57a long COVID, which is people with.
31:59Milder disease who are never
32:01hospitalized who are developing these?
32:03You know,
32:04very long term symptom after either
32:06asymptomatic or mild infection and
32:08that tends to be the the group that
32:11is more dominated by younger women.
32:13And so I think the Long Cove it.
32:16It's easy to kind of bunch
32:18everything into one basket,
32:20but it in terms of pathogenesis we
32:22really need to separate these groups
32:25and so I would say that the long Cove
32:28it is really referring to this milder.
32:31Infection that's causing long
32:32term symptom as opposed to the
32:35hospitalized patients who are still
32:36feeling ill from the damage that
32:39they sustained from the COVID.
32:40So I hope that answers that question.
32:44Absolutely thank you through all answer.
32:45So we are starting to get some
32:47questions in the chat, which is great.
32:49I'm going to send the first one
32:52over to you and. Read it verbatim.
32:55So given autoimmunity likely
32:56plays an important role in the
32:59pathogenesis of long COVID,
33:00I want to find out if these patients
33:02have an increased prevalence of
33:04family history or personal history
33:06of autoimmune diseases like collagen,
33:09vascular disease preceding
33:10the diagnosis of COVID-19.
33:13Yeah, that's an excellent question,
33:15so I'm not sure how much the kind
33:17of inherited susceptibility to
33:19autoimmune diseases were known in
33:22the long haulers right now we are
33:25collecting this kind of information.
33:27First. We have this very extensive
33:30survey of symptoms and history.
33:32You know whether they've had any
33:35autoimmune disease in the past,
33:37what kind of medications they were giving,
33:40so we should be able to collect
33:43some of these.
33:45Important information soon,
33:46but obviously our family history
33:47of all the different diseases that's,
33:49I think the next next step we're
33:51going to have to reach out to
33:54these patients and find out.
33:56Great, thank you.
33:57The next question is has the REACH
34:00technology been applied to other
34:02viral illnesses and if So what sort
34:04of differences in number and or
34:06diversity of responses are seen?
34:09Yeah, another very excellent question,
34:12so we don't think that COVID is
34:15alone in inducing these types
34:18of auto mean oldani bodies.
34:21So we are currently testing or in the in
34:24the midst of planning a test for other
34:27acute respiratory viral infections and
34:30potentially other types of infections,
34:33so we don't know the answer yet.
34:36This brief technology is quite knew.
34:38It's really the first of
34:40many application was kovid,
34:42but I believe Doctor Ring is going to be
34:45expanding his analysis to other diseases,
34:48and in fact he has done reap analysis of.
34:52Known autoimmune diseases
34:54and have found that lupus,
34:56the diversity of antibodies that are
34:59found in COVID exceeds that of lupus,
35:02so it's really kind of a remarkable picture
35:05of autoimmune activation happening in Kovan,
35:08and whether that happens
35:10after flu infection and virus.
35:12Other kind of viral infection.
35:14We are really in the midst of
35:17doing this kind of research.
35:20Great, thank
35:21you so the next one is.
35:24Are there any emerging therapies
35:26that show early promise?
35:28Yeah, so the only only glimpse we
35:31have of anything helping long COVID
35:33really appears to be this vaccines.
35:36There are other anecdotal reportes of people
35:39feeling better with other medications.
35:41I you know we don't have enough
35:44number to conclude what other
35:46therapies might be working there.
35:48There may be some clinical trials that are
35:52ongoing that's going to inform us soon,
35:54but this is an important question because.
35:58You know, depending on the hypothesis,
36:00if the reservoir the viral
36:02reservoir is causing long COVID,
36:04we really need to go after that virus,
36:07which means we can treat these patients with
36:10monoclonal antibody cocktails or antivirals.
36:12Or, you know, fear on something like that.
36:15They really get the virus,
36:17whereas if it's really caused by,
36:20you know autoimmune disease,
36:21then we really need to be
36:23dampening the immune response.
36:25So therapies that are used in
36:28autoimmune diseases can be used for.
36:30More COVID may be potentially more targeted.
36:32Approach can be developed based on what kind
36:35of autoantigens that they were detecting,
36:37so there's a lot of different
36:39ways to go about therapy,
36:41but we really need to know the disease
36:44pathogenesis before we can engage in those.
36:47I thank you for the next writer.
36:50Has had two doses of the Pfizer
36:53vaccine and lives in Georgia and
36:55is reluctant to go out in public
36:58and was wondering if you could
37:00speak to is anyone working on
37:02neutralizing antibodies and antibody
37:04test or CMI test for vaccines?
37:06He's a little concerned about the
37:09neutralizing antibodies
37:09or cell mediated immunity.
37:11Yeah, that's also a common,
37:13you know concern that people even
37:15though they got the two doses.
37:17There are rare cases,
37:19a breakthrough infection that happen,
37:22and that's with all vaccines.
37:24Fortunately,
37:25the M RNA vaccines like the Pfizer one
37:28that the question or just indicated.
37:31I have really high efficacy and
37:34effectiveness against infection,
37:35so that's really great news,
37:38but the breakthrough does occur
37:40in rare cases and we don't
37:43know why some people with fully
37:46vaccinate status are getting.
37:48Infected again,
37:48it could be that there there was an
37:51underlying immune deficiency in these people,
37:54or it could be that they got exposed to
37:57a variant that you know wasn't quite
38:00well neutralized by their antibodies,
38:02and so I agree with this person 100%.
38:05I think we need a neutralizing antibody test.
38:09It's right now to do this with the
38:12real virus. It's a huge endeavor.
38:14We do this in the lab,
38:16but it requires the biosafety Level 3.
38:20Days and days of hard work.
38:22And so to do this in millions of
38:25people would not be possible.
38:27However,
38:27I hope that the companies are coming
38:30up with similar approach where it's
38:33a little bit more more streamlined
38:35and less less cumbersome to be able
38:38to look at the neutralizing titer,
38:40and one of the proxy for the
38:42neutralizing titer is the anti RBD
38:45antibody these so they sort of
38:47receptor binding domain of the spike protein.
38:50That's being targeted.
38:51Bispecific antibodies and that tend
38:53to have a pretty good correlation
38:56with neutralizing titer.
38:57So one way to get around the entire
38:59sort of cumbersome neutralizing assays
39:01to use anti RBD Eliza to monitor antibodies.
39:06But I just wanted to reiterate
39:08that the Pfizer vaccine Moderna
39:10these are extremely effective.
39:12So vast majority of people are
39:14going to be protected and so I think
39:18the the person should be able.
39:20Little bit more comforted by that.
39:22Thank you.
39:23I'm
39:23going to read this one verbatim.
39:25It's a little long when you mentioned
39:27the multisystem nature of long COVID-19
39:29and a potential reservoir of the virus,
39:31and many of the different tissue types.
39:34Do you? Do we have any idea of how
39:36the virus reside in these tissue?
39:39My understanding is that some of
39:41these tissue types mentioned do
39:42not express ace two SP receptors.
39:46Yes, so I think the consensus is that this
39:50virus obviously uses a Stew as a receptor.
39:54It also has other requirement like TEMPRESS,
39:57which is a protease that enables entry
40:00process and so there there are different
40:04types of host cell requirement for
40:07infection and if you survey the literature,
40:10vast majority of the target cells
40:13are epithelial in nature so.
40:16Nasal cavity the long the
40:18intestinal tract kidney.
40:19The epithelial cells appear to
40:21be a major target of infection,
40:24so that's number one and that they
40:27have high levels of ACE 2 and #2
40:30is that there are some reports
40:33including our own that detected
40:35virus in the neurons in the brain.
40:39And so there's controversy about
40:41whether it's two is expressed well in
40:44the neurons or the brain, and in fact,
40:47if you look at the M RNA level for a Stew,
40:51it's quite low.
40:52However, if you look at the protein,
40:54it's there an we've also demonstrated
40:57a functional requirement phase two
40:59by neutralizing ace two or blocking
41:00a Stew and showing that the virus
41:03not lingering effects these cells,
41:05indicating that it is it is possible
41:07to have these kind of persistent
41:09infection in organs that are.
41:11Not positive for S2 by M RNA in the
41:14standard way of looking at things.
41:16But if you look at the protein,
41:19they're actually quite positive and
41:20that also goes for the placenta.
41:23Placenta also has very low levels
41:25of the M RNA,
41:26and yet if you look at the protein
41:28expression it's quite positive there.
41:39Hear me OK, OK Now I can hear yes
41:41just a little bit. It's good.
41:46OK. Are there pediatric cases
41:49of lung COVID either post?
41:53I'm sorry I don't know the acronym ISC
41:56or in children who have not had this an
42:00ISC right? So the MISC like I
42:03mentioned earlier is a rare event
42:06that happened in some children.
42:08It is very severe.
42:11That requires hospitalization and treatment,
42:13whereas there are pediatric
42:15cases of long COVID.
42:16Again, I want to distinguish that from MI.
42:20See is these are the children who
42:22have mild to asymptomatic COVID
42:24infection and then develop overtime.
42:27This long term symptoms an I know that
42:30many children actually suffer from
42:32lung COVID people who are athletes
42:35in our very active in different
42:38sports no longer able to run.
42:40You know, because they,
42:42they they they they get post exertional
42:45malaise as well as shortness of breath.
42:48They just can't engage in these
42:50kinds of sports anymore.
42:52There are people who are getting anxiety,
42:55depression,
42:55and other mental issues as a
42:58result of long COVID in the
43:01in the pediatric population.
43:03You know,
43:03and then there are these very
43:05severe cases that happen.
43:07The Missy kids,
43:08so it's a range of different things,
43:10but the long Cove is a very
43:13distinct phenotype from the
43:15Missy and as as far as I know,
43:17I haven't heard of anyone
43:19with Missy developing long,
43:20Long Cove it,
43:21but it's such a rare intersection
43:23that you know maybe future
43:26investigation will reveal those.
43:28Thank
43:28you, how can a long hauler determine
43:30whether there is an issue with viral
43:33reservoir problem or an autoimmune problem?
43:36Yeah, excellent question,
43:38and that's precisely why we're doing
43:41this deep immunological dive into
43:43these patients because I believe
43:45that these two possibilities may
43:47be happening either in subset of
43:50patients having one or the other,
43:53or another subset having both.
43:55Or maybe it's a varying degree that's
43:58happening in within a patient.
44:00So in order to we would love
44:03to find a biomarker for either.
44:06A person having a persistent infection
44:09or those who are having autoimmunity
44:11and with this deep dive we will be able
44:14to determine if there are these two
44:17different baskets of disease and what
44:19parameters are correlating with each.
44:21And so you know,
44:23I I've actually seen the first
44:25glimpse of the data from the long
44:27holders and it's really striking.
44:30I would love to report this.
44:32It's such a such an early look that
44:35I I can't even talk about it, but.
44:38But I know that there is a signature
44:41so very excited to be able to.
44:43You don't figure this out soon
44:45and report it and to help people.
44:49It's really exciting to hear
44:51there's more to come in that area.
44:53I'm going to read this
44:55one verbatim split along.
44:56You said earlier that if a virus
44:58reservoir is causing long COVID,
45:00you'd have to hop up immune system.
45:02On the other hand,
45:03if the immune system response is
45:05causing it by attacking antibodies,
45:07you need to slow the Union system down.
45:10What happens if both are
45:11true went that greatly
45:13complicate treatment.
45:13Yeah, very tricky, right?
45:15But I think there is a way to do this so.
45:19The fact that, OK,
45:21let's assume a person has both a
45:24viral reservoir, an auto, anybody.
45:26We could tackle the viral reservoir
45:28using synthetic treatment like
45:30monoclonal antibody cocktail an.
45:32If we get rid of that reservoir we
45:35get rid of that part of the disease
45:38and then for the autoimmune part
45:41we can basically use treatments
45:44that are immunosuppressive,
45:46which will dampen the autoreactive
45:48cells in those patients so.
45:50I think combination combination of
45:52different approaches and therapy
45:54that are not going to be interfering
45:57with each other is possible.
46:01OK, great and we're getting
46:03low on questions folks,
46:04so if you have anymore we
46:06have a few more minutes.
46:09Why wouldn't vaccine?
46:10Why wouldn't vaccines cause immune
46:12mediated COVID like symptoms
46:13like the natural one does?
46:15Yeah, another very good question.
46:17So the natural infection has a myriad of
46:21different effects on the immune system.
46:23One of the things that we saw very
46:26early on in the COVID patient is
46:29a severe decline in the T cells.
46:32So the virus infection causes a rapid
46:35drop in the T cells and T cells are the
46:38central command of the immune system.
46:40If you don't have T cells,
46:42B cells don't know what to do another.
46:45You know innate immune cells
46:46don't know what to do,
46:48so the T cells are this.
46:50This command center is being degraded
46:52or you know diminished by the virus and
46:55so all the subsequent immune responses
46:57that occur are misdirected or not very well.
47:00You know conducted,
47:01whereas in the case of vaccines we have
47:04absolutely no impact on the T cell I mean.
47:06They're not going to touch the T cells
47:09with respect to numbers or their function,
47:12but rather the stimulate them so
47:14that the antibody secreting cells
47:16the B cells can be engaged,
47:18and so the vaccine is really designed only
47:21to provide the best kind of immune response,
47:24whereas the infection does a whole bunch
47:27of other things that interfere with our
47:29ability to fight the viral infection.
47:32And that's really with all viruses,
47:34right?
47:34They have so many evasion mechanisms.
47:37That that they without them they
47:39cannot be a successful pathogen.
47:41So there's a huge difference between
47:43the immune response that happened to
47:46live infectious virus versus those
47:47that happened during a vaccination,
47:49and that may be why we're seeing
47:52such an amazing effect of the vaccine
47:54in inducing super physiological
47:56levels of antibody.
47:57Meaning most people don't develop that
48:00kind of anybody with a natural infection.
48:03But with the two dose of vaccine,
48:05we're seeing like incredible titers of
48:08anybody that's going to hopefully give
48:10us protection for at least a year or so.
48:13So that's really the difference.
48:16Thank you, I think we might have
48:18time for one or two more questions,
48:21so the topic of children hasn't really
48:24been discussed much in this area.
48:26So could you talk to us about long COVID and
48:30do children get it right?
48:32So I have heard you know the children.
48:35The data are still coming out because you
48:38know they just became eligible recently,
48:40so we don't know what the impact
48:43of the vaccines are for the
48:45long COVID in children yet.
48:47However, we know that Long
48:49Cove it does happen in children
48:52even in very young children,
48:54so I think that you know that this
48:57unfortunate doesn't spare people over
49:00younger age and unlike the infection itself,
49:03most people who are younger
49:05are having very mild or some
49:07asymptomatic infection was alone.
49:09COVID can happen in this group,
49:12so I think that's really more
49:14reason why we need to accelerate.
49:17Vaccination in the younger
49:19people because you know,
49:20even though they might recover with
49:23a mild infection with the kovid,
49:25they may suffer from long term symptoms.
49:28An I think the vaccines done.
49:32And the last question of the morning is.
49:37Add Seed's answer suggests that
49:39vaccines will provide better long
49:41term immunity than natural infection.
49:44Yes, I believe it does because of
49:47what I just said that the the vaccines
49:50are inducing incredible levels of
49:52neutralizing anybody as well as just
49:55a high tide or anybody and they're
49:57seeming to be pretty well maintained.
50:00Over time there was a study that
50:03examined them at six months point an
50:05the titers are still staying very high,
50:08so that kind of very slow regression
50:11of the antibody levels suggests that.
50:14The longevity as well as potency
50:16of antibody may be better after
50:18vaccination than unnatural infection,
50:20and so hopefully I mean this
50:23is really our way out of this.
50:25Pandemic is to get vaccinated and to be
50:28protected from acute and long cobin.
50:32Wonderful well keep going keep
50:34going just have to say thank you
50:36so much for spending your Saturday
50:37morning with this wonderful group
50:39of Yale School of Medicine alumni.
50:41It was a fascinating talk.
50:42I everyones questions were
50:43answered so thank you so much
50:45and enjoy the rest of your day.
50:48Thank you so much
50:49Aaron. OK thanks everybody and I will
50:52share that Dean stun Bermond is talking
50:55at 11:00 o'clock if anyone's interested.
50:58He's the School of Public Health teen
51:01and he's also talking about COVID.
51:05In the public health setting,
51:06so you can switch over for an 11:00 o'clock
51:09presentation if you're interested and
51:11enjoy the rest of your alumni weekend.