WELCOME TO TODAY'S COVID
LECTURE.
IT REALLY IS A PLEASURE FOR ME
TO INTRODUCE MY GOOD FRIEND AND
FELLOW NEUROLOGIST DR. CLINTON
WRIGHT.
DR. WRIGHT IS A VASCULAR
NEUROLOGIST AND A SPECIALIST IN
COGNITIVE DISORDERS.
HE'S ASSOCIATE DIRECTOR OF THE
NATIONAL INSTITUTE OF
NEUROLOGICAL DISORDERS AND
STROKE AND THE DIRECTOR OF THE
DIVISION OF CLINICAL RESEARCH.
HE'S A MEMBER OF THE STROKE
BRANCH WITHIN THE DIVISION OF
INTRAMURAL RESEARCH.
DR. WRIGHT RECEIVED HIS MD FROM
THE COLLEGE OF PHYSICIANS AND
SURGEONS AT COLUMBIA UNIVERSITY
AND HIS MASTERS DEGREE IN
EPIDEMIOLOGY FROM THE MAILMAN
SCHOOL OF PUBLIC HEALTH ALSO AT
COLUMBIA.
HE COMPLETED A NEUROLOGY
RESIDENCY AT COLUMBIA'S
UNIVERSITY NEUROLOGICAL
INSTITUTE OF NEW YORK AND THEN
DID A VASCULAR NEUROLOGY
FELLOWSHIP.
BEFORE JOINING NINDS, DR. WRIGHT
SERVED AS THE EVELYN F.
Mc KNIGHT CHAIR FOR LEARNING
AND MEMORY IN THE AGING AND WAS
A TENURED PROFESSOR OF
NEUROLOGY, PUBLIC HEALTH
SCIENCES AND NEUROSCIENCE AS
WELL AS CHIEF OF THE DIVISION OF
COGNITIVE DISORDERS AT THE
LEONARD M. MILLER SCHOOL OF
MEDICINE AT THE UNIVERSITY OF
MIAMI.
HE SERVED AS SCIENTIFIC DIRECTOR
OF THE Mc KNIGHT BRAIN
INSTITUTE AT THE UNIVERSITY OF
MIAMI UNTIL HE JOINED THE NIH IN
2008.
SO TODAY DR. WRIGHT IS GOING TO
TALK WITH US ABOUT THE RECOVER
INITIATIVE EARLY FINDINGS AND
OTHER EMERGING LONG COVID
SCIENCE.
CLINT, THE VIRTUAL PODIUM IS
YOURS.
>>THANK YOU VERY MUCH, NINA.
IT'S A PLEASURE TO BE HERE
TODAY.
THANK YOU SO MUCH FOR THAT KIND
INTRODUCTION AND THANKS TO
EVERYONE FOR INVITING ME.
IT'S A REAL PLEASURE TO TALK TO
YOU TODAY ABOUT RECOVER, BUT
ALSO ABOUT THIS EMERGING AREA OF
EXCITING RESEARCH.
SO OVERALL THE ESTIMATES OF
INDIVIDUALS EXPERIENCING LONG
COVID HAVE BEEN DECREASING OVER
TIME.
SURVEY RESULTS FROM THE NATIONAL
CENTER FOR L-STATISTICS OF
ADULTS WHO HAD COVID-19 AS OF
AUGUST SHOWED THAT ABOUT 28%
REPORTED EVERY EXPERIENCING LONG
COVID AND 10% EXPERIENCING LONG
COVID.
AND THEN OF COURSE CURRENTLY
EXPERIENCING LONG COVID ABOUT
80% REPORT ACTIVITY LIMITATIONS
AND 25% REPORT SIGNIFICANT
ACTIVITY LIMITATIONS.
SO THIS IS A VERY SIGNIFICANT
AND SERIOUS PROBLEM THAT
OBVIOUSLY AFFECTS A VERY LARGE
NUMBER OF PEOPLE GIVEN THE
NUMBER OF PEOPLE THAT HAVE BEEN
AFFECTED BY COVID.
BUT HERE'S THE PROBLEM.
THE PROBLEM IS THAT IT IS A VERY
COMPLEX SET OF DISORDERS THAT WE
DON'T COMPLETELY UNDERSTAND EVEN
NOW.
AND I THINK THIS SLIDE IS VERY
ILLUSTRATIVE OF IT BECAUSE YOU
SEE THAT THERE ARE SO MANY
SYSTEMS THAT ARE INVOLVED AND
THEN YOU SEE SOME OF THE
SYMPTOMS AND SOME OF THE
PATHOLOGIES THAT ARE ASSOCIATED
WITH EACH 1 OF THOSE ORGAN
SYSTEMS.
SO WHEN NIH SET ABOUT TO
UNDERSTAND THE POST ACUTE SEQUEL
I OF COVID AND NOW WE'RE
REFERRING TO LONG COVID, IT WAS
REALLY IMPORTANT TO REALLY DIG
INTO WHAT--SO WE NEEDED TO
UNDERSTAND IT AND YOU SEE HOW
COMPLEX IT WAS, YOU NEED TO BE
ABLE TO PREDICT IT, TREAT IT AND
PREVENT IT SO THE KEY AIMS OF
THE RECOVER INITIATIVE WHEN IT
WAS SET UP TO DO THAT WERE TO
UNDERSTAND FIRST THE CLINICAL
SPECTRUM AND THE BIOLOGY
UNDERLYING RECOVERY FROM COVID
INFECTION OVER TIME TO DEFINE
RISK FACTORS, TO UNDERSTAND THE
EPIDEMIOLOGY, THE INCIDENCE, THE
PREVALENCE, TO UNDERSTAND THE
PHENOTYPES THEMSELVES, YOU KNOW
WHAT ARE THE DIFFERENT
PHENOTYPES.
STUDY PATHOGENESIS OVER TIME AND
THE RELATION TO OTHER ORGAN
SYSTEMS AND DISORDERS AND THEN
IDENTIFY INTERVENTIONS, YOU KNOW
OBVIOUSLY TO HOPEFULLY PREVENT
AND TREAT IT.
BUT 1 OF THE THINGS THAT WAS
RECOGNIZED WAS GIVEN THAT THERE
WAS SO MUCH AT STAKE, IT WAS
ABSOLUTELY CRITICAL TO DO A
NUMBER OF THINGS AND THE GUIDING
PRINCIPLES ON THIS SLIDE, I
THINK ARE EXTREMELY IMPORTANT.
FIRST OF ALL, IT HAD TO BE AND
I'M GOING TO SKIP THE
PATIENT-CENTERED PIECE BECAUSE I
WILL TALK ABOUT IT MORE BUT THE
FIRST THING WAS JUST TO
RECOGNIZE THAT IN ORDER TO GET
DATA THAT WAS OF VALUE OUT OF
THIS, YOU KNOW MORAS OF
INFORMATION THAT WAS COMING OUT
OF SO MANY DIFFERENT AREAS, WE
NEEDED TO HAVE A STUDY OF
NATIONAL SCALE THAT WAS ALSO
VERY ENCLUESIVE OF DIVERSE
POPULATIONS THAT MAY BE MORE
AFFECTED, NOT KNOWING WHICH
SUBGRUPS MY BE MORE AFFECTED AND
THEN ALSO TO BE ABLE TO
HARMONIZE THAT DATA SO THAT IT
COULD BE LOOKED AT ACROSS THE
DIFFERENT STUDIES AND THEN THE
OTHER RECOGNITION WAS THAT
BECAUSE OF THE NUMBER OF
DIFFERENT WAVES OF THE VIRUS
THAT HAD HAPPENED, IT WAS
RECOGNIZED IT WOULD HAVE TO BE
ADAPTIVE AS THESE DIFFERENT
WAVES HAPPEN, THERE MIGHT BE
DIFFERENT EFFECTS BASED ON THE
DIFFERENT VARIANTS.
SO ALL THOSE THINGS WERE DRIVING
FACTORS.
THE PATIENT ENGAGEMENT AND
COMMUNITY ENGAGEMENT PIECE WAS
ALSO RECOGNIZED TO BE EXTREMELY
IMPORTANT FROM THE VERY, VERY
BEGINNING AND I THINK 1 OF THE
ININIVATIVE THINGS ABOUT RECOVER
WAS INCLUDING PATIENTS AT ALL
LEVELS OF THE STRUCTURE OF THE
RECOVER PROGRAM.
SO HAVING THE PATIENT
PERSPECTIVE INVOLVED NOT ONLY AT
THE BEGINNING SORT OF
IDENTIFYING, YOU KNOW WHAT ARE
THE SYMPTOMS AND PROBLEMS THAT
WERE OF MOST IMPORTANCE TO THE
PATIENTS, BUT ALSO GETTING THEM
INVOLVED IN THE STEERING
COMMITTEES AND THE SCIENTIFIC
WORKING GROUPS, THE EXECUTIVE
COMMITTEE, THE OVERSIGHT
COMMITTEES TO MAKE SURE THAT
THEIR INPUT WAS CARRIED ALL THE
WAY THROUGH THE PROGRAM AND MAKE
SURE THAT THOSE VOICES WERE
HEARD.
SO RECOVER WAS SET UP AND IT HAS
A NUMBER OF COMPONENTS AND I
WILL WALK YOU THROUGH THAT
QUICKLY SO YOU SEE THE KEY
SCIENTIFIC AIMS AND THEN ALONG
THE TOP IN THE YELLOW BEND, YOU
SEE THE THINGS I ALREADY TALKED
ABOUT AND THEN, IN TERMS OF THE
AIMS, WHICH WE ALREADY TALKED
ABOUT, IDENTIFYING THE DIFFERENT
ASPECT OF LONG COVID, WE NEEDED
TO SET UP A NUMBER OF DIFFERENT
TYPES OF DATA COLLECTION
EFFORTS.
SO AN ELECTRONIC HEALTH RECORD
PROGRAM, COHORT STUDY PROGRAM
THAT WOULD INCLUDE NOT ONLY DE
NOVO COHORT THAT WOULD COLLECT
DATA ON PATIENT SUFFERING FROM
ACUTE INFECTION TO SEE WHO
DEVELOPED A LONG COVID BUT ALSO
PEOPLE HA ALREADY HAD LONG COVID
THAT WANTED TO PARTICIPATE IN
RESEARCH BUT ALSO TAKING
ADVANTAGE OF SOME LONG STANDING
COHORT STUDIES, FAMOUS COHORT
STUDIES THAT HAD BEEN FUNDED BY
NIH FOR A LONG TIME SIMILAR TO
LIKE THE FRAMINGHAM STUDY AND
OTHER STUDIES THAT HAVE BEEN
DEEPLY PHENOTYPING PARTICIPANTS
FOR MANY, MANY YEARS AND NOW
MANY OF THEM WERE HAVING ACUTE
COVID INFECTIONS AND SOME OF
THEM GO ON TO DEVELOP LONG
COVID.
AND THEN, TISSUE AND PATHOLOGY
STUDIES AND PATHOBIOLOGY STUDIES
TO UNDERSTAND THE PATHOGENESIS
AS I MENTIONED, YOU KNOW VERY,
VERY CRITICAL AND THEN, MOVING
ON A COHORT OF CLINICAL TRIALS,
THAT WOULD THEN HAVE DATA COMING
OUT OF THESE OTHER 4 FEEDING
INTO THE INFORMATION THAT WENT
INTO SETTING UP THE CLINICAL
TRIALS.
AND SO ASSOCIATED WITH THAT,
THERE ARE MANY DIFFERENT TYPES
OF DATA THAT NEEDED TO BE
COLLECTED AND YOU SEE THOSE, YOU
KNOW ALONG THE BOTTOM INCLUDING
MOBILE HEALTH, IMAGING,
PATHOLOGY AND SO ON.
SO I WILL TALK A LITTLE BIT
ABOUT THE ELECTRONIC HEALTH
RECORD DATA.
THIS WAS A PROGRAM THAT ANALYZED
60 MILLION RECORDS WITH
11 MILLION COVID CASES ACROSS
DIVERSE POPULATIONS, TO
UNDERSTAND, YOU KNOW
EPIDEMIOLOGY, PARTICIPANT BURDEN
AND SOME PHENOTYPES.
1 OF THE STUDIES I WANT TO
TALK ABOUT WAS THE RECOVER, FROM
THE RECOVER EHR FINDINGS WAS
JUST THE ABILITY TO UNDERSTAND
THE INCREASED RISK OF NEW ONSET
CONDITIONS IN PAST PATIENTS.
SO, YOU KNOW THAT WAS 1 OF THE
BIG QUESTIONS, JUST STARTING
OUT.
DO PEOPLE WHO SUFFER FROM P A SC
HAVE A HIGHER INCIDENCE OF NEW
ONSET CONDITIONS AND YOU CAN SEE
A WHOLE LIST OF CONTICKSES THAT
WERE GENERATED BY EHR DATA.
SO 1 OF THE BENEFITS OF RECOVER
IS YOU KNOW HAVING THOSE
DIFFERENT DATA TYPES WE CAN TAKE
FOR EXAMPLE, THE EHR DATA AND
RELATE IT TO THE DATA COMING OUT
OF THE COHORT STUDY AND
VALENTINED DIADIC AND CROSS
VALIDATE THE DATA COMES OUT OF
THOSE SO THE MESSAGE I WILL GIVE
YOU ACROSS THESE DIFFERENT TYPES
OF DATA ARE SORT OF A--IT'S A
SYNERGY OF DATA FINDINGS THAT
ARE COMING OUT TO LEAD US YOU
KNOW TO THE NEXT STEP.
THIS PARTICULAR SLIDE, ALTHOUGH
SLIGHTLY COMPLICATED IS REALLY
JUST MEANT TO ILLUSTRATE THAT
THE EHR STUDIES WERE USED TO MAP
SUBPHENOTYPES OF P A SC USING
MACHINE LEARNING TECHNIQUES JUST
TO UNDERSTAND IN THE MEDICAL
RECORD WHAT ARE THE
SUBPHENOTYPES THAT ARE BEING
SEEN IN THESE HEALTH SYSTEMS.
SO THIS INVOLVED PATIENTS WHO
HAD A POSITIVE PC R TEST, IN THE
EHR BETWEEN 2020-2021, ABOUT
24,000 PEOPLE, AND SOME
PHENOTYPES WERE BASED ON NEW
CONDITIONS IN THE POST ACUTE
INFECTION PERIOD ABOUT A MONTH
TO 6 MONTHS AFTER THE DATE OF
THE CONFIRMED INFECTION AND SO,
THE RESEARCHERS IDENTIFIED 4
SUBPHENOTYPES THROUGH THE
ELECTRONIC HEALTH RECORD AND
THERE WERE 137 PRESPECIFIED P A
SC SEQUELLAI STUDIED TO BE
IMPORTANT.
HERE ARE THE TOP 2.
SO 1 OF THEM INVOLVED CARDIAC
AND RENAL SYMPTOMS WHICH
AFFECTED 33% OF PATIENTS AND
THEN ANOTHER PHENOTYPE INVOLVING
RESPIRATORY SYMPTOMS, SLISM
DISORDERS AND ANXIETY WHICH ALSO
INVOLVED ABOUT 30% OF THE
PATIENTS.
SO THIS WAS JUST A LOOK AT THE
PHENOTYPES THAT WERE POPPING OUT
OF THE ELECTRONIC HEALTH RECORD
TO HELP TELL US WHETHER WE MIGHT
SEE IN THIS THE COHORT STUDIES
AS WELL.
THE OTHER THING THAT THE HR DAT
WAS VERY HELPFUL IN DOING WAS
LOOKING AT P A SCAND LONG COVID
IN CHILDREN.
SO THE RESEARCHERS IN THIS CASE,
USE THE EHR TO IDENTIFY THE
INCIDENCE AND PREVALENCE OF P A
SC IN CHILDREN, AS WELL AS THE
RISK FACTORS THAT WERE ASSOCIAE
WIDE IT.
SO THESE WERE CHILDREN, SAME
TIME FRAME, ABOUT 660,000 TOTAL
PATIENTS AND BASICALLY WHAT DID
THEY--WHAT DISCIPLINARY THEY
PRESENT WITH AND YOU COULD SEE
HERE THAT IT E --IDENTIFIED A
ABOUT A 4% PREVALENCE OF
DEVELOPING LONG COVID IN THIS
GROUP, AND THEN RISK FACTORS,
VERY YOUNG AGE, ICU ADMISSION
AND PRESENCE OF OTHER COMPLEX
CONDITIONS.
AND YOU CAN SEE SOME OF THE
HIGHER RATES OF DIFFERENT
SYMPTOMS THAT WERE SHOWING UP IN
THOSE WHO WERE INFECTED VERSUS
NOT IN THE OTHER FOREST PLOT.
AND THEN ANOTHER THING, THAT THE
EHR DATA WAS EXTREMELY HELPFUL
WITH BECAUSE WE KNOW FROM THE
PANDEMIC ITSELF THAT RACIAL AND
ETHNIC DISPARITIES OCCURRED AND
THAT THOSE WHO WERE TYPICALLY
UNDERREPRESENTED IN RESEARCH
WERE MORE AFFECTED BY COVID, SO
THE QUESTION WAS, YOU KNOW IS
THIS HAPPENING ALSO IN LONG
COVID?
SO THE EHR DATA WAS HELPFUL FOR
THAT.
THIS IS A STUDY OF COVID
POSITIVE PATIENTS EITHER BASED
ON A TEST OR ICD CODE IN THE
SAME SORT OF TIME PERIOD THEY
WAS TALKING ABOUT AND THIS
LOOKED AT 137 PRESPECIFIED PAST
CONDITIONS OR LONG COVID
CONDITIONS AND THEN NEW
CONDITIONS A MONTH TO 6 MONTHS
AFTER THE POSITIVE COVID-19 TEST
AND BASICALLY WHAT IT SHOWED WAS
THAT COMPARED TO WHITE PATIENTS,
HISPANIC AND BLACK PATIENTS WERE
MORE LIKELY TO DEVELOP A P A
SC SEQUELLAI, AND THAT WORSE
COVID WERE OBSERVED IN
HOSPITALIZED PATIENTS.
AND IT ALSO VARIED BY
RACE/ETHNICITY SO SOME OF
SYMPTOMS LIKE DIABETES THAT WAS
PRESENT MORE IN BLACKS,
HEADACHES, CHEST PAIN, JOINT
PAIN, AND SOME OF THOSE THINGS
WERE PRESENT IN BLACKS AND
HISPANICS MORE THAN WHITES AND
THEN WHITES HAVE MORE SYMPTOMS
OF COGNITIVE IMPAIRMENT AND
FATIGUE THAN BLACKS OR
HISPANICS.
SO THIS WAS A HELPFUL TO HAVE
THIS INFORMATION COMING OUT FROM
RELATIVELY EARLY IN THE PANDEMIC
ABOUT LONG ASHING TO HELP INFORM
FUTURE RESEARCH.
I'M GOING TO TALK NOW ABOUT THE
LONGITUDINAL COHORT STUDIES AND
I ALREADY MENTIONED THAT THERE
WERE 2 DIFFERENT AREAS THAT, YOU
KNOW THE DE NOVO STUDY AND THEN
EXISTING STUDIES, THE STRATEGY
HERE WAS TO DEEPLY PHENOTYPE
DIVERSE PARTICIPANTS ACROSS THE
LIFE SPAN AND CLINICAL
CONTINUUM.
THE IDEA WAS TO HAVE DIFFERENT
TIERS OF TESTING, SO HAVE A TIER
OF SCREENING TESTS THAT WOULD BE
DONE WITH A VERY LARGE GROUP AND
THEN, BASED ON TRIGGERS, DO
DEEPER AND DEEPER DIVES INTO
WHAT WAS HAPPENING WITH THESE
PARTICIPANTS.
AND SO THE IDEA WAS TO ENROLL
NOT ONLY ACUTE FOLKS THAT WERE
ACUTELY INFECTED TO SEE WHO
DEVELOPED IT LONG COVID BUT ALSO
TO LOOK AT POST ACUTE FOLKS AND
SEE WHAT SYMPTOMS THEY WERE
REPORTING AND THEN DEFINE THE
TRAJECTORY AND OTHER THINGS AND
ALSO TO HAVE AN OPPORTUNITY TO
LOOK AT BIOMARKERS IN THE MORE
DEEPLY PHENOTYPE LEVELS.
IT'S ENROLLED AT THIS POINT AND
THERE'S DATA COMING OUT OF
THESE.
BUT IT--IT HAS SO FAR BEEN ABLE
TO CHARACTERIZE THE IMPACTS OF
DIFFERENT VARIANTS AND
VACCINATIONS AND THAT'S AN
INTERESTING PIECE THAT'S COME
OUT OF IT IS JUST THE SENSE THAT
YOU KNOW SYMPTOMS ARE CONSISTENT
ACROSS THE DIFFERENT INFECTION
WAVES, SO IT HASN'T BORNE OUT
THAT IT'S CHANGED DRAMATICALLY
BETWEEN THE EARLY WAVES WHEN
PEOPLE WERE OBVIOUSLY MUCH MORE
ACUTELY ILL ALTHOUGH
HOSPITALIZATION STATUS DOES HAVE
AN EFFECT BUT A LOT OF THE
SYMPTOMS REMAIN STABLE.
IT ALSO SHOWED HELPFULLY THAT
VACCINATION APPEARED TO BE SAFE
IN CHILDREN WHO HAD MIS-C.
AND THEN THERE'S A LOT OF
BIOMARKER TESTING THAT'S
ONGOING.
SO THE FIRST SORT OF LARGE PIECE
OF DATA TO COME OUT OF THE
COHORT STUDY WAS THIS PAPER IN
JAMA THAT INCLUDED ABOUT 10,000
PARTICIPANTS THAT ALL HAD 6
MONTHS OF FOLLOW UP AND THE
PURPOSE OF THIS STUDY WAS TO TRY
TO DEVELOP A DEFINITION OF POST
ACUTE SEQUELLACE INFECTION WITH
THE IDEA THAT THIS WOULD BE
EVOLVING OVER TIME BUT JUST A
FIRST LOOK.
THE PROSPECTIVE OBSERVATIONAL
COHORT STUDY OF PEOPLE WITH AND
WITHOUT COVID-19 INFECTION AT 85
SITES ACROSS THE U.S. LOOKED AT
KNOWN HISTORY OF INFECTION OR
PAST COVID-19 STATUS ENROLLMENT
PRIOR TO APRIL IN 2023 AND THEY
HAD TO HAVE LIKE I SAID, A STUDY
VISIT WITHIN 6 MONTHS OR MORE
AFTER THE INDEX CASE.
SO, EACH SYMPTOM WAS ASSIGNED A
SCORE, BASED ON THE CO
EFFICIENTS AND YOU KNOW THERE
WAS COMPLEX MODELING AND AS I
SAID, THERE WERE 10,000
PARTICIPANTS THAT ENDED UP IN
THE STUDY AND BASICALLY PEOPLE
WERE GIVEN A SCORE.
THEY WERE ABLE TO CREATE A
SYMPTOM-BASED TOOL THAT COULD BE
USED TO IDENTIFY PEOPLE WITH P A
SC, FOR RESEARCH STUDY
INCLUSION, THAT'S SORT OF THE
IDEA BEHIND THE STUDY AND AGAIN
IT WOULD EVOLVE OVER TIME.
AND SO, THIS IS NOT IF YOU READ
THE PAPER, A FIXED DEFINITION OF
P A SC, BUT MORE WHAT THE
SPOTLIGHT LOOKED AT AT THAT
PARTICULAR MOMENT.
SO IT BASICALLY SHOWED THAT P A
SC POSITIVITY WAS MORE COMMON
AND ASSOCIATED WITH MORE SEVERE
COVID-19 INFECTIONS PREOMICRON.
SO THE SYMPTOMS REMAIN SOMEWHAT
THE SAME, BUT MORE SEVERE.
AND THEN IT CAME UP WITH A SCORE
THAT COULD BE USED HOPEFULLY IN
FUTURE RESEARCH TO DEFINE WHAT
IS LONG COVID AS WELL AS SOME
DIFFERENT SUBPHENOTYPES OF LONG
COVID THAT COULD BE THEN USED IN
THE FUTURE.
SO THERE'S MORE DAILY BASIS THEA
THAT WILL INCREASINGLY BE COMING
OUT OF THIS VERY LARGE STUDY.
NOW RHYME --I'M GOING TO SHIFT O
2 OTHER PILLARS OF THE PROGRAM
TO TALK ABOUT SOME OF THE
EMERGING DATA TO GIVE US AN IDEA
OF THE DIRECTIONS THAT WE SHOULD
GO IN THE FUTURE.
SO THE NIH FUNDED A SUITE OF
MORE THAN 42 MULTIDISCIPLINARY
PATHOBIOLOGY STUDIES THAT ARE
NOW UNDERWAY.
THIS IS A COMPLEX SLIDE BUT THE
WHYED IS THAT COVID-19 PATIENTS
WITHIN AND WITHOUT LONG COVID
ARE STUDIED IN THESE LARGE
COHORTS.
THERE ARE MECHANISTING ASSAYS
THAT ARE RUN ON ALL OF THESE
PARTICIPANTS AND THEN DATA FROM
THE MECHANISTIC ASSAYS WILL BE
INTEGRATED WITH THE CLINICAL
DATA AND THEN WE CAN STUDY THE
THINGS IN THE HEXAGONS BELOW
SUCH AS THE CONSEQUENCES, THE
QUESTION ABOUT WHAT IS GOING ON
IN THE PATHOBIOLOGY, IS THERE
VIRAL PERSISTENCE, IS THERE VIAL
RESERVOIRS, IS THERE SECONDARY
DAMAGE AND SO ON.
I WILL SHOW YOU EXAMPLES, THIS
IS NOT A RECOVER STUDY BUT IT'S
AN IMPORTANT STUDY BECAUSE IT'S
GETTING AT 1 OF THE MAIN
HYPOTHESIS IN LONG COVID WHICH
IS THAT THERE IS IMMUNE
DISREGULATION, SO ACUTE SEVERE
COVID-19 OFTEN DEMONSTRATED IN
INNATE IMMUNE CELL ACTIVATION
AND DELAYED ADAPTIVE IMMUNE AND
INTERFERON RESPONSES BUT REALLY
UNKNOWN LAWEDDER DALE THE
LONG-TERM EFFECTS ARE IN THE
IMMUNE SYSTEM AND IF ANY OF THEM
ARE PERSISTENT AND IMPORTANTLY,
INNATE IMMUNE CELLS AND
PROGENITOR TO THOSE CELLS CAN
MAINTAIN A MEMORY OF PRIOR
INFECTION AND INFLAMMATION WHICH
THEN MIGHT AFFAIRS TEAM
LEADERRER THE RESPONSE TO LATER
IMMUNE CHALLENGES, SO THIS STUDY
LOOKED AT HEMATOPOIETIC STEM AND
PROGENITOR CELLS AND HPCs THAT
ARE LONG LIVED SELF-RENEWING
PRECURSORS TO DIFFERENT IMMUNE
CELLS, AND THEY'RE ABLE TO STORE
INFLAMMATION INDUCED EPIGENETIC
MEMORIES AND SO THEY CAN LOOK AT
THE DURABILITY OF EPIGENETIC
MEMORY, SO THIS STUDY LOOKED AT
4 GROUPS OF PARTICIPANTS THAT
WERE EITHER HEALTHY, THEY WERE
EITHER COVID-19 NEGATIVE BUT
RECOVERING FROM A CRITICAL
ILLNESS THAT WAS NOT COVID
RELATED OR THEY WERE EITHER
EARLY 2-4 MONTHS AFTER COVID-19
OR LATE 4-12 MONTHS AFTER
COVID-19 INFECTION.
AND BASIC LE WHAT THE RESULTS
SHOWED WAS THAT THERE WERE
LASTING EPIGENETIC AND
TRANSCRIPTION CHANGES IN THESE
PRECURSOR CELLS AND MONOCYTES
THAT INDICATED AN ALTERED IMMUNE
RESPONSE THAT WAS SEEN UP TO A
YEAR POST INFECTION.
SO THESE CHANGES APPEARED TO BE
CONTROLLED IN PART BY THE
ACTIVITY OF IL6 WHICH AS MANY
PEOPLE KNOW WAS VERY IMPORTANT
IN THE INFLAMMATORY CASCADE
STIMULATED BY COVID INFECTION.
SO THESE EPIGENETIC AND
TRANSCRIPTION CHANGES CAN
CONTRIBUTE TO ONGOING PATHOLOGY
IN TISSUES WITH INFLAMMATION,
AND ACTIVATION, POTENTICALLY OF
THE VASCULATURE, SO THAT'S
SOMETHING THAT NEEDS TO BE
FOLLOWED UP FURTHER.
ANOTHER STUDY THAT I THINK
SOUNDED VERY IMPORTANT TO THE
DIRECTION THAT RESEARCH IS GOING
WAS THIS STUDY THAT WAS ALSO NOT
A PART OF THE RECOVER STUDY, BUT
IT WAS AN AUTOPSIES STUDY OF 44
PATIENT WHO IS DIED OF COVID-19
AND 11 OF THEM THAT INCLUDED
BRAIN AUTOPSIES AND THE IDEA WAS
TO MAP AND QUANTIFY THE
DISTRIBUTION, REPLICATION AND
CELL SPECIFICITY OF SARS-COV-2
ACROSS THE HUMAN BODY AND THEY
USED DINLITTAL DROPLET PC R TO
QUANTIFY SARS-COV-2 AND THEY
USED INSITU HYBRIDIZATION TO GET
THE PC R FINDINGS AND BRAIN
TISSUE THEY USED IMMUNO
FLUORESCENCE AND HISTOCHEMIST
RADIOY AND THE FINDINGS FOUND
THAT SARS-COV-2 WAS WIDELY
DISTRIBUTED INCLUDING IN EARLY
DISEASE AND IN THE BRAIN.
SO YOU COULD SEE THIS SORT OF
COMPLEX HEAT MAP BASICALLY
WHEREVER YOU'RE SEEING COLOR,
YOU ARE SEEING THAT THERE WAS
RNA THAT WAS MEASURED IN A
NUMBER OF DIFFERENT BODY TYPES
AND YOU COULD SEE THAT OUR BODY
PARTS AND YOU COULD SEE THAT
THAT INCLUDED THE CNS AND THAT'S
ALONG THE BOTTOM AND YOU COULD
SEE IT WAS PRESENT NOT ONLY IN
LESS THAN 2 WEEKS AFTER THE
INFECTION BUT ALSO UP A MONTH
AND ALSO EVEN GREATER THAN A
MONTH.
SO THIS WAS PRESENT PRETTY MUCH
ACROSS THE BOARD IN THESE
DIFFERENT PATIENTS.
SO THERE'S 6 PATIENTS IN THE
ACUTE AND THOSE ARE THE COLUMNS.
AND THEN THE DIFFERENT COLORS
JUST REPRESENT THE DIFFERENT
AMOUNT OF RNA THAT WAS MEASURED
SO THIS STUDY WAS A VERY
IMPORTANT STUDY TO UNDERSTAND
THE TISSUES WHERE WE WERE
SEEING--WHERE WE WERE SEEING THE
VIRUS BECAUSE 1 OF THE MAIN
QUESTIONS IS CAN WE GO AFTER,
YOU KNOW IN LONG COVID, CAN WE
GO AFTER THAT AND I WILL TALK
MORE ABOUT THAT LATER.
THIS IS ALSO NOT A RECOVER STUDY
BUT COMES OUT OF
DR. [INDISCERNIBLE]'S GROUP AT
THE INTRAMURAL AT NINDS, IT WAS
A STUDY OF 12 PATIENTS WHO
REPORTED ONGOING NEUROLOGICAL
ABNORMALITIES AFTER THEIR COVID
ILLNESS, BY PC R AND THE
SYMPTOMS LASTING 9 MONTHS AFTER
THE INFECTION WITH A HEALTHY
CONTROL GROUP.
AND SOME OF THE COMMON SYMPTOMS
THAT WERE REPORTED BY FOLKS WERE
COGNITIVE DIFFICULTYINGS WHICH
WE KNOW TO BE VERY COMMON AND
FATIGUE AND THE MAJORITY HAD A
DISABLING DISEASE, YOU KNOW THEY
FELT DISABLED BY THE SYMPTOMS.
AND MANY OF THEM HAD NORMAL
BRAIN IMAGING.
SO THE DEEP PHENOTYPING HERE
INCLUDED A LOT OF CLINICAL WORK
UP AND IMAGING, BUT ALSO BRAIN
AND SORRY, BLOOD AND SPINAL
FLUID AS WELL AS AUTONOMIC
TESTING.
SO, AND YOU COULD SEE THE CHARTS
HERE, SO ON THE LEFT, THE
RESULTS SHOWED THAT PEOPLE WITH
LONG COVID HAD LOWER LEVELS OF
CD4 AND CD8 T-CELLS COMPARED TO
HEALTHY CONTROLS AND IT ALSO
SHOWED INCREASES IN THE NUMBER
OF B-CELLS, AND OTHER TYPES OF
IMMUNE CELLS, SO AGAIN,
SUGGESTING THERE MAY BE
VASCULAR--SORRY IMMUNOLOGICAL
PROBLEMS GOING ON HERE.
AND ON THE RIGHT SIDE SHOWS
ABNORMALITIES AND VASCULAR TONE,
HEART RATE, AND BLOOD PRESSURE
WITH A CHANGE IN POSTURE IN ALL
OF THESE PATIENTS AND THAT'S 1
OF THE MOST IMPORTANT THINGS
THAT WE'VE BEEN TRYING TO
UNDERSTAND IS WHAT IS THE
RELATIONSHIP BETWEEN COVID AND
THE VASCULAR SYSTEM, ANDENTIOUS
SPECIALLY WITH LONG ASHING.
--LONG COVID.
THIS STUDY HERE IS ALSO NOT A
RECOVER STUDY BUT IT'S A LARGE
PERSPECTIVE LONGITUDINAL COHORT
STUDY OF ABOUT 2000 PEOPLE IN
THE UK THAT WERE HOSPITALIZED
WITH COVID-19 PRETTY EARLY ON
FROM 2020 TO 2021.
AND IT EXAMINED A LARGE GROUP OF
BLOOD BIOMARKER PROFILES IN
ASSOCIATION WITH COGNITIVE
DYSFUNCTION ISSUES THE
BIOMARKERS WERE TAKEN DURING A
HOSPITAL VISIT BUT THE POST
ACUTE COGNITIVE DYSFUNCTION WAS
MEASURED 6 MONTHS LATER AND IT
WAS MEASURED BY NOT ONLY A LOCA
SCORE, WHICH IS A MEASURE OF
COGNITIVE FUNCTION BUT IT ALSO
ASKED ABOUT COGNITIVE FUNCTION.
AND WHAT YOU SEE HERE IS ON THE
LEFT, THE ASSOCIATION BETWEEN
HIGH FIEB RIN O GENERATED WITH
RELATIVELY LOW CRP AND WORSE
REPORTED SYMPTOMS AT 6 AND 12
MONTHS AS WELL AS LOWER SCORES,
ASSESSMENT SCORES IN THE SAME
TIME PERIOD.
SO IT MAY BE THAT THESE SYMPTOMS
ARE CAUSED BY IMMUNO THROMBOTIC
EVENTS.
AND THEN ON THE RIGHT SIDE, IT
LOOKS AT D-DIMER, AGAIN WITH
RELATIVELY LOW CRP, AND IT
SHOWED AN ASSOCIATION WITH THE
SYMPTOMS AND IT DOESN'T SHOW AN
ASSOCIATION WITH OBJECTIVE
COGNITIVE FUNCTION BUT IT DID
SHOW AN ASSOCIATION WITH
OCCUPATIONAL CHANGES AT 6
MONTHS.
SO IT MAY BE AGAIN, THAT THE
D-DIMER FINDINGS SUGGEST A
RELATIONSHIP WITH THE THROMBOTIC
SYSTEM AND NEITHER OF THESE
PROFILES WAS MEDIATED BY
DEPRESSION OR ANXIETY WHICH IS
IMPORTANT TO UNDERSTAND.
AND THENIME GOING TO SHOW
ANOTHER NONRECOVER STUDY.
SO STUDIES HAVE DESCRIBED THAT
COVID-19 YOU KNOW IS
MULTISYSTEMIC AND THAT IT MAY BE
A VASCULAR DISEASE ASSOCIATED
WITH SEVERE MICROVASCULAR
IMPAIRMENT AND ENDOTHELIAL
INJURY BUT THERE HASN'T BEEN
MUCH DATA IN THIS AREA.
SO THIS STUDY CHARACTERIZED
MICROVASCULAR CHANGES IN LONG
COVID PATIENTS AND IT DID IT IN
AN INNOVATIVE WAY LOOKING AT
SUBLINGUAL MICROVESSELS LOOKING
AT THE DIAMETER OF THE VESSELS
AS WELL AS COMPLEXITY OF NETWORK
AS WELL AS THE SPEED OF BLOOD
FLOW RBC FLOW THROUGH THESE
VESSELS.
SO IT INCLUDED 27 PARTICIPANTS
WITH LONG COVID WHO HAD SYMPTOMS
MORE THAN 12 WEEKS AFTER THE
INITIAL SYMPTOMS THAT WERE
REFERRED TO LONG COVID CLINIC
AND THEN A BUNCH OF CONTROLS
THAT WERE EITHER HEALTHY OR
CRITICALLY ILL SO IMPORTANT TO
SEPARATE OUT YOU KNOW PEOPLE
THAT HAD LONG ASHING FROM THOSE
WHO MIGHT HAVE HAD A PRIOR
CRITICAL ILLNESS.
AND SO, THE MEASUREMENTS WERE
TAKEN WHEN THEY WERE FIRST
EXAMINED AND THEN THEY WERE
FOLLOWED UP.
SO WHAT IT SHOWED WAS THAT
COMPARED TO CONTROLS, THERE WERE
DIFFERENCES IN DENNITY, SO ON
THE LEFT, YOU SEE THE DENSITY
AND VASCULAR DIAMETER, SO THE
VASCULAR DENSITY WAS DECREASED
COMPARED TO HEALTHY CONTROLS AND
ALSO THE COMPLEX SCORING THAT
THEY CALLED MICROVASCULAR
HEALTHCARE.
THERE WAS WORSE MICROVASCULAR
HEALTH COMPARED TO HEALTHY
CONTROLS AFTER THEY ADJUSTED FOR
OTHER CO-MORBIDITIES.
AND THEN ON THE RIGHT SIDE, IT
SHOWED THAT THE RED BLOOD CELL,
VELOCITY WAS SIGNIFICANTLY
HIGHER IN CAPILLARIES AND FEED
VESSELS IN THE LONG COVID
PATIENTS COMPARED TO HEALTHY
CONTROLS AND SO, BOTH OF THESE
EXAM NATIONS AND TYPES OF
LOOKING AT THE DATA, SHOW THAT
THERE MAY BE A RELATIONSHIP WITH
THESE MICROVESSEL WHICH IS IS
EXTREMELY IMPORTANT AS A
POTENTIAL TARGET TO UNDERSTAND
HOW TO MOVE FORWARD.
THEN I'M GOING TO TALK ABOUT
THIS BEFORE I MOVE ON TO TALK
ABOUT THE CLINICAL TRIALS, SO
THIS IS ALSO NOT A RECOVER STUY
BUT IT'S A STUDY THAT MEASURED A
LOT OF VASCULAR BLOOD BIOMARKERS
FROM LONG COVID PATIENTS VERSUS
ACUTELY ILL COVID PATIENTS OR
VERSUS HEALTHY CONTROLS.
SO AGAIN, REALLY IMPORTANT TO
SEPARATE OUT THE LONG COVID FROM
PEOPLE WHO MIGHT HAVE BEEN
ACUTELY VERY ILL WITH COVID-19
AND ALL TO SEPARATE THAT OUT
FROM HEALTHY CONTROLS.
AND SO, THE PURPOSE WAS TO
DETERMINE THE IMPORTANCE OF
THESE DIFFERENT VASCULAR
BIOMARKERS TO PREDICT LONG COVID
AND TO DETERMINE WHETHER
RELATIONSHIPS BETWEEN SOME OF
THESE BIOMARKERS AND DEMOGRAPHIC
OR CLINICAL FACTORS.
SO, THE VASCULAR BIOMARKERS THAT
WERE LOOKED AT INVOLVED
ANGIOGENESIS AND ENDOTHELIAL AND
PLATELET ACTIVATION AND
COAGULATION AND VASCULAR
JUNCTIONAL INTEGRITY AND
PERMIABILITY AND IN PARTICULAR,
I WILL JUST POINT OUT THE LEFT
SIDE OF THE FIGURE SHOWS 2 BOX
PLOTS FOR 2 VASCULAR BIOMARKERS
WHICH ARE P-SELECTIN AND ANCHLIO
POETIN 1 THAT SHOWED
CONCENTRATIONS COMPARED TO
CONTROLS.
YOU CAN SEE THAT THEY'RE QUITE
DIFFERENT, QUITE ELEVATED, THE
SAME WAY THAT THE RIGHT SIDE
WHERE THE ROC CURVES THAT
DEPRIVATIONON STRAIGHT EXCELLENT
DIAGNOSTIC POTENTIAL FOR BOTH
THE ANG IOPOETIN, AND THE
P-SELECTIN BIOMARKERS IN THE
VALIDATION ANALYSIS.
SO AGAIN, ANOTHER POTENTIAL AREA
AND TARGET TO GO AFTER IN THE
CLINICAL TRIALS.
SO NOW I'M GOING TO SHIFT GEARS
AND TALK A LITTLE BIT ABOUT THE
CLINICAL TRIALS AND YOU KNOW AS
I MENTIONED YOU KNOW AT THE
BEGINNING, IT'S VERY HARD TO--I
MEAN, YOU CAN--YOU CAN DO
CLINICAL TRIALS TO EXAMINE
SYMPTOMS, YOU KNOW THE LOW
HANGING FRUIT IS CERTAINLY, YOU
KNOW YOU HAVE CERTAIN SYMPTOMS,
YOU HAVE KNOWN DRUGS THAT CAN
TREAT THOSE SYMPTOMS, YOU CAN GO
AFTER THAT, BUT IT'S VERY
IMPORTANT TO UNDERSTAND WHAT THE
MECHANISMS ARE AND REALLY TRY TO
ATTACK THE MECHANISMS AT THEIR
SEED AND IF YOU'RE REALLY GOING
TO PREVENT LONG COVID, OR YOU'RE
REALLY GOING TO BE ABLE TO MAKE
A DIFFERENCE.
AND SO THAT IS THE REASON THAT
RECOVER WAS BUILT ALONG THOSE
OTHER 4 PILLARS TO GENERATE DATA
THAT COULD THEN FEED INTO
CLINICAL TRIALS AND THEN ANOTHER
PIECE OF IT, I WILL EXPLAIN A
BIT LATER IS JUST, THE NEED TO
DO THIS IN AN EFFICIENT MANNER
AND SO TO SET UP AN ADAPTIVE
PLATFORM WITH MULTIPLE
THERAPEUTIC DOMAINS SO WE CAN
HAVE MANY SHOTS ON GOAL INSTEAD
OF DOING MANY SEQUENTIAL TRIALS
THAT WOULD TAKE A LONG TIME.
SO THIS FIRST SLIDE IS NOT A
RECOVER SLIDE, BUT IT'S 2 RECENT
STUDIES THAT HELPED TO GENERATE
DATA THAT LED TO SOME OF THE
TRIALS THAT ARE BEING INITIATED
IN RECOVER.
SO LOOKING AT ANTIVIRAL
MEDICATION TO SEE IF IT HAD AN
IMPACT ON P A SC, WITH THE IDEA
THAT LONG COVID MAY HAVE
PERSISTENT VIRUS AND THAT THAT
PERSISTENT VIRUS IS WREAKING
HAVOC AND YOU COULD TREAT THAT.
SO THE STUDY ON THE LEFT LOOKED
AT WHETHER P A XLOVID DURING THE
ACUTE CASE OF COVID WOULD REDUCE
THE RISK OF P A SC.
AND THEN THE STUDY ON THE RIGHT
IS A MORE RECENT STUDY THAT
ACTUALLY EXAMINED TREATING
INDIVIDUALS WITH P A SC.
SO THE LEFT 1 WAS A
RETROSPECTIVE OF THE A-COHORT
STUDY USING ELECTRONIC HEALTH
RECORD DATA OF PARTICIPANTS THAT
HAD A POSITIVE COVID-19 TEST
BETWEEN JANUARY OF 22 AND
DECEMBER OF 22.
AND THEY HAD AT LEAST 1 RISK
FACTOR FOR PROGRESSION TO SEVERE
DISEASE.
AND THEN THEY WERE COMPARED,
COMPARED THOSE WHO WERE TREATED
WITH P A XLOVID WITH 5 DAYS TO
THEIR TEST AND THEN NOT, AND
LOOK AT ANY POST ACUTE
COMPLICATIONS THAT WOULD HAVE
ARISED FROM THAT AND THE
FINDINGS FROM THAT EHR STUDY
INDICATE THAD P A SC WAS
TREATMENT WITH REDUCED RISK OF P
A SC SYMPTOMS ABOUT 10 OUT OF 13
AND INCLUDING A WIDER RANGE OF
SYMPTOMS THAT INCLUDED PULMONARY
SYMPTOMS, THROMBOTIC SYMPTOMS,
RENAL SYMPTOMS, MUSCLE COGNITIVE
SYMPTOMS AND OTHER NERVOUS
SYSTEM SYMPTOMS.
IT DID NOT FIND A DECREASE IN
DIABETES OR LIVER DISEASE OR
COUGH.
SO BASICALLY THE TREATMENT WAS
FOUND THAT IN ACUTE INFECTION IT
COULD REDUCE THE RISK FOR P A SC
SEQUELLACE, SO ON THE RIGHT SIDE
IS THE STOP P A SC TRIAL THAT
WAS A STOP COLLABORATION BETWEEN
PFIZER AND STANFORD THAT HAS
BEEN STOPPED AND THIS INCLUDED
PATIENTS THAT WERE ADULT AND HAD
A HISTORY OF CONFIRMED COVID-19
INFECTION, HAD P A SC SYMPTOMS
MORE THAN 3 MONTHS AND HAD 2OR
MORE P A SC SYMPTOMS THAT ARE
EITHER MODERATE OR SEVERE IN
SEVERITY AND THE DATA ARE NOT
YET PUBLISHED BUT IT'S LOOKING
AT THAT TREATMENT AND THE STUDY
WAS HALTED EARLY WITH INTERIM
ANALYSIS EXPECTED VERY SOON.
SO THAT LED SORT OF IN PARALLEL
TO SETTING UP SOME OF THE
RECOVER TRIALS.
SO THE CLINICAL TRIALS IN
RECOVER FOLLOWED AN OVERALL
STRATEGY OF BEING VERY RIGOROUS,
BEING INTEGRATED, HAVING
ADAPTIVE PLATFORM PROTOCOLS TO
LOOK AT SAFETY AND EFFICACY AND
TO HAVE INTEGRATED MECHANISTIC
STUDIES SO THAT IT COULD ALSO
YIELD DATA THAT WOULD HELP
UNDERSTAND THE CAUSE AND THEN TO
TEST KNOWN AND NOVEL
INTERVENTIONS ACROSS DIFFERENT
DOMAINS LIKE DRUGS AND DEVICES
AND REHABILITATION TO TREAT LONG
COVID SYMPTOMS AND ADDRESS THE
UNDERLYING CAUSES AND AND SO, IT
STARTED BY ENGAGING THE
COMMUNITY IN PATIENT ADVOCACY
GROUPS THROUGHOUT THE
DEVELOPMENT TO UNDERSTAND THE
INTERVENTION PRIORITIZATION, TO
USE THE CROSS CONSORTIUM
CLINICAL DATA AND LITERATURE TO
INFORM THE DEVELOPMENT OF THE
TRIALS AS I ALREADY REFERRED TO,
AND THEN TO ESTABLISH
SYNERGISTIC COLLABORATIONS AS A
WAY OF MULTIPLE INTERVENTIONS
AND AS A RESULT TWEP PLATFORM
PROTOCOLS AND THIS SLIDE GIVES
YOU AN OVERVIEW OF THE INPUTS,
THE SOURCES AND INPUTS TO THAT
PROCESS WHICH INCLUDED THE
THINGS THAT I'VE ALREADY
MENTIONED, REALLY BUT THERE WAS
A LANDSCAPE ANALYSIS OF WHAT WAS
OUT THERE, THE EHR DATA, WE
BROUGHT IN CONCEPT PROPOSALS.
THERE WAS CLIN ITIONZ INPUT,
PATIENT INPUT, FEDERAL AGENCIES
PARTNERS WERE INVOLVED, INDUSTRY
WAS INVOLVED AND SO ON.
AND THEN THESE WERE DESIGNED AS
MASTER PROTOCOLS TO RUN
PLATFORMS WHERE YOU CAN TAKE
PATIENTS IN, YOU CAN HAVE
DIFFERENT INTERVENTIONS BEING
TESTED AT THE SAME TIME.
YOU CAN COMPLETE ENROLLMENT IN 1
STUDY AND HAVE THAT STOP AND
GENERATE DATA FROM THAT 1 ARM.
YOU CAN ALSO HAVE INTERVENTIONS
THAT ARE ADDED LATER ON LIKE
NUMBER 3 AND 4 THAT ARE
INTRODUCED YOU COULD EVEN
POTENTIALLY COMBINE
INTERVENTIONS LATER ON AND
THAT'S THE IDEA.
AND SOME OF THE INTEGRATED
INFRASTRUCTURE THAT WAS USED
INCLUDE THINGS LIKE SINGLE IRB,
SINGLE DSMB, TRIAL OVERSIGHT,
TRIAL MANAGEMENT, ALL THOSE
THINGS AND THEN FUNCTIONAL
INTEGRATION WHICH SHARED END
POINTS, APPROACH TO PATIENT
PARTICIPATION, CLINICAL GROUPS
WORKING ON THE PROBLEM, COMMON
DATA ELEMENTS AND THEN
MECHANISTIC STUDIES THAT ARE
CROSS CUTTING ACROSS THE
DIFFERENT AREAS AND SO, THE
INITIAL PROGRAM OF 5 MASTER
PROTOCOLS INCLUDE A VIRAL
PERSISTENCE AND IMMUNE
DISREGULATION, 1 INCLUDING
NEUROQUESTIONS, 1 INCLUDING
AUTONOMIC, 1 INCLUDING SLEEP AND
1 INCLUDING CARDIO PULMONARY
EXERCISING TOLERANCE AND
FATIGUE.
AND SO THERE ARE 2 TRIALS THAT
ARE ALREADY OPEN FOR ENROLLMENT,
THE FIRST IS THE VITAL TRIAL
WHICH IS FOCUSED ON TREATING
SARS-COV-2 PERSISTENCE AND THEN
THE NEUROTRIAL WHICH IS FOCUSED
ON BRAIN FOG.
I WILL TALK A BIT ABOUT THOSE
ANDEN THIS WE WILL FOCUS ON THE
OTHERS SLEEP DISREGULATION,
AUTONOMIC DYSFUNCTION AND THE
THEN THE ENERGIZE PIECE.
SO I WILL TALK BRIEFLY ABOUT THE
VITAL STUDY, THE OBJECTIVE OF
WHICH IS TO EVALUATE THE EFFECT
OF THE SARS-COV-2 TREATMENT ON
SYMPTOM SPECIFIC AND PATIENT
REPORTED MEASURES WITHIN EACH P
A SC SYMPTOM CLUSTER AT
DISCIPLINARY 90 AND THIS FIRST
SET OF STUDY ARMS INCLUDES P A
XLOVID, AND IT ALSO INCLUDES
RITONAVIR AND PLACEBO AND THERE
WILL BE UP TO A HUNDRED SITES
WITH 900 PARTICIPANTS AND TELL
LOOK AT THESE COMBINATIONS AND
IT LENGTHENS THE TREATMENT OF P
A XLOVID COMPARED TO THE
IMPROVED TREATMENT TO UNDERSTAND
IN 1 ARM WHETHER LONGER
TREATMENT IS NECESSARY.
AND THEN THE RECOVER
NEUROPLATFORM FOR THE EVALUATION
OF INTERVENTIONS FOR COGNITIVE
DYSFUNCTION IN LONG COVID, SO
THE HYPOTHESIS HERE IS THAT P A
SC ASSOCIATED DECLINES IN
COGNITIVE DOMAINS SUCH AS
EXECUTIVE FUNCTION AND RETENTION
MAY BE IMPROVED BY INTERVENTIONS
THAT SELECTIVELY FOCUS ON
ENHANCING THOSE DOMAINS AND SO
THE STUDY ARMS HERE INCLUDE AN
ACTIVE COMPARRITIOR ARM OR
CONTROL ARM WHERE PARTICIPANTS
WILL USE VIDEO GAMES THEN BRAIN
HQ WHICH DOES COGNITIVE TRAINING
OR BRAIN HQ BECAUSE ANOTHER
INTERVENTION THAT IS KIND OF A
BEHAVIORIAL INTERVENTION AND
THEN 1 THAT LOOKS AT DIRECT
CURRENT STIMULATION WHICH IS
EITHER ACTIVE OR SHAM.
AND THIS WILL INCLUDE UP TO 45
SITES AND 300 PARTICIPANTS.
SO THESE ARE THE INITIAL STUDIES
AND AGAIN INFORMED BY THE DATA.
AND THEN THE LAST THING THAT I
WANTED TO MENTION WAS JUST THAT
ALL OF THE DATA THAT ARE COMING
OUT OF THE ELECTRONIC HEALTH
RECORD, OUT OF ALL THESE
MECHANISTIC STUDIES, OUT OF THE
COHORT STUDIES ARE GOING INTO
BIODATA CATALYST, SO THAT WE CAN
REALLY HAVE AN OPEN SCIENCE
WHERE THERE'S CROSS LINKING OF
THE DATA, THERE'S COLLABORATION
OPPORTUNITIES FOR THE SCIENTIFIC
COMMUNITY AT LARGE AND IT'S
INTEROPERABLE AND SHAREABLE.
AND THIS WILL HOPEFULLY LEAD TO
MORE DIAGNOSTIC TOOLS AND MORE
THERAPEUTIC OPTIONS AND MORE
POTENTIAL PREVENTION STRATEGIES,
SO THE SUM AND MUCH GREATER THAN
THE PARTS WHEN THE SCIENTIFIC
METHOD CAN BE APPLIED AND IT'S
OPEN TO EVERYONE AND THEN THE
END RESULT IS THAT IT WILL
HOPEFULLY HELP LONG COVID
PATIENTS.
SO IN SUMMARY, THESE RESEARCH
FINDINGS HAVE IDENTIFIED
DIFFERENT HEALTH AND DEMOGRAPHIC
FACTORS THAT PUT INDIVIDUALS AT
A HIGHER RISK FOR LONG COVID.
DETERMINING THESE PHENOTYPES MAY
HELP TO TARGET TREATMENT AND
INCREASE RECRUITMENT FOR
RESEARCH STUDIES.
THE PATHOBIOLOGY AND POGHT O
PHYSIOLOGY OF P A, C IS COMPLEX
AND MULTIDISSEMESTERRIC BUT
APPEARS TO INVOLVE ALTERED
IMMUNE RESPONSES AND VASCULAR
RELATED CHANGES THAT WE NEED TO
LEARN MORE ABOUT, AND NO DOUBT
THERE ARE MANY OTHER MECHANISMS
THAT WILL NEED TO BE STUDIED AND
WILL COME OUT OF THESE DIFFERENT
PROGRAMS AND BOTH WITHIN RECOVER
AND WITHOUT.
SO THEREYA A LOT TO UNDERSTAND
ABOUT POTENTIAL TREATMENTS FOR P
A SC, BUT WE'RE HOPING THAT AT
LEAST THE FIRST SHOT ON GOAL, IF
THERE IS VIRAL PERSISTENCE, THAT
THIS TREATMENT WILL BE EFFECTIVE
BUT AGAIN, IT'S A MASTER
PROTOCOL AND OTHER AGENTS CAN BE
ADDED TO THIS PROTOCOL TO BE
TESTED AS MORE DATA ARE
GENERATED.
SO WHILE THE NUMBER OF
INDIVIDUALS EXPERIENCING P A SC
HAVE DECREASED OVER TIME, THERE
ARE STILL MEN PEOPLE SUFFERING
AND I THINK IT'S REALLY
IMPORTANT TO RECKIFIES THAT THE
IMPORTANCE OF THIS, THAT THERE
ARE MANY MULTISYSTEM SYMPTOMS
THAT ARE CAUSING A LOT OF
SUFFERING.
IT'S COMPLEX.
IT NEEDS TO BE STUDIED MORE AND
WE NEED ALL HANDS ON DECK BOTH
WITHIN THE RECOVER PROGRAM BUT
OUTSIDE OF THE RECOVER PROGRAM
AND IN THE WHOLE ECOSYSTEM THAT
IS SERVED BY FEDERAL AGENCIES
FUNDING RESEARCH IN THIS AREA.
AND HOPEFULLY THIS WILL ALL LEAD
TO A BETTER UNDERSTANDING SO WE
CAN PREDICT, PREVENT AND TREAT
THE LONG-TERM EFFECTS OF
COVID-19.
AND I WILL STOP THERE.
>>THANK YOU SO MUCH CLINT, FOR
THIS FASCINATING TALK.
THERE ARE QUITE A FEW QUESTIONS
SO IF YOU DON'T MIND HANGING OUT
AND I WILL READ YOU SOME OF THE
QUESTIONS.
ONE GENERAL QUESTION THAT CAME
UP A COUPLE OF TIMES IS HOW TO
ENROLL IN THIS INITIATIVE.
ONE OF THE QUESTIONERS SAID THEY
CAN SEE THE ENROLLMENT BY
INVITATION AT THE TOP OF THE%
CLINICAL TRIALS .GOV WEBPAGES
FOR THE VIRAL AND NEUROTRIALS,
THEY'RE ASKING, WHAT ABOUT THAT
MEAN BY ENROLLING BY INVITATION?
>>IT IS NECESSARY WHEN RUNNING
CLINICAL TRIALS TO HAVE CERTAIN
INCLUSION AND EXCLUSION CRITERIA
SO IT'S IMPORTANT FOR PEOPLE TO
CONTACT THE STUDY AND THEN THERE
ARE QUESTIONNAIRES THAT PEOPLE
GO THROUGH TO UNDERSTAND WHETHER
THE PERSON IS ELIGIBLE OR NOT.
SO I THINK THAT'S WHAT IT'S
REFERRING TO.
THE RECOVER WEBSITE IS VERY
HELPFUL IN TERMS OF
UNDERSTANDING HOW TO GET
INTEREST THESE STUDIES.
SO RECOVERCOVID.ORG VERY
INFORMATIVE STUDY WEBSITE.
>>THANK YOU.
THE DURATION OF LONG COVID IN
CHILDREN VERSUS ADULTS, DO YOU
HAVE ANY COMMENT ON THAT?
>>NO, I THINK IT'S EARLY TO
REALLY UNDERSTAND THAT.
THE PEDIATRIC COHORT STUDY WILL
BE EXTREMELY HELPFUL AT
DISENTANGLING SOME OF THOSE
QUESTIONS AND WE'RE LOOKING
FORWARD TO THE, YOU KNOW LARGE
DATA THAT'S BEING GENERATED BY
THAT PEDIATRIC COHORT.
THE RATE OF LONG COVID SEEMS TO
BE SOMEWHAT LOWER IN THE
PEDIATRIC POPULATION BUT HOW
LONG IT LASTS IS A QUESTION THAT
I'M NOT ABLE TO ANSWER AT THIS
TIME.
>>QUESTION REGARDING THE
MANAGEMENT OF THESE P A SC
SYMPTOMS, AT LEAST ACROSS THE
U.S. ARE THEY COMMON, FIRST ARE
THEY BEING RECOGNIZED BY
PHYSICIANS AS A P A SC SYMPTOM?
HOW MUCH COHERENCE IS THERE IN
THE RECOGNITION OF THESE
SYMPTOMS BY DIFFERENT TYPES OF
PHYSICIANS?
ARE THERE COMMON TREATMENTS
BEING IMPLEMENTED?
AND HOW DO THOSE TREATMENTS THEN
AFFECT THE LONGER P A
SC SEQUELLACE.
>>I WOULD SAY IT'S BEEN A
CHALLENGE FOR COVID PATIENTS,
WHENEVER THERE'S A NEW DISEASE
OR SET OF DISORDERS, THERE IS A
TENDENCY NOT TO RECOGNIZE IT ON
THE PART OF THE MEDICAL
COMMUNITY THIS WILL THEY REALLY
KNOW WHAT IT IS AND A LOT OF
PATIENTS HAVE SHOWN UP AT THE
DESCR AND THE DOCTOR DOESN'T
KNOW WHAT'S GOING ON AND
ATTRIBUTES IT TO SOME OTHER
THING AND THERE HAVE BEEN
PATIENTS THAT HAVE BEEN
DISMISSED AND I THINK IT'S VERY
IMPORTANT FOR THE WORD TO GET
OUT THAT LONG COVID IS REAL AND
WE DON'T COMPLETELY UNDERSTAND
IT AND FOR PATIENTS TO REALLY
LOOK FOR CAREGIVERS THAT CAN
HEAR THEM AND THAT--VALIDATE,
YOU KNOW WHAT IS GOING ON WITH
THEM SO THAT WAS THE FIRST PART
OF YOUR QUESTION.
I THINK IN TERMS OF THE SECOND
PART THAT THERE ARE SYMPTOMATIC
TREATMENTS THAT PEOPLE CAN TRY
AND I THINK DOCTORS ARE WILLING
TO TRY, YOU KNOW DIFFERENT
MOR
MODALITIES THAT ARE OFF-LABEL
FOR THE SYMPTOMS TO SEE IF THEY
WORK BUT IN THE END WE NEED
RIGOROUS TRIALS.
UNFORTUNATELY THERE'S A LOT OF
MISINFORMATION OUT THERE ON THE
INTERNET, CLAIMING THAT CERTAIN
TREATMENTS ARE EFFECTIVE IN HAD
LONG COVID THAT HAVE REALLY NO
BASIS IN EVIDENCE AND IT'S
CRITICAL THAT PATIENTS
UNDERSTAND WHAT IS REQUIRED TO
REALLY PROVE THAT SOMETHING
WORKS IF IT'S NOT SOMETHING
THAT'S ALREADY BEEN USED FOR THE
SAME SYMPTOM IN ANOTHER DISEASE,
WHICH A DOCTOR MAY BE WILLING TO
PRESCRIBE.
>>THE VASCULAR BIOMARKERS THAT
YOU PRESENTED, THE HIGH LEVELS
OF PLASMA ANGIO TENSEIN 1 FOR
INSTANCE, CORRELATING WITH THE
LONGER--LONG COVID, HAS THAT
BEEN SEEN BEFORE WITH OTHER
VIRAL INFECTIONS?
HAS IT BEEN LOOKED AT BEFORE FOR
INSTANCE IN FLU OR OTHER TYPES
OF RESPIRATORY VIRAL INFECTIONS?
>>WELL, I THINK--I DON'T KNOW
THE ANSWER TO THAT.
I DO KNOW THAT WE'RE MOTIVATED
WHEN I SAY WE, I MEAN THE
SCIENTIFIC COMMUNITY WAS
MOTIVATED TO LOOK AT THIS
BECAUSE OF THE EARLY THROMBOTIC
EFFECTS OF COVID ITSELF, THERE
WAS A LOT OF EVIDENCE OF
MICROTHROMBOSIS, PLATELET
ACTIVATION, AND THEN OF COURSE,
THERE WAS A CYTOKINE STORM, IN
SOME CASES THERE WERE A LOT OF
INFLAMMATORY MARKERS THAT WERE
ELEVATED INCLUDING IL6 FOR
EXAMPLE, AND THEN THAT
CONNECTION WITH THE THROMBOTIC
SYSTEM WAS OF GREAT INTEREST SO
I THAT WAS I THINK WAS THE
MOTIVATION FOR TRYING TO
UNDERSTAND, SOME OF THESE LONG
COVID SYMPTOMS DUE TO THROMBOTIC
PROBLEMS, THE WAY THEY WERE IN
THE ACUTE COVID.
SO THAT I THINK WAS THE
MOTIVATOR BUT--AND HOW THEY
DIFFERENTIATE FROM OTHER ILLNESS
AND OTHER SEVERE ILLNESSES, IT
MAY HAVE BEEN STUDIED, I DON'T
KNOW.
>>QUESTION REGARDING VIRAL
PERSISTENCE, HOW AND WHAT
TISSUES ARE BEING SAMPLED FOR
THAT IN THESE PATIENTS?
>>YEAH.
>>[INDISCERNIBLE].
>>VERY TOUGH.
BECAUSE SOME OF THE VIRAL
RESERVOIRS MAY INVOLVE AREAS
THAT ARE VERY DIFFICULT TO HAVE
ACCESS TO SO IN ORDER TO LOOK IN
THE CENTRAL SERVOUS SYSTEM, YOU
NEED CEREBRAL SPINAL FLUID WHICH
REQUIRES A LUMBAR PUNCTURE AND A
LOT OF PATIENTS ARE NOT ALWAYS
WILLING TO UNDERGO THAT, ANOTHER
1 IS IN THE GASTROINTESTINAL
TRACT WHICH IS DIFFICULT ON IT
ACCESS, CAN YOU TRY TO ELECTRIC
AT IT WITH STOOL SAMPLES BUT
TIMES YOU MIGHT NEED TO LOOK BY
TAKING A SAMPLE IN THE
GASTROINTESTINAL TRACT ITSELF
AND SO AGAIN, THAT'S HARDER TO
GET ACCESS TO.
YOU OF COURSE CAN LOOK AT BLOOD,
AND SO, THESE ARE THE WAYS OF
LOOKING FOR THE VIRAL RESERVOIR
AND MANY OF THESE MECHANISTIC
STUDIES THAT ARE BEING DONE ARE
OFFERING THOSE TYPES OF TESTS SO
THAT WE CAN TRY TO GET TO THE
BOTTOM OF IT.
>>DOES THE DECREASE IN P A SC
USE A DIFFERENCE IN VARIANCE
LIKE IN OMICRON, ACTUAL LOWER
DISEASE SEVERITY, COMPARED TO
EARLIER STRAINS LIKE DELTA?
IS THERE ANY DATA ON THAT?
>>WHEN WE TALK ABOUT LONG COVID
SEVERITY, IT GETS A LITTLE BIT
MORE COMPLICATED.
YOU KNOW CERTAINLY THE EARLIER
COVID VARIANTS LED TO MORE
SEVERE ILLNESS IN THE ACUTE
INFECTION WHICH OF COURSE WAS
YOU KNOW WORSE FOR PATIENTS IN
TERMS OF THE AFTER EFFECTS AND
THAT'S BEEN 1 OF THE CHALLENGES
TRYING TO SEPARATE OUT ALL THE
ACUTE ILLNESS FROM THE LONG
COVID TO UNDERSTAND WHETHER THIS
IS SOMETHING THAT IS PERPETUATED
OR SOMETHING STARTING AT THE
BEGINNING AND STILL CONTINUING
WHICH IS ALSO IMPORTANT AS WELL
AND NEEDS TO BE ADDRESSED.
SO I THINK THAT IT'S IMPORTANT
TO GO AFTER BOTH OF THOSE ANGLES
BUT IN TERMS OF THE SEVERITY, I
THINK THAT MANY OF THE PEOPLE
THAT HAVE MILD ACUTE INFECTIONS
HAVE A LOT OF DISABILITY IN
THEIR LONG COVID ARE COMPLAINING
OF A LOT OF DISABILITY, UNABLE
TO WORK, UNABLE TO FUNCTION AND
SO I THINK THAT'S QUITE SEVERE.
SO YES, WE ARE SEEING, STILL
SEEING THAT SEVERITY EVEN THOUGH
THE INITIAL INFECTION MIGHT BE
MILD.
>>HOW DO YOU OPERATIONALIZE THE
SYMPTOM OF BRAIN FOG IN THE
SYMPTOM STUDY, WHY WAS THIS TERM
USED SUCH OTHER THAN ITS
COUNTERPART SUCH AS MEMORY OR
CONCENTRATION IMPAIRMENT.
>>I THINK THE LATTER 1S ARE THE
OBJECTIVE REFERENCES TO NEUROs
LIKE DOMAINS THAT WE THINK ABOUT
WHEN WE DO A FULL NEUROPSYCHE
BATTERY ON SOMEONE FOR EXAMPLE,
OR WE DO TESTING.
BRAIN FOG IS WHAT PEOPLE
COMPLAIN OF.
AND SO WE USE THE TERM SO THAT
PATIENTS AND PARTICIPANTS
UNDERSTAND WHAT WE'RE GOING
AFTER.
BUT CERTAINLY TO STUDY IT, YOU
NEED TO LOOK AT THINGS LIKE
ATTENTION AND EXECUTIVE FUNCTION
AND MEMORY AND ALL OF THE
DIFFERENT DOMAINS THAT ARE
IMPORTANT ON GIVE YOU AN
OBJECTIVE MEASURE OF WHAT'S
GOING ON AND AS YOU SAW FROM
THAT 1 STUDY THAT I SHOWED,
SOMETIMES THE OBJECTIVE MEASURE
EVEN THOUGH THAT MEASURE WAS A
VERY CRUDE SORT OF MEASURE, YOU
KNOW A GLOBAL MEASURE OF THE
[INDISCERNIBLE] DIDN'T SHOW
ANYTHING IN THE SYMPTOMS, DID
SHOW SOMETHING AND AT THE TIME
THAT THE SYMPTOMS SHOWED
SOMETHING, THE SUBJECTIVE
SYMPTOMS, THEY ALSO HAD
OCCUPATIONAL IMPAIRMENT.
SO THERE ISN'T A COMPLETE
OVERLAP BETWEEN THE SPECIFIC
DOMAINS BEING AFFECTED AND THE
SUFFERING THAT THE PATIENT IS
HAVING AND THE WAY THEY EXPLAIN
THE SYMPTOMS THAT THEY'RE HAVING
AND HOW IT'S AFFECTING THEIR
LIVES AND SO WE NEED TO GO AFTER
THE LARGER PICTURE, NOT JUST THE
OBJECTIVE STUFF.
>>AND THE FINAL QUESTION: DO
YOU HAVE ANY INSIGHT INTO THE
DIFFERENCES IN P A SC BETWEEN
MALES AND FEMALES?
>>THAT'S A REALLY GREAT
QUESTION.
THAT'S A VERY IMPORTANT QUESTION
THAT NEEDINGS TO BE LOOKED AT
FURTHER.
THEREYA --THERE'S A LOT OF
POTENTIAL DATA OUT THERE.
I REFER BACK TO 1 OF MY LAST
SLIDES ABOUT THE BIODATA
CATALYST AND ALL THE DATA
FEEDING INTO IT THAT WILL ALLOW
SCIENTISTS TO LOOK AT THAT I AM
NOT AWARE OFF THE TOP OF MY HEAD
OF MALE/FEMALE DIFFERENCES BUT
THAT COULD BE THAT I'M NOT ABLE
TO THINK OF IT AT THE MOMENT BUT
IT'S A VERY IMPORTANT SET OF
QUESTIONS AND I THINK IT COULD
ACTUALLY BE VERY HELPFUL IN
TERMS OF UNDERSTANDING
MECHANISMS IF WE COULD SEE SEX
DIFFERENCES, BECAUSE IT MIGHT
GIVE US SOME IDEA OF
DIFFERENT--DIFFERENT PATHWAYS
THAT ARE INVOLVED.
>>WELL, THANK YOU SO MUCH
DR. WRIGHT AND THIS CONCLUDES
TODAY'S SEMINAR.
THANK YOU.
>>MY PLEASURE, THANK YOU.
>>BYE-BYE.